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Sample records for promising drug candidate

  1. Zeolites: promising candidates for drug delivery systems (DDSs)

    OpenAIRE

    Vilaça, Natália; Amorim, Ricardo; Baltazar, Fátima; Fonseca, António Manuel; Neves, Isabel C.

    2012-01-01

    [Excerpt] The aim of controlled drug delivery systems (DDSs) is to administer the necessary amount of drug safely and effectively to specific sites in the human body and to regulate the temporal drug profile for maximum therapeutic benefits.[1] Zeolites are crystalline aluminosilicates solids with very regular microporous structures and they have been recently considered for medical use due to their biological properties and stability in biological environments.[1,2] The large variety in ...

  2. In vitro production of huperzine A, a promising drug candidate for Alzheimer's disease.

    Science.gov (United States)

    Ma, Xiaoqiang; Gang, David R

    2008-07-01

    Alzheimer's disease (AD) is growing in impact on human health. With no known cure, AD is one of the most expensive diseases in the world to treat. Huperzine A (HupA), a anti-AD drug candidate from the traditional Chinese medicine Qian Ceng Ta (Huperzia serrata), has been shown to be a powerful and selective inhibitor of acetylcholinesterase and has attracted widespread attention because of its unique pharmacological activities and low toxicity. As a result, HupA is becoming an important lead compound for drugs to treat AD. HupA is obtained naturally from very limited and slowly growing natural resources, members of the Huperziaceae. Unfortunately, the content of HupA is very low in the raw plant material. This has led to strong interest in developing sources of HupA. We have developed a method to propagate in vitro tissues of Phlegmariurus squarrosus, a member of the Huperziaceae, that produce high levels of HupA. The in vitro propagated tissues produce even higher levels of HupA than the natural plant, and may represent an excellent source for HupA.

  3. Organotin(IV) Carboxylates as Promising Potential Drug Candidates in the Field of Cancer Chemotherapy.

    Science.gov (United States)

    Sirajuddin, Muhammad; Ali, Saqib

    2016-01-01

    Medicinal inorganic chemistry plays an important role in exploring the properties of metal ions for the designing of new drugs. The field has been stimulated by the success of cis-platin, the world best selling anticancer drug and platinum complexes with reduced toxicity, oral activity and activity against resistant tumors are currently on clinical trial. The use of cis-platin is, however, severely limited by its toxic side-effects. This has stimulated chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. The discovery of new non-covalent interactions with the classical target, DNA, was the first developing step in the treatment of cancer. The use of organometallic compounds as a medicine is very common now a days because it offers potential advantages over the more common organic-based drugs. In this article we have highlighted the anticancer activity of the organotin(IV) carboxylates published in the last few years (from 2008 to 2016). In most cases they present lower IC50 values than those of cisplatin, which indicates their high activity against the cancer cell lines. The summarized data reveal that every year new organotin(IV) carboxylate complexes are synthesized with the aim of new anticancer agent with much better results than the than the corresponding activity of cis-platin or other clinically approved drugs. In addition to the advantages of high activity, compared to the platinum compound, tin complexes are much cheaper. Thus by using organotin carboxylate for clinical medicine, cost reduction, dosage reduction and effect enhancement will be reached. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Natural products as promising drug candidates for the treatment of Alzheimer's disease: molecular mechanism aspect.

    Science.gov (United States)

    Ansari, Niloufar; Khodagholi, Fariba

    2013-07-01

    Alzheimer's disease (AD) is the most common neurodegenerative disorder to date, with no curative or preventive therapy. Histopathological hallmarks of AD include deposition of β-amyloid plaques and formation of neurofibrillary tangles. Extent studies on pathology of the disease have made important discoveries regarding mechanism of disease and potential therapeutic targets. Many cellular changes including oxidative stress, disruption of Ca2+ homeostasis, inflammation, metabolic disturbances, and accumulation of unfolded/misfolded proteins can lead to programmed cell death in AD. Despite intensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look at alternative therapies. Use of natural products and culinary herbs in medicine has gained popularity in recent years. Several natural substances with neuroprotective effects have been widely studied. Most of these compounds have remarkable antioxidant properties and act mainly by scavenging free radical species. Some of them increase cell survival and improve cognition by directly affecting amyloidogenesis and programmed cell death pathways. Further studies on these natural products and their mechanism of action, parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine. This review discussed some natural products with potential neuroprotective properties against Aβ with respect to their mechanism of action.

  5. Evaluation of Pterin, a Promising Drug Candidate from Cyanide Degrading Bacteria.

    Science.gov (United States)

    Mahendran, Ramasamy; Thandeeswaran, Murugesan; Kiran, Gopikrishnan; Arulkumar, Mani; Ayub Nawaz, K A; Jabastin, Jayamanoharan; Janani, Balraj; Anto Thomas, Thomas; Angayarkanni, Jayaraman

    2018-06-01

    Pterin is a member of the compounds known as pteridines. They have the same nucleus of 2-amino-4-hydroxypteridine (pterin); however, the side-chain is different at the position 6, and the state of oxidation of the ring may exist in different form viz. tetrahydro, dihydro, or a fully oxidized form. In the present study, the microorganisms able to utilize cyanide, and heavy metals have been tested for the efficient production of pterin compound. The soil samples contaminated with cyanide and heavy metals were collected from Salem steel industries, Tamil Nadu, India. Out of 77 isolated strains, 40 isolates were found to utilize sodium cyanate as nitrogen source at different concentrations. However, only 13 isolates were able to tolerate maximum concentration (60 mM) of sodium cyanate and were screened for pterin production. Among the 13 isolates, only 1 organism showed maximum production of pterin, and the same was identified as Bacillus pumilus SVD06. The compound was extracted and purified by preparative high-performance liquid chromatography and analyzed by UV/visible, FTIR, and fluorescent spectrum. The antioxidant property of the purified pterin compound was determined by cyclic voltammetry. In addition, antimicrobial activity of pterin was also studied which was substantiated by antagonistic activity against Escherichia coli, and Pseudomonas aeruginosa. Besides that the pterin compound was proved to inhibit the formation of biofilm. The extracted pterin compounds could be proposed further not only for antioxidant and antimicrobial but also for its potency to aid as anticancer and psychotic drugs in future.

  6. Ebselen, a useful tool for understanding cellular redox biology and a promising drug candidate for use in human diseases.

    Science.gov (United States)

    Noguchi, Noriko

    2016-04-01

    Ebselen is an organoselenium compound with glutathione peroxidase (GPx)-like hydroperoxide reducing activity. Moreover, ebselen has its own unique reactivity, with functions that GPx does not have, since it reacts with many kinds of thiols other than glutathione. Ebselen may affect the thioredoxin systems, through which it may contribute to regulation of cell function. With high reactivity toward thiols, hydroperoxides, and peroxynitrite, ebselen has been used as a useful tool in research on cellular redox mechanisms. Unlike α-tocopherol, ebselen does not scavenge lipid peroxyl radicals, which is another advantage of ebselen for use as a research tool in comparison with radical scavenging antioxidants. Selenium is not released from the ebselen molecule, which explains the low toxicity of ebselen. To further understand the mechanism of cellular redox biology, it should be interesting to compare the effects of ebselen with that of selenoprotein P, which supplies selenium to GPx. New medical applications of ebselen as a drug candidate for human diseases such as cancer and diabetes mellitus as well as brain stroke and ischemia will be expected. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Halopentacenes: Promising Candidates for Organic Semiconductors

    International Nuclear Information System (INIS)

    Gong-He, Du; Zhao-Yu, Ren; Ji-Ming, Zheng; Ping, Guo

    2009-01-01

    We introduce polar substituents such as F, Cl, Br into pentacene to enhance the dissolubility in common organic solvents while retaining the high charge-carrier mobilities of pentacene. Geometric structures, dipole moments, frontier molecule orbits, ionization potentials and electron affinities, as well as reorganization energies of those molecules, and of pentacene for comparison, are successively calculated by density functional theory. The results indicate that halopentacenes have rather small reorganization energies (< 0.2 eV), and when the substituents are in position 2 or positions 2 and 9, they are polarity molecules. Thus we conjecture that they can easily be dissolved in common organic solvents, and are promising candidates for organic semiconductors. (condensed matter: electronicstructure, electrical, magnetic, and opticalproperties)

  8. Natural Flavonoids as Promising Analgesic Candidates: A Systematic Review.

    Science.gov (United States)

    Xiao, Xiao; Wang, Xiaoyu; Gui, Xuan; Chen, Lu; Huang, Baokang

    2016-11-01

    Due to the chemical structural diversity and various analgesic mechanisms, an increasing number of studies indicated that some flavonoids from medicinal plants could be promising candidates for new natural analgesic drugs, which attract high interests of advanced users and academic researchers. The aim of this systematic review is to report flavonoids and its derivatives as new analgesic candidates based on the pharmacological evidences. Sixty-four papers were found concerning the potential analgesic activity of 46 flavonoids. In this case, the evidence for analgesic activity of flavonoids and total flavonoids was investigated. Meanwhile, the corresponding analgesic mechanism of flavonoids was discussed by generalizing and analyzing the current publications. Based on this review, the conclusion can be drawn that some flavonoids are promising candidates for painful conditions and deserve particular attention in further research and development. © 2016 Wiley-VHCA AG, Zurich, Switzerland.

  9. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    International Nuclear Information System (INIS)

    Tamura, Akitoshi; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-01-01

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  10. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Akitoshi, E-mail: akitoshi-tamura@ds-pharma.co.jp; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  11. Promising new vaccine candidates against Campylobacter in broilers.

    Directory of Open Access Journals (Sweden)

    Marine Meunier

    Full Text Available Campylobacter is the leading cause of human bacterial gastroenteritis in the European Union. Birds represent the main reservoir of the bacteria, and human campylobacteriosis mainly occurs after consuming and/or handling poultry meat. Reducing avian intestinal Campylobacter loads should impact the incidence of human diseases. At the primary production level, several measures have been identified to reach this goal, including vaccination of poultry. Despite many studies, however, no efficient vaccine is currently available. We have recently identified new vaccine candidates using the reverse vaccinology strategy. This study assessed the in vivo immune and protective potential of six newly-identified vaccine antigens. Among the candidates tested on Ross broiler chickens, four (YP_001000437.1, YP_001000562.1, YP_999817.1, and YP_999838.1 significantly reduced cecal Campylobacter loads by between 2 and 4.2 log10 CFU/g, with the concomitant development of a specific humoral immune response. In a second trial, cecal load reductions results were not statistically confirmed despite the induction of a strong immune response. These vaccine candidates need to be further investigated since they present promising features.

  12. Biochemical Markers for Osteoarthritis: Is There any Promising Candidate?

    Directory of Open Access Journals (Sweden)

    Elif Aydın

    2016-04-01

    Full Text Available Osteoarthritis (OA is the most common degenerative joint disease. OA affects millions of individuals each year and becoming the most important cause of pain in geriatric population. Progressive destruction of articular cartilage is one of the prominent features of the disease. The diagnosis of OA is generally based on clinical and radiographical findings, which are insufficient to determine early-stage OA and predict disease course. There is a need for biomarkers that help clinicians early diagnose, assess disease activity, predict prognosis and monitor response to therapy. There are a growing number of publications regarding candidate markers in this field. The aim of this paper was to review recent studies on biochemical markers that reflect cartilage, synovial and bone turnover and their clinical use in patients with OA.

  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. Novel and Efficient Synthesis of the Promising Drug Candidate Discodermolide

    Science.gov (United States)

    2010-02-01

    of its production may require its wide use as a livestock antibiotic , a market that seems to have disappeared. Therefore, as a purely practical...building block 9. Thus, chiral syn, anti stereotriad building blocks, useful for the preparation of polypropionate antibiotics , may be efficiently accessed... antibiotics that are used in human and veterinary medicine. In this paper, we illustrate the potential of a deconstruction-reconstruction strategy for the

  15. PPARγ Ligand as a Promising Candidate for Colorectal Cancer Chemoprevention: A Pilot Study

    Directory of Open Access Journals (Sweden)

    Hirokazu Takahashi

    2010-01-01

    Full Text Available Activating synthetic ligands for peroxisome proliferator-activated receptor gamma (PPARγ, such as pioglitazone, are commonly used to treat persons with diabetes mellitus with improvement of insulin resistance. Several reports have clearly demonstrated that PPARγ ligands could inhibit colorectal cancer cell growth and induce apoptosis. Meanwhile, aberrant crypt foci (ACF have come to be established as a biomarker of the risk of CRC in azoxymethane-treated mice and rats. In humans, ACF can be detected using magnifying colonoscopy. Previously, CRC and adenoma were used as a target for chemopreventive agents, but it needs a long time to evaluate, however, ACF can be a surrogate marker of CRC even for a brief period. In this clinical study, we investigated the chemopreventive effect of pioglitazone on the development of human ACF as a surrogate marker of CRC. Twenty-nine patients were divided into two groups, 20 were in the endoscopically normal control group and 9 were in the pioglitazone (15 mg/day group, and ACF and adenoma were examined before and after 1-month treatment. The number of ACF was significantly decreased (5.8±1.1 to 3.3±2.3 after 1 month of pioglitazone treatment, however, there was no significant change in the number of crypts/ACF or in the number and size of adenomas. Pioglitazone may have a clinical application as a cancer-preventive drug. This investigation is just a pilot study, therefore, further clinical studies are needed to show that the PPARγ ligand may be a promising candidate as a chemopreventive agent for colorectal carcinogenesis.

  16. Microencapsulation: A promising technique for controlled drug delivery.

    Science.gov (United States)

    Singh, M N; Hemant, K S Y; Ram, M; Shivakumar, H G

    2010-07-01

    MICROPARTICLES OFFER VARIOUS SIGNIFICANT ADVANTAGES AS DRUG DELIVERY SYSTEMS, INCLUDING: (i) an effective protection of the encapsulated active agent against (e.g. enzymatic) degradation, (ii) the possibility to accurately control the release rate of the incorporated drug over periods of hours to months, (iii) an easy administration (compared to alternative parenteral controlled release dosage forms, such as macro-sized implants), and (iv) Desired, pre-programmed drug release profiles can be provided which match the therapeutic needs of the patient. This article gives an overview on the general aspects and recent advances in drug-loaded microparticles to improve the efficiency of various medical treatments. An appropriately designed controlled release drug delivery system can be a foot ahead towards solving problems concerning to the targeting of drug to a specific organ or tissue, and controlling the rate of drug delivery to the target site. The development of oral controlled release systems has been a challenge to formulation scientist due to their inability to restrain and localize the system at targeted areas of gastrointestinal tract. Microparticulate drug delivery systems are an interesting and promising option when developing an oral controlled release system. The objective of this paper is to take a closer look at microparticles as drug delivery devices for increasing efficiency of drug delivery, improving the release profile and drug targeting. In order to appreciate the application possibilities of microcapsules in drug delivery, some fundamental aspects are briefly reviewed.

  17. Promising Practices in Drug Treatment: Findings from Southeast Asia

    Science.gov (United States)

    Libretto, Salvatore; Nemes, Susanna; Namur, Jenny; Garrett, Gerald; Hess, Lauren; Kaplan, Linda

    2005-01-01

    In a study to evaluate the drug treatment and aftercare efforts sponsored by the State Department's International Narcotics and Law Enforcement Affairs Bureau, residential Therapeutic Community (TC) treatment programs in three countries in Southeast Asia--Malaysia, Singapore, and Thailand--were examined to identify promising practices and to…

  18. Advertising and drugs: a world of images and promises

    Directory of Open Access Journals (Sweden)

    Jurema Barros Dantas

    2010-11-01

    Full Text Available The aim of this article is to discuss the relation between the contemporary use and advertising of pharmaceutical drugs based on the so-called culture of consumption. We discuss advertising as a means of strengthening the belief in the power of these drugs, presenting them as a synthesis of science and technology to promote health and well being and, particularly, as a quick solution for typical problems of the contemporary world. The obligation to buy the latest medicines is becoming a symbol of social affirmation as well as the only way to weaken our daily problems. Using a logic of consumption as ownership, we create, with the help of advertising, a world of promises concerning immediate solutions, easily sold through on line shopping, supermarkets, department stores and shopping centers. We discuss this set of contemporary practices and values which are turning our way of life into a disposable product.   Keywords: advertising; consumption; pharmaceutical drugs.

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

    Science.gov (United States)

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

    2018-02-01

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

  20. Metabolomics-based promising candidate biomarkers and pathways in Alzheimer's disease.

    Science.gov (United States)

    Kang, Jian; Lu, Jingli; Zhang, Xiaojian

    2015-05-01

    Pathologically, loss of synapses and neurons, extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) are observed in the brains of patients with Alzheimer's disease (AD). These features are associated with changes Aβ (amyloid β) 40, Aβ42, total tau and phosphorylated tau (p-tau), which are as definitely biomarkers for severe AD state. However, biomarkers for effectively diagnosing AD in the pre-clinical state for directing therapeutic strategies are lacking. Metabolic profiling as a powerful tool to identify new biomarkers is receiving increasing attention in AD. This review will focus on metabolomics-based detection of promising candidate biomarkers and pathways in AD to facilitate the discovery of new medicines and disease pathways.

  1. Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

    Directory of Open Access Journals (Sweden)

    María Martínez-Hoyos

    2016-06-01

    Full Text Available Despite being one of the first antitubercular agents identified, isoniazid (INH is still the most prescribed drug for prophylaxis and tuberculosis (TB treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI of the enoyl-ACP reductase (InhA has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb, but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR and extensively (XDR drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

  2. Pharmacology of biosimilar candidate drugs in rheumatology: a literature review.

    Science.gov (United States)

    Araújo, F; Cordeiro, I; Teixeira, F; Gonçalves, J; Fonseca, J E

    2014-01-01

    To review current evidence concerning pharmacology of biosimilar candidates to be used in rheumatology. A PubMed search up to August 2013 was performed using relevant search terms to include all studies assessing pharmacological properties of biosimilar candidates to be used in rheumatology. Data on study characteristics, type of intervention, pharmacokinetics (PK), pharmacodynamics (PD) and bioequivalence ratios was extracted. Of 280 articles screened, 5 fulfilled our inclusion criteria. Two trials, PLANETAS and PLANETRA, compared CT-P13 and infliximab in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively. PK bioequivalence was demonstrated in the phase 1 PLANETAS trial by highly comparable area under the curve (AUC) and maximum drug concentrations (Cmax), whose geometric mean ratios fell between the accepted bioequivalence range of 80-125%. Equivalence in efficacy and safety was demonstrated in the phase 3 PLANETRA trial. Two phase 1 trials comparing etanercept biosimilar candidates TuNEX and HD203 in healthy volunteers showed a high degree of similarity in AUC and Cmax, with respective geometric mean ratios between PK bioequivalence range. The last included trial referred to GP2013, a rituximab biosimilar candidate, which demonstrated PK and PD bioequivalence to reference product in three different dosing regimens in cynomolgus monkeys. Infliximab, etanercept and rituximab biosimilar candidates have demonstrated PK bioequivalence in the trials included in this review. CT-P13 has recently been approved for use in the European market and the remaining biosimilar candidates are currently being tested in patients with rheumatoid arthritis.

  3. Plants’ Natural Products as Alternative Promising Anti-Candida Drugs

    Science.gov (United States)

    Soliman, Sameh; Alnajdy, Dina; El-Keblawy, Ali A.; Mosa, Kareem A.; Khoder, Ghalia; Noreddin, Ayman M.

    2017-01-01

    Candida is a serious life-threatening pathogen, particularly with immunocompromised patients. Candida infections are considered as a major cause of morbidity and mortality in a broad range of immunocompromised patients. Candida infections are common in hospitalized patients and elderly people. The difficulty to eradicate Candida infections is owing to its unique switch between yeast and hyphae forms and more likely to biofilm formations that render resistance to antifungal therapy. Plants are known sources of natural medicines. Several plants show significant anti-Candida activities and some of them have lower minimum inhibitory concentration, making them promising candidates for anti-Candida therapy. However, none of these plant products is marketed for anti-Candida therapy because of lack of sufficient information about their efficacy, toxicity, and kinetics. This review revises major plants that have been tested for anti-Candida activities with recommendations for further use of some of these plants for more investigation and in vivo testing including the use of nanostructure lipid system. PMID:28989245

  4. Menahydroquinone-4 Prodrug: A Promising Candidate Anti-Hepatocellular Carcinoma Agent.

    Science.gov (United States)

    Enjoji, Munechika; Watase, Daisuke; Matsunaga, Kazuhisa; Kusuda, Mariko; Nagata-Akaho, Nami; Karube, Yoshiharu; Takata, Jiro

    2015-07-22

    Recently, new therapeutics have been developed for hepatocellular carcinoma (HCC). However, the overall survival rate of HCC patients is still unsatisfactory; one of the reasons for this is the high frequency of recurrence after radical treatment. Consequently, to improve prognosis, it will be important to develop a novel anti-tumor agent that is especially effective against HCC recurrence. For clinical application, long-term safety, together with high anti-tumor efficacy, is desirable. Recent studies have proposed menahydroquinone-4 1,4-bis- N,N -dimethylglycinate hydrochloride (MKH-DMG), a prodrug of menahydroquinone-4 (MKH), as a promising candidate for HCC treatment including the inhibition of recurrence; MKH-DMG has been shown to achieve good selective accumulation of MKH in tumor cells, resulting in satisfactory inhibition of cell proliferation in des-γ-carboxyl prothrombin (DCP)-positive and DCP-negative HCC cell lines. In a spleen-liver metastasis mouse model, MKH-DMG has been demonstrated to have anti-proliferation and anti-metastatic effects in vivo . The characteristics of MKH-DMG as a novel anti-HCC agent are presented in this review article.

  5. Anti-chemokine small molecule drugs: a promising future?

    Science.gov (United States)

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

    2010-03-01

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

  6. Candidate Targets for New Anti-Virulence Drugs: Selected Cases of Bacterial Adhesion and Biofilm Formation

    DEFF Research Database (Denmark)

    Klemm, Per; Hancock, Viktoria; Kvist, Malin

    2007-01-01

    is particularly problematic in medical contexts because biofilm-associated bacteria are particularly hard to eradicate. Several promising candidate drugs that target bacterial adhesion and biofilm formation are being developed. Some of these might be valuable weapons for fighting infectious diseases in the future...... formation are highly attractive targets for new drugs. Specific adhesion provides bacteria with target selection and prevents removal by hydrodynamic flow forces. Bacterial adhesion is of paramount importance for bacterial pathogenesis. Adhesion is also the first step in biofilm formation. Biofilm formation...

  7. Polyphenols as Promising Drugs against Main Breast Cancer Signatures

    Directory of Open Access Journals (Sweden)

    María Losada-Echeberría

    2017-11-01

    Full Text Available Breast cancer is one of the most common neoplasms worldwide, and in spite of clinical and pharmacological advances, it is still a clinical problem, causing morbidity and mortality. On the one hand, breast cancer shares with other neoplasms some molecular signatures such as an imbalanced redox state, cell cycle alterations, increased proliferation and an inflammatory status. On the other hand, breast cancer shows differential molecular subtypes that determine its prognosis and treatment. These are characterized mainly by hormone receptors especially estrogen receptors (ERs and epidermal growth factor receptor 2 (HER2. Tumors with none of these receptors are classified as triple negative breast cancer (TNBC and are associated with a worse prognosis. The success of treatments partially depends on their specificity and the adequate molecular classification of tumors. New advances in anticancer drug discovery using natural compounds have been made in the last few decades, and polyphenols have emerged as promising molecules. They may act on various molecular targets because of their promiscuous behavior, presenting several physiological effects, some of which confer antitumor activity. This review analyzes the accumulated evidence of the antitumor effects of plant polyphenols on breast cancer, with special attention to their activity on ERs and HER2 targets and also covering different aspects such as redox balance, uncontrolled proliferation and chronic inflammation.

  8. Polyphenols as Promising Drugs against Main Breast Cancer Signatures

    Science.gov (United States)

    Herranz-López, María; Micol, Vicente

    2017-01-01

    Breast cancer is one of the most common neoplasms worldwide, and in spite of clinical and pharmacological advances, it is still a clinical problem, causing morbidity and mortality. On the one hand, breast cancer shares with other neoplasms some molecular signatures such as an imbalanced redox state, cell cycle alterations, increased proliferation and an inflammatory status. On the other hand, breast cancer shows differential molecular subtypes that determine its prognosis and treatment. These are characterized mainly by hormone receptors especially estrogen receptors (ERs) and epidermal growth factor receptor 2 (HER2). Tumors with none of these receptors are classified as triple negative breast cancer (TNBC) and are associated with a worse prognosis. The success of treatments partially depends on their specificity and the adequate molecular classification of tumors. New advances in anticancer drug discovery using natural compounds have been made in the last few decades, and polyphenols have emerged as promising molecules. They may act on various molecular targets because of their promiscuous behavior, presenting several physiological effects, some of which confer antitumor activity. This review analyzes the accumulated evidence of the antitumor effects of plant polyphenols on breast cancer, with special attention to their activity on ERs and HER2 targets and also covering different aspects such as redox balance, uncontrolled proliferation and chronic inflammation. PMID:29112149

  9. A conceptual framework for the identification of candidate drugs and drug targets in acute promyelocytic leukemia

    DEFF Research Database (Denmark)

    Marstrand, T T; Borup, R; Willer, A

    2010-01-01

    regulation, and (ii) the identification of candidate drugs and drug targets for therapeutic interventions. Significantly, our study provides a conceptual framework that can be applied to any subtype of AML and cancer in general to uncover novel information from published microarray data sets at low cost...

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

    Directory of Open Access Journals (Sweden)

    Piero Olliaro

    2011-06-01

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

  11. Pharmacogenetics in drug regulation: promise, potential and pitfalls

    Science.gov (United States)

    Shah, Rashmi R

    2005-01-01

    Pharmacogenetic factors operate at pharmacokinetic as well as pharmacodynamic levels—the two components of the dose–response curve of a drug. Polymorphisms in drug metabolizing enzymes, transporters and/or pharmacological targets of drugs may profoundly influence the dose–response relationship between individuals. For some drugs, although retrospective data from case studies suggests that these polymorphisms are frequently associated with adverse drug reactions or failure of efficacy, the clinical utility of such data remains unproven. There is, therefore, an urgent need for prospective data to determine whether pre-treatment genotyping can improve therapy. Various regulatory guidelines already recommend exploration of the role of genetic factors when investigating a drug for its pharmacokinetics, pharmacodynamics, dose–response relationship and drug interaction potential. Arising from the global heterogeneity in the frequency of variant alleles, regulatory guidelines also require the sponsors to provide additional information, usually pharmacogenetic bridging data, to determine whether data from one ethnic population can be extrapolated to another. At present, sponsors explore pharmacogenetic influences in early clinical pharmacokinetic studies but rarely do they carry the findings forward when designing dose–response studies or pivotal studies. When appropriate, regulatory authorities include genotype-specific recommendations in the prescribing information. Sometimes, this may include the need to adjust a dose in some genotypes under specific circumstances. Detailed references to pharmacogenetics in prescribing information and pharmacogenetically based prescribing in routine therapeutics will require robust prospective data from well-designed studies. With greater integration of pharmacogenetics in drug development, regulatory authorities expect to receive more detailed genetic data. This is likely to complicate the drug evaluation process as well as

  12. Nanoparticle-based drug delivery systems: promising approaches against infections

    Energy Technology Data Exchange (ETDEWEB)

    Ranghar, Shweta; Sirohi, Parul [Department of Applied Mechanics, Motilal Nehru National Institute of Technology, Allahabad (India); Verma, Pritam; Agarwal, Vishnu [Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad (India)

    2014-03-15

    Despite the fact that many new drugs and technologies have been developed to combat the infectious diseases, these have continued to be global health challenges. The use of conventional antimicrobial agents against these infections is always associated with problems such as the development of multiple drug resistance and adverse side effects. In addition, the inefficient traditional drug delivery system results in inadequate therapeutic index, low bioavailability of drugs and many other limitations. In this regard, antimicrobial nanoparticles and nanosized drug delivery carriers have emerged as potent effective agents against the infections. Nanoparticles have unique properties owing to their ultra small and controllable size such as high surface area, enhanced reactivity, and functionalizable structure. This review focused on different classes of antimicrobial nanoparticles, including metal, metal oxide and others along with their mechanism of action and their potential use against the infections. The review also focused on the development of nanoparticle systems for antimicrobial drug delivery and use of these systems for delivery of various antimicrobial agents, giving an overview about modern nanoparticle based therapeutic strategies against the infections. (author)

  13. Nanoparticle-based drug delivery systems: promising approaches against infections

    International Nuclear Information System (INIS)

    Ranghar, Shweta; Sirohi, Parul; Verma, Pritam; Agarwal, Vishnu

    2014-01-01

    Despite the fact that many new drugs and technologies have been developed to combat the infectious diseases, these have continued to be global health challenges. The use of conventional antimicrobial agents against these infections is always associated with problems such as the development of multiple drug resistance and adverse side effects. In addition, the inefficient traditional drug delivery system results in inadequate therapeutic index, low bioavailability of drugs and many other limitations. In this regard, antimicrobial nanoparticles and nanosized drug delivery carriers have emerged as potent effective agents against the infections. Nanoparticles have unique properties owing to their ultra small and controllable size such as high surface area, enhanced reactivity, and functionalizable structure. This review focused on different classes of antimicrobial nanoparticles, including metal, metal oxide and others along with their mechanism of action and their potential use against the infections. The review also focused on the development of nanoparticle systems for antimicrobial drug delivery and use of these systems for delivery of various antimicrobial agents, giving an overview about modern nanoparticle based therapeutic strategies against the infections. (author)

  14. Mucoadhesive microspheres: a promising tool in drug delivery.

    Science.gov (United States)

    Patil, Sanjay B; Sawant, Krutika K

    2008-10-01

    Mucoadhesive polymers have recently gained interest among pharmaceutical scientists as a means of improving drug delivery by promoting the residence time and contact time of the dosage form with the mucous membranes. Mucoadhesion is the process whereby synthetic and natural polymers adhere to mucosal surfaces in the body. If these materials are then incorporated into pharmaceutical formulations, drug absorption by mucosal cells may be enhanced or the drug will be released at the site for an extended period of time. Microspheres, in general, have the potential to be used for targeted and controlled release drug delivery; however, coupling of mucoadhesive properties to microspheres has additional advantages like, a much more intimate contact with the mucus layer, efficient absorption and enhanced bioavailability of the drugs due to a high surface to volume ratio. The present review describes the potential applications of mucoadhesive microspheres as a novel carrier system to improve drug delivery by various routes of administration like buccal, oral, nasal, ocular, vaginal and rectal, either for systemic or for local effects. The mucoadhesive polymers, methods of preparation of microspheres and their in vitro and in vivo evaluation are also described.

  15. Tyrosine aminotransferase from Leishmania infantum: A new drug target candidate

    Directory of Open Access Journals (Sweden)

    Miguel Angel Moreno

    2014-12-01

    Full Text Available Leishmania infantum is the etiological agent of zoonotic visceral leishmaniasis in the Mediterranean basin. The disease is fatal without treatment, which has been based on antimonial pentavalents for more than 60 years. Due to resistances, relapses and toxicity to current treatment, the development of new drugs is required. The structure of the L. infantum tyrosine aminotransferase (LiTAT has been recently solved showing important differences with the mammalian orthologue. The characterization of LiTAT is reported herein. This enzyme is cytoplasmic and is over-expressed in the more infective stages and nitric oxide resistant parasites. Unlike the mammalian TAT, LiTAT is able to use ketomethiobutyrate as co-substrate. The pharmacophore model of LiTAT with this specific co-substrate is described herein. This may allow the identification of new inhibitors present in the databases. All the data obtained support that LiTAT is a good target candidate for the development of new anti-leishmanial drugs.

  16. ASASSN-16dt and ASASSN-16hg: Promising candidate period bouncers

    Science.gov (United States)

    Kimura, Mariko; Isogai, Keisuke; Kato, Taichi; Taguchi, Kenta; Wakamatsu, Yasuyuki; Hambsch, Franz-Josef; Monard, Berto; Myers, Gordon; Dvorak, Shawn; Starr, Peter; Brincat, Stephen M.; de Miguel, Enrique; Ulowetz, Joseph; Itoh, Hiroshi; Stone, Geoff; Nogami, Daisaku

    2018-04-01

    We present optical photometry of superoutbursts that occurred in 2016 of two WZ Sge-type dwarf novae (DNe), ASASSN-16dt and ASASSN-16hg. Their light curves showed a dip in brightness between the first plateau stage with no ordinary superhumps (or early superhumps) and the second plateau stage with ordinary superhumps. We find that the dip is produced by the slow evolution of the 3 : 1 resonance tidal instability and that it would likely be observed in low mass-ratio objects. An estimated mass ratio (q ≡ M2/M1) from the period of developing (stage A) superhumps [0.06420(3) d] was 0.036(2) in ASASSN-16dt. Additionally, its superoutburst has many properties similar to those in other low-q WZ Sge-type DNe: long-lasting stage-A superhumps, small superhump amplitudes, long delay of ordinary-superhump appearances, and a slow decline rate in the plateau stage with superhumps. Its very small mass ratio and observational characteristics suggest that this system is one of the best candidates for a period bouncer—a binary accounting for the missing population of post-period minimum cataclysmic variables. Although it is not clearly verified due to the lack of detection of stage-A superhumps, ASASSN-16hg might be a possible candidate for period bouncers on the basis of the morphology of its light curves and the small superhump amplitudes. Many outburst properties of period bouncer candidates would originate from the small tidal effects of their secondary stars.

  17. Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites.

    Science.gov (United States)

    Kevin Ii, Dion A; Meujo, Damaris Af; Hamann, Mark T

    2009-02-01

    As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics.

  18. Recent advances in liposomal nanohybrid cerasomes as promising drug nanocarriers.

    Science.gov (United States)

    Yue, Xiuli; Dai, Zhifei

    2014-05-01

    Liposomes have been extensively investigated as possible carriers for diagnostic or therapeutic agents due to their unique properties. However, liposomes still have not attained their full potential as drug and gene delivery vehicles because of their insufficient morphological stability. Recently, a super-stable and freestanding hybrid liposomal cerasome (partially ceramic- or silica-coated liposome) has drawn much attention as a novel drug delivery system because its atomic layer of polyorganosiloxane surface imparts higher morphological stability than conventional liposomes and its liposomal bilayer structure reduces the overall rigidity and density greatly compared to silica nanoparticles. Cerasomes are more biocompatible than silica nanoparticles due to the incorporation of the liposomal architecture into cerasomes. Cerasomes combine the advantages of both liposomes and silica nanoparticles but overcome their disadvantages so cerasomes are ideal drug delivery systems. The present review will first highlights some of the key advances of the past decade in the technology of cerasome production and then review current biomedical applications of cerasomes, with a view to stimulating further research in this area of study. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Identification and development of a promising novel mumps vaccine candidate strain.

    Science.gov (United States)

    Liang, Yan; Ma, Shaohui; Liu, Longding; Zhao, Hongling; Wang, Lichun; Jiang, Li; Xie, Zhongping; Dong, Chenghong; Li, Qihan

    2010-12-01

    Mumps epidemics are usually caused by airborne transmission of mumps virus (MuV) and have high morbidity in non-immunized children. Epidemiological studies in many regions of China show that the genotype F viral strain is the most prevalent. However, the genotype A strain is currently used to prepare vaccines. Regional epidemiological MuV data suggest a significant application for the development of live attenuated mumps vaccines targeting specific genotypes. This article reports the isolation and culture of a genotype F MuV candidate strain that could be used to prepare a live attenuated mumps vaccine. This strain is shown to have good immunological efficacy and stability in neurovirulence evaluations. This work should facilitate the implementation of mumps vaccination in mainland China by targeting the most prevalent MuV genotype, genotype F. Copyright © 2010 Institut Pasteur. Published by Elsevier SAS. All rights reserved.

  20. Targeting aerobic glycolysis: 3-bromopyruvate as a promising anticancer drug.

    Science.gov (United States)

    Cardaci, Simone; Desideri, Enrico; Ciriolo, Maria Rosa

    2012-02-01

    The Warburg effect refers to the phenomenon whereby cancer cells avidly take up glucose and produce lactic acid under aerobic conditions. Although the molecular mechanisms underlying tumor reliance on glycolysis remains not completely clear, its inhibition opens feasible therapeutic windows for cancer treatment. Indeed, several small molecules have emerged by combinatorial studies exhibiting promising anticancer activity both in vitro and in vivo, as a single agent or in combination with other therapeutic modalities. Therefore, besides reviewing the alterations of glycolysis that occur with malignant transformation, this manuscript aims at recapitulating the most effective pharmacological therapeutics of its targeting. In particular, we describe the principal mechanisms of action and the main targets of 3-bromopyruvate, an alkylating agent with impressive antitumor effects in several models of animal tumors. Moreover, we discuss the chemo-potentiating strategies that would make unparalleled the putative therapeutic efficacy of its use in clinical settings.

  1. Cytolysin a expressing E. coli a promising candidate for imageable therapeutic probe

    International Nuclear Information System (INIS)

    Nguyen, Vu Hong; Phan, Thuy Xuan; Hong, Yeoung Jin; Min, Jung Joon

    2007-01-01

    Using bacteria for cancer treatment has a long history. Discovery of optical reporter genes consisting of fluorescent and luminescent protein facilitates the monitor of bacteria in vivo, non-invasively and repeatedly. E. coli, the natural enteric bacteria possessing capacity of tumor-targeting ability, seems to be suitable candidate for cancer treatment. In this study, we established the strain light-emitting E. coli for diagnostic purpose and Cytolysin A (Cly A) expressing E. coli for therapeutic purpose. E. coli (MG1655, wild type strain) was transformed plasmid pUC19 carrying lux gene to create the light expressing bacteria and test the tumor targeting-capacity by injecting the bacteria into CT26-tumor bearing mice via tail vein. On the other hand, for therapeutic purpose, plasmid containing Cly A gene, which is encoded for a pore-forming protein toxin, was introduced into E. coli. The toxicity of Cly A was evaluated in vitro by inoculating the bacteria with various cultured cancer cell lines. On the other hand, to test the therapeutic effect, the bacteria were injected intratumorally and intravenously into s.c.CT26-bearing as well as CT26-lung metastasized Balb/c mice. In vivo imaging data showed that the E. coli strains selectively located in the tumor. The in vitro result showed that the number of death cells were significantly higher in the samples containing E. coli expressing Cly A (E. coli Cly A) compared with the samples containing wild type strain. The growth of tumors was repressed in mice injected with either E. coli Cly A (significantly) or wild type E. coli (mildly), while tumors in no treatment group still grew fast. Furthermore, the tumors inoculated with E. coli cly A were necrotized but not with wild type E. coli. In the CT26-lung metastasized mouse model, the life span of mice was elongated when inject E. coli and longer in the group injected with E. coli cly A. Cly A expressing E. coli can become an effective candidate for imageable

  2. Prediction methods and databases within chemoinformatics: emphasis on drugs and drug candidates

    DEFF Research Database (Denmark)

    Jonsdottir, Svava Osk; Jorgensen, FS; Brunak, Søren

    2005-01-01

    about drugs and drug candidates, and of databases with relevant properties. Access to experimental data and numerical methods for selecting and utilizing these data is crucial for developing accurate predictive in silico models. Many interesting predictive methods for classifying the suitability......MOTIVATION: To gather information about available databases and chemoinformatics methods for prediction of properties relevant to the drug discovery and optimization process. RESULTS: We present an overview of the most important databases with 2-dimensional and 3-dimensional structural information...... of chemical compounds as potential drugs, as well as for predicting their physico-chemical and ADMET properties have been proposed in recent years. These methods are discussed, and some possible future directions in this rapidly developing field are described....

  3. Drugs that modulate aging: the promising yet difficult path ahead.

    Science.gov (United States)

    Kennedy, Brian K; Pennypacker, Juniper K

    2014-05-01

    Once a backwater in medical sciences, aging research has emerged and now threatens to take the forefront. This dramatic change of stature is driven from 3 major events. First and foremost, the world is rapidly getting old. Never before have we lived in a demographic environment like today, and the trends will continue such that 20% percent of the global population of 9 billion will be over the age of 60 by 2050. Given current trends of sharply increasing chronic disease incidence, economic disaster from the impending silver tsunami may be ahead. A second major driver on the rise is the dramatic progress that aging research has made using invertebrate models such as worms, flies, and yeast. Genetic approaches using these organisms have led to hundreds of aging genes and, perhaps surprisingly, strong evidence of evolutionary conservation among longevity pathways between disparate species, including mammals. Current studies suggest that this conservation may extend to humans. Finally, small molecules such as rapamycin and resveratrol have been identified that slow aging in model organisms, although only rapamycin to date impacts longevity in mice. The potential now exists to delay human aging, whether it is through known classes of small molecules or a plethora of emerging ones. But how can a drug that slows aging become approved and make it to market when aging is not defined as a disease. Here, we discuss the strategies to translate discoveries from aging research into drugs. Will aging research lead to novel therapies toward chronic disease, prevention of disease or be targeted directly at extending lifespan? Copyright © 2014 Mosby, Inc. All rights reserved.

  4. Buccal bioadhesive drug delivery--a promising option for orally less efficient drugs.

    Science.gov (United States)

    Sudhakar, Yajaman; Kuotsu, Ketousetuo; Bandyopadhyay, A K

    2006-08-10

    Rapid developments in the field of molecular biology and gene technology resulted in generation of many macromolecular drugs including peptides, proteins, polysaccharides and nucleic acids in great number possessing superior pharmacological efficacy with site specificity and devoid of untoward and toxic effects. However, the main impediment for the oral delivery of these drugs as potential therapeutic agents is their extensive presystemic metabolism, instability in acidic environment resulting into inadequate and erratic oral absorption. Parenteral route of administration is the only established route that overcomes all these drawbacks associated with these orally less/inefficient drugs. But, these formulations are costly, have least patient compliance, require repeated administration, in addition to the other hazardous effects associated with this route. Over the last few decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth muscle which is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells. Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with the optimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging. With the right dosage form design, local environment of the mucosa can be controlled and manipulated in order to

  5. Electric vehicle batteries. Development status for the promising candidates; Elbilsbatterier. Utvecklingsstatus foer de fraemsta kandidaterna

    Energy Technology Data Exchange (ETDEWEB)

    Andersson, Bo; Johansson, Arne [Catella Generics AB, Jaerfaella (Sweden)

    2000-04-01

    One driver for the EV and HEV programme of KFB is to study the effects of a large scale introduction of electric vehicles in the future. Catella Generics was contracted to investigate and report on the development status for EV batteries and the success potential for the different candidates, their development obstacles and alternative usage and on the links between different players. The batteries studied in greater detail have been evaluated according to special criteria like performance, cost, ruggedness, resource efficiency, safety and environmental impact and how that will influence their likely success. Models for the evaluation of EV batteries have been developed by the car manufacturers and authorities. We have based our investigation on the criteria established by USABC and the modifications made by PNGV for the energy storage in hybrid electric vehicles. Some basic conclusions reported as a result of this investigation are listed below: Lead-acid may have a role as energy storage in HEVs. Ni/Cd batteries are attractive from a technical standpoint, but questioned based on the environmental concern for cadmium. Ni/MH batteries are attracting a great attention in the medium term. Na/NiCl{sub 2} batteries have been successful in the German demonstration programme. Lithium batteries have a great potential in the long term. Metal/air batteries have been operated without problems, however there need for a special infrastructure is a major draw-back. Fuel cells and ultra capacitors are new alternative power sources for propulsion of EVs, however these are not included in this report.

  6. Melarsoprol cyclodextrin inclusion complexes as promising oral candidates for the treatment of human African trypanosomiasis.

    Directory of Open Access Journals (Sweden)

    Jean Rodgers

    2011-09-01

    Full Text Available Human African trypanosomiasis (HAT, or sleeping sickness, results from infection with the protozoan parasites Trypanosoma brucei (T. b. gambiense or T. b. rhodesiense and is invariably fatal if untreated. There are 60 million people at risk from the disease throughout sub-Saharan Africa. The infection progresses from the haemolymphatic stage where parasites invade the blood, lymphatics and peripheral organs, to the late encephalitic stage where they enter the central nervous system (CNS to cause serious neurological disease. The trivalent arsenical drug melarsoprol (Arsobal is the only currently available treatment for CNS-stage T. b. rhodesiense infection. However, it must be administered intravenously due to the presence of propylene glycol solvent and is associated with numerous adverse reactions. A severe post-treatment reactive encephalopathy occurs in about 10% of treated patients, half of whom die. Thus melarsoprol kills 5% of all patients receiving it. Cyclodextrins have been used to improve the solubility and reduce the toxicity of a wide variety of drugs. We therefore investigated two melarsoprol cyclodextrin inclusion complexes; melarsoprol hydroxypropyl-β-cyclodextrin and melarsoprol randomly-methylated-β-cyclodextrin. We found that these compounds retain trypanocidal properties in vitro and cure CNS-stage murine infections when delivered orally, once per day for 7-days, at a dosage of 0.05 mmol/kg. No overt signs of toxicity were detected. Parasite load within the brain was rapidly reduced following treatment onset and magnetic resonance imaging showed restoration of normal blood-brain barrier integrity on completion of chemotherapy. These findings strongly suggest that complexed melarsoprol could be employed as an oral treatment for CNS-stage HAT, delivering considerable improvements over current parenteral chemotherapy.

  7. PHB, crystalline and amorphous magnesium alloys: Promising candidates for bioresorbable osteosynthesis implants?

    International Nuclear Information System (INIS)

    Celarek, Anna; Kraus, Tanja; Tschegg, Elmar K.; Fischerauer, Stefan F.; Stanzl-Tschegg, Stefanie; Uggowitzer, Peter J.; Weinberg, Annelie M.

    2012-01-01

    In this study various biodegradable materials were tested for their suitability for use in osteosynthesis implants, in particular as elastically stable intramedullary nails for fracture treatment in paediatric orthopaedics. The materials investigated comprise polyhydroxybutyrate (PHB), which belongs to the polyester family and is produced by microorganisms, with additions of ZrO 2 and a bone graft substitute; two crystalline magnesium alloys with significantly different degradation rates ZX50 (MgZnCa, fast) and WZ21 (MgYZnCa, slow); and MgZnCa bulk metallic glasses (BMG). Push-out tests were conducted after various implantation times in rat femur meta-diaphysis to evaluate the shear forces between the implant material and the bone. The most promising materials are WZ21 and BMG, which exhibit high shear forces and push-out energies. The degradation rate of ZX50 is too fast and thus the alloy does not maintain its mechanical stability long enough during the fracture-healing period. PHB exhibits insufficient mechanical properties: it degrades very slowly and the respective low shear forces and push-out energy levels are unsatisfactory. - Highlights: ► In-vivo (rat model) investigation of biodegradable materials suitable for ESIN. ► Materials: polymer PHB, crystalline Mg ZX50 and Mg WZ21, MgZnCa bulk metallic glasses. ► Evaluated interface shear strength, push-out energies, stiffness, histology. ► Mg WZ21 suitable, other materials only after alterations.

  8. PHB, crystalline and amorphous magnesium alloys: Promising candidates for bioresorbable osteosynthesis implants?

    Energy Technology Data Exchange (ETDEWEB)

    Celarek, Anna [Institute for Building Construction and Technology E-206-4, Vienna University of Technology, Karlsplatz 13, 1040 Vienna (Austria); Kraus, Tanja [Department of Paediatric Orthopaedics, Medical University of Graz, Auenbruggerplatz 34, 8036 Graz (Austria); Tschegg, Elmar K., E-mail: elmar.tschegg@tuwien.ac.at [Institute for Building Construction and Technology E-206-4, Vienna University of Technology, Karlsplatz 13, 1040 Vienna (Austria); Fischerauer, Stefan F. [Department of Paediatric and Adolescent Surgery, Medical University of Graz, Auenbruggerplatz 34, 8036 Graz (Austria); Stanzl-Tschegg, Stefanie [Department of Material Sciences and Process Engineering, Institute of Physics and Materials Science, University of Natural Resources and Life Sciences, Peter Jordan Str. 82, 1190 Vienna (Austria); Uggowitzer, Peter J. [Department of Materials, Laboratory for Metal Physics and Technology, ETH Zurich, 8093 Zurich (Switzerland); Weinberg, Annelie M. [Department of Paediatric and Adolescent Surgery, Medical University of Graz, Auenbruggerplatz 34, 8036 Graz (Austria)

    2012-08-01

    In this study various biodegradable materials were tested for their suitability for use in osteosynthesis implants, in particular as elastically stable intramedullary nails for fracture treatment in paediatric orthopaedics. The materials investigated comprise polyhydroxybutyrate (PHB), which belongs to the polyester family and is produced by microorganisms, with additions of ZrO{sub 2} and a bone graft substitute; two crystalline magnesium alloys with significantly different degradation rates ZX50 (MgZnCa, fast) and WZ21 (MgYZnCa, slow); and MgZnCa bulk metallic glasses (BMG). Push-out tests were conducted after various implantation times in rat femur meta-diaphysis to evaluate the shear forces between the implant material and the bone. The most promising materials are WZ21 and BMG, which exhibit high shear forces and push-out energies. The degradation rate of ZX50 is too fast and thus the alloy does not maintain its mechanical stability long enough during the fracture-healing period. PHB exhibits insufficient mechanical properties: it degrades very slowly and the respective low shear forces and push-out energy levels are unsatisfactory. - Highlights: Black-Right-Pointing-Pointer In-vivo (rat model) investigation of biodegradable materials suitable for ESIN. Black-Right-Pointing-Pointer Materials: polymer PHB, crystalline Mg ZX50 and Mg WZ21, MgZnCa bulk metallic glasses. Black-Right-Pointing-Pointer Evaluated interface shear strength, push-out energies, stiffness, histology. Black-Right-Pointing-Pointer Mg WZ21 suitable, other materials only after alterations.

  9. Candidate genes for cross-resistance against DNA-damaging drugs

    DEFF Research Database (Denmark)

    Wittig, Rainer; Nessling, Michelle; Will, Rainer D

    2002-01-01

    Drug resistance of tumor cells leads to major drawbacks in the treatment of cancer. To identify candidate genes for drug resistance, we compared the expression patterns of the drug-sensitive human malignant melanoma cell line MeWo and three derived sublines with acquired resistance to the DNA...... as several apoptosis-related genes, in particular STK17A and CRYAB. As MPP1 and CRYAB are also among the 14 genes differentially expressed in all three of the drug-resistant sublines, they represent the strongest candidates for resistance against DNA-damaging drugs....

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

    Science.gov (United States)

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

    2017-04-01

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

  11. Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system

    Directory of Open Access Journals (Sweden)

    Virginie eBonnamain

    2012-04-01

    Full Text Available Neural transplantation is a promising therapeutic strategy for neurodegenerative diseases and other affections of the central nervous system (CNS like Parkinson and Huntington diseases, multiple sclerosis or stroke. If cell replacement therapy already went through clinical trials for some of these diseases using fetal human neuroblasts, several important limitations led to the search for alternative cell sources that would be more suitable for intracerebral transplantation. Taking into account logistical and ethical issues linked to the use of tissue derived from human fetuses, and the immunologically special status of the CNS allowing the occurrence of deleterious immune reactions, Neural Stem/Progenitor Cells (NSPCs appear as an interesting cell source candidate. In addition to their ability for replacing cell populations lost during the pathological events, NSPCs also display surprising therapeutic effects of neuroprotection and immunomodulation. A better knowledge of the mechanisms involved in these specific characteristics will hopefully lead in the future to a successful use of NSPCs in regenerative medicine for CNS affections.

  12. RNA-Seq reveals seven promising candidate genes affecting the proportion of thick egg albumen in layer-type chickens.

    Science.gov (United States)

    Wan, Yi; Jin, Sihua; Ma, Chendong; Wang, Zhicheng; Fang, Qi; Jiang, Runshen

    2017-12-22

    Eggs with a much higher proportion of thick albumen are preferred in the layer industry, as they are favoured by consumers. However, the genetic factors affecting the thick egg albumen trait have not been elucidated. Using RNA sequencing, we explored the magnum transcriptome in 9 Rhode Island white layers: four layers with phenotypes of extremely high ratios of thick to thin albumen (high thick albumen, HTA) and five with extremely low ratios (low thick albumen, LTA). A total of 220 genes were differentially expressed, among which 150 genes were up-regulated and 70 were down-regulated in the HTA group compared with the LTA group. Gene Ontology (GO) analysis revealed that the up-regulated genes in HTA were mainly involved in a wide range of regulatory functions. In addition, a large number of these genes were related to glycosphingolipid biosynthesis, focal adhesion, ECM-receptor interactions and cytokine-cytokine receptor interactions. Based on functional analysis, ST3GAL4, FUT4, ITGA2, SDC3, PRLR, CDH4 and GALNT9 were identified as promising candidate genes for thick albumen synthesis and metabolism during egg formation. These results provide new insights into the molecular mechanisms of egg albumen traits and may contribute to future breeding strategies that optimise the proportion of thick egg albumen.

  13. Overview on zein protein: a promising pharmaceutical excipient in drug delivery systems and tissue engineering.

    Science.gov (United States)

    Labib, Gihan

    2018-01-01

    Natural pharmaceutical excipients have been applied extensively in the past decades owing to their safety and biocompatibility. Zein, a natural protein of plant origin offers great benefit over other synthetic polymers used in controlled drug and biomedical delivery systems. It was used in a variety of medical fields including pharmaceutical and biomedical drug targeting, vaccine, tissue engineering, and gene delivery. Being biodegradable and biocompatible, the current review focuses on the history and the medical application of zein as an attractive still promising biopolymer. Areas covered: The current review gives a broadscope on zein as a still promising protein excipient in different fields. Zein- based drug and biomedical delivery systems are discussed with special focus on current and potential application in controlled drug delivery systems, and tissue engineering. Expert opinion: Zein as a protein of natural origin can still be considered a promising polymer in the field of drug delivery systems as well as in tissue engineering. Although different researchers spotted light on zein application in different industrial fields extensively, the feasibility of its use in the field of drug delivery replenished by investigators in recent years has not yet been fully approached.

  14. Polymeric Micelles, a Promising Drug Delivery System to Enhance Bioavailability of Poorly Water-Soluble Drugs

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    Wei Xu

    2013-01-01

    Full Text Available Oral administration is the most commonly used and readily accepted form of drug delivery; however, it is find that many drugs are difficult to attain enough bioavailability when administered via this route. Polymeric micelles (PMs can overcome some limitations of the oral delivery acting as carriers able to enhance drug absorption, by providing (1 protection of the loaded drug from the harsh environment of the GI tract, (2 release of the drug in a controlled manner at target sites, (3 prolongation of the residence time in the gut by mucoadhesion, and (4 inhibition of efflux pumps to improve the drug accumulation. To explain the mechanisms for enhancement of oral bioavailability, we discussed the special stability of PMs, the controlled release properties of pH-sensitive PMs, the prolongation of residence time with mucoadhesive PMs, and the P-gp inhibitors commonly used in PMs, respectively. The primary purpose of this paper is to illustrate the potential of PMs for delivery of poorly water-soluble drugs with bioavailability being well maintained.

  15. The promises and pitfalls of retrieval-extinction procedures in preventing relapse to drug seeking

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    Gavan P McNally

    2013-03-01

    Full Text Available Relapse to drug seeking after treatment or a period of abstinence remains a fundamental challenge for drug users. The retrieval – extinction procedure offers promise in augmenting the efficacy of exposure based treatment for drug use and for protecting against relapse to drug seeking. Preceding extinction training with a brief retrieval or reminder trial, retrieval – extinction training, has been shown to reduce reinstatement of extinguished drug seeking in animal models and also to produce profound and long lasting decrements in cue-induced craving in human heroin users. However, the mechanisms that mediate these effects of retrieval - extinction training are unclear. Moreover, under some circumstances, the retrieval – extinction procedure can significantly increase vulnerability to reinstatement in animal models.

  16. Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

    Science.gov (United States)

    San Lucas, F Anthony; Fowler, Jerry; Chang, Kyle; Kopetz, Scott; Vilar, Eduardo; Scheet, Paul

    2014-12-01

    Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA. ©2014 American Association for Cancer Research.

  17. Identify drug repurposing candidates by mining the protein data bank.

    Science.gov (United States)

    Moriaud, Fabrice; Richard, Stéphane B; Adcock, Stewart A; Chanas-Martin, Laetitia; Surgand, Jean-Sébastien; Ben Jelloul, Marouane; Delfaud, François

    2011-07-01

    Predicting off-targets by computational methods is gaining increasing interest in early-stage drug discovery. Here, we present a computational method based on full 3D comparisons of 3D structures. When a similar binding site is detected in the Protein Data Bank (PDB) (or any protein structure database), it is possible that the corresponding ligand also binds to that similar site. On one hand, this target hopping case is probably rare because it requires a high similarity between the binding sites. On the other hand, it could be a strong rational evidence to highlight possible off-target reactions and possibly a potential undesired side effect. This target-based drug repurposing can be extended a significant step further with the capability of searching the full surface of all proteins in the PDB, and therefore not relying on pocket detection. Using this approach, we describe how MED-SuMo reproduces the repurposing of tadalafil from PDE5A to PDE4A and a structure of PDE4A with tadalafil. Searching for local protein similarities generates more hits than for whole binding site similarities and therefore fragment repurposing is more likely to occur than for drug-sized compounds. In this work, we illustrate that by mining the PDB for proteins sharing similarities with the hinge region of protein kinases. The experimentally validated examples, biotin carboxylase and synapsin, are retrieved. Further to fragment repurposing, this approach can be applied to the detection of druggable sites from 3D structures. This is illustrated with detection of the protein kinase hinge motif in the HIV-RT non-nucleosidic allosteric site.

  18. A strategy to find novel candidate anti-Alzheimer's disease drugs by constructing interaction networks between drug targets and natural compounds in medical plants.

    Science.gov (United States)

    Chen, Bi-Wen; Li, Wen-Xing; Wang, Guang-Hui; Li, Gong-Hua; Liu, Jia-Qian; Zheng, Jun-Juan; Wang, Qian; Li, Hui-Juan; Dai, Shao-Xing; Huang, Jing-Fei

    2018-01-01

    screening of anti-AD drugs. In this work, we established networks to systematically study the connections among natural compounds, approved drugs, TCM plants and AD target proteins with the goal of identifying promising drug candidates. We hope that our study will facilitate in-depth research for the treatment of AD in Chinese medicine.

  19. Diatomite: A promising natural candidate as carrier material for low, middle and high temperature phase change material

    International Nuclear Information System (INIS)

    Qian, Tingting; Li, Jinhong; Min, Xin; Deng, Yong; Guan, Weimin; Ning, Lei

    2015-01-01

    Graphical abstract: Low-temperature PCMs are always the objects of prime investigations, however, the field of PCMs’ applications is not limited to low temperatures only. In the present study, three kinds of PCMs: polyethylene glycol (PEG), lithium nitrate, and sodium sulfate were respectively employed as the low-, middle- and high-temperature storage medium. A series of novel form-stable phase change materials (fs-PCMs) were tailor-made by blending diatomite and the three kinds of PCMs via a vacuum impregnation method or a facile mixing and sintering method. Various techniques were employed to characterize their structural and thermal properties. - Highlights: • Low-temperature PEG/diatomite was prepared. • Middle-temperature LiNO 3 /diatomite was prepared. • High-temperature Na 2 SO 4 /diatomite was prepared. - Abstract: Low-temperature PCMs are always the objects of prime investigations, however, the field of PCM’s application is not only limited to low temperatures. In this study, polyethylene glycol (PEG), lithium nitrate (LiNO 3 ), and sodium sulfate (Na 2 SO 4 ) were respectively employed as the low-, middle- and high-temperature storage medium. A series of novel form-stable phase change materials (fs-PCMs) were tailor-made by blending diatomite and the three PCMs via a vacuum impregnation method or a facile mixing and sintering method. Various techniques were employed to characterize their structural and thermal properties. The maximum loads of PEG, LiNO 3 , and Na 2 SO 4 in diatomite powder could respectively reach 58%, 60%, and 65%, while PCM melts during the solid–liquid phase transformation. SEM, XRD, and FT-IR results indicated that PCMs were well dispersed into diatomite pores and no chemical changes took place during the heating and cooling process. The prepared fs-PCMs were quite stable in terms of thermal and chemical manner even after a 200-cycle of melting and freezing. The resulting composite fs-PCMs were promising candidates to

  20. Bacillus subtilis spore with surface display of paramyosin from Clonorchis sinensis potentializes a promising oral vaccine candidate.

    Science.gov (United States)

    Sun, Hengchang; Lin, Zhipeng; Zhao, Lu; Chen, Tingjin; Shang, Mei; Jiang, Hongye; Tang, Zeli; Zhou, Xinyi; Shi, Mengchen; Zhou, Lina; Ren, Pengli; Qu, Honglin; Lin, Jinsi; Li, Xuerong; Xu, Jin; Huang, Yan; Yu, Xinbing

    2018-03-07

    Clonorchiasis caused by Clonorchis sinensis has become increasingly prevalent in recent years. Effective prevention strategies are urgently needed to control this food-borne infectious disease. Previous studies indicated that paramyosin of C. sinensis (CsPmy) is a potential vaccine candidate. We constructed a recombinant plasmid of PEB03-CotC-CsPmy, transformed it into Bacillus subtilis WB600 strain (B.s-CotC-CsPmy), and confirmed CsPmy expression on the spore surface by SDS-PAGE, Western blotting and immunofluorescence assay. The immune response and protective efficacy of the recombinant spore were investigated in BALB/c mice after intragastrical or intraperitoneal immunization. Additionally, biochemical enzyme activities in sera, the intestinal histopathology and gut microflora of spore-treated mice were investigated. CsPmy was successfully expressed on the spore surface and the fusion protein on the spore surface with thermostability. Specific IgG in sera and intestinal mucus were increased after intraperitoneal and intragastrical immunization. The sIgA level in intestinal mucus, feces and bile of B.s-CotC-CsPmy orally treated mice were also significantly raised. Furthermore, numerous IgA-secreting cells were detected in intestinal mucosa of intragastrically immunized mice. No inflammatory injury was observed in the intestinal tissues and there was no significant difference in levels of enzyme-indicated liver function among the groups. Additionally, the diversity and abundance of gut microbiota were not changed after oral immunization. Intragastric and intraperitoneal immunization of B.s-CotC-CsPmy spores in mice resulted in egg reduction rates of 48.3 and 51.2% after challenge infection, respectively. Liver fibrosis degree in B.s-CotC-CsPmy spores treated groups was also significantly reduced. CsPmy expressed on the spore surface maintained its immunogenicity. Both intragastrical and intraperitoneal immunization with B.s-CotC-CsPmy spores induced systemic and

  1. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening

    Directory of Open Access Journals (Sweden)

    Pothineni VR

    2016-04-01

    Full Text Available Venkata Raveendra Pothineni,1 Dhananjay Wagh,1 Mustafeez Mujtaba Babar,1 Mohammed Inayathullah,1 David Solow-Cordero,2 Kwang-Min Kim,1 Aneesh V Samineni,1 Mansi B Parekh,1 Lobat Tayebi,3 Jayakumar Rajadas1 1Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, 2Chemical & Systems Biology, Stanford University School of Medicine, Stanford, CA, 3Department of Developmental Sciences, Marquette University School of Dentistry, Milwaukee, WI, USA Abstract: Lyme disease is the most common zoonotic bacterial disease in North America. It is estimated that >300,000 cases per annum are reported in USA alone. A total of 10%–20% of patients who have been treated with antibiotic therapy report the recrudescence of symptoms, such as muscle and joint pain, psychosocial and cognitive difficulties, and generalized fatigue. This condition is referred to as posttreatment Lyme disease syndrome. While there is no evidence for the presence of viable infectious organisms in individuals with posttreatment Lyme disease syndrome, some researchers found surviving Borrelia burgdorferi population in rodents and primates even after antibiotic treatment. Although such observations need more ratification, there is unmet need for developing the therapeutic agents that focus on removing the persisting bacterial form of B. burgdorferi in rodent and nonhuman primates. For this purpose, high-throughput screening was done using BacTiter-Glo assay for four compound libraries to identify candidates that stop the growth of B. burgdorferi in vitro. The four chemical libraries containing 4,366 compounds (80% Food and Drug Administration [FDA] approved that were screened are Library of Pharmacologically Active Compounds (LOPAC1280, the National Institutes of Health Clinical Collection, the Microsource Spectrum, and the Biomol FDA. We subsequently identified 150

  2. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) AGONISTS AS PROMISING NEW MEDICATIONS FOR DRUG ADDICTION: PRECLINICAL EVIDENCE

    Science.gov (United States)

    Foll, Bernard Le; Ciano, Patricia Di; Panlilio, Leigh V.; Goldberg, Steven R.; Ciccocioppo, Roberto

    2013-01-01

    This review examines the growing literature on the role of peroxisome proliferator-activated receptors (PPARs) in addiction. There are two subtypes of PPAR receptors that have been studied in addiction: PPAR-α and PPAR-γ. The role of each PPAR subtype in common models of addictive behavior, mainly pre-clinical models, is summarized. In particular, studies are reviewed that investigated the effects of PPAR-α agonists on relapse, sensitization, conditioned place preference, withdrawal and drug intake, and effects of PPAR-γ agonists on relapse, withdrawal and drug intake. Finally, studies that investigated the effects of PPAR agonists on neural pathways of addiction are reviewed. Taken together this preclinical data indicates that PPAR agonists are promising new medications for drug addiction treatment. PMID:23614675

  3. New drugs for the treatment of tuberculosis: needs, challenges, promise, and prospects for the future.

    Science.gov (United States)

    Lienhardt, Christian; Raviglione, Mario; Spigelman, Mel; Hafner, Richard; Jaramillo, Ernesto; Hoelscher, Michael; Zumla, Alimuddin; Gheuens, Jan

    2012-05-15

    For the first time in 40 years, a portfolio of promising new compounds for the treatment of tuberculosis is on the horizon. The introduction of new drugs in combination treatment for all forms of tuberculosis raises several issues related to patients' access to novel treatments, programmatic feasibility, cost effectiveness, and implications for monitoring and surveillance, particularly with regard to the development of drug resistance. Particular attention should be given to the identification of optimal drug combination(s) for the treatment of all forms of tuberculosis, particularly in high-risk and vulnerable groups, such as human immunodeficiency virus-coinfected persons and children, and to the rational use of new drugs. Addressing these issues adequately requires the establishment of clear guidelines to assist countries in the development of policies for the proper use of tuberculosis drugs in a way that guarantees access to best treatments for all those in need and avoids inappropriate use of new drugs. After a description of these various challenges, we present activities that will be carried out by the World Health Organization in collaboration with key stakeholders for the development of policy guidelines for optimal treatment of tuberculosis.

  4. Candidate biomarkers for the diagnosis and prognosis of drug-induced liver injury: An international collaborative effort.

    Science.gov (United States)

    Church, Rachel J; Kullak-Ublick, Gerd A; Aubrecht, Jiri; Bonkovsky, Herbert L; Chalasani, Naga; Fontana, Robert J; Goepfert, Jens C; Hackman, Frances; King, Nicholas M P; Kirby, Simon; Kirby, Patrick; Marcinak, John; Ormarsdottir, Sif; Schomaker, Shelli J; Schuppe-Koistinen, Ina; Wolenski, Francis; Arber, Nadir; Merz, Michael; Sauer, John-Michael; Andrade, Raul J; van Bömmel, Florian; Poynard, Thierry; Watkins, Paul B

    2018-01-22

    Current blood biomarkers are suboptimal in detecting drug-induced liver injury (DILI) and predicting its outcome. We sought to characterize the natural variabilty and performance characteristics of fourteen promising DILI biomarker candidates. Serum or plasma from multiple cohorts of healthy volunteers (n=192 and =81), subjects who safely took potentially hepatotoxic drugs without adverse effects (n=55 and =92) and DILI patients (n=98, =28, and =143) were assayed for microRNA-122 (miR-122), glutamate dehydrogenase (GLDH), total keratin 18 (K18), caspase cleaved K18 (ccK18), glutathione S-transferase alpha (GSTα), alpha fetoprotein (AFP), arginase-1 (ARG1), osteopontin (OPN), sorbitol dehydrogenase (SDH), fatty acid binding protein (FABP1), cadherin-5 (CDH5), macrophage colony stimulating factor receptor (MCSFR), paraoxonase 1 (PON1, normalized to prothrombin protein), and leucocyte cell-derived chemotaxin-2 (LECT2). Most candidate biomarkers were significantly altered in DILI cases compared to healthy volunteers. GLDH correlated more closely with gold standard alanine aminotransferase (ALT) than miR-122 and there was a surprisingly wide inter- and intra-individual variability of miR-122 levels among the healthy volunteers. Serum K18, OPN, and MCSFR levels were most strongly associated with liver-related death or transplant within 6 months of DILI-onset. Prediction of prognosis among DILI patients using Model for End-stage Liver Disease (MELD) was improved by incorporation of K18 and MCSFR levels. GLDH appears to be more useful than miR-122 in identifying DILI patients. K18, OPN and MCSFR are promising candidates for prediction of prognosis during an acute DILI event. Serial assessment of these biomarkers in large prospective studies will help further delineate their role in DILI diagnosis and management. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

  5. Drug repurposing: a systematic approach to evaluate candidate oral neuroprotective interventions for secondary progressive multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Hanna M Vesterinen

    Full Text Available To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil as lead candidates for clinical evaluation.We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.

  6. Static magnetic field exposure reproduces cellular effects of the Parkinson's disease drug candidate ZM241385.

    Directory of Open Access Journals (Sweden)

    Zhiyun Wang

    2010-11-01

    Full Text Available This study was inspired by coalescing evidence that magnetic therapy may be a viable treatment option for certain diseases. This premise is based on the ability of moderate strength fields (i.e., 0.1 to 1 Tesla to alter the biophysical properties of lipid bilayers and in turn modulate cellular signaling pathways. In particular, previous results from our laboratory (Wang et al., BMC Genomics, 10, 356 (2009 established that moderate strength static magnetic field (SMF exposure altered cellular endpoints associated with neuronal function and differentiation. Building on this background, the current paper investigated SMF by focusing on the adenosine A(2A receptor (A(2AR in the PC12 rat adrenal pheochromocytoma cell line that displays metabolic features of Parkinson's disease (PD.SMF reproduced several responses elicited by ZM241385, a selective A(2AR antagonist, in PC12 cells including altered calcium flux, increased ATP levels, reduced cAMP levels, reduced nitric oxide production, reduced p44/42 MAPK phosphorylation, inhibited proliferation, and reduced iron uptake. SMF also counteracted several PD-relevant endpoints exacerbated by A(2AR agonist CGS21680 in a manner similar to ZM241385; these include reduction of increased expression of A(2AR, reversal of altered calcium efflux, dampening of increased adenosine production, reduction of enhanced proliferation and associated p44/42 MAPK phosphorylation, and inhibition of neurite outgrowth.When measured against multiple endpoints, SMF elicited qualitatively similar responses as ZM241385, a PD drug candidate. Provided that the in vitro results presented in this paper apply in vivo, SMF holds promise as an intriguing non-invasive approach to treat PD and potentially other neurological disorders.

  7. Static Magnetic Field Exposure Reproduces Cellular Effects of the Parkinson's Disease Drug Candidate ZM241385

    Science.gov (United States)

    Wang, Zhiyun; Che, Pao-Lin; Du, Jian; Ha, Barbara; Yarema, Kevin J.

    2010-01-01

    Background This study was inspired by coalescing evidence that magnetic therapy may be a viable treatment option for certain diseases. This premise is based on the ability of moderate strength fields (i.e., 0.1 to 1 Tesla) to alter the biophysical properties of lipid bilayers and in turn modulate cellular signaling pathways. In particular, previous results from our laboratory (Wang et al., BMC Genomics, 10, 356 (2009)) established that moderate strength static magnetic field (SMF) exposure altered cellular endpoints associated with neuronal function and differentiation. Building on this background, the current paper investigated SMF by focusing on the adenosine A2A receptor (A2AR) in the PC12 rat adrenal pheochromocytoma cell line that displays metabolic features of Parkinson's disease (PD). Methodology and Principal Findings SMF reproduced several responses elicited by ZM241385, a selective A2AR antagonist, in PC12 cells including altered calcium flux, increased ATP levels, reduced cAMP levels, reduced nitric oxide production, reduced p44/42 MAPK phosphorylation, inhibited proliferation, and reduced iron uptake. SMF also counteracted several PD-relevant endpoints exacerbated by A2AR agonist CGS21680 in a manner similar to ZM241385; these include reduction of increased expression of A2AR, reversal of altered calcium efflux, dampening of increased adenosine production, reduction of enhanced proliferation and associated p44/42 MAPK phosphorylation, and inhibition of neurite outgrowth. Conclusions and Significance When measured against multiple endpoints, SMF elicited qualitatively similar responses as ZM241385, a PD drug candidate. Provided that the in vitro results presented in this paper apply in vivo, SMF holds promise as an intriguing non-invasive approach to treat PD and potentially other neurological disorders. PMID:21079735

  8. Antibody-drug conjugates: Promising and efficient tools for targeted cancer therapy.

    Science.gov (United States)

    Nasiri, Hadi; Valedkarimi, Zahra; Aghebati-Maleki, Leili; Majidi, Jafar

    2018-09-01

    Over the recent decades, the use of antibody-drug conjugates (ADCs) has led to a paradigm shift in cancer chemotherapy. Antibody-based treatment of various human tumors has presented dramatic efficacy and is now one of the most promising strategies used for targeted therapy of patients with a variety of malignancies, including hematological cancers and solid tumors. Monoclonal antibodies (mAbs) are able to selectively deliver cytotoxic drugs to tumor cells, which express specific antigens on their surface, and has been suggested as a novel category of agents for use in the development of anticancer targeted therapies. In contrast to conventional treatments that cause damage to healthy tissues, ADCs use mAbs to specifically attach to antigens on the surface of target cells and deliver their cytotoxic payloads. The therapeutic success of future ADCs depends on closely choosing the target antigen, increasing the potency of the cytotoxic cargo, improving the properties of the linker, and reducing drug resistance. If appropriate solutions are presented to address these issues, ADCs will play a more important role in the development of targeted therapeutics against cancer in the next years. We review the design of ADCs, and focus on how ADCs can be exploited to overcome multiple drug resistance (MDR). © 2018 Wiley Periodicals, Inc.

  9. Novel 3D Culture Systems for Studies of Human Liver Function and Assessments of the Hepatotoxicity of Drugs and Drug Candidates.

    Science.gov (United States)

    Lauschke, Volker M; Hendriks, Delilah F G; Bell, Catherine C; Andersson, Tommy B; Ingelman-Sundberg, Magnus

    2016-12-19

    The liver is an organ with critical importance for drug treatment as the disposition and response to a given drug is often determined by its hepatic metabolism. Patient-specific factors can entail increased susceptibility to drug-induced liver injury, which constitutes a major risk for drug development programs causing attrition of promising drug candidates or costly withdrawals in postmarketing stages. Hitherto, mainly animal studies and 2D hepatocyte systems have been used for the examination of human drug metabolism and toxicity. Yet, these models are far from satisfactory due to extensive species differences and because hepatocytes in 2D cultures rapidly dedifferentiate resulting in the loss of their hepatic phenotype and functionality. With the increasing comprehension that 3D cell culture systems more accurately reflect in vivo physiology, in the recent decade more and more research has focused on the development and optimization of various 3D culture strategies in an attempt to preserve liver properties in vitro. In this contribution, we critically review these developments, which have resulted in an arsenal of different static and perfused 3D models. These systems include sandwich-cultured hepatocytes, spheroid culture platforms, and various microfluidic liver or multiorgan biochips. Importantly, in many of these models hepatocytes maintain their phenotype for prolonged times, which allows probing the potential of newly developed chemical entities to cause chronic hepatotoxicity. Moreover, some platforms permit the investigation of drug action in specific genetic backgrounds or diseased hepatocytes, thereby significantly expanding the repertoire of tools to detect drug-induced liver injuries. It is concluded that the development of 3D liver models has hitherto been fruitful and that systems are now at hand whose sensitivity and specificity in detecting hepatotoxicity are superior to those of classical 2D culture systems. For the future, we highlight the

  10. Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

    Energy Technology Data Exchange (ETDEWEB)

    Mai, Binh Khanh [Institute for Computational Science and Technology, 6 Quarter, Linh Trung Ward, Thu Duc District, Ho Chi Minh City (Viet Nam); Li, Mai Suan, E-mail: masli@ifpan.edu.pl [Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw (Poland)

    2011-07-08

    Highlights: {yields} We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. {yields} It is shown that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. {yields} We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. {yields} The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design. -- Abstract: Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.

  11. Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

    International Nuclear Information System (INIS)

    Mai, Binh Khanh; Li, Mai Suan

    2011-01-01

    Highlights: → We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. → It is shown that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. → We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. → The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design. -- Abstract: Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.

  12. Promise and deceit: pharmakos, drug replacement therapy, and the perils of experience.

    Science.gov (United States)

    Meyers, Todd

    2014-06-01

    The problem of lying as a feature of medication compliance has been well documented in anthropological and clinical literatures. Yet the role of the lie-its destabilizing effects on the continuity of drug treatment and therapy, as a technology of drug misuse, or as a way to understand the neuro-chemical processes of treatment (pharmacotherapy "tricking" or lying to the brain)-has been less considered, particularly in the context of opioid replacement therapy. The following paper is set against the backdrop of a three-year study of adolescents receiving a relatively new drug (buprenorphine) for the treatment of opiate dependency inside and outside of highly monitored treatment environments in the United States. Lies give order not only to the experience of addiction but also to the experience of therapy as well. In order to better understand this ordering of experience, the paper puts the widely discussed conceptual duality of the pharmakon (healing and poison) in conversation with a perilously overlooked subject in the critical study of pharmacotherapy, namely the pharmakos or the personification of sacrifice. The paper demonstrates how the patient-subject comes to represent therapeutic promise by allowing for the possibility of (and often performing) deceit.

  13. Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

    Science.gov (United States)

    Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

    2016-11-10

    Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

  14. A highly efficient silole-containing dithienylethene with excellent thermal stability and fatigue resistance: a promising candidate for optical memory storage materials.

    Science.gov (United States)

    Chan, Jacky Chi-Hung; Lam, Wai Han; Yam, Vivian Wing-Wah

    2014-12-10

    Diarylethene compounds are potential candidates for applications in optical memory storage systems and photoswitchable molecular devices; however, they usually show low photocycloreversion quantum yields, which result in ineffective erasure processes. Here, we present the first highly efficient photochromic silole-containing dithienylethene with excellent thermal stability and fatigue resistance. The photochemical quantum yields for photocyclization and photocycloreversion of the compound are found to be high and comparable to each other; the latter of which is rarely found in diarylethene compounds. These would give rise to highly efficient photoswitchable material with effective writing and erasure processes. Incorporation of the silole moiety as a photochromic dithienylethene backbone also was demonstrated to enhance the thermal stability of the closed form, in which the thermal backward reaction to the open form was found to be negligible even at 100 °C, which leads to a promising candidate for use as photoswitchable materials and optical memory storage.

  15. Structure-activity relationship analysis of cytotoxic cyanoguanidines: selection of CHS 828 as candidate drug

    Directory of Open Access Journals (Sweden)

    Gullbo Joachim

    2009-06-01

    Full Text Available Abstract Background N-(6-(4-chlorophenoxyhexyl-N'-cyano-N''-4-pyridyl guanidine (CHS 828 is the first candidate drug from a novel group of anti-tumour agents – the pyridyl cyanoguanidines, shown to be potent compounds interfering with cellular metabolism (inhibition of nicotinamide phosphoribosyl transferase and NF-κB signalling. Substituted cyanoguanidines are also found in anti-hypertensive agents such as the potassium channel opener pinacidil (N-cyano-N'-(4-pyridyl-N''-(1,2,2-trimethylpropylguanidine and histamine-II receptor antagonists (e.g. cimetidine, N-cyano-N'-methyl-N''-[2-[[(5-methylimidazol-4-yl]methyl]thio]ethylguanidine. In animal studies, CHS 828 has shown very promising activity, and phase I and II studies resulted in further development of a with a water soluble prodrug. Findings To study the structural requirements for cyanoguanidine cytotoxicity a set of 19 analogues were synthesized. The cytotoxic effects were then studied in ten cell lines selected for different origins and mechanisms of resistance, using the fluorometric microculture cytotoxicity assay (FMCA. The compounds showed varying cytotoxic activity even though the dose-response curves for some analogues were very shallow. Pinacidil and cimetidine were found to be non-toxic in all ten cell lines. Starting with cyanoguanidine as the crucial core it was shown that 4-pyridyl substitution was more efficient than was 3-pyridyl substitution. The 4-pyridyl cyanoguanidine moiety should be linked by an alkyl chain, optimally a hexyl, heptyl or octyl chain, to a bulky end group. The exact composition of this end group did not seem to be of crucial importance; when the end group was a mono-substituted phenyl ring it was shown that the preferred position was 4-substitution, followed by 3- and, finally, 2-substitution as the least active. Whether the substituent was a chloro, nitro or methoxy substituent seemed to be of minor importance. Finally, the activity patterns in the

  16. β-secretase inhibitor; a promising novel therapeutic drug in AD

    Directory of Open Access Journals (Sweden)

    Kelly Willemijn Menting

    2014-07-01

    Full Text Available Alzheimer’s disease (AD and vascular dementia are responsible for up to 90% of dementia cases. According to the World Health Organization (WHO, a staggering number of 35.6 million people are currently diagnosed with dementia. Blocking disease progression or preventing AD altogether is desirable for both social and economic reasons and recently focus has shifted to a new and promising drug: the β-secretase inhibitor. Much of AD research has investigated the amyloid cascade hypothesis, which postulates that AD is caused by changes in amyloid beta (Aβ stability and aggregation. Blocking Aβ production by inhibiting the first protease required for its generation, β-secretase/BACE1, may be the next step in blocking AD progression. In April 2012, promising phase I data on inhibitor MK-8931 was presented. This drug reduced Aβ CSF levels up to 92% and was well tolerated by patients. In March 2013 data was added from a one week trial in 32 mild to moderate AD patients, showing CSF Aβ levels decreased up to 84%. However, BACE1 inhibitors require further research. First, greatly reducing Aβ levels through BACE1 inhibition may have harmful side effects. Second, BACE1 inhibitors have yet to pass clinical trial phase II/III and no data on possible side effects on AD patients are available. And third, there remains doubt about the clinical efficacy of BACE1 inhibitors. In moderate AD patients, Aβ plaques have already been formed. BACE1 inhibitors prevent production of new Aβ plaques, but hypothetically do not influence already existing Aβ peptides. Therefore, BACE1 inhibitors are potentially better at preventing AD instead of having therapeutic use.

  17. Repurposing of Aspirin and Ibuprofen as Candidate Anti-Cryptococcus Drugs

    Science.gov (United States)

    Ogundeji, Adepemi O.; Pohl, Carolina H.

    2016-01-01

    The usage of fluconazole and amphotericin B in clinical settings is often limited by, among other things, drug resistance development and undesired side effects. Thus, there is a constant need to find new drugs to better manage fungal infections. Toward this end, the study described in this paper considered the repurposing of aspirin (acetylsalicylic acid) and ibuprofen as alternative drugs to control the growth of cryptococcal cells. In vitro susceptibility tests, including a checkerboard assay, were performed to assess the response of Cryptococcus neoformans and Cryptococcus gattii to the above-mentioned anti-inflammatory drugs. Next, the capacity of these two drugs to induce stress as well as their mode of action in the killing of cryptococcal cells was determined. The studied fungal strains revealed a response to both aspirin and ibuprofen that was dose dependent, with ibuprofen exerting greater antimicrobial action. More importantly, the MICs of these drugs did not negatively (i) affect growth or (ii) impair the functioning of macrophages; rather, they enhanced the ability of these immune cells to phagocytose cryptococcal cells. Ibuprofen was also shown to act in synergy with fluconazole and amphotericin B. The treatment of cryptococcal cells with aspirin or ibuprofen led to stress induction via activation of the high-osmolarity glycerol (HOG) pathway, and cell death was eventually achieved through reactive oxygen species (ROS)-mediated membrane damage. The presented data highlight the potential clinical application of aspirin and ibuprofen as candidate anti-Cryptococcus drugs. PMID:27246782

  18. L1188: A Promising Candidate for Cloud–Cloud Collisions Triggering the Formation of Low- and Intermediate-mass Stars

    Energy Technology Data Exchange (ETDEWEB)

    Gong, Yan; Fang, Min; Mao, Ruiqing; Zhang, Shaobo; Wang, Yuan; Su, Yang; Chen, Xuepeng; Yang, Ji; Wang, Hongchi; Lu, Dengrong, E-mail: ygong@pmo.ac.cn [Purple Mountain Observatory and Key Laboratory of Radio Astronomy, Chinese Academy of Sciences, 2 West Beijing Road, 210008 Nanjing (China)

    2017-01-20

    We present a new large-scale (2° × 2°) simultaneous {sup 12}CO, {sup 13}CO, and C{sup 18}O (J = 1–0) mapping of L1188 with the Purple Mountain Observatory 13.7 m telescope. Our observations have revealed that L1188 consists of two nearly orthogonal filamentary molecular clouds at two clearly separated velocities. Toward the intersection showing large velocity spreads, we find several bridging features connecting the two clouds in velocity, and an open arc structure that exhibits high excitation temperatures, enhanced {sup 12}CO and {sup 13}CO emission, and broad {sup 12}CO line wings. This agrees with the scenario that the two clouds are colliding with each other. The distribution of young stellar object (YSO) candidates implies an enhancement of star formation in the intersection of the two clouds. We suggest that a cloud–cloud collision happened in L1188 about 1 Myr ago, possibly triggering the formation of low- and intermediate-mass YSOs in the intersection.

  19. AVN-101: A Multi-Target Drug Candidate for the Treatment of CNS Disorders.

    Science.gov (United States)

    Ivachtchenko, Alexandre V; Lavrovsky, Yan; Okun, Ilya

    2016-05-25

    Lack of efficacy of many new highly selective and specific drug candidates in treating diseases with poorly understood or complex etiology, as are many of central nervous system (CNS) diseases, encouraged an idea of developing multi-modal (multi-targeted) drugs. In this manuscript, we describe molecular pharmacology, in vitro ADME, pharmacokinetics in animals and humans (part of the Phase I clinical studies), bio-distribution, bioavailability, in vivo efficacy, and safety profile of the multimodal drug candidate, AVN-101. We have carried out development of a next generation drug candidate with a multi-targeted mechanism of action, to treat CNS disorders. AVN-101 is a very potent 5-HT7 receptor antagonist (Ki = 153 pM), with slightly lesser potency toward 5-HT6, 5-HT2A, and 5HT-2C receptors (Ki = 1.2-2.0 nM). AVN-101 also exhibits a rather high affinity toward histamine H1 (Ki = 0.58 nM) and adrenergic α2A, α2B, and α2C (Ki = 0.41-3.6 nM) receptors. AVN-101 shows a good oral bioavailability and facilitated brain-blood barrier permeability, low toxicity, and reasonable efficacy in animal models of CNS diseases. The Phase I clinical study indicates the AVN-101 to be well tolerated when taken orally at doses of up to 20 mg daily. It does not dramatically influence plasma and urine biochemistry, nor does it prolong QT ECG interval, thus indicating low safety concerns. The primary therapeutic area for AVN-101 to be tested in clinical trials would be Alzheimer's disease. However, due to its anxiolytic and anti-depressive activities, there is a strong rational for it to also be studied in such diseases as general anxiety disorders, depression, schizophrenia, and multiple sclerosis.

  20. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

    Science.gov (United States)

    Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S Stevens

    2015-06-01

    Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d -amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

  1. In vitro inhibitory effects of plumbagin, the promising antimalarial candidate, on human cytochrome P450 enzymes.

    Science.gov (United States)

    Sumsakul, Wiriyaporn; Chaijaroenkul, Wanna; Na-Bangchang, Kesara

    2015-11-01

    To investigate the propensity of plumbagin to inhibit the three isoforms of human cytochrome P450 (CYP), i.e., CYP1A2, CYP2C19, and CYP3A4 using human liver microsomes in vitro. Inhibitory effects of plumbagin on the three human CYP isoforms were investigated using pooled human liver microsomes. Phenacetin O-deethylation, omeprazole hydroxylation and nifedipine oxidation were used as selective substrates for CYP1A2, CYP2C19 and CYP3A4 activities, respectively. Concentrations of paracetamol, 5-hydroxyomeprazole, and oxidized nifedipine were determined in microsomal incubation mixture using high-performance liquid chromatography. Plumbagin showed significant inhibitory effects on all CYP isoforms, but with the most potent activity on CYP2C19-mediated omeprazole hydroxylation. The IC50 (concentration that inhibits enzyme activity by 50%) values of plumbagin and nootkatone (selective inhibitor) for CYP2C19 were (0.78 ± 0.01) and (27.31 ± 0.66) μM, respectively. The inhibitory activities on CYP1A2-mediated phenacetin O-deethylation and CYP3A4-mediated nifedipine oxidation were moderate. The IC50 values of plumbagin and α-naphthoflavone (selective inhibitor) for CYP1A2 were (1.39 ± 0.01) and (0.02 ± 0.36) μM, respectively. The corresponding IC50 values of plumbagin and ketoconazole (selective inhibitor) for CYP3A4 were (2.37 ± 0.10) and (0.18 ± 0.06) μM, respectively. Clinical relevance of the interference of human drug metabolizing enzymes should be aware of for further development scheme of plumbagin as antimalarial drug when used in combination with other antimalarial drugs which are metabolized by these CYP isoforms. Copyright © 2015 Hainan Medical College. Production and hosting by Elsevier B.V. All rights reserved.

  2. Zinc and magnesium ions synergistically inhibit superoxide generation by cultured human neutrophils--a promising candidate formulation for amnioinfusion fluid.

    Science.gov (United States)

    Uchida, Toshiyuki; Itoh, Hiroaki; Nakamura, Yuki; Kobayashi, Yukiko; Hirai, Kyuya; Suzuki, Kazunao; Sugihara, Kazuhiro; Kanayama, Naohiro; Hiramatsu, Mitsuo

    2010-06-01

    Oligohydramnios is often caused by the premature rupturing of membranes and subsequent intrauterine infections, such as chorioamnionitis, in which event oxidative stress is hypothesized to be closely associated with the damage to the fetal organs. The clinical efficiency of amnioinfusion using warmed saline in cases of premature rupture of membranes is still controversial, especially concerning the prognosis for the fetus. In the present study, we found that human amniotic fluid per se suppresses the release of superoxide from cultured human neutrophils, suggesting an acute or chronic shortage of amniotic fluid in cases of premature rupture of membranes can affect the shielding of intrauterine organs from oxidative stress. The aim of this study was to propose a formula of zinc and magnesium ions in saline for amnioinfusion, by assessing antioxidative activities. A combination of 5 microM zinc and 5mM magnesium in saline synergistically inhibited superoxide production by cultured human neutrophils, equivalent to human amniotic fluid. The intraperitoneal administration of this formula significantly improved the survival rate in a rat model of peritonitis compared to the saline control (46.7% vs. 10%). The combination of these metals with saline may thus be a promising formula for an amnioinfusion fluid with the capacity to protect fetal organs from oxidative stress. Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  3. Lavandula angustifolia essential oil as a novel and promising natural candidate for tick (Rhipicephalus (Boophilus) annulatus) control.

    Science.gov (United States)

    Pirali-Kheirabadi, Khodadad; Teixeira da Silva, Jaime A

    2010-10-01

    Lavandula angustifolia is a well known herbal medicine with a variety of useful properties, including its acaricidal effect. This experiment was carried out to study the bioacaricidal activity of L. angustifolia essential oil (EO) against engorged Rhipicephalus (Boophilus) annulatus (Acari; Ixodidae) females. For this purpose six serial concentrations (0.5, 1.0, 2.0, 4.0, 6.0 and 8.0% w/v) of L. angustifolia EO were used. There was considerable mortality in concentrations more than 4.0% although there were no differences between 6.0 and 8.0% in all measured criteria. The mortality rate 24 h after inoculation was 73.26 and 100% in groups treated with 4.0 and 8.0% EO, respectively. Lavender EO also reduced tick egg weight in a concentration-dependent manner. The amount of eggs produced varied from 0.12 g (at 0.5% EO) to 0.00 g (at 8.0% EO) but did not differ statistically from the control. L. angustifolia EO caused 100% failure in egg laying at 6.0 and 8.0% whereas this value in the control group was zero. A positive correlation between L. angustifolia EO concentration and tick control, assessed by relative mortality rate and egg-laying weight, was observed by the EO LC/EC(50), which, when calculated using the Probit test, was 2.76-fold higher than the control. Lavender is a promising acaricidal against R. (B.) annulatus in vitro. Copyright 2010 Elsevier Inc. All rights reserved.

  4. Ursolic acid liposomes with chitosan modification: Promising antitumor drug delivery and efficacy

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Meili; Zhao, Tingting; Liu, Yanping; Wang, Qianqian; Xing, Shanshan; Li, Lei; Wang, Longgang [Applying Chemistry Key Lab of Hebei Province, Yanshan University, No.438 Hebei Street, Qinhuangdao 066004 (China); Liu, Lanxiang [The First Hospital of Qinhuangdao, No. 258 Cultural Road, Qinhuangdao 066000 (China); Gao, Dawei, E-mail: dwgao@ysu.edu.cn [Applying Chemistry Key Lab of Hebei Province, Yanshan University, No.438 Hebei Street, Qinhuangdao 066004 (China)

    2017-02-01

    There are tremendous challenges on antitumor and its therapeutic drugs, and preparation of highly efficient nano-vehicles represents one of the novel topics in antitumor pharmaceutical field. Herein, the novel chitosan-coated ursolic acid (UA) liposome (CS-UA-L) was efficiently prepared with highly tumor targeting, drug controlled release and low side-effect. The CS-UA-L was uniformly spherical particles with diameter of ~ 130 nm, and the size was more easily trapped into the tumor tissues. Chitosan modification can make liposomes carrying positive charges, which were inclined to combine with the negative charges on the surface of tumor cells, and then the CS-UA-L could release UA rapidly at pH 5.0 comparing with pH 7.4. Meanwhile, the CS-UA-L exhibited obvious anti-proliferative effect (76.46%) on HeLa cells and significantly antitumor activity (61.26%) in mice bearing U14 cervical cancer. The tumor tissues of CS-UA-L treated mice had enhanced cell apoptosis, extensive necrosis and low cell proliferation activity. These results demonstrated that the multifunctional CS-UA-L allowed a precision treatment for localized tumor, and reducing the total drug dose and side-effect, which hold a great promise in new safe and effective tumor therapy. - Graphical abstract: Schematic diagram representing the principle of synthesis of CS-UA-L and pH-triggered sequential UA release after treatment on tumor bearing mouse. - Highlights: • The novel chitosan-coated ursolic acid liposomes (CS-UA-L) were successfully prepared. • CS-UA-L possessed sensitive pH-response, which could release UA rapidly at pH 5.0 comparing with pH 7.4. • CS-UA-L exhibited obvious anti-proliferative effect (76.46%) on HeLa cells than UA and UA-L. • CS-UA-L suppressed tumor growth more efficiently than those with UA and UA-L in mice bearing U14 cervical cancer. • The CS-UA-L allow for precision treatment of the tumor and potential to reduce the total drug dose and side-effect.

  5. NIR-Cyanine Dye Linker: a Promising Candidate for Isochronic Fluorescence Imaging in Molecular Cancer Diagnostics and Therapy Monitoring.

    Science.gov (United States)

    Komljenovic, Dorde; Wiessler, Manfred; Waldeck, Waldemar; Ehemann, Volker; Pipkorn, Ruediger; Schrenk, Hans-Hermann; Debus, Jürgen; Braun, Klaus

    2016-01-01

    Personalized anti-cancer medicine is boosted by the recent development of molecular diagnostics and molecularly targeted drugs requiring rapid and efficient ligation routes. Here, we present a novel approach to synthetize a conjugate able to act simultaneously as an imaging and as a chemotherapeutic agent by coupling functional peptides employing solid phase peptide synthesis technologies. Development and the first synthesis of a fluorescent dye with similarity in the polymethine part of the Cy7 molecule whose indolenine-N residues were substituted with a propylene linker are described. Methylating agent temozolomide is functionalized with a tetrazine as a diene component whereas Cy7-cell penetrating peptide conjugate acts as a dienophilic reaction partner for the inverse Diels-Alder click chemistry-mediated ligation route yielding a theranostic conjugate, 3-mercapto-propionic-cyclohexenyl-Cy7-bis-temozolomide-bromide-cell penetrating peptide. Synthesis route described here may facilitate targeted delivery of the therapeutic compound to achieve sufficient local concentrations at the target site or tissue. Its versatility allows a choice of adequate imaging tags applicable in e.g. PET, SPECT, CT, near-infrared imaging, and therapeutic substances including cytotoxic agents. Imaging tags and therapeutics may be simultaneously bound to the conjugate applying click chemistry. Theranostic compound presented here offers a solid basis for a further improvement of cancer management in a precise, patient-specific manner.

  6. Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates.

    Science.gov (United States)

    Braggio, Simone; Montanari, Dino; Rossi, Tino; Ratti, Emiliangelo

    2010-07-01

    As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

  7. Detecting peptidic drugs, drug candidates and analogs in sports doping: current status and future directions.

    Science.gov (United States)

    Thevis, Mario; Thomas, Andreas; Schänzer, Wilhelm

    2014-12-01

    With the growing availability of mature systems and strategies in biotechnology and the continuously expanding knowledge of cellular processes and involved biomolecules, human sports drug testing has become a considerably complex field in the arena of analytical chemistry. Proving the exogenous origin of peptidic drugs and respective analogs at lowest concentration levels in biological specimens (commonly blood, serum and urine) of rather limited volume is required to pursue an action against cheating athletes. Therefore, approaches employing chromatographic-mass spectrometric, electrophoretic, immunological and combined test methods have been required and developed. These allow detecting the misuse of peptidic compounds of lower (such as growth hormone-releasing peptides, ARA-290, TB-500, AOD-9604, CJC-1295, desmopressin, luteinizing hormone-releasing hormones, synacthen, etc.), intermediate (e.g., insulins, IGF-1 and analogs, 'full-length' mechano growth factor, growth hormone, chorionic gonadotropin, erythropoietin, etc.) and higher (e.g., stamulumab) molecular mass with desired specificity and sensitivity. A gap between the technically possible detection and the day-to-day analytical practice, however, still needs to be closed.

  8. Polymeric nanoparticles affect the intracellular delivery, antiretroviral activity and cytotoxicity of the microbicide drug candidate dapivirine.

    Science.gov (United States)

    das Neves, José; Michiels, Johan; Ariën, Kevin K; Vanham, Guido; Amiji, Mansoor; Bahia, Maria Fernanda; Sarmento, Bruno

    2012-06-01

    To assess the intracellular delivery, antiretroviral activity and cytotoxicity of poly(ε-caprolactone) (PCL) nanoparticles containing the antiretroviral drug dapivirine. Dapivirine-loaded nanoparticles with different surface properties were produced using three surface modifiers: poloxamer 338 NF (PEO), sodium lauryl sulfate (SLS) and cetyl trimethylammonium bromide (CTAB). The ability of nanoparticles to promote intracellular drug delivery was assessed in different cell types relevant for vaginal HIV transmission/microbicide development. Also, antiretroviral activity of nanoparticles was determined in different cell models, as well as their cytotoxicity. Dapivirine-loaded nanoparticles were readily taken up by different cells, with particular kinetics depending on the cell type and nanoparticles, resulting in enhanced intracellular drug delivery in phagocytic cells. Different nanoparticles showed similar or improved antiviral activity compared to free drug. There was a correlation between increased antiviral activity and increased intracellular drug delivery, particularly when cell models were submitted to a single initial short-course treatment. PEO-PCL and SLS-PCL nanoparticles consistently showed higher selectivity index values than free drug, contrasting with high cytotoxicity of CTAB-PCL. These results provide evidence on the potential of PCL nanoparticles to affect in vitro toxicity and activity of dapivirine, depending on surface engineering. Thus, this formulation approach may be a promising strategy for the development of next generation microbicides.

  9. Preclinical quantitative MicroPET imaging in evaluation of neuroprotective drug candidates

    International Nuclear Information System (INIS)

    Son, Ji Yeon; Kim, Yu Kyeong; Kim, Ji Sun; Lee, Byung Chul; Kim, Kyeong Min; Choi, Tae Hyun; Cheon, Gi Jeong; Lee, Won Woo; Kim, Sang Eun

    2007-01-01

    Using in vivo molecular imaging with microPET/SPECT has been expected to facilitate drug discovery and development. In this study, we applied quantitative microPET to the preclinical evaluation of the effects of two neuroprotective drug candidates to the nigrostriatal dopaminergic neuronal damage. Fifteen SD rats were divided into three groups. The rats of each group were orally administrated one of neuroprotective candidate; NeuProtec (100mg/kg bid) and SureCero (10mg/kg, qd) or normal saline (0.1ml, qd) for 3 weeks. 6-OHDA was sterotactically placed to the right striatum on eighth day after starting while continuing the medication for additional 14 days. [ 124 I]FP-ClT PET scans were obtained using microPET R4 scanner. The behavioral test by amphetamine-induced rotation and the histological examination after thyrosine hydroxylase (TH) immunohistochemical staining were performed. Different uptake in the lesioned striatum among the groups were demonstrated on [ 124 I]FP-CIT PET images. The rats with NeuProtec showed higher binding in the lesion than controls. No differences were observed in SureCere groups. The FP-CIT uptake in the lesioned striatum was well correlated with the % reduction of TH(+) cells (rho =0.73, p=0.025), and also correlated with rotation test (rho =0.79, p=0.001) [ 124 I]FP-CIT animal PET depicted the neuroprotective effects of NeuProtec to the 6-OHDA neurotoxicity in the rat striatum. No demonstrable effect of SureCero might indicate that inadequate dosage was used in this study. MicroPET imaging with small animal could be a great tool in preclinical evaluation of drug efficacy

  10. Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

    Science.gov (United States)

    Aflaki, Elma; Stubblefield, Barbara K; Maniwang, Emerson; Lopez, Grisel; Moaven, Nima; Goldin, Ehud; Marugan, Juan; Patnaik, Samarjit; Dutra, Amalia; Southall, Noel; Zheng, Wei; Tayebi, Nahid; Sidransky, Ellen

    2014-06-11

    Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development. Copyright © 2014, American Association for the Advancement of Science.

  11. In vitro resistance profile of the candidate HIV-1 microbicide drug dapivirine.

    Science.gov (United States)

    Schader, Susan M; Oliveira, Maureen; Ibanescu, Ruxandra-Ilinca; Moisi, Daniela; Colby-Germinario, Susan P; Wainberg, Mark A

    2012-02-01

    Antiretroviral-based microbicides may offer a means to reduce the sexual transmission of HIV-1. Suboptimal use of a microbicide may, however, lead to the development of drug resistance in users that are already, or become, infected with HIV-1. In such cases, the efficacy of treatments may be compromised since the same (or similar) antiretrovirals used in treatments are being developed as microbicides. To help predict which drug resistance mutations may develop in the context of suboptimal use, HIV-1 primary isolates of different subtypes and different baseline resistance profiles were used to infect primary cells in vitro in the presence of increasing suboptimal concentrations of the two candidate microbicide antiretrovirals dapivirine (DAP) and tenofovir (TFV) alone or in combination. Infections were ongoing for 25 weeks, after which reverse transcriptase genotypes were determined and scrutinized for the presence of any clinically recognized reverse transcriptase drug resistance mutations. Results indicated that suboptimal concentrations of DAP alone facilitated the emergence of common nonnucleoside reverse transcriptase inhibitor resistance mutations, while suboptimal concentrations of DAP plus TFV gave rise to fewer mutations. Suboptimal concentrations of TFV alone did not frequently result in the development of resistance mutations. Sensitivity evaluations for stavudine (d4T), nevirapine (NVP), and lamivudine (3TC) revealed that the selection of resistance as a consequence of suboptimal concentrations of DAP may compromise the potential for NVP to be used in treatment, a finding of potential relevance in developing countries.

  12. Proteomic candidate biomarkers of drug-induced nephrotoxicity in the rat.

    Directory of Open Access Journals (Sweden)

    Rodney Rouse

    Full Text Available Improved biomarkers of acute nephrotoxicity are coveted by the drug development industry, regulatory agencies, and clinicians. In an effort to identify such biomarkers, urinary peptide profiles of rats treated with two different nephrotoxins were investigated. 493 marker candidates were defined that showed a significant response to cis-platin comparing a cis-platin treated cohort to controls. Next, urine samples from rats that received three consecutive daily doses of 150 or 300 mg/kg gentamicin were examined. 557 potential biomarkers were initially identified; 108 of these gentamicin-response markers showed a clear temporal response to treatment. 39 of the cisplatin-response markers also displayed a clear response to gentamicin. Of the combined 147 peptides, 101 were similarly regulated by gentamicin or cis-platin and 54 could be identified by tandem mass spectrometry. Most were collagen type I and type III fragments up-regulated in response to gentamicin treatment. Based on these peptides, classification models were generated and validated in a longitudinal study. In agreement with histopathology, the observed changes in classification scores were transient, initiated after the first dose, and generally persistent over a period of 10-20 days before returning to control levels. The data support the hypothesis that gentamicin-induced renal toxicity up-regulates protease activity, resulting in an increase in several specific urinary collagen fragments. Urinary proteomic biomarkers identified here, especially those common to both nephrotoxins, may serve as a valuable tool to investigate potential new drug candidates for the risk of nephrotoxicity.

  13. Novel Tacrine-Hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer's disease.

    Science.gov (United States)

    Hiremathad, Asha; Keri, Rangappa S; Esteves, A Raquel; Cardoso, Sandra M; Chaves, Sílvia; Santos, M Amélia

    2018-03-25

    Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks. The novel series of tacrine-hydroxyphenylbenzimidazole (TAC-BIM) hybrid molecules has been designed, synthesized and studied for their multiple biological activities. These agents showed improved AChE inhibitory activity (IC 50 in nanomolar range), as compared with the single drug tacrine (TAC), and also a high inhibition of self-induced- and Cu-induced-Aβ aggregation (up to 75%). They also present moderate radical scavenging activity and metal chelating ability. In addition, neuroprotective studies revealed that all these tested compounds are able to inhibit the neurotoxicity induced by Aβ and Fe/AscH(-) in neuronal cells. Hence, for this set of hybrids, structure-activity relationships are discussed and finally it is highlighted their real promising interest as potential anti-AD drugs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  14. Medicinal benefits of marine invertebrates: sources for discovering natural drug candidates.

    Science.gov (United States)

    De Zoysa, Mahanama

    2012-01-01

    Marine invertebrates are one of the major groups of organisms, which could be diversified under the major taxonomic groups of Porifera, Cnidaria, Mollusca, Arthropoda, Echinodermata, and many other minor phyla. To date, range of medicinal benefits and a significant number of marine natural products (MNPs) have been discovered from marine invertebrates. Seafood diet from edible marine invertebrates such as mollusks and crustaceans has been linked with various medicinal benefits to improve human health. Among marine invertebrates, spongers from phylum Porifera is the most dominant group responsible for discovering large number of MNPs, which have been used as template to develop therapeutic drugs. MNPs isolated from invertebrates have shown wide range of therapeutic properties including antimicrobial, antioxidant, antihypertensive, anticoagulant, anticancer, anti-inflammatory, wound healing and immune modulator, and other medicinal effects. Therefore, marine invertebrates are rich sources of chemical diversity and health benefits for developing drug candidates, cosmetics, nutritional supplements, and molecular probes that can be supported to increase the healthy life span of human. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

    Science.gov (United States)

    Muenster, Uwe; Mueck, Wolfgang; van der Mey, Dorina; Schlemmer, Karl-Heinz; Greschat-Schade, Susanne; Haerter, Michael; Pelzetter, Christian; Pruemper, Christian; Verlage, Joerg; Göller, Andreas H; Ohm, Andreas

    2016-05-01

    The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Drug susceptibility testing in microaerophilic parasites: Cysteine strongly affects the effectivities of metronidazole and auranofin, a novel and promising antimicrobial

    Directory of Open Access Journals (Sweden)

    David Leitsch

    2017-12-01

    Full Text Available The microaerophilic parasites Entamoeba histolytica, Trichomonas vaginalis, and Giardia lamblia annually cause hundreds of millions of human infections which are treated with antiparasitic drugs. Metronidazole is the most often prescribed drug but also other drugs are in use, and novel drugs with improved characteristics are constantly being developed. One of these novel drugs is auranofin, originally an antirheumatic which has been relabelled for the treatment of parasitic infections. Drug effectivity is arguably the most important criterion for its applicability and is commonly assessed in susceptibility assays using in vitro cultures of a given pathogen. However, drug susceptibility assays can be strongly affected by certain compounds in the growth media. In the case of microaerophilic parasites, cysteine which is added in large amounts as an antioxidant is an obvious candidate because it is highly reactive and known to modulate the toxicity of metronidazole in several microaerophilic parasites.In this study, it was attempted to reduce cysteine concentrations as far as possible without affecting parasite viability by performing drug susceptibility assays under strictly anaerobic conditions in an anaerobic cabinet. Indeed, T. vaginalis and E. histolytica could be grown without any cysteine added and the cysteine concentration necessary to maintain G. lamblia could be reduced to 20%. Susceptibilities to metronidazole were found to be clearly reduced in the presence of cysteine. With auranofin the protective effect of cysteine was extreme, providing protection to concentrations up to 100-fold higher as observed in the absence of cysteine. With three other drugs tested, albendazole, furazolidone and nitazoxanide, all in use against G. lamblia, the effect of cysteine was less pronounced. Oxygen was found to have a less marked impact on metronidazole and auranofin than cysteine but bovine bile which is standardly used in growth media for G

  17. A Promising New Method to Estimate Drug-Polymer Solubility at Room Temperature

    DEFF Research Database (Denmark)

    Knopp, Matthias Manne; Gannon, Natasha; Porsch, Ilona

    2016-01-01

    The established methods to predict drug-polymer solubility at room temperature either rely on extrapolation over a long temperature range or are limited by the availability of a liquid analogue of the polymer. To overcome these issues, this work investigated a new methodology where the drug-polymer...... solubility is estimated from the solubility of the drug in a solution of the polymer at room temperature using the shake-flask method. Thus, the new polymer in solution method does not rely on temperature extrapolations and only requires the polymer and a solvent, in which the polymer is soluble, that does...... not affect the molecular structure of the drug and polymer relative to that in the solid state. Consequently, as this method has the potential to provide fast and precise estimates of drug-polymer solubility at room temperature, we encourage the scientific community to further investigate this principle both...

  18. PLGA based drug delivery systems: Promising carriers for wound healing activity.

    Science.gov (United States)

    Chereddy, Kiran Kumar; Vandermeulen, Gaëlle; Préat, Véronique

    2016-03-01

    Wound treatment remains one of the most prevalent and economically burdensome healthcare issues in the world. Current treatment options are limited and require repeated administrations which led to the development of new therapeutics to satisfy the unmet clinical needs. Many potent wound healing agents were discovered but most of them are fragile and/or sensitive to in vivo conditions. Poly(lactic-co-glycolic acid) (PLGA) is a widely used biodegradable polymer approved by food and drug administration and European medicines agency as an excipient for parenteral administrations. It is a well-established drug delivery system in various medical applications. The aim of the current review is to elaborate the applications of PLGA based drug delivery systems carrying different wound healing agents and also present PLGA itself as a wound healing promoter. PLGA carriers encapsulating drugs such as antibiotics, anti-inflammatory drugs, proteins/peptides, and nucleic acids targeting various phases/signaling cycles of wound healing, are discussed with examples. The combined therapeutic effects of PLGA and a loaded drug on wound healing are also mentioned. © 2016 by the Wound Healing Society.

  19. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2018-03-01

    Full Text Available Medullary thyroid cancer (MTC is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1 plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K, which is the key enzyme in the mammalian target of rapamycin (mTOR pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53-sestrins-AMPK-mTOR signaling pathway.

  20. New Drug Candidate Targeting the 4A1 Orphan Nuclear Receptor for Medullary Thyroid Cancer Therapy.

    Science.gov (United States)

    Zhang, Lei; Liu, Wen; Wang, Qun; Li, Qinpei; Wang, Huijuan; Wang, Jun; Teng, Tieshan; Chen, Mingliang; Ji, Ailing; Li, Yanzhang

    2018-03-02

    Medullary thyroid cancer (MTC) is a relatively rare thyroid cancer responsible for a substantial fraction of thyroid cancer mortality. More effective therapeutic drugs with low toxicity for MTC are urgently needed. Orphan nuclear receptor 4A1 (NR4A1) plays a pivotal role in regulating the proliferation and apoptosis of a variety of tumor cells. Based on the NR4A1 protein structure, 2-imino-6-methoxy-2H-chromene-3-carbothioamide (IMCA) was identified from the Specs compounds database using the protein structure-guided virtual screening approach. Computationally-based molecular modeling studies suggested that IMCA has a high affinity for the ligand binding pocket of NR4A1. MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] and apoptosis assays demonstrated that IMCA resulted in significant thyroid cancer cell death. Immunofluorescence assays showed that IMCA induced NR4A1 translocation from the nucleus to the cytoplasm in thyroid cancer cell lines, which may be involved in the cell apoptotic process. In this study, the quantitative polymerase chain reaction results showed that the IMCA-induced upregulation of sestrin1 and sestrin2 was dose-dependent in thyroid cancer cell lines. Western blot showed that IMCA increased phosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and decreased phosphorylation of ribosomal protein S6 kinase (p70S6K), which is the key enzyme in the mammalian target of rapamycin (mTOR) pathway. The experimental results suggest that IMCA is a drug candidate for MTC therapy and may work by increasing the nuclear export of NR4A1 to the cytoplasm and the tumor protein 53 (p53)-sestrins-AMPK-mTOR signaling pathway.

  1. Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

    Energy Technology Data Exchange (ETDEWEB)

    Pillai, Rajapillai L.I.; Tipre, Dnyanesh N. [Stony Brook University Health Science Center, Department of Psychiatry, Stony Brook, NY (United States)

    2016-06-15

    This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

  2. Metabotropic glutamate receptor 5 - a promising target in drug development and neuroimaging

    International Nuclear Information System (INIS)

    Pillai, Rajapillai L.I.; Tipre, Dnyanesh N.

    2016-01-01

    This review summarizes the contributions by various teams of scientists in assessing the metabotropic glutamate receptor 5 (mGluR5) as a biomarker in neuropsychiatric disorders and diseases. Development of positive and negative allosteric modulators of mGluR5 is reviewed, as is the development of PET radioligands that have the potential to measure mGluR5 receptor density in neurological disorders and during therapeutic interventions. PET imaging provides an effective tool to assess the specificity of new drugs, select dose regimens in clinical trials, and study drug mechanisms of action. We summarize and deliver comparative analyses of mGluR5-specific PET radiotracers and their applications in understanding the pathophysiology of mGluR5-related nervous system disorders and to speed up drug development. (orig.)

  3. Biochemical Characterization of Glutamate Racemase-A New Candidate Drug Target against Burkholderia cenocepacia Infections.

    Directory of Open Access Journals (Sweden)

    Aygun Israyilova

    Full Text Available The greatest obstacle for the treatment of cystic fibrosis patients infected with the Burkholderia species is their intrinsic antibiotic resistance. For this reason, there is a need to develop new effective compounds. Glutamate racemase, an essential enzyme for the biosynthesis of the bacterial cell wall, is an excellent candidate target for the design of new antibacterial drugs. To this aim, we recombinantly produced and characterized glutamate racemase from Burkholderia cenocepacia J2315. From the screening of an in-house library of compounds, two Zn (II and Mn (III 1,3,5-triazapentadienate complexes were found to efficiently inhibit the glutamate racemase activity with IC50 values of 35.3 and 10.0 μM, respectively. Using multiple biochemical approaches, the metal complexes have been shown to affect the enzyme activity by binding to the enzyme-substrate complex and promoting the formation of an inhibited dimeric form of the enzyme. Our results corroborate the value of glutamate racemase as a good target for the development of novel inhibitors against Burkholderia.

  4. Critical analysis of 3-D organoid in vitro cell culture models for high-throughput drug candidate toxicity assessments.

    Science.gov (United States)

    Astashkina, Anna; Grainger, David W

    2014-04-01

    Drug failure due to toxicity indicators remains among the primary reasons for staggering drug attrition rates during clinical studies and post-marketing surveillance. Broader validation and use of next-generation 3-D improved cell culture models are expected to improve predictive power and effectiveness of drug toxicological predictions. However, after decades of promising research significant gaps remain in our collective ability to extract quality human toxicity information from in vitro data using 3-D cell and tissue models. Issues, challenges and future directions for the field to improve drug assay predictive power and reliability of 3-D models are reviewed. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Discovery and characterization of novel imidazopyridine derivative CHEQ-2 as a potent CDC25 inhibitor and promising anticancer drug candidate.

    Science.gov (United States)

    Song, Yu'ning; Lin, Xiaoqian; Kang, Dongwei; Li, Xiao; Zhan, Peng; Liu, Xinyong; Zhang, Qingzhu

    2014-07-23

    Cell division cycle (CDC) 25 proteins are key phosphatases regulating cell cycle transition and proliferation via the interactions with CDK/Cyclin complexes. Overexpression of CDC25 proteins is frequently observed in cancer and is related to aggressiveness, high-grade tumors and poor prognosis. Thus, inhibiting CDC25 activity in cancer treatment appears a good therapeutic strategy. In this article, refinement of the initial hit XDW-1 by synthesis and screening of a focused compound library led to the identification of a novel set of imidazopyridine derivatives as potent CDC25 inhibitors. Among them, the most potent molecule was CHEQ-2, which could efficiently inhibit the activities of CDC25A/B enzymes as well as the proliferation of various different types of cancer cell lines in vitro assay. Moreover, CHEQ-2 triggered S-phase cell cycle arrest in MCF-7, HepG2 and HT-29 cell lines, accompanied by generation of ROS, mitochondrial dysfunction and apoptosis. Besides, oral administration of CHEQ-2 (10 mg/kg) significantly inhibited xenografted human liver tumor growth in nude mice, while demonstrated extremely low toxicity (LD50 > 2000 mg/kg). These findings make CHEQ-2 a good starting point for further investigation and structure modification. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  6. SPME as a promising tool in translational medicine and drug discovery: From bench to bedside.

    Science.gov (United States)

    Goryński, Krzysztof; Goryńska, Paulina; Górska, Agnieszka; Harężlak, Tomasz; Jaroch, Alina; Jaroch, Karol; Lendor, Sofia; Skobowiat, Cezary; Bojko, Barbara

    2016-10-25

    Solid phase microextraction (SPME) is a technology where a small amount of an extracting phase dispersed on a solid support is exposed to the sample for a well-defined period of time. The open-bed geometry and biocompatibility of the materials used for manufacturing of the devices makes it very convenient tool for direct extraction from complex biological matrices. The flexibility of the formats permits tailoring the method according the needs of the particular application. Number of studies concerning monitoring of drugs and their metabolites, analysis of metabolome of volatile as well as non-volatile compounds, determination of ligand-protein binding, permeability and compound toxicity was already reported. All these applications were performed in different matrices including biological fluids and tissues, cell cultures, and in living animals. The low invasiveness of in vivo SPME, ability of using very small sample volumes and analysis of cell cultures permits to address the rule of 3R, which is currently acknowledged ethical standard in R&D labs. In the current review systematic evaluation of the applicability of SPME to studies required to be conduct at different stages of drug discovery and development and translational medicine is presented. The advantages and challenges are discussed based on the examples directly showing given experimental design or on the studies, which could be translated to the models routinely used in drug development process. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions.

    Science.gov (United States)

    Adiwidjaja, Jeffry; McLachlan, Andrew J; Boddy, Alan V

    2017-09-01

    Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided. Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has important implications for optimal treatment of cancers other than those in gastrointestinal tract. Curcumin-drug pharmacokinetic interactions are also almost exclusively in the enterocytes, owing to extensive first pass metabolism and poor curcumin bioavailability. Greater scope of these interactions, i.e. modulation of the systemic elimination of co-administered drugs, may be expected from more-bioavailable curcumin formulations. Further studies are still warranted, especially with newer formulations to support the inclusion of curcumin in cancer therapy regimens.

  8. Nanomedicine formulations for the delivery of antiviral drugs: a promising solution for the treatment of viral infections.

    Science.gov (United States)

    Lembo, David; Donalisio, Manuela; Civra, Andrea; Argenziano, Monica; Cavalli, Roberta

    2018-01-01

    Viral infections represent a public health problem and one of the leading causes of global mortality. Nanomedicine strategies can be considered a powerful tool to enhance the effectiveness of antiviral drugs, often associated with solubility and bioavailability issues. Consequently, high doses and frequent administrations are required, resulting in adverse side effects. To overcome these limitations, various nanomedicine platforms have been designed. Areas covered: This review focuses on the state of the art of organic-based nanoparticles for the delivery of approved antivirals. A brief description of the main characteristics of nanocarriers is followed by an overview of the most promising research addressing the treatment of most important viral infections. Expert opinion: The activity of antiviral drugs could be improved with nanomedicine formulations. Indeed, nanoparticles can affect the fate of the encapsulated drugs, allowing controlled release kinetics, enhanced bioavailability, modified pharmacokinetics, and reduced side effects. In addition, the physicochemical properties of nanocarriers can enable their capability to target specific sites and to interact with virus structures. In this regard, nanomedicines can be considered an opportunity to enhance the therapeutic index of antivirals. Efficacy, safety, and manufacturing issues need to be carefully assessed to bring this promising approach to the clinic.

  9. Crosslinked hydrogels—a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs

    Directory of Open Access Journals (Sweden)

    Dajun D. Sun

    2014-02-01

    Full Text Available Water-insoluble materials containing amorphous solid dispersions (ASD are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate (PHEMA can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

  10. Crosslinked hydrogels-a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs.

    Science.gov (United States)

    Sun, Dajun D; Lee, Ping I

    2014-02-01

    Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.

  11. 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

  12. Snake Venom PLA2, a Promising Target for Broad-Spectrum Antivenom Drug Development

    Directory of Open Access Journals (Sweden)

    Huixiang Xiao

    2017-01-01

    Full Text Available Snakebite envenomation is a neglected global health problem, causing substantial mortality, disability, and psychological morbidity, especially in rural tropical and subtropical zones. Antivenin is currently the only specific medicine for envenomation. However, it is restricted by cold storage, snakebite diagnosis, and high price. Snake venom phospholipase A2s (svPLA2s are found in all kinds of venomous snake families (e.g., Viperidae, Elapidae, and Colubridae. Along with their catalytic activity, svPLA2s elicit a wide variety of pharmacological effects that play a pivotal role in envenomation damage. Hence, neutralization of the svPLA2s could weaken or inhibit toxic damage. Here we overviewed the latest knowledge on the distribution, pathophysiological effects, and inhibitors of svPLA2s to elucidate the potential for a novel, wide spectrum antivenom drug targeting svPLA2s.

  13. 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

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

    Science.gov (United States)

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

    2014-10-01

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

  15. Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

    DEFF Research Database (Denmark)

    Kopec, Wojciech; Khandelia, Himanshu

    2014-01-01

    Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various propose......-membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds....... mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations...

  16. Mini-tablets versus pellets as promising multiparticulate modified release delivery systems for highly soluble drugs.

    Science.gov (United States)

    Gaber, Dina M; Nafee, Noha; Abdallah, Osama Y

    2015-07-05

    Whether mini-tablets (tablets, diameters ≤6mm) belong to single- or multiple-unit dosage forms is still questionable. Accordingly, Pharmacopoeial evaluation procedures for mini-tablets are lacking. In this study, the aforementioned points were discussed. Moreover, their potential for oral controlled delivery was assessed. The antidepressant venlafaxine hydrochloride (Vx), a highly soluble drug undergoing first pass effect, low bioavailability and short half-life was selected as a challenging payload. In an attempt to weigh up mini-tablets versus pellets as multiparticulate carriers, Vx-loaded mini-tablets were compared to formulated pellets of the same composition and the innovator Effexor(®)XR pellets. Formulations were prepared using various polymer hydrogels in the core and ethyl cellulose film coating with increasing thickness. Mini-tablets (diameter 2mm) showed extended Vx release (<60%, 8h). Indeed, release profiles comparable to Effexor(®)XR pellets were obtained. Remarkably higher coating thickness was required for pellets to provide equivalent retardation. Ethyl cellulose in the core ensured faster release due to polymer migration to the surface and pore formation in the coat. mini-tablets showed higher stability to pellets upon storage. Industrially speaking, mini-tablets proved to be superior to pellets in terms of manufacturing, product quality and economical aspects. Results point out the urgent need for standardized evaluation procedures for mini-tablets. Copyright © 2015. Published by Elsevier B.V.

  17. A Promising Approach to Provide Appropriate Colon Target Drug Delivery Systems of Vancomycin HCL: Pharmaceutical and Microbiological Studies

    Directory of Open Access Journals (Sweden)

    Kadria A. Elkhodairy

    2014-01-01

    Full Text Available Vancomycin HCl was prepared as orally administered colon target drug delivery tablets for systemic therapy. Tablet matrices containing 10–60% of tablet weight of guar gum (F1–F6 were prepared by direct compression and subjected to in vitro release studies to explore their sustained release in the colon. Various synthetic and natural polymers were incorporated to F6 to modify the drug release rate. Different 15 matrix tablet formulations (F6–F20 were enteric coated with hydroxypropyl methyl cellulose phthalate. F6, F13 and F20 showed promising sustained release results having median dissolution time (MDT values: 8.25, 7.97, and 7.64, respectively. Microbiological assay was performed to test the efficacy of F6, F13, and F20 to inhibit clinical Staphylococcus aureus (SA isolates. Bactericidal activity of F6 was reached after 2, 4, and 24 hours of incubation against MSSA 18, MRSA 29, and MRSA 11 strains, respectively, while it was reached within 6–8 hours in case of F13, and F20 against all strains tested. F13 enhanced log microbial reduction by 1.74, 0.65 and 2.4 CFU/mL compared to F6 while it was 1, 2.57 and 1.57 compared to F20 against MSSA18, MRSA11 and MRSA29, respectively. Vancomycin HCl tablets displayed a promising sustained release in vitro and microbiological inhibitory action on all isolates tested.

  18. A promising approach to provide appropriate colon target drug delivery systems of vancomycin HCL: pharmaceutical and microbiological studies.

    Science.gov (United States)

    Elkhodairy, Kadria A; Afifi, Samar A; Zakaria, Azza S

    2014-01-01

    Vancomycin HCl was prepared as orally administered colon target drug delivery tablets for systemic therapy. Tablet matrices containing 10-60% of tablet weight of guar gum (F1-F6) were prepared by direct compression and subjected to in vitro release studies to explore their sustained release in the colon. Various synthetic and natural polymers were incorporated to F6 to modify the drug release rate. Different 15 matrix tablet formulations (F6-F20) were enteric coated with hydroxypropyl methyl cellulose phthalate. F6, F13 and F20 showed promising sustained release results having median dissolution time (MDT) values: 8.25, 7.97, and 7.64, respectively. Microbiological assay was performed to test the efficacy of F6, F13, and F20 to inhibit clinical Staphylococcus aureus (SA) isolates. Bactericidal activity of F6 was reached after 2, 4, and 24 hours of incubation against MSSA 18, MRSA 29, and MRSA 11 strains, respectively, while it was reached within 6-8 hours in case of F13, and F20 against all strains tested. F13 enhanced log microbial reduction by 1.74, 0.65 and 2.4 CFU/mL compared to F6 while it was 1, 2.57 and 1.57 compared to F20 against MSSA18, MRSA11 and MRSA29, respectively. Vancomycin HCl tablets displayed a promising sustained release in vitro and microbiological inhibitory action on all isolates tested.

  19. Oleanolic acid liposomes with polyethylene glycol modification: promising antitumor drug delivery

    Directory of Open Access Journals (Sweden)

    Gao D

    2012-07-01

    Full Text Available Dawei Gao, Shengnan Tang, Qi TongApplied Chemical Key Laboratory of Hebei Province, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, ChinaBackground: Oleanolic acid is a pentacyclic triterpene present in many fruits and vegetables, and has received much attention on account of its biological properties. However, its poor solubility and low bioavailability limit its use. The objective of this study was to encapsulate oleanolic acid into nanoliposomes using the modified ethanol injection method.Methods: The liposomes contain a hydrophobic oleanolic acid core, an amphiphilic soybean lecithin monolayer, and a protective hydrophilic polyethylene glycol (PEG coating. During the preparation process, the formulations described were investigated by designing 34 orthogonal experiments as well as considering the effects of different physical characteristics. The four factors were the ratios of drug to soybean phosphatidylcholine (w/w, cholesterol (w/w, PEG-2000 (w/w, and temperature of phosphate-buffered saline at three different levels. We identified the optimized formulation which showed the most satisfactory lipid stability and particle formation. The morphology of the liposomes obtained was determined by transmission electron microscopy and atomic force microscopy. The existence of PEG in the liposome component was validated by Fourier transform infrared spectrum analysis.Results: The PEGylated liposomes dispersed individually and had diameters of around 110–200 nm. Encapsulation efficiency was more than 85%, as calculated by high-performance liquid chromatography and Sephadex® gel filtration. Furthermore, when compared with native oleanolic acid, the liposomal formulations showed better stability in vitro. Finally, the cytotoxicity of the oleanolic acid liposomes was evaluated using a microtiter tetrazolium assay.Conclusion: These results suggest that PEGylated liposomes would serve as a potent delivery vehicle

  20. Exoproteome and Secretome Derived Broad Spectrum Novel Drug and Vaccine Candidates in Vibrio cholerae Targeted by Piper betel Derived Compounds

    Science.gov (United States)

    Barh, Debmalya; Barve, Neha; Gupta, Krishnakant; Chandra, Sudha; Jain, Neha; Tiwari, Sandeep; Leon-Sicairos, Nidia; Canizalez-Roman, Adrian; Rodrigues dos Santos, Anderson; Hassan, Syed Shah; Almeida, Síntia; Thiago Jucá Ramos, Rommel; Augusto Carvalho de Abreu, Vinicius; Ribeiro Carneiro, Adriana; de Castro Soares, Siomar; Luiz de Paula Castro, Thiago; Miyoshi, Anderson; Silva, Artur; Kumar, Anil; Narayan Misra, Amarendra; Blum, Kenneth; Braverman, Eric R.; Azevedo, Vasco

    2013-01-01

    Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC) for most of the pathogenic Vibrio strains. Two targets (uppP and yajC) are novel to Vibrio, and two targets (uppP and ompU) can be used to develop both drugs and vaccines (dual targets) against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species. PMID:23382822

  1. Exoproteome and secretome derived broad spectrum novel drug and vaccine candidates in Vibrio cholerae targeted by Piper betel derived compounds.

    Directory of Open Access Journals (Sweden)

    Debmalya Barh

    Full Text Available Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC for most of the pathogenic Vibrio strains. Two targets (uppP and yajC are novel to Vibrio, and two targets (uppP and ompU can be used to develop both drugs and vaccines (dual targets against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species.

  2. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

    Energy Technology Data Exchange (ETDEWEB)

    Marks, Louise, E-mail: louise.marks@astrazeneca.com [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Kirk, Sarah [Innovative Medicines, Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom); Valentin, Jean-Pierre [Safety Assessment UK, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG (United Kingdom)

    2012-09-01

    Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt{sub max} and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability.

  3. The role of the anaesthetised guinea-pig in the preclinical cardiac safety evaluation of drug candidate compounds

    International Nuclear Information System (INIS)

    Marks, Louise; Borland, Samantha; Philp, Karen; Ewart, Lorna; Lainée, Pierre; Skinner, Matthew; Kirk, Sarah; Valentin, Jean-Pierre

    2012-01-01

    Despite rigorous preclinical and clinical safety evaluation, adverse cardiac effects remain a leading cause of drug attrition and post-approval drug withdrawal. A number of cardiovascular screens exist within preclinical development. These screens do not, however, provide a thorough cardiac liability profile and, in many cases, are not preventing the progression of high risk compounds. We evaluated the suitability of the anaesthetised guinea-pig for the assessment of drug-induced changes in cardiovascular parameters. Sodium pentobarbitone anaesthetised male guinea-pigs received three 15 minute intravenous infusions of ascending doses of amoxicillin, atenolol, clonidine, dobutamine, dofetilide, flecainide, isoprenaline, levosimendan, milrinone, moxifloxacin, nifedipine, paracetamol, verapamil or vehicle, followed by a 30 minute washout. Dose levels were targeted to cover clinical exposure and above, with plasma samples obtained to evaluate effect/exposure relationships. Arterial blood pressure, heart rate, contractility function (left ventricular dP/dt max and QA interval) and lead II electrocardiogram were recorded throughout. In general, the expected reference compound induced effects on haemodynamic, contractility and electrocardiographic parameters were detected confirming that all three endpoints can be measured accurately and simultaneously in one small animal. Plasma exposures obtained were within, or close to the expected clinical range of therapeutic plasma levels. Concentration–effect curves were produced which allowed a more complete understanding of the margins for effects at different plasma exposures. This single in vivo screen provides a significant amount of information pertaining to the cardiovascular risk of drug candidates, ultimately strengthening strategies addressing cardiovascular-mediated compound attrition and drug withdrawal. -- Highlights: ► Evaluation of the anaesthetised guinea-pig to determine cardiac liability. ► Haemodynamic

  4. Trafficking of drug candidates relevant for sports drug testing: detection of non-approved therapeutics categorized as anabolic and gene doping agents in products distributed via the Internet.

    Science.gov (United States)

    Thevis, Mario; Geyer, Hans; Thomas, Andreas; Schänzer, Wilhelm

    2011-05-01

    Identifying the use of non-approved drugs by cheating athletes has been a great challenge for doping control laboratories. This is due to the additional complexities associated with identifying relatively unknown and uncharacterized compounds and their metabolites as opposed to known and well-studied therapeutics. In 2010, the prohibited drug candidates and gene doping substances AICAR and GW1516, together with the selective androgen receptor modulator (SARM) MK-2866 were obtained by the Cologne Doping Control Laboratory from Internet suppliers and their structure, quantity, and formulation elucidated. All three compounds proved authentic as determined by liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry and comparison to reference material. While AICAR was provided as a colourless powder in 100 mg aliquots, GW1516 was obtained as an orange/yellow suspension in water/glycerol (150 mg/ml), and MK-2866 (25 mg/ml) was shipped dissolved in polyethylene glycol (PEG) 300. In all cases, the quantified amounts were considerably lower than indicated on the label. The substances were delivered via courier, with packaging identifying them as containing 'amino acids' and 'green tea extract', arguably to circumvent customs control. Although all of the substances were declared 'for research only', their potential misuse in illicit performance-enhancement cannot be excluded; moreover sports drug testing authorities should be aware of the facile availability of black market copies of these drug candidates. Copyright © 2011 John Wiley & Sons, Ltd.

  5. Promising cardiovascular and blood pressure effects of the SGLT2 inhibitors: a new class of antidiabetic drugs.

    Science.gov (United States)

    Chrysant, S G

    2017-03-01

    Patients with type 2 diabetes mellitus (T2DM) exhibit an increased risk of cardiovascular (CV) events. Treatment of these patients with traditional as well as newer glucose-lowering drugs has not demonstrated superiority in CV outcomes compared to placebo, despite effective control of diabetes. However, the recently FDA-approved sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of T2DM have demonstrated promising CV-protecting and blood pressure-lowering effects in addition to their effectiveness in glucose lowering, making them a novel class of drugs for the treatment of T2DM. So far, there are three SGLT2 inhibitors approved by the FDA and EMA for the treatment of T2DM: canagliflozin, dapagliflozin and empagliflozin. They exert their antihyperglycemic effect through inhibition of SGLT2 in the kidney and significantly reduce glucose reabsorption from the proximal renal tubule. By blocking glucose reabsorption, they lead to loss of calories, weight, abdominal and total body fat, blood pressure and CV complications. One CV outcomes randomized trial and several short-term studies have shown reductions in CV events and blood pressure in patients with T2DM. It is the hope that large ongoing long-term outcome studies will provide further much-needed information, when they are completed. Copyright 2017 Clarivate Analytics.

  6. Zika antiviral chemotherapy: identification of drugs and promising starting points for drug discovery from an FDA-approved library [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Bruno S. Pascoalino

    2016-10-01

    Full Text Available Background The recent epidemics of Zika virus (ZIKV implicated it as the cause of serious and potentially lethal congenital conditions such microcephaly and other central nervous system defects, as well as the development of the Guillain-Barré syndrome in otherwise healthy patients. Recent findings showed that anti-Dengue antibodies are capable of amplifying ZIKV infection by a mechanism similar to antibody-dependent enhancement, increasing the severity of the disease. This scenario becomes potentially catastrophic when the global burden of Dengue and the advent of the newly approved anti-Dengue vaccines in the near future are taken into account. Thus, antiviral chemotherapy should be pursued as a priority strategy to control the spread of the virus and prevent the complications associated with Zika. Methods Here we describe a fast and reliable cell-based, high-content screening assay for discovery of anti-ZIKV compounds. This methodology has been used to screen the National Institute of Health Clinical Collection compound library, a small collection of FDA-approved drugs. Results and conclusion From 725 FDA-approved compounds triaged, 29 (4% were found to have anti-Zika virus activity, of which 22 had confirmed (76% of confirmation by dose-response curves. Five candidates presented selective activity against ZIKV infection and replication in a human cell line. These hits have abroad spectrum of chemotypes and therapeutic uses, offering valuable opportunities for selection of leads for antiviral drug discovery.

  7. Political Reputations and Campaign Promises

    OpenAIRE

    Aragones, Enriqueta; Palfrey, Thomas R.; Postlewaite, Andrew

    2006-01-01

    We analyze conditions under which candidates' reputations may affect voters' beliefs over what policy will be implemented by the winning candidate of an election. We develop a model of repeated elections with complete information in which candidates are purely ideological. We analyze an equilibrium in which voters' strategies involve a credible threat to punish candidates who renege on their campaign promises and in which all campaign promises are believed by voters and honored by candidates....

  8. Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

    Directory of Open Access Journals (Sweden)

    Fatma E. El-Khouly

    2017-10-01

    Full Text Available Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG, patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB. We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG.

  9. Parenteral formulation of an antileishmanial drug candidate--tackling poor solubility, chemical instability, and polymorphism.

    Science.gov (United States)

    Kupetz, Eva; Preu, Lutz; Kunick, Conrad; Bunjes, Heike

    2013-11-01

    The paullon chalcone derivative KuRei300 is active against Leishmania donovani, the protozoans causing visceral leishmaniasis. The aim of this study was the development of a parenteral formulation of the virtually water insoluble compound in order to enable future studies in mice. Mixed lecithin/bile salt micelles, liposomes, supercooled smectic cholesterol myristate nanoparticles, cubic phase nanoparticles and a triglyceride emulsion were screened for their solubilizing properties. Due to the limited available amount of KuRei300 a passive loading approach with pre-formulated carriers that were incubated with drug substance deposited onto the walls of glass vials was used. The loading capacities of the nanocarriers, the influence of the solid state properties of the drug and its deposits on the loading results and chemical stability aspects of KuRei300 were investigated. Employed methods included HPLC, UV spectroscopy, (1)H NMR, XRPD, and DSC. All nanocarriers substantially improved the solubility of KuRei300; the mixed micelles exhibited the highest drug load. Related to the lipid matrix, however, the smectic nanoparticles solubilized the significantly highest amount of drug. Loading from physically altered drug deposits improved the obtainable concentration to the threefold compared with untreated drug powder. Formulations with KuRei300 must be stored excluded from light under a nitrogen atmosphere as the substance is susceptible to photoisomerization and decomposition. Copyright © 2013 Elsevier B.V. All rights reserved.

  10. 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.

  11. Dry Gel Containing Optimized Felodipine-Loaded Transferosomes: a Promising Transdermal Delivery System to Enhance Drug Bioavailability.

    Science.gov (United States)

    Kassem, Mohammed Ali; Aboul-Einien, Mona Hassan; El Taweel, Mai Magdy

    2018-04-30

    Felodipine has a very low bioavailability due to first-pass metabolism. The aim of this study was to enhance its bioavailability by transdermal application. Felodipine-loaded transferosomes were prepared by thin-film hydration using different formulation variables. An optimized formula was designed using statistical experimental design. The independent variables were the used edge activator, its molar ratio to phosphatidylcholine, and presence or absence of cholesterol. The responses were entrapment efficiency of transferosomes, their size, polydispersity index, zeta potential, and percent drug released after 8 h. The optimized formula was subjected to differential scanning calorimetry studies and its stability on storage at 4°C for 6 months was estimated. This formula was improved by incorporation of different permeation enhancers where ex vivo drug flux through mice skin was estimated and the best improved formula was formulated in a gel and lyophilized. The prepared gel was subjected to in vivo study using Plendil® tablets as a reference. According to the calculated desirability, the optimized transferosome formula was that containing sodium deoxycholate as edge activator at 5:1 M ratio to phosphatidylcholine and no cholesterol. The thermograms of this formula indicated the incorporation of felodipine inside the prepared vesicles. None of the tested parameters differed significantly on storage. The lyophilized gel of labrasol-containing formula was chosen for in vivo study. The relative bioavailability of felodipine from the designed gel was 1.7. In conclusion, topically applied lyophilized gel containing felodipine-loaded transferosomes is a promising transdermal delivery system to enhance its bioavailability.

  12. Are zebrafish larvae suitable for assessing the hepatotoxicity potential of drug candidates?

    NARCIS (Netherlands)

    Mesens, N.; Crawfordb, A.D.; Menke, A.; Hung, P.D.; Goethem, F. van; Nuyts, R.; Hansen, E.; Wolterbeek, A.; Gompel, J. van; Witte, P. de; Esguerra, C.V.

    2015-01-01

    Drug-induced liver injury (DILI) is poorly predicted by single-cell-based assays, probably because of the lack of physiological interactions with other cells within the liver. An intact whole liver system such as one present in zebrafish larvae could provide added value in a screening strategy for

  13. Novel candidate metastasis genes as putative drug targets for breast cancer

    NARCIS (Netherlands)

    Roosmalen, Wilhelmina Paulina Elisabeth van

    2012-01-01

    Despite extensive studies to unravel molecular mechanisms underlying breast cancer metastasis, still 3500 women die of the results of this disease in the Netherlands each year. Improving our understanding of metastasis formation remains a challenge for further drug development. The scope of this

  14. Promising applications in drug delivery systems of a novel β-cyclodextrin derivative obtained by green synthesis.

    Science.gov (United States)

    García, Agustina; Leonardi, Darío; Lamas, María C

    2016-01-15

    An efficient and green method has been developed for the synthesis of succinyl-β-cyclodextrin in aqueous media obtaining very good yield. Acidic groups have been introduced in the synthesized carrier molecule to improve the guest-host affinity. To evaluate the suitability of the novel excipient focused to develop oral dosage forms, albendazole, a BSC class II compound, was chosen as a model drug. The β-cyclodextrin derivative and the inclusion complex were thoroughly characterized in solution and solid state by phase solubility studies, FT-IR spectroscopy, SEM, XRD, ESI-MS, DSC, 1D (1)H NMR, 1D (13)C NMR, selective 1D TOCSY, 2D COSY, 2D HSQC, 2D HMBC and ROESY NMR spectroscopy. Phase solubility studies indicated that both of them β-cyclodextrin and succinyl-β-cyclodextrin formed 1:1 inclusion complexes with albendazole, and the stability constants were 68M(-1) (β-cyclodextrin), 437M(-1) (succinyl-β-cyclodextrin), respectively. Water solubility and dissolution rate of albendazole were significantly improved in complex forms. Thus, the succinyl-β-cyclodextrin derivative could be a promising excipient to design oral dosage forms. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Potential candidate genomic biomarkers of drug induced vascular injury in the rat

    International Nuclear Information System (INIS)

    Dalmas, Deidre A.; Scicchitano, Marshall S.; Mullins, David; Hughes-Earle, Angela; Tatsuoka, Kay; Magid-Slav, Michal; Frazier, Kendall S.; Thomas, Heath C.

    2011-01-01

    Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip® analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan™) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development. -- Highlights: ► A gene panel was developed to help predict rat drug-induced mesenteric MAN. ► A gene panel was identified following treatment of rats with 28

  16. Plant lectins as carriers for oral drugs: Is wheat germ agglutinin a suitable candidate?

    International Nuclear Information System (INIS)

    Dalla Pellegrina, Chiara; Rizzi, Corrado; Mosconi, Silvia; Zoccatelli, Gianni; Peruffo, Angelo; Chignola, Roberto

    2005-01-01

    Wheat germ agglutinin (WGA) is a plant protein that binds specifically to sugars expressed also by gastrointestinal epithelial cells. WGA is currently investigated as an anti-tumor drug and as a carrier for oral drugs. Information on whether it can cross the gastrointestinal epithelium and on its possible effects on the integrity of the epithelial layer is however scanty or lacking, and herein we address these issues. Differentiated Caco2 cells have been used as a model of polarized intestinal epithelium. WGA concentration at both the apical and the basolateral side of the epithelium has been quantified using a sensitive ELISA assay (sensitivity threshold 0.84 nM). Trans epithelial electrical resistance (TEER) has been measured to evaluate the integrity of the epithelium upon treatments with WGA. 3 H-Mannitol (182.2 Da) and FITC-dextran (3000 Da) have been used to measure the permeability of the epithelium. Cell viability has been measured by the MTT, by 7-AAD uptake, and Annexin-V binding assays. Up to a concentration of 5.6 μM, ∼0.1% of intact WGA molecules only could cross the epithelial layer. WGA perturbed the integrity of the epithelium and increased the permeability of the tissue in a dose- and time-dependent manner. WGA did not induce cell death but increased the permeability of individual cells to 7-AAD which is normally not uptaken by viable cells. These data allowed us to define a toxicity threshold for WGA on epithelial cells. WGA suitability as a carrier for oral drugs can therefore be evaluated on a rational basis

  17. Flaviviridae virus nonstructural proteins 5 and 5A mediate viral immune evasion and are promising targets in drug development.

    Science.gov (United States)

    Chen, Shun; Yang, Chao; Zhang, Wei; Mahalingam, Suresh; Wang, Mingshu; Cheng, Anchun

    2018-05-06

    Infections with viruses in the Flaviviridae family have a vast global and economic impact because of the high morbidity and mortality. The pathogenesis of Flaviviridae infections is very complex and not fully understood because these viruses can inhibit multiple immune pathways including the complement system, NK cells, and IFN induction and signalling pathways. The non-structural (NS) 5 and 5A proteins of Flaviviridae viruses are highly conserved and play an important role in resisting host immunity through various evasion mechanisms. This review summarizes the strategies used by the NS5 and 5A proteins of Flaviviridae viruses for evading the innate immune response by inhibiting pattern recognition receptor (PRR) signalling pathways (TLR/MyD88, IRF7), suppressing interferon (IFN) signalling pathways (IFN-γRs, STAT1, STAT2), and impairing the function of IFN-stimulated genes (ISGs) (e.g. protein kinase R [PKR], oligoadenylate synthase [OAS]). All of these immune evasion mechanisms depend on the interaction of NS5 or NS5A with cellular proteins, such as MyD88 and IRF7, IFN-αRs, IFN-γRs, STAT1, STAT2, PKR and OAS. NS5 is the most attractive target for the discovery of broad spectrum compounds against Flaviviridae virus infection. The methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) activities of NS5 are the main therapeutic targets for antiviral drugs against Flaviviridae virus infection. Based on our site mapping, the sites involved in immune evasion provide some potential and promising targets for further novel antiviral therapeutics. Copyright © 2018 Elsevier Inc. All rights reserved.

  18. Salt formation improved the properties of a candidate drug during early formulation development.

    Science.gov (United States)

    Sigfridsson, Kalle; Ahlqvist, Matti; Lindsjö, Martin; Paulsson, Stefan

    2018-07-30

    The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Crystalline material of a maleic acid salt and a fumaric acid salt of AZD5329 were obtained. X-ray powder diffractiometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the two salts. The fumarate salt of AZD5329 is anhydrous, the crystallization is reproducible and the hygroscopicity is acceptable. Early polymorphism assessment work using slurry technique did not reveal any better crystal modification or crystallinity for the fumarate salt. For the maleate salt, the form isolated originally was found to be a solvate, but an anhydrous form was found in later experiments; by suspension in water or acetone, by drying of the solvate to 100-120 °C or by subjecting the solvate form to conditions of 40 °C/75%RH for 3 months. The dissolution behavior and the chemical stability (in aqueous solutions, formulations and solid-state) of both salts were also studied and found to be satisfactory. The compound displays sensitivity to low pH, and the salt of the maleic acid, which is the stronger acid, shows more degradation during stability studies, in line with this observation. The presented data indicate that the substance fulfils basic requirements for further development of an IR dosage form, based on the characterization on crystalline salts of AZD5329. Copyright © 2018 Elsevier B.V. All rights reserved.

  19. Viral induced oxidative and inflammatory response in Alzheimer's disease pathogenesis with identification of potential drug candidates: A systematic review using systems biology approach.

    Science.gov (United States)

    Talwar, Puneet; Gupta, Renu; Kushwaha, Suman; Agarwal, Rachna; Saso, Luciano; Kukreti, Shrikant; Kukreti, Ritushree

    2018-04-19

    Alzheimer's disease (AD) is genetically complex with multifactorial etiology. Here, we aim to identify the potential viral pathogens leading to aberrant inflammatory and oxidative stress response in AD along with potential drug candidates using systems biology approach. We retrieved protein interactions of amyloid precursor protein (APP) and tau protein (MAPT) from NCBI and genes for oxidative stress from NetAge, for inflammation from NetAge and InnateDB databases. Genes implicated in aging were retrieved from GenAge database and two GEO expression datasets. These genes were individually used to create protein-protein interaction network using STRING database (score≥0.7). The interactions of candidate genes with known viruses were mapped using virhostnet v2.0 database. Drug molecules targeting candidate genes were retrieved using the Drug-Gene Interaction Database (DGIdb). Data mining resulted in 2095 APP, 116 MAPT, 214 oxidative stress, 1269 inflammatory genes. After STRING PPIN analysis, 404 APP, 109 MAPT, 204 oxidative stress and 1014 inflammation related high confidence proteins were identified. The overlap among all datasets yielded eight common markers (AKT1, GSK3B, APP, APOE, EGFR, PIN1, CASP8 and SNCA). These genes showed association with hepatitis C virus (HCV), Epstein-Barr virus (EBV), human herpes virus 8 and Human papillomavirus (HPV). Further, screening of drugs targeting candidate genes, and possessing anti-inflammatory property, antiviral activity along with suggested role in AD pathophysiology yielded 12 potential drug candidates. Our study demonstrated the role of viral etiology in AD pathogenesis by elucidating interaction of oxidative stress and inflammation causing candidate genes with common viruses along with the identification of potential AD drug candidates. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Efflux pumps of Mycobacterium tuberculosis play a significant role in antituberculosis activity of potential drug candidates.

    Science.gov (United States)

    Balganesh, Meenakshi; Dinesh, Neela; Sharma, Sreevalli; Kuruppath, Sanjana; Nair, Anju V; Sharma, Umender

    2012-05-01

    Active efflux of drugs mediated by efflux pumps that confer drug resistance is one of the mechanisms developed by bacteria to counter the adverse effects of antibiotics and chemicals. To understand these efflux mechanisms in Mycobacterium tuberculosis, we generated knockout (KO) mutants of four efflux pumps of the pathogen belonging to different classes. We measured the MICs and kill values of two different compound classes on the wild type (WT) and the efflux pump (EP) KO mutants in the presence and absence of the efflux inhibitors verapamil and l-phenylalanyl-l-arginyl-β-naphthylamide (PAβN). Among the pumps studied, the efflux pumps belonging to the ABC (ATP-binding cassette) class, encoded by Rv1218c, and the SMR (small multidrug resistance) class, encoded by Rv3065, appear to play important roles in mediating the efflux of different chemical classes and antibiotics. Efflux pumps encoded by Rv0849 and Rv1258c also mediate the efflux of these compounds, but to a lesser extent. Increased killing is observed in WT M. tuberculosis cells by these compounds in the presence of either verapamil or PAβN. The efflux pump KO mutants were more susceptible to these compounds in the presence of efflux inhibitors. We have shown that these four efflux pumps of M. tuberculosis play a vital role in mediating efflux of different chemical scaffolds. Inhibitors of one or several of these efflux pumps could have a significant impact in the treatment of tuberculosis. The identification and characterization of Rv0849, a new efflux pump belonging to the MFS (major facilitator superfamily) class, are reported.

  1. Discovery and characterization of antibody variants using mass spectrometry-based comparative analysis for biosimilar candidates of monoclonal antibody drugs.

    Science.gov (United States)

    Li, Wenhua; Yang, Bin; Zhou, Dongmei; Xu, Jun; Ke, Zhi; Suen, Wen-Chen

    2016-07-01

    Liquid chromatography mass spectrometry (LC-MS) is the most commonly used technique for the characterization of antibody variants. MAb-X and mAb-Y are two approved IgG1 subtype monoclonal antibody drugs recombinantly produced in Chinese hamster ovary (CHO) cells. We report here that two unexpected and rare antibody variants have been discovered during cell culture process development of biosimilars for these two approved drugs through intact mass analysis. We then used comprehensive mass spectrometry-based comparative analysis including reduced light, heavy chains, and domain-specific mass as well as peptide mapping analysis to fully characterize the observed antibody variants. The "middle-up" mass comparative analysis demonstrated that the antibody variant from mAb-X biosimilar candidate was caused by mass variation of antibody crystalline fragment (Fc), whereas a different variant with mass variation in antibody antigen-binding fragment (Fab) from mAb-Y biosimilar candidate was identified. Endoproteinase Lys-C digested peptide mapping and tandem mass spectrometry analysis further revealed that a leucine to glutamine change in N-terminal 402 site of heavy chain was responsible for the generation of mAb-X antibody variant. Lys-C and trypsin coupled non-reduced and reduced peptide mapping comparative analysis showed that the formation of the light-heavy interchain trisulfide bond resulted in the mAb-Y antibody variant. These two cases confirmed that mass spectrometry-based comparative analysis plays a critical role for the characterization of monoclonal antibody variants, and biosimilar developers should start with a comprehensive structural assessment and comparative analysis to decrease the risk of the process development for biosimilars. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. A single-source precursor route to anisotropic halogen-doped zinc oxide particles as a promising candidate for new transparent conducting oxide materials

    Directory of Open Access Journals (Sweden)

    Daniela Lehr

    2015-11-01

    Full Text Available Numerous applications in optoelectronics require electrically conducting materials with high optical transparency over the entire visible light range. A solid solution of indium oxide and substantial amounts of tin oxide for electronic doping (ITO is currently the most prominent example for the class of so-called TCOs (transparent conducting oxides. Due to the limited, natural occurrence of indium and its steadily increasing price, it is highly desired to identify materials alternatives containing highly abundant chemical elements. The doping of other metal oxides (e.g., zinc oxide, ZnO is a promising approach, but two problems can be identified. Phase separation might occur at the required high concentration of the doping element, and for successful electronic modification it is mandatory that the introduced heteroelement occupies a defined position in the lattice of the host material. In the case of ZnO, most attention has been attributed so far to n-doping via substitution of Zn2+ by other metals (e.g., Al3+. Here, we present first steps towards n-doped ZnO-based TCO materials via substitution in the anion lattice (O2− versus halogenides. A special approach is presented, using novel single-source precursors containing a potential excerpt of the target lattice 'HalZn·Zn3O3' preorganized on the molecular scale (Hal = I, Br, Cl. We report about the synthesis of the precursors, their transformation into halogene-containing ZnO materials, and finally structural, optical and electronic properties are investigated using a combination of techniques including FT-Raman, low-T photoluminescence, impedance and THz spectroscopies.

  3. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling.

    Science.gov (United States)

    Chew, Wee Siong; Wang, Wei; Herr, Deron R

    2016-11-01

    Sphingosine 1-phosphate (S1P) is an extracellular lipid signaling molecule that acts as a selective, high-affinity ligand for a family of five G protein-coupled receptors. This signaling system was first identified twenty years ago, and has since been shown to regulate a diverse range of physiological processes and disease states, such as cardiovascular development, immune function, hypoxic responses, and cancer. The therapeutic potential of targeting this system took center stage when it was demonstrated that the immune modulator, fingolimod (FTY720/Gilenya), exerts it lymphopenic effect by acting on S1P receptors, primarily on S1P receptor 1 (S1P 1 ). In 2010, fingolimod became the first oral medication approved for the treatment of multiple sclerosis (MS). Since then, second-generation S1P receptor modulators have been under development in an effort to provide improved safety and efficacy profiles for MS, and to broaden their use to other autoimmune indications. Beyond the development of S1P 1 -modulators, there has been considerable effort in targeting other components of the S1P signaling pathway for the treatment of other diseases, such as cardiovascular disease, sepsis, and cancer. This manuscript provides an overview of the clinical and preclinical development of drugs targeting S1P signaling. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. BIOPHARMACEUTICAL SUBSTANTIATION OF THE SOLVENT IN THE COMPOSITION OF THE IMMUNOBIOLOGICAL DRUG FOR PREVENTION AND TREATMENT OF CANDIDAL INFECTION

    Directory of Open Access Journals (Sweden)

    Rybalkin М. V

    2014-10-01

    Full Text Available Today diseases caused by potentially pathogenic microorganisms become increasingly important. This phenomenon is connected with increase of power of influence of the environment: chemical pollution, radiation, irrational use of antibiotics and hormone therapy; it leads to decrease of the immune response and human nonspecific resistance. For the last years one of the indicators of failure of the human body immune protection is chronic and local candidiases caused by potentially pathogenic fungi of Candida genus. Prevalence and risk of candidal infections determine the need for searching new medicines with a high efficiency and safety for human. Development of a vaccine for prevention and treatment of candidal infection is being actively conducted in many countries of the world. It should be noted that currently no domestic vaccine is produced in Ukraine and no candidiasis vaccines have been registered. Therefore, development of such vaccine is the topical issue of modern pharmacy and medicine. In our previous studies it was found that the immunobiological drug based on the antigens of fungi of C. albicans with the protein concentration of 3 mg/ml and C. tropicalis with the protein concentration of 5 mg/ml in the ratio of 1:1 possesses the protective and therapeutic effect. At the current stage of research it is necessary to substantiate the solvent in the composition of the immunobiological drug. The aim of this work is the experimental substantiation of the solvent in the composition of the immunobiological drug based on the antigens of C. albicans and C. tropicalis fungi. Materials and Methods. The immunobiological drug with the protein concentration of 4 mg/ml was investigated using various solvents. The following solvents was studied: water for injections, 0.9 % isotonic saline solution, phosphate buffer solution. To determine the protective and therapeutic activity of the immunobiological drug based on the antigens of C. albicans and C

  5. California drug courts: outcomes, costs and promising practices: an overview of Phase II in a statewide study.

    Science.gov (United States)

    Carey, Shannon M; Finigan, Michael; Crumpton, Dave; Waller, Mark

    2006-11-01

    The rapid expansion of drug courts in California and the state's uncertain fiscal climate highlighted the need for definitive cost information on drug court programs. This study focused on creating a research design that can be utilized for statewide and national cost-assessment of drug courts by conducting in-depth case studies of the costs and benefits in nine adult drug courts in California. A Transactional Institutional Costs Analysis (TICA) approach was used, allowing researchers to calculate costs based on every individual's transactions within the drug court or the traditional criminal justice system. This methodology also allows the calculation of costs and benefits by agency (e.g., Public Defender's office, court, District Attorney). Results in the nine sites showed that the majority of agencies save money in processing an offender though drug court. Overall, for these nine study sites, participation in drug court saved the state over 9 million dollars in criminal justice and treatment costs due to lower recidivism in drug court participants. Based on the lessons learned in Phases I and II, Phase III of this study focuses on the creation of a web-based drug court cost self-evaluation tool (DC-CSET) that drug courts can use to determine their own costs and benefits.

  6. Crosslinked hydrogels?a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs

    OpenAIRE

    Sun, Dajun D.; Lee, Ping I.

    2014-01-01

    Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a ...

  7. Identification of new candidate drugs for lung cancer using chemical-chemical interactions, chemical-protein interactions and a K-means clustering algorithm.

    Science.gov (United States)

    Lu, Jing; Chen, Lei; Yin, Jun; Huang, Tao; Bi, Yi; Kong, Xiangyin; Zheng, Mingyue; Cai, Yu-Dong

    2016-01-01

    Lung cancer, characterized by uncontrolled cell growth in the lung tissue, is the leading cause of global cancer deaths. Until now, effective treatment of this disease is limited. Many synthetic compounds have emerged with the advancement of combinatorial chemistry. Identification of effective lung cancer candidate drug compounds among them is a great challenge. Thus, it is necessary to build effective computational methods that can assist us in selecting for potential lung cancer drug compounds. In this study, a computational method was proposed to tackle this problem. The chemical-chemical interactions and chemical-protein interactions were utilized to select candidate drug compounds that have close associations with approved lung cancer drugs and lung cancer-related genes. A permutation test and K-means clustering algorithm were employed to exclude candidate drugs with low possibilities to treat lung cancer. The final analysis suggests that the remaining drug compounds have potential anti-lung cancer activities and most of them have structural dissimilarity with approved drugs for lung cancer.

  8. Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.

    Directory of Open Access Journals (Sweden)

    Els Torreele

    2010-12-01

    , 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max of 500, 14171 and 13651 ng/mL respectively, and an AUC₀₋₂₄ of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats.The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.

  9. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates

    Directory of Open Access Journals (Sweden)

    Katrina eBrudzynski

    2015-07-01

    Full Text Available The emergence of extended- spectrum β-lactamase (ESBL is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1 precursor that harbors three antimicrobial peptides: Jelleins 1, 2 and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised 3 MRSA, 4 Pseudomonas aeruginosa, 2 Klebsiella pneumoniae, 2 VRE and 5 Extended-spectrum beta-lactamase (ESBL identified as 1 Proteus mirabilis, 3 Escherichia coli and 1 Escherichia coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differred in their susceptibility to glps with MIC90 values ranging from 4.8μg/ml against B. subtilis to 14.4μg/ml against ESBL K. pneumoniae, Klebsiella spp ESBL and E. coli and up to 33μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a their mode of action is distinct from other classes of β-lactams and that (b the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate.

  10. Behavior of the magnetocaloric effect in La0.7Ba0.2Ca0.1Mn1-xSnxO3 manganite oxides as promising candidates for magnetic refrigeration

    Science.gov (United States)

    Dhahri, Ja.; Mnefgui, Safa; Ben Hassine, A.; Tahri, Ta.; Oumezzine, M.; Hlil, E. K.

    2018-05-01

    The magnetocaloric effect along with magnetic phase transition in the peroveskite polycrystalline samples La0.7Ba0.2Ca0.1Mn1-xSnxO3 (x = 0 and 0.1) was investigated. The samples were synthesized using conventional solid state reaction at 1400 °C temperature. Magnetization vs. temperature measurements, under a magnetic field of μ0H = 0.05 T, showed a paramagnetic-ferromagnetic transition at Curie temperature, TC, which decreases from 310 K for x = 0-290 K for x = 0.1. A large magnetic entropy change | ΔSM | deduced from isothermal magnetization curves, has been observed in our samples with a peak centered on their respective TC. Interesting values of the relative cooling power (RCP), 237 J kg-1 for x = 0 and 248 J kg-1 x = 0.1, make these samples promising candidates for magnetic refrigeration around room temperature.

  11. Carnauba wax as a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of highly soluble drugs.

    Science.gov (United States)

    Nart, Viviane; Beringhs, André O'Reilly; França, Maria Terezinha; de Espíndola, Brenda; Pezzini, Bianca Ramos; Stulzer, Hellen Karine

    2017-01-01

    Mini-tablets are a new tendency in solid dosage form design for overcoming therapeutic obstacles such as impaired swallowing and polypharmacy therapy. Among their advantages, these systems offer therapeutic benefits such as dose flexibility and combined drug release patterns. The use of lipids in the formulation has also drawn considerable interest as means to modify the drug release from the dosage form. Therefore, this paper aimed at developing sustained release mini-tablets containing the highly soluble drugs captopril and metformin hydrochloride. Carnauba wax was used as a lipid component in melt granulation, targeting the improvement of the drugs poor flowability and tabletability, as well as to sustain the drug release profiles in association with other excipients. To assist sustaining the drug release, Ethocel™ (EC) and Kollicoat® SR 30D associated with Opadry® II were employed as matrix-forming and reservoir-forming materials, respectively. The neat drugs, granules and the bulk formulations were evaluated for their angle of repose, compressibility index, Hausner ratio and tabletability. Mini-tablets were evaluated for their weight variation, hardness, friability, drug content and in-vitro drug release. The results indicated that melt granulation with carnauba wax improved the flow and the tabletability of the drugs, allowing the preparation of mini-tablets with adequate tensile strength under reduced compaction pressures. All mini-tablet formulations showed acceptable hardness (within the range of 1.16 to 3.93Kp) and friability (carnauba wax proved to be a promising excipient in melt granulation targeting the preparation of mini-tablets for sustained release of soluble drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Open-source approaches for the repurposing of existing or failed candidate drugs: learning from and applying the lessons across diseases.

    Science.gov (United States)

    Allarakhia, Minna

    2013-01-01

    Repurposing has the objective of targeting existing drugs and failed, abandoned, or yet-to-be-pursued clinical candidates to new disease areas. The open-source model permits for the sharing of data, resources, compounds, clinical molecules, small libraries, and screening platforms to cost-effectively advance old drugs and/or candidates into clinical re-development. Clearly, at the core of drug-repurposing activities is collaboration, in many cases progressing beyond the open sharing of resources, technology, and intellectual property, to the sharing of facilities and joint program development to foster drug-repurposing human-capacity development. A variety of initiatives under way for drug repurposing, including those targeting rare and neglected diseases, are discussed in this review and provide insight into the stakeholders engaged in drug-repurposing discovery, the models of collaboration used, the intellectual property-management policies crafted, and human capacity developed. In the case of neglected tropical diseases, it is suggested that the development of human capital be a central aspect of drug-repurposing programs. Open-source models can support human-capital development through collaborative data generation, open compound access, open and collaborative screening, preclinical and possibly clinical studies. Given the urgency of drug development for neglected tropical diseases, the review suggests elements from current repurposing programs be extended to the neglected tropical diseases arena.

  13. Comparative genomics study for the identification of drug and vaccine targets in Staphylococcus aureus: MurA ligase enzyme as a proposed candidate.

    Science.gov (United States)

    Ghosh, Soma; Prava, Jyoti; Samal, Himanshu Bhusan; Suar, Mrutyunjay; Mahapatra, Rajani Kanta

    2014-06-01

    Now-a-days increasing emergence of antibiotic-resistant pathogenic microorganisms is one of the biggest challenges for management of disease. In the present study comparative genomics, metabolic pathways analysis and additional parameters were defined for the identification of 94 non-homologous essential proteins in Staphylococcus aureus genome. Further study prioritized 19 proteins as vaccine candidates where as druggability study reports 34 proteins suitable as drug targets. Enzymes from peptidoglycan biosynthesis, folate biosynthesis were identified as candidates for drug development. Furthermore, bacterial secretory proteins and few hypothetical proteins identified in our analysis fulfill the criteria of vaccine candidates. As a case study, we built a homology model of one of the potential drug target, MurA ligase, using MODELLER (9v12) software. The model has been further selected for in silico docking study with inhibitors from the DrugBank database. Results from this study could facilitate selection of proteins for entry into drug design and vaccine production pipelines. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Pulmonary Arterial Hypertension in Adults: Novel Drugs and Catheter Ablation Techniques Show Promise? Systematic Review on Pharmacotherapy and Interventional Strategies

    Directory of Open Access Journals (Sweden)

    Salvatore Rosanio

    2014-01-01

    Full Text Available This systematic review aims to provide an update on pharmacological and interventional strategies for the treatment of pulmonary arterial hypertension in adults. Currently US Food and Drug Administration approved drugs including prostanoids, endothelin-receptor antagonists, phosphodiesterase type-5 inhibitors, and soluble guanylate-cyclase stimulators. These agents have transformed the prognosis for pulmonary arterial hypertension patients from symptomatic improvements in exercise tolerance ten years ago to delayed disease progression today. On the other hand, percutaneous balloon atrioseptostomy by using radiofrequency perforation, cutting balloon dilatation, or insertion of butterfly stents and pulmonary artery catheter-based denervation, both associated with very low rate of major complications and death, should be considered in combination with specific drugs at an earlier stage rather than late in the progression of pulmonary arterial hypertension and before the occurrence of overt right-sided heart failure.

  15. A nanomedicine-promising approach to provide an appropriate colon-targeted drug delivery system for 5-fluorouracil

    Directory of Open Access Journals (Sweden)

    Singh S

    2015-11-01

    Full Text Available Sima Singh,1,* Niranjan G Kotla,2,* Sonia Tomar,3 Balaji Maddiboyina,4 Thomas J Webster,5,6 Dinesh Sharma,7 Omprakash Sunnapu2 1Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 2Technologies for the Advancement of Science, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, 3Department of Pharmaceutics, Ram Gopal College of Pharmacy, Rohtak, Haryana, 4Department of Pharmaceutics, Maharishi Markandeshwar University, Mullana, Ambala, Haryana, India; 5Department of Chemical Engineering, Northeastern University, Boston, MA, USA; 6Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah, Saudi Arabia; 7Ranbaxy Laboratory Ltd, Gurgaon, Haryana, India *These authors contributed equally to this work Abstract: Targeted drug delivery plays a significant role in disease treatment associated with the colon, affording therapeutic responses for a prolonged period of time with low side effects. Colorectal cancer is the third most common cancer in both men and women with an estimated 102,480 cases of colon cancer and 40,340 cases of rectal cancer in 2013 as reported by the American Cancer Society. In the present investigation, we developed an improved oral delivery system for existing anticancer drugs meant for colon cancer via prebiotic and probiotic approaches. The system comprises three components, namely, nanoparticles of drug coated with natural materials such as guar gum, xanthan gum (that serve as prebiotics, and probiotics. The natural gums play a dual role of protecting the drug in the gastric as well as intestinal conditions to allow its release only in the colon. In vitro results obtained from these experiments indicated the successful targeted delivery of 5-fluorouracil to the colon. Electron microscopy results demonstrated that the prepared nanoparticles were spherical in shape and 200 nm in size. The in vitro release data

  16. 1-[2-(2-Methoxyphenylaminoethylamino]-3-(naphthalene-1- yloxypropan-2-ol May Be a Promising Anticancer Drug

    Directory of Open Access Journals (Sweden)

    Tomoyuki Nishizaki

    2014-12-01

    Full Text Available We have originally synthesized the naftopidil analogue 1-[2-(2-methoxyphenylaminoethylamino]-3-(naphthalene-1-yloxypropan-2-ol (HUHS 1015 as a new anticancer drug. HUHS1015 induces cell death in a wide variety of human cancer cell lines originated from malignant pleural mesothelioma, lung cancer, hepatoma, gastric cancer, colorectal cancer, bladder cancer, prostate cancer, and renal cancer. HUHS1015-induced cell death includes necrosis (necroptosis and apoptosis, and the underlying mechanism differs depending upon cancer cell types. HUHS1015 effectively suppresses tumor growth in mice inoculated with NCI-H2052, MKN45, or CW2 cells, with a potential similar to or higher than that of currently used anticancer drugs. Here we show how HUHS1015 might offer brilliant hope for cancer therapy.

  17. Promise and peril: Dissemination of findings from studies of drugs used in pregnancy and their association with birth defects.

    Science.gov (United States)

    Patrick, Stephen W; Cooper, William O

    2015-08-01

    When and how to publish birth defects research can be complex, especially in the context of drugs used in pregnancy. Such research frequently involves multiple stakeholders, including regulatory agencies. Researchers must balance the potential peril of an unnecessarily panicked populace versus the benefit of protecting the public's health. We use a case presentation and contemporary literature to highlight the potential tradeoffs that researchers must consider. We highlight important considerations including the public health impact, examining the likelihood of causality, understanding common considerations when using large data sources, the role of peer review and working in partnership with regulatory agencies. We suggest that plans for analyses, dissemination and risk communication are done best a priori and not post hoc. Rigorous research evaluating the impact of drugs used in pregnancy, coupled with effective dissemination strategies, has the potential improve outcomes for mothers and their infants for generations. © 2015 Wiley Periodicals, Inc.

  18. Current-day precision oncology: from cancer prevention, screening, drug development, and treatment - have we fallen short of the promise?

    Science.gov (United States)

    Morgan, Gilberto; Aftimos, Philippe; Awada, Ahmad

    2016-09-01

    Precision oncology has been a strategy of prevention, screening, and treatment. Although much has been invested, have the results fallen so far short of the promise? The advancement of technology and research has opened new doors, yet a variety of pitfalls are present. This review presents the successes, failures, and opportunities of precision oncology in the current landscape. The use of targeted gene sequencing and the overwhelming results of superresponders have generated much excitement and support for precision oncology from the medical community. Despite notable successes, many challenges still pave the way of precision oncology: intratumoral heterogeneity, the need for serial biopsies, availability of treatments, target prioritization, ethical issues with germline incidental findings, medical education, clinical trial design, and costs. Precision oncology shows much potential through the use of next-generation sequencing and molecular advances, but does this potential warrant the investment? There are many obstacles on the way of this technology that should make us question if the investment (both monetary and man-hours) will live up to the promise. The review aims to not criticize this technology, but to give a realistic view of where we are, especially regarding cancer treatment and prevention.

  19. The role of natural selection in shaping genetic variation in a promising Chagas disease drug target: Trypanosoma cruzi trans-sialidase.

    Science.gov (United States)

    Gallant, Joseph P; Lima-Cordón, Raquel Asunción; Justi, Silvia A; Monroy, Maria Carlota; Viola, Toni; Stevens, Lori

    2018-04-21

    Rational drug design creates innovative therapeutics based on knowledge of the biological target to provide more effective and responsible therapeutics. Chagas disease, endemic throughout Latin America, is caused by Trypanosoma cruzi, a protozoan parasite. Current therapeutics are problematic with widespread calls for new approaches. Researchers are using rational drug design for Chagas disease and one target receiving considerable attention is the T. cruzi trans-sialidase protein (TcTS). In T. cruzi, trans-sialidase catalyzes the transfer of sialic acid from a mammalian host to coat the parasite surface membrane and avoid immuno-detection. However, the role of TcTS in pathology variance among and within genetic variants of the parasite is not well understood despite numerous studies. Previous studies reported the crystalline structure of TcTS and the TS protein structure in other trypanosomes where the enzyme is often inactive. However, no study has examined the role of natural selection in genetic variation in TcTS. To understand the role of natural selection in TcTS DNA sequence and protein variation, we examined a 471 bp portion of the TcTS gene from 48 T. cruzi samples isolated from insect vectors. Because there may be multiple parasite genotypes infecting one insect and there are multiple copies of TcTS per parasite genome, all 48 sequences had multiple polymorphic bases. To resolve these polymorphisms, we examined cloned sequences from two insect vectors. The data are analyzed to understand the role of natural selection in shaping genetic variation in TcTS and interpreted in light of the possible role of TcTS as a drug target. The analysis highlights negative or purifying selection on three amino acids previously shown to be important in TcTS transfer activity. One amino acid in particular, Tyr342, is a strong candidate for a drug target because it is under negative selection and amino acid substitutions inactivate TcTS transfer activity. Chagas disease

  20. Activated Charge-Reversal Polymeric Nano-System: The Promising Strategy in Drug Delivery for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Yichen Hu

    2016-04-01

    Full Text Available Various polymeric nanoparticles (NPs with optimal size, tumor-targeting functionalization, or microenvironment sensitive characteristics have been designed to solve several limitations of conventional chemotherapy. Nano-sized polymeric drug carrier systems have remarkably great advantages in drug delivery and cancer therapy, which are still plagued with severe deficiencies, especially insufficient cellular uptake. Recently, surface charge of medical NPs has been demonstrated to play an important role in cellular uptake. NPs with positive charge show higher affinity to anionic cell membranes such that with more efficient cellular internalization, but otherwise cause severe aggregation and fast clearance in circulation. Thus, surface charge-reversal NPs, specifically activated at the tumor site, have shown to elegantly resolve the enhanced cellular uptake in cancer cells vs. non-specific protein adsorption dilemma. Herein, this review mainly focuses on the effect of tumor-site activated surface charge reversal NPs on tumor treatment, including the activated mechanisms and various applications in suppressing cancer cells, killing cancer stem cell and overcoming multidrug resistance, with the emphasis on recent research in these fields. With the comprehensive and in-depth understanding of the activated surface charge reversal NPs, this approach might arouse great interest of scientific research on enhanced efficient polymeric nano-carriers in cancer therapy.

  1. Fuzzy promises

    DEFF Research Database (Denmark)

    Anker, Thomas Boysen; Kappel, Klemens; Eadie, Douglas

    2012-01-01

    as narrative material to communicate self-identity. Finally, (c) we propose that brands deliver fuzzy experiential promises through effectively motivating consumers to adopt and play a social role implicitly suggested and facilitated by the brand. A promise is an inherently ethical concept and the article...... concludes with an in-depth discussion of fuzzy brand promises as two-way ethical commitments that put requirements on both brands and consumers....

  2. Differential representation of liver proteins in obese human subjects suggests novel biomarkers and promising targets for drug development in obesity.

    Science.gov (United States)

    Caira, Simonetta; Iannelli, Antonio; Sciarrillo, Rosaria; Picariello, Gianluca; Renzone, Giovanni; Scaloni, Andrea; Addeo, Pietro

    2017-12-01

    The proteome of liver biopsies from human obese (O) subjects has been compared to those of nonobese (NO) subjects using two-dimensional gel electrophoresis (2-DE). Differentially represented proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)-based peptide mass fingerprinting (PMF) and nanoflow-liquid chromatography coupled to electrospray-tandem mass spectrometry (nLC-ESI-MS/MS). Overall, 61 gene products common to all of the liver biopsies were identified within 65 spots, among which 25 ones were differently represented between O and NO subjects. In particular, over-representation of short-chain acyl-CoA dehydrogenase, Δ(3,5)-Δ(2,4)dienoyl-CoA isomerase, acetyl-CoA acetyltransferase, glyoxylate reductase/hydroxypyruvate reductase, fructose-biphosphate aldolase B, peroxiredoxin I, protein DJ-1, catalase, α- and β-hemoglobin subunits, 3-mercaptopyruvate S-transferase, calreticulin, aminoacylase 1, phenazine biosynthesis-like domain-containing protein and a form of fatty acid-binding protein, together with downrepresentation of glutamate dehydrogenase, glutathione S-transferase A1, S-adenosylmethionine synthase 1A and a form of apolipoprotein A-I, was associated with the obesity condition. Some of these metabolic enzymes and antioxidant proteins have already been identified as putative diagnostic markers of liver dysfunction in animal models of steatosis or obesity, suggesting additional investigations on their role in these syndromes. Their differential representation in human liver was suggestive of their consideration as obesity human biomarkers and for the development of novel antiobesity drugs.

  3. Mutagenic potential of Cordia ecalyculata alone and in association with Spirulina maxima for their evaluation as candidate anti-obesity drugs.

    Science.gov (United States)

    Araldi, R P; Rechiutti, B M; Mendes, T B; Ito, E T; Souza, E B

    2014-07-07

    Obesity is one of the most important nutritional disorders, and can be currently considered as an epidemic. Although there are few weight reduction drugs available on the market, some new drug candidates have been proposed, including Cordia ecalyculata, a Brazilian plant with anorectic properties, and Spirulina maxima, a cyanobacterium with antioxidant and anti-genotoxic activity. In this study, we evaluated the mutagenic potential of C. ecalyculata at doses of 150, 300, and 500 mg/kg alone and in association with S. maxima at doses of 75, 150, and 250 mg/kg, respectively, through an in vivo micronucleus test, using mice of both sexes, and an in vitro micronucleus test and comet assay, using human peripheral blood. For all tests, cyclophosphamide was used as a positive control. The results showed that treatment of 300 mg/kg C. ecalyculata and the combination treatment of 500 mg/kg C. ecalyculata with 250 mg/kg S. maxima resulted in anorectic effects. The mutagenic tests did not reveal any clastogenic or genotoxic activity for any treatment, indicating that these candidates could be marketed as weight-reduction drugs. Moreover, the drugs contain chemo-preventive substances that can protect against tumorigenesis, which has been associated with obesity.

  4. Promising Diabetes Therapy Based on the Molecular Mechanism for Glucose Toxicity: Usefulness of SGLT2 Inhibitors as well as Incretin-Related Drugs.

    Science.gov (United States)

    Kaneto, Hideaki; Obata, Atsushi; Shimoda, Masashi; Kimura, Tomohiko; Hirukawa, Hidenori; Okauchi, Seizo; Matsuoka, Taka-Aki; Kaku, Kohei

    2016-01-01

    Pancreatic β-cell dysfunction and insulin resistance are the main characteristics of type 2 diabetes. Chronic exposure of β-cells to hyperglycemia leads to the deterioration of β-cell function. Such phenomena are well known as pancreatic β-cell glucose toxicity. MafA, a strong transactivator of insulin gene, is particularly important for the maintenance of mature β-cell function, but its expression level is significantly reduced under diabetic conditions which is likely associated with β-cell failure. Reduction of incretin receptor expression level in β-cells in diabetes is also likely associated with β-cell failure. On the other hand, incretin-related drugs and sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising diabetes therapy based on the mechanism for pancreatic β-cell glucose toxicity. Indeed, it was shown that incretin-related drugs exerted protective effects on β-cells through the augmentation of IRS-2 expression especially in the presence of pioglitazone. It was also shown that incretin-related drug and/or pioglitazone exerted more protective effects on β-cells at the early stage of diabetes compared to the advanced stage. SGLT2 inhibitors, new hypoglycemic agents, also exert beneficial effects for the protection of pancreatic β-cells as well as for the reduction of insulin resistance in various insulin target tissues. Taken together, it is important to select appropriate therapy based on the molecular mechanism for glucose toxicity.

  5. Recent advances in candidate-gene and whole-genome approaches to the discovery of anthelmintic resistance markers and the description of drug/receptor interactions

    Directory of Open Access Journals (Sweden)

    Andrew C. Kotze

    2014-12-01

    Full Text Available Anthelmintic resistance has a great impact on livestock production systems worldwide, is an emerging concern in companion animal medicine, and represents a threat to our ongoing ability to control human soil-transmitted helminths. The Consortium for Anthelmintic Resistance and Susceptibility (CARS provides a forum for scientists to meet and discuss the latest developments in the search for molecular markers of anthelmintic resistance. Such markers are important for detecting drug resistant worm populations, and indicating the likely impact of the resistance on drug efficacy. The molecular basis of resistance is also important for understanding how anthelmintics work, and how drug resistant populations arise. Changes to target receptors, drug efflux and other biological processes can be involved. This paper reports on the CARS group meeting held in August 2013 in Perth, Australia. The latest knowledge on the development of molecular markers for resistance to each of the principal classes of anthelmintics is reviewed. The molecular basis of resistance is best understood for the benzimidazole group of compounds, and we examine recent work to translate this knowledge into useful diagnostics for field use. We examine recent candidate-gene and whole-genome approaches to understanding anthelmintic resistance and identify markers. We also look at drug transporters in terms of providing both useful markers for resistance, as well as opportunities to overcome resistance through the targeting of the transporters themselves with inhibitors. Finally, we describe the tools available for the application of the newest high-throughput sequencing technologies to the study of anthelmintic resistance.

  6. Bile salts-containing vesicles: promising pharmaceutical carriers for oral delivery of poorly water-soluble drugs and peptide/protein-based therapeutics or vaccines.

    Science.gov (United States)

    Aburahma, Mona Hassan

    2016-07-01

    Most of the new drugs, biological therapeutics (proteins/peptides) and vaccines have poor performance after oral administration due to poor solubility or degradation in the gastrointestinal tract (GIT). Though, vesicular carriers exemplified by liposomes or niosomes can protect the entrapped agent to a certain extent from degradation. Nevertheless, the harsh GIT environment exemplified by low pH, presence of bile salts and enzymes limits their capabilities by destabilizing them. In response to that, more resistant bile salts-containing vesicles (BS-vesicles) were developed by inclusion of bile salts into lipid bilayers constructs. The effectiveness of orally administrated BS-vesicles in improving the performance of vesicles has been demonstrated in researches. Yet, these attempts did not gain considerable attention. This is the first review that provides a comprehensive overview of utilizing BS-vesicles as a promising pharmaceutical carrier with a special focus on their successful applications in oral delivery of therapeutic macromolecules and vaccines. Insights on the possible mechanisms by which BS-vesicles improve the oral bioavailability of the encapsulated drug or immunological response of entrapped vaccine are explained. In addition, methods adopted to prepare and characterize BS-vesicles are described. Finally, the gap in the scientific researches tackling BS-vesicles that needs to be addressed is highlighted.

  7. Molecular interaction study of commercial cyclic peptides and MERS-COV papain-like protease as novel drug candidate for MERS-COV

    Science.gov (United States)

    Nasution, M. A. F.; Azzuhdi, M. G.; Tambunan, U. S. F.

    2017-07-01

    Middle-east respiratory syndrome coronavirus (MERS-CoV) has become the current outbreak, MERS-CoV infection results in illness at the respiratory system, digestive, and even lead to death with an average mortality caused by MERS-CoV infection reaches 50 %. Until now, there is not any effective vaccine or drug to ward off MERS-CoV infection. Papain-like protease (PLpro) is responsible for cleavage of a nonstructural protein that is essential for viral maturation. Inhibition of PLpro with a ligand will block the cleavage process of nonstructural protein, thus reduce the infection of MERS-CoV. Through of bioinformatics study with molecular docking and binding interaction analysis of commercial cyclic peptides, aldosterone secretion inhibiting factor (1-35) (bovine) was obtained as an inhibitor for PLpro. Thus, aldosterone secretion inhibiting factor (1-35) (bovine) has a potential as a novel candidate drug for treating MERS-CoV.

  8. Assessment of chimeric mice with humanized livers in new drug development: generation of pharmacokinetics, metabolism and toxicity data for selecting the final candidate compound.

    Science.gov (United States)

    Kamimura, Hidetaka; Ito, Satoshi

    2016-01-01

    1. Chimeric mice with humanized livers are expected to be a novel tool for new drug development. This review discusses four applications where these animals can be used efficiently to collect supportive data for selecting the best compound in the final stage of drug discovery. 2. The first application is selection of the final compound based on estimated pharmacokinetic parameters in humans. Since chimeric mouse livers are highly repopulated with human hepatocytes, hepatic clearance values in vivo could be used preferentially to estimate pharmacokinetic profiles for humans. 3. The second is prediction of human-specific or disproportionate metabolites. Chimeric mice reproduce human-specific metabolites of drugs under development to conform to ICH guidance M3(R2), except for compounds that were extensively eliminated by co-existing mouse hepatocytes. 4. The third is identifying metabolites with distinct pharmacokinetic profiles in humans. Slow metabolite elimination specifically in humans increases its exposure level, but if its elimination is faster in laboratory animals, the animal exposure level might not satisfy ICH guidance M3(R2). 5. Finally, two examples of reproducing acute liver toxicity in chimeric mice are introduced. Integrated pharmacokinetics, metabolism and toxicity information are expected to assist pharmaceutical scientists in selecting the best candidate compound in new drug development.

  9. User evaluations offer promise for pod-intravaginal ring as a drug delivery platform: A mixed methods study of acceptability and use experiences.

    Science.gov (United States)

    Guthrie, Kate M; Rosen, Rochelle K; Vargas, Sara E; Getz, Melissa L; Dawson, Lauren; Guillen, Melissa; Ramirez, Jaime J; Baum, Marc M; Vincent, Kathleen L

    2018-01-01

    evaluations elicited by them, could both challenge use or be used to leverage use in future trials and product rollout once fully articulated. High willingness-to-use data and lack of salient differences in user experiences related to use of the pod-IVR platform (regardless of agents delivered) suggests that the pod-IVR is a feasible and acceptable drug delivery device in and of itself. This finding holds promise both for an anti-HIV pod-IVR and, potentially, a multipurpose prevention pod-IVR that could deliver both prevention for sexually transmitted infections (STIs) including HIV and contraception. Given the very early clinical trial context, further acceptability, perceptibility, and adherence data should continue to be explored, in the context of longer use periods (e.g., 28-day ring use), and in the contexts of sexual activity and menses. Using early design and development contexts to gain insights into potential challenges and facilitators of drug delivery systems such as the pod-IVR could save valuable resources and time as a potential biomedical technology moves through the clinical trial pipeline and into real-world use.

  10. The promising anticancer drug 3-bromopyruvate is metabolized through glutathione conjugation which affects chemoresistance and clinical practice: An evidence-based view.

    Science.gov (United States)

    El Sayed, Salah Mohamed; Baghdadi, Hussam; Zolaly, Mohammed; Almaramhy, Hamdi H; Ayat, Mongi; Donki, Jagadish G

    2017-03-01

    3-Bromopyruvate (3BP) is a promising effective anticancer drug against many different tumors in children and adults. 3BP exhibited strong anticancer effects in both preclinical and human studies e.g. energy depletion, oxidative stress, anti-angiogenesis, anti-metastatic effects, targeting cancer stem cells and antagonizing the Warburg effect. There is no report about 3BP metabolism to guide researchers and oncologists to improve clinical practice and prevent drug resistance. In this article, we provide evidences that 3BP is metabolized through glutathione (GSH) conjugation as a novel report where 3BP was confirmed to be attached to GSH followed by permanent loss of pharmacological effects in a picture similar to cisplatin. Both cisplatin and 3BP are alkylating agents. Reported decrease in endogenous cellular GSH content upon 3BP treatment was confirmed to be due to the formation of 3BP-GSH complex i.e. GSH consumption for conjugation with 3BP. Cancer cells having high endogenous GSH exhibit resistance to 3BP while 3BP sensitive cells acquire resistance upon adding exogenous GSH. Being a thiol blocker, 3BP may attack thiol groups in tissues and serum proteins e.g. albumin and GSH. That may decrease 3BP-induced anticancer effects and the functions of those proteins. We proved here that 3BP metabolism is different from metabolism of hydroxypyruvate that results from metabolism of D-serine using D-amino acid oxidase. Clinically, 3BP administration should be monitored during albumin infusion and protein therapy where GSH should be added to emergency medications. GSH exerts many physiological effects and is safe for human administration both orally and intravenously. Based on that, reported GSH-induced inhibition of 3BP effects makes 3BP effects reversible, easily monitored and easily controlled. This confers a superiority of 3BP over many anticancer agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Model based on GRID-derived descriptors for estimating CYP3A4 enzyme stability of potential drug candidates

    Science.gov (United States)

    Crivori, Patrizia; Zamora, Ismael; Speed, Bill; Orrenius, Christian; Poggesi, Italo

    2004-03-01

    A number of computational approaches are being proposed for an early optimization of ADME (absorption, distribution, metabolism and excretion) properties to increase the success rate in drug discovery. The present study describes the development of an in silico model able to estimate, from the three-dimensional structure of a molecule, the stability of a compound with respect to the human cytochrome P450 (CYP) 3A4 enzyme activity. Stability data were obtained by measuring the amount of unchanged compound remaining after a standardized incubation with human cDNA-expressed CYP3A4. The computational method transforms the three-dimensional molecular interaction fields (MIFs) generated from the molecular structure into descriptors (VolSurf and Almond procedures). The descriptors were correlated to the experimental metabolic stability classes by a partial least squares discriminant procedure. The model was trained using a set of 1800 compounds from the Pharmacia collection and was validated using two test sets: the first one including 825 compounds from the Pharmacia collection and the second one consisting of 20 known drugs. This model correctly predicted 75% of the first and 85% of the second test set and showed a precision above 86% to correctly select metabolically stable compounds. The model appears a valuable tool in the design of virtual libraries to bias the selection toward more stable compounds. Abbreviations: ADME - absorption, distribution, metabolism and excretion; CYP - cytochrome P450; MIFs - molecular interaction fields; HTS - high throughput screening; DDI - drug-drug interactions; 3D - three-dimensional; PCA - principal components analysis; CPCA - consensus principal components analysis; PLS - partial least squares; PLSD - partial least squares discriminant; GRIND - grid independent descriptors; GRID - software originally created and developed by Professor Peter Goodford.

  12. A microscale synthesis of a promising radiolabelled antitumor drug: cis-1,1-cyclobutanedicarboxylato (2R)-2-methyl-1,4-butanediamine platinum(II), NK121

    International Nuclear Information System (INIS)

    Suwa, Masato; Kogawa, Osamu; Hashimoto, Yutaka

    1992-01-01

    A promising antitumor drug, cis-1,1-cyclobutane-dicarboxylato (2R)-2-methyl-1,4-butanediamine platinum (II), NK121, was synthesized from radionuclides of platinum such as 193m Pt, 195m Pt and 191 Pt which were produced by neutron irradiation of enriched 192 Pt. The overall yield was 38.6% in a synthesis time of 10 hours. The radioactivities present in 8.39 mg of NK121 were 115.3 μCi as 193m Pt, 29.9 μCi as 197 Pt, 22.0 μCi as 195m Pt, and 4.8 μCi as 191 Pt at the end of synthesis. The specific activity of the NK121 was 13.7 μCi ( 193m Pt)/mg NK121 at the end of synthesis. The radiochemical purity of NK121 was typically 99%. HPLC analyses confirmed that NK121 was in an adequate chemical purity and suitable for animal experimentation. (author)

  13. A microscale synthesis of a promising radiolabelled antitumor drug: cis-1,1-cyclobutanedicarboxylato (2R)-2-methyl-1,4-butanediamine platinum(II), NK121

    Energy Technology Data Exchange (ETDEWEB)

    Suwa, Masato; Kogawa, Osamu; Hashimoto, Yutaka (Nippon Kayaku Co. Ltd., Tokyo (Japan). Research Labs. of Pharmaceuticals Group); Nowatari, Hiroyoshi (Nippon Kayaku Co. Ltd., Takasaki, Gumma (Japan). Takasaki Research Labs.); Murase, Yuko; Homma, Yoshio (Kyoritsu Coll. of Pharmacy, Tokyo (Japan))

    1992-05-01

    A promising antitumor drug, cis-1,1-cyclobutane-dicarboxylato (2R)-2-methyl-1,4-butanediamine platinum (II), NK121, was synthesized from radionuclides of platinum such as {sup 193m}Pt, {sup 195m}Pt and {sup 191}Pt which were produced by neutron irradiation of enriched {sup 192}Pt. The overall yield was 38.6% in a synthesis time of 10 hours. The radioactivities present in 8.39 mg of NK121 were 115.3 {mu}Ci as {sup 193m}Pt, 29.9 {mu}Ci as {sup 197}Pt, 22.0 {mu}Ci as {sup 195m}Pt, and 4.8 {mu}Ci as {sup 191}Pt at the end of synthesis. The specific activity of the NK121 was 13.7 {mu}Ci ({sup 193m}Pt)/mg NK121 at the end of synthesis. The radiochemical purity of NK121 was typically 99%. HPLC analyses confirmed that NK121 was in an adequate chemical purity and suitable for animal experimentation. (author).

  14. Differences in morphometrics and reproductive physiology between two populations of Trissolcus japonicus, a promising biological control agent candidate for brown marmorated stink bug (Halyomorpha halys Stal) in the US

    Science.gov (United States)

    Trissolcus japonicus (Ashmead), a solitary egg parasitoid of Pentatomidae native to Southeast Asia, has been undergoing host-range testing in U.S. quarantine facilities since 2009 as a candidate for the biological control of brown marmorated stink bug (Halyomorpha halys Stål)(BMSB), an invasive agri...

  15. Cebranopadol, a novel first-in-class analgesic drug candidate: first experience in patients with chronic low back pain in a randomized clinical trial.

    Science.gov (United States)

    Christoph, Annette; Eerdekens, Marie-Henriette; Kok, Maurits; Volkers, Gisela; Freynhagen, Rainer

    2017-09-01

    Chronic low back pain (LBP) is a common condition, usually with the involvement of nociceptive and neuropathic pain components, high economic burden and impact on quality of life. Cebranopadol is a potent, first-in-class drug candidate with a novel mechanistic approach, combining nociceptin/orphanin FQ peptide and opioid peptide receptor agonism. We conducted the first phase II, randomized, double-blind, placebo- and active-controlled trial, evaluating the analgesic efficacy, safety, and tolerability of cebranopadol in patients with moderate-to-severe chronic LBP with and without neuropathic pain component. Patients were treated for 14 weeks with cebranopadol 200, 400, or 600 μg once daily, tapentadol 200 mg twice daily, or placebo. The primary efficacy endpoints were the change from baseline pain to the weekly average 24-hour pain during the entire 12 weeks and during week 12 of the maintenance phase. Cebranopadol demonstrated analgesic efficacy, with statistically significant and clinically relevant improvements over placebo for all doses as did tapentadol. The responder analysis (≥30% or ≥50% pain reduction) confirmed these results. Cebranopadol and tapentadol displayed beneficial effects on sleep and functionality. Cebranopadol treatment was safe, with higher doses leading to higher treatment discontinuations because of treatment-emergent adverse events occurring mostly during titration. Those patients reaching the target doses had an acceptable tolerability profile. The incidence rate of most frequently reported treatment-emergent adverse events during maintenance phase was ≤10%. Although further optimizing the titration scheme to the optimal dose for individual patients is essential, cebranopadol is a new drug candidate with a novel mechanistic approach for potential chronic LBP treatment.

  16. Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation.

    Science.gov (United States)

    Lindholm, Pauliina; Lamusuo, Salla; Taiminen, Tero; Pesonen, Ullamari; Lahti, Ari; Virtanen, Arja; Forssell, Heli; Hietala, Jarmo; Hagelberg, Nora; Pertovaara, Antti; Parkkola, Riitta; Jääskeläinen, Satu

    2015-07-01

    High-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has analgesic effect; however, the efficacy of other cortical targets and the mode of action remain unclear. We examined the effects of rTMS in neuropathic orofacial pain, and compared 2 cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, we assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyltransferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized, placebo-controlled, crossover study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood, and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (P = 0.0071) or the sham (P = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than those at pretreatment baseline (P = 0.0127 for the intensity of pain and P = 0.0074 for the interference of pain) or after the S1/M1 (P = 0.001 and P = 0.0001) and sham (P = 0.0491 and P = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS.

  17. Styrene-maleic acid-copolymer conjugated zinc protoporphyrin as a candidate drug for tumor-targeted therapy and imaging.

    Science.gov (United States)

    Fang, Jun; Tsukigawa, Kenji; Liao, Long; Yin, Hongzhuan; Eguchi, Kanami; Maeda, Hiroshi

    2016-01-01

    Previous studies indicated the potential of zinc protoporphyrin (ZnPP) as an antitumor agent targeting to the tumor survival factor heme oxygenase-1, and/or for photodynamic therapy (PDT). In this study, to achieve tumor-targeted delivery, styrene-maleic acid-copolymer conjugated ZnPP (SMA-ZnPP) was synthesized via amide bond, which showed good water solubility, having ZnPP loading of 15%. More importantly, it forms micelles in aqueous solution with a mean particle size of 111.6 nm, whereas it has an apparent Mw of 65 kDa. This micelle formation was not detracted by serum albumin, suggesting it is stable in circulation. Further SMA-ZnPP conjugate will behave as an albumin complex in blood with much larger size (235 kDa) by virtue of the albumin binding property of SMA. Consequently, SMA-ZnPP conjugate exhibited prolonged circulating retention and preferential tumor accumulation by taking advantage of enhanced permeability and retention (EPR) effect. Clear tumor imaging was thus achieved by detecting the fluorescence of ZnPP. In addition, the cytotoxicity and PDT effect of SMA-ZnPP conjugate was confirmed in human cervical cancer HeLa cells. Light irradiation remarkably increased the cytotoxicity (IC50, from 33 to 5 μM). These findings may provide new options and knowledge for developing ZnPP based anticancer theranostic drugs.

  18. Drug-induced hypotension SEP test and acetazolamide test using sup 133 Xe SPECT in patients with occlusive carotid disease; Selection of candidates for extracranial-intracranial bypass

    Energy Technology Data Exchange (ETDEWEB)

    Kuroda, Satoshi; Kamiyama, Hiroyasu; Abe, Hiroshi; Takigawa, Shugo [Hokkaido Univ., Sapporo (Japan). School of Medicine; Mitsumori, Kenji; Nomura, Mikio; Saitoh, Hisatoshi

    1991-01-01

    The correlation between the drug-induced hypotension somatosensory evoked potential (SEP) test and regional cerebral blood flow changes after acetazolamide administration was studied. Fourteen patients presenting with transient ischemic attack, reversible ischemic neurological deficits, or minor completed stroke were evaluated. All patients had no or only localized low-density areas on computed tomographic scans, and unilateral occlusion or severe stenosis of the internal carotid or middle cerebral artery on cerebral angiograms. The Diamox asymmetry enhancement (DAE) was studied to detect reduced cerebral perfusion reserve in the affected hemispheres. The DAE was 7.9+-5.8% in seven patients positive in the SEP test, significantly higher than -1.5+-2.9% in patients negative in the SEP test. Postoperative SEP tests were negative in all five patients who underwent extracranial-intracranial (EC-IC) bypass surgery, suggesting that the EC-IC bypass improved the cerebral perfusion reserve in the affected hemispheres. The DAE decreased significantly in four of these patients. This study disclosed a significant correlation between the drug-induced hypotension SEP test and DAE. These parameters are considered important for evaluating patients with hemodynamic compromise and/or suitable candidates for EC-IC bypass. (author).

  19. Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

    Energy Technology Data Exchange (ETDEWEB)

    Hargrove, Tatiana Y.; Garvey, Edward P.; Hoekstra, William J.; Yates, Christopher M.; Wawrzak, Zdzislaw; Rachakonda, Girish; Villalta, Fernando; Lepesheva, Galina I.

    2017-05-01

    ABSTRACT

    Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14α-demethylase (CYP51B) from the filamentous fungusAspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 ± 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatusCYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broad-spectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis ofA. fumigatusCYP51/voriconazole andCandida albicansCYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using twoA. fumigatusstrains (strains 32820 and 1022) displayed a direct

  20. The Role of Efflux Pumps in Tuberculosis Treatment and Their Promise as a Target in Drug Development: Unraveling the Black Box

    NARCIS (Netherlands)

    te Brake, Lindsey H.M.; de Knegt, Gerjo J.; de Steenwinkel, Jurriaan E.; van Dam, Teunis J.P.; Burger, David M; Russel, Frans G M; van Crevel, Reinout; Koenderink, Jan B.; Aarnoutse, Rob E.

    2018-01-01

    Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs

  1. The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates.

    Science.gov (United States)

    Tsonkova, Violeta Georgieva; Sand, Fredrik Wolfhagen; Wolf, Xenia Asbæk; Grunnet, Lars Groth; Kirstine Ringgaard, Anna; Ingvorsen, Camilla; Winkel, Louise; Kalisz, Mark; Dalgaard, Kevin; Bruun, Christine; Fels, Johannes Josef; Helgstrand, Charlotte; Hastrup, Sven; Öberg, Fredrik Kryh; Vernet, Erik; Sandrini, Michael Paolo Bastner; Shaw, Allan Christian; Jessen, Carsten; Grønborg, Mads; Hald, Jacob; Willenbrock, Hanni; Madsen, Dennis; Wernersson, Rasmus; Hansson, Lena; Jensen, Jan Nygaard; Plesner, Annette; Alanentalo, Tomas; Petersen, Maja Borup Kjær; Grapin-Botton, Anne; Honoré, Christian; Ahnfelt-Rønne, Jonas; Hecksher-Sørensen, Jacob; Ravassard, Philippe; Madsen, Ole D; Rescan, Claude; Frogne, Thomas

    2018-02-01

    To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins. Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate. By screening of various proteins and peptides, we found Bombesin (BB) receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP) to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation. ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST) was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated insulin secretion capabilities. The cell line has an active

  2. The EndoC-βH1 cell line is a valid model of human beta cells and applicable for screenings to identify novel drug target candidates

    Directory of Open Access Journals (Sweden)

    Violeta Georgieva Tsonkova

    2018-02-01

    Full Text Available Objective: To characterize the EndoC-βH1 cell line as a model for human beta cells and evaluate its beta cell functionality, focusing on insulin secretion, proliferation, apoptosis and ER stress, with the objective to assess its potential as a screening platform for identification of novel anti-diabetic drug candidates. Methods: EndoC-βH1 was transplanted into mice for validation of in vivo functionality. Insulin secretion was evaluated in cells cultured as monolayer and as pseudoislets, as well as in diabetic mice. Cytokine induced apoptosis, glucolipotoxicity, and ER stress responses were assessed. Beta cell relevant mRNA and protein expression were investigated by qPCR and antibody staining. Hundreds of proteins or peptides were tested for their effect on insulin secretion and proliferation. Results: Transplantation of EndoC-βH1 cells restored normoglycemia in streptozotocin induced diabetic mice. Both in vitro and in vivo, we observed a clear insulin response to glucose, and, in vitro, we found a significant increase in insulin secretion from EndoC-βH1 pseudoislets compared to monolayer cultures for both glucose and incretins.Apoptosis and ER stress were inducible in the cells and caspase 3/7 activity was elevated in response to cytokines, but not affected by the saturated fatty acid palmitate.By screening of various proteins and peptides, we found Bombesin (BB receptor agonists and Pituitary Adenylate Cyclase-Activating Polypeptides (PACAP to significantly induce insulin secretion and the proteins SerpinA6, STC1, and APOH to significantly stimulate proliferation.ER stress was readily induced by Tunicamycin and resulted in a reduction of insulin mRNA. Somatostatin (SST was found to be expressed by 1% of the cells and manipulation of the SST receptors was found to significantly affect insulin secretion. Conclusions: Overall, the EndoC-βH1 cells strongly resemble human islet beta cells in terms of glucose and incretin stimulated

  3. Prediction of overall in vitro microsomal stability of drug candidates based on molecular modeling and support vector machines. Case study of novel arylpiperazines derivatives.

    Directory of Open Access Journals (Sweden)

    Szymon Ulenberg

    Full Text Available Other than efficacy of interaction with the molecular target, metabolic stability is the primary factor responsible for the failure or success of a compound in the drug development pipeline. The ideal drug candidate should be stable enough to reach its therapeutic site of action. Despite many recent excellent achievements in the field of computational methods supporting drug metabolism studies, a well-recognized procedure to model and predict metabolic stability quantitatively is still lacking. This study proposes a workflow for developing quantitative metabolic stability-structure relationships, taking a set of 30 arylpiperazine derivatives as an example. The metabolic stability of the compounds was assessed in in vitro incubations in the presence of human liver microsomes and NADPH and subsequently quantified by liquid chromatography-mass spectrometry (LC-MS. Density functional theory (DFT calculations were used to obtain 30 models of the molecules, and Dragon software served as a source of structure-based molecular descriptors. For modeling structure-metabolic stability relationships, Support Vector Machines (SVM, a non-linear machine learning technique, were found to be more effective than a regression technique, based on the validation parameters obtained. Moreover, for the first time, general sites of metabolism for arylpiperazines bearing the 4-aryl-2H-pyrido[1,2-c]pyrimidine-1,3-dione system were defined by analysis of Q-TOF-MS/MS spectra. The results indicated that the application of one of the most advanced chemometric techniques combined with a simple and quick in vitro procedure and LC-MS analysis provides a novel and valuable tool for predicting metabolic half-life values. Given the reduced time and simplicity of analysis, together with the accuracy of the predictions obtained, this is a valid approach for predicting metabolic stability using structural data. The approach presented provides a novel, comprehensive and reliable tool

  4. High-Content Screening in hPSC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain.

    Science.gov (United States)

    Zhou, Ting; Tan, Lei; Cederquist, Gustav Y; Fan, Yujie; Hartley, Brigham J; Mukherjee, Suranjit; Tomishima, Mark; Brennand, Kristen J; Zhang, Qisheng; Schwartz, Robert E; Evans, Todd; Studer, Lorenz; Chen, Shuibing

    2017-08-03

    Zika virus (ZIKV) infects fetal and adult human brain and is associated with serious neurological complications. To date, no therapeutic treatment is available to treat ZIKV-infected patients. We performed a high-content chemical screen using human pluripotent stem cell-derived cortical neural progenitor cells (hNPCs) and found that hippeastrine hydrobromide (HH) and amodiaquine dihydrochloride dihydrate (AQ) can inhibit ZIKV infection in hNPCs. Further validation showed that HH also rescues ZIKV-induced growth and differentiation defects in hNPCs and human fetal-like forebrain organoids. Finally, HH and AQ inhibit ZIKV infection in adult mouse brain in vivo. Strikingly, HH suppresses viral propagation when administered to adult mice with active ZIKV infection, highlighting its therapeutic potential. Our approach highlights the power of stem cell-based screens and validation in human forebrain organoids and mouse models in identifying drug candidates for treating ZIKV infection and related neurological complications in fetal and adult patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Dual activities of the anti-cancer drug candidate PBI-05204 provide neuroprotection in brain slice models for neurodegenerative diseases and stroke.

    Science.gov (United States)

    Van Kanegan, Michael J; Dunn, Denise E; Kaltenbach, Linda S; Shah, Bijal; He, Dong Ning; McCoy, Daniel D; Yang, Peiying; Peng, Jiangnan; Shen, Li; Du, Lin; Cichewicz, Robert H; Newman, Robert A; Lo, Donald C

    2016-05-12

    We previously reported neuroprotective activity of the botanical anti-cancer drug candidate PBI-05204, a supercritical CO2 extract of Nerium oleander, in brain slice and in vivo models of ischemic stroke. We showed that one component of this neuroprotective activity is mediated through its principal cardiac glycoside constituent, oleandrin, via induction of the potent neurotrophic factor brain-derived neurotrophic factor (BDNF). However, we also noted that the concentration-relation for PBI-05204 in the brain slice oxygen-glucose deprivation (OGD) model is considerably broader than that for oleandrin as a single agent. We thus surmised that PBI-05204 contains an additional neuroprotective component(s), distinct from oleandrin. We report here that neuroprotective activity is also provided by the triterpenoid constituents of PBI-05204, notably oleanolic acid. We demonstrate that a sub-fraction of PBI-05204 (Fraction 0-4) containing oleanolic and other triterpenoids, but without cardiac glycosides, induces the expression of cellular antioxidant gene transcription programs regulated through antioxidant transcriptional response elements (AREs). Finally, we show that Fraction 0-4 provides broad neuroprotection in organotypic brain slice models for neurodegeneration driven by amyloid precursor protein (APP) and tau implicated in Alzheimer's disease and frontotemporal dementias, respectively, in addition to ischemic injury modeled by OGD.

  6. Eudragit ® FS 30 D polymeric films containing chondroitin sulfate as candidates for use in coating seeking modified delivery of drugs

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    Camila Borges dos Reis

    Full Text Available ABSTRACT Polymeric films associating different concentrations of Eudragit(r FS 30 D (EFS and chondroitin sulfate (CS were produced by casting for the development of a new target-specific site material. Formed films kept a final polymer mass of 4% (w/v in the following proportions: EFS 100:00 CS (control, EFS 95:05 CS, EFS 90:10 CS and EFS 80:20 CS. They were analyzed for physical and chemical characteristics using Fourier transform infrared spectroscopy (FTIR, scanning electron microscopy (SEM and Raman spectroscopy. Furthermore, they were characterized by their water vapor permeability and degree of hydration at different conditions simulating the gastrointestinal tract. No chemical interactions were observed between CS and EFS, suggesting only a physical interaction between them in the different combinations tested. The results suggest that EFS and CS, when combined, may form films that are candidates for coating processes seeking a modified drug delivery, especially due to the synergism between pH dependency and specific biodegradability properties by the colonic microbiota. EFS 90:10 CS proved to be the most suitable for this purpose considering hydration and permeability characteristics of different associations analyzed.

  7. An invertebrate model for CNS drug discovery

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  8. Antimicrobial Peptides: a promising class of antimicrobial compounds against BWA and multi-drug resistant bacteria: in the spotlight: the lactoferrin chimera

    NARCIS (Netherlands)

    Bikker, F.J.; Sijbrandij, T.; Nazmi, K.; Bolscher, J.G.M.; Veerman, E.C.I.; Jansen, H-J.

    2014-01-01

    Anti-Microbial Peptides (AMPs) are part of the innate immune defense system and considered as promising lead compounds for the development of novel anti-bacterial agents. In general, AMPs are simple, short peptides with broad-spectrum activity against Gram-negative and Gram-positive bacteria, fungi,

  9. Monte Carlo random walk simulation of electron transport in confined porous TiO2 as a promising candidate for photo-electrode of nano-crystalline solar cells

    Science.gov (United States)

    Javadi, M.; Abdi, Y.

    2015-08-01

    Monte Carlo continuous time random walk simulation is used to study the effects of confinement on electron transport, in porous TiO2. In this work, we have introduced a columnar structure instead of the thick layer of porous TiO2 used as anode in conventional dye solar cells. Our simulation results show that electron diffusion coefficient in the proposed columnar structure is significantly higher than the diffusion coefficient in the conventional structure. It is shown that electron diffusion in the columnar structure depends both on the cross section area of the columns and the porosity of the structure. Also, we demonstrate that such enhanced electron diffusion can be realized in the columnar photo-electrodes with a cross sectional area of ˜1 μm2 and porosity of 55%, by a simple and low cost fabrication process. Our results open up a promising approach to achieve solar cells with higher efficiencies by engineering the photo-electrode structure.

  10. Monte Carlo random walk simulation of electron transport in confined porous TiO{sub 2} as a promising candidate for photo-electrode of nano-crystalline solar cells

    Energy Technology Data Exchange (ETDEWEB)

    Javadi, M.; Abdi, Y., E-mail: y.abdi@ut.ac.ir [Nanophysics Research Laboratory, Department of Physics, University of Tehran, North Kargar, Tehran (Iran, Islamic Republic of)

    2015-08-14

    Monte Carlo continuous time random walk simulation is used to study the effects of confinement on electron transport, in porous TiO{sub 2}. In this work, we have introduced a columnar structure instead of the thick layer of porous TiO{sub 2} used as anode in conventional dye solar cells. Our simulation results show that electron diffusion coefficient in the proposed columnar structure is significantly higher than the diffusion coefficient in the conventional structure. It is shown that electron diffusion in the columnar structure depends both on the cross section area of the columns and the porosity of the structure. Also, we demonstrate that such enhanced electron diffusion can be realized in the columnar photo-electrodes with a cross sectional area of ∼1 μm{sup 2} and porosity of 55%, by a simple and low cost fabrication process. Our results open up a promising approach to achieve solar cells with higher efficiencies by engineering the photo-electrode structure.

  11. Monte Carlo random walk simulation of electron transport in confined porous TiO2 as a promising candidate for photo-electrode of nano-crystalline solar cells

    International Nuclear Information System (INIS)

    Javadi, M.; Abdi, Y.

    2015-01-01

    Monte Carlo continuous time random walk simulation is used to study the effects of confinement on electron transport, in porous TiO 2 . In this work, we have introduced a columnar structure instead of the thick layer of porous TiO 2 used as anode in conventional dye solar cells. Our simulation results show that electron diffusion coefficient in the proposed columnar structure is significantly higher than the diffusion coefficient in the conventional structure. It is shown that electron diffusion in the columnar structure depends both on the cross section area of the columns and the porosity of the structure. Also, we demonstrate that such enhanced electron diffusion can be realized in the columnar photo-electrodes with a cross sectional area of ∼1 μm 2 and porosity of 55%, by a simple and low cost fabrication process. Our results open up a promising approach to achieve solar cells with higher efficiencies by engineering the photo-electrode structure

  12. In Silico Identification and In Vitro and In Vivo Validation of Anti-Psychotic Drug Fluspirilene as a Potential CDK2 Inhibitor and a Candidate Anti-Cancer Drug.

    Directory of Open Access Journals (Sweden)

    Xi-Nan Shi

    Full Text Available Hepatocellular carcinoma (HCC is one of the leading causes of cancer-related deaths worldwide. Surgical resection and conventional chemotherapy and radiotherapy ultimately fail due to tumor recurrence and HCC's resistance. The development of novel therapies against HCC is thus urgently required. The cyclin-dependent kinase (CDK pathways are important and well-established targets for cancer treatment. In particular, CDK2 is a key factor regulating the cell cycle G1 to S transition and a hallmark for cancers. In this study, we utilized our free and open-source protein-ligand docking software, idock, prospectively to identify potential CDK2 inhibitors from 4,311 FDA-approved small molecule drugs using a repurposing strategy and an ensemble docking methodology. Sorted by average idock score, nine compounds were purchased and tested in vitro. Among them, the anti-psychotic drug fluspirilene exhibited the highest anti-proliferative effect in human hepatocellular carcinoma HepG2 and Huh7 cells. We demonstrated for the first time that fluspirilene treatment significantly increased the percentage of cells in G1 phase, and decreased the expressions of CDK2, cyclin E and Rb, as well as the phosphorylations of CDK2 on Thr160 and Rb on Ser795. We also examined the anti-cancer effect of fluspirilene in vivo in BALB/C nude mice subcutaneously xenografted with human hepatocellular carcinoma Huh7 cells. Our results showed that oral fluspirilene treatment significantly inhibited tumor growth. Fluspirilene (15 mg/kg exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil (10 mg/kg. Moreover, the cocktail treatment with fluspirilene and 5-fluorouracil exhibited the highest therapeutic effect. These results suggested for the first time that fluspirilene is a potential CDK2 inhibitor and a candidate anti-cancer drug for the treatment of human hepatocellular carcinoma. In view of the fact that fluspirilene has a long history

  13. P-glycoprotein mediated efflux limits the transport of the novel anti-Parkinson's disease candidate drug FLZ across the physiological and PD pathological in vitro BBB models.

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    Qian Liu

    Full Text Available FLZ, a novel anti-Parkinson's disease (PD candidate drug, has shown poor blood-brain barrier (BBB penetration based on the pharmacokinetic study using rat brain. P-glycoprotein (P-gp and breast cancer resistance protein (BCRP are two important transporters obstructing substrates entry into the CNS as well as in relation to PD neuropathology. However, it is unclear whether P-gp and BCRP are involved in low BBB permeability of FLZ and what the differences of FLZ brain penetration are between normal and Parkinson's conditions. For this purpose, in vitro BBB models mimicking physiological and PD pathological-related BBB properties were constructed by C6 astroglial cells co-cultured with primary normal or PD rat cerebral microvessel endothelial cells (rCMECs and in vitro permeability experiments of FLZ were carried out. High transepithelial electrical resistance (TEER and low permeability for sodium fluorescein (NaF confirmed the BBB functionality of the two models. Significantly greater expressions of P-gp and BCRP were detected in PD rCMECs associated with the lower in vitro BBB permeability of FLZ in pathological BBB model compared with physiological model. In transport studies only P-gp blocker effectively inhibited the efflux of FLZ, which was consistent with the in vivo permeability data. This result was also confirmed by ATPase assays, suggesting FLZ is a substrate for P-gp but not BCRP. The present study first established in vitro BBB models reproducing PD-related changes of BBB functions in vivo and demonstrated that poor brain penetration of FLZ and low BBB permeability were due to the P-gp transport.

  14. A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABAA Receptors in the Lung.

    Science.gov (United States)

    Forkuo, Gloria S; Nieman, Amanda N; Kodali, Revathi; Zahn, Nicolas M; Li, Guanguan; Rashid Roni, M S; Stephen, Michael Rajesh; Harris, Ted W; Jahan, Rajwana; Guthrie, Margaret L; Yu, Olivia B; Fisher, Janet L; Yocum, Gene T; Emala, Charles W; Steeber, Douglas A; Stafford, Douglas C; Cook, James M; Arnold, Leggy A

    2018-05-07

    We describe lead compound MIDD0301 for the oral treatment of asthma based on previously developed positive allosteric α 5 β 3 γ 2 selective GABA A receptor (GABA A R) ligands. MIDD0301 relaxed airway smooth muscle at single micromolar concentrations as demonstrated with ex vivo guinea pig tracheal rings. MIDD0301 also attenuated airway hyperresponsiveness (AHR) in an ovalbumin murine model of asthma by oral administration. Reduced numbers of eosinophils and macrophages were observed in mouse bronchoalveolar lavage fluid without changing mucous metaplasia. Importantly, lung cytokine expression of IL-17A, IL-4, and TNF-α were reduced for MIDD0301-treated mice without changing antiinflammatory cytokine IL-10 levels. Automated patch clamp confirmed amplification of GABA induced current mediated by α 1-3,5 β 3 γ 2 GABA A Rs in the presence of MIDD0301. Pharmacodynamically, transmembrane currents of ex vivo CD4 + T cells from asthmatic mice were potentiated by MIDD0301 in the presence of GABA. The number of CD4 + T cells observed in the lung of MIDD0301-treated mice were reduced by an oral treatment of 20 mg/kg b.i.d. for 5 days. A half-life of almost 14 h was demonstrated by pharmacokinetic studies (PK) with no adverse CNS effects when treated mice were subjected to sensorimotor studies using the rotarod. PK studies also confirmed very low brain distribution. In conclusion, MIDD0301 represents a safe and improved oral asthma drug candidate that relaxes airway smooth muscle and attenuates inflammation in the lung leading to a reduction of AHR at a dosage lower than earlier reported GABA A R ligands.

  15. Carbamazepine solubility enhancement in tandem with swellable polymer osmotic pump tablet: A promising approach for extended delivery of poorly water-soluble drugs

    Directory of Open Access Journals (Sweden)

    Hadjira Rabti

    2014-06-01

    Full Text Available Elementary osmotic pump (EOP is a unique extended release (ER drug delivery system based on the principle of osmosis. It has the ability to minimize the amount of the drug, accumulation and fluctuation in drug level during chronic uses. Carbamazepine (CBZ, a poorly water-soluble antiepileptic drug, has serious side effects on overdoses and chronic uses. The aim of the present study was to design a new EOP tablet of CBZ containing a solubility enhancers and swellable polymer to reduce its side effects and enhance the patient compliance. Firstly, a combination of solubilizing carriers was selected to improve the dissolution of the slightly soluble drug. Then, designing the new EOP tablet and investigating the effect of different variables of core and coat formulations on drug release behavior by single parameter optimization and by Taguchi orthogonal design with analysis of variance (ANOVA, respectively. The results showed that CBZ solubility was successfully enhanced by a minimum amount of combined polyvinyl pyrrolidone (PVP K30 and sodium lauryl sulfate (SLS. The plasticizer amount and molecular weight (MW together with the osmotic agent amount directly affect the release rate whereas the swellable polymer amount and viscosity together with the semi-permeable membrane (SPM thickness inversely influence the release rate. In addition, the tendency of following zero order kinetics was mainly affected by the coat components rather than those of the core. Further, orifice size does not have any significant effect on the release behavior within the range of 0.1 mm to 0.8 mm. In this study we report the successful formulation of CBZ-EOP tablets, which were similar to the marketed product Tegretol CR 200 and able to satisfy the USP criterion limits and to deliver about 80% of CBZ at a rate of approximately zero order for up to 12 h.

  16. Next-generation sequencing-based user-friendly platforms for drug-resistant tuberculosis diagnosis: A promise for the near future

    Directory of Open Access Journals (Sweden)

    David L Dolinger

    2016-01-01

    Full Text Available Since 2002, there has been a gradual worldwide 1.3% annual decrease in the incidence of tuberculosis (TB. This is an encouraging statistic; however, it will not achieve the World Health Organization's goal of eliminating TB by 2050, and it is being compounded by the persistent global incidence of drug-resistant tuberculosis (DR-TB acquired by transmission and by treatment pressure. One key to effectively control tuberculosis and the spread of multiresistant strains is accurate information pertaining to drug resistance and susceptibility. Next-generation sequencing (NGS has the potential to effectively change global health and the management of TB. Industry has focused primarily on using NGS for oncology diagnostics and human genomics, but the area in which NGS can rapidly impact health care is in the area of infectious disease diagnostics in low- and middle-income countries. To date, there has been a failure as a community to capitalize on the potential of NGS, especially at the reference laboratory level where it can provide actionable information pertaining to treatment options for patients. The rapid evolution of knowledge about the genetic foundations of tuberculosis drug resistance makes sequencing a versatile technology platform for providing rapid, accurate, and actionable results for treating this disease. No “plug-and-play” and “end-to-end” NGS solutions exist that provide clinically relevant sequence data from the Mycobacterium tuberculosis complex genome from primary clinical samples (e.g., sputum in high-burden country reference laboratories, which is where they are most needed. However, such a system-based solution is underdeveloped by Foundation for Innovative Diagnostics (FIND, in collaboration with partners from academia, nongovernmental organizations, and industry. The solution is modular and is designed and developed to perform targeted amplicon sequencing directly from a patient's primary sputum sample. This solution

  17. Multi-constituent cardiovascular pills (MCCP)--challenges and promises of population-based prophylactic drug therapy for prevention of heart attack.

    Science.gov (United States)

    Jamieson, Michael J; Naghavi, Morteza

    2007-01-01

    Risk factors for atherosclerotic cardiovascular disease (CVD) are highly co-prevalent but poorly identified and treated. The Screening for Heart Attack Prevention and Education (SHAPE) Task Force from the Association for Eradication of Heart Attack (AEHA) has recently proposed a new strategy that recommends screening for subclinical atherosclerosis and implementing aggressive treatment of "vulnerable patients". The Task Force has also envisioned future developments that may shift mass screening strategies to mass prophylactic therapy. The "Polypill" concept, introduced by Wald and Law suggests a combination of statin, low-dose antihypertensives, aspirin and folic acid, in a single pill, taken prophylactically by high risk population can cut CVD event rates by as much as 80%. In this communication, we review the challenges and promises of such a strategy. "Polypill" is but one of an astronomical number of possible multiconstituent pills (MCCP). Attractive as the MCCP concept is, it lacks evidence from randomized controlled trials, and begs numerous questions about the credibility of the concept, the design and synthesis of such complex pills, pharmacokinetics, pharmacodynamics, bioequivalence, "class" vs. unique properties, interactions, evidence of clinical efficacy and safety, regulatory approval, post-marketing surveillance, prescription vs. over-the-counter use, responsibility for initiating and monitoring therapy, patient education, counterfeiting and importation, reimbursement, advertisement, patent protection, commercial viability, etc. If these issues are favorably addressed, MCCP stand to dramatically change the manner in which CVD is prevented particularly in developing societies. Notwithstanding, assuming low commercial interests, realizing the promises of MCCP will demand serious attention from national public health policymakers. The clinical and regulatory implications of population-based secondary prevention (which rely on a different evidence base

  18. A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

    NARCIS (Netherlands)

    Kaeaeb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; Van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H. -Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

    Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

  19. A Large Candidate Gene Survey Identifies the KCNE1 D85N Polymorphism as a Possible Modulator of Drug-Induced Torsades de Pointes

    NARCIS (Netherlands)

    Kääb, Stefan; Crawford, Dana C.; Sinner, Moritz F.; Behr, Elijah R.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Guicheney, Pascale; Bishopric, Nanette H.; Myerburg, Robert J.; Schott, Jean-Jacques; Pfeufer, Arne; Beckmann, Britt-Maria; Martens, Eimo; Zhang, Taifang; Stallmeyer, Birgit; Zumhagen, Sven; Denjoy, Isabelle; Bardai, Abdennasser; van Gelder, Isabelle C.; Jamshidi, Yalda; Dalageorgou, Chrysoula; Marshall, Vanessa; Jeffery, Steve; Shakir, Saad; Camm, A. John; Steinbeck, Gerhard; Perz, Siegfried; Lichtner, Peter; Meitinger, Thomas; Peters, Annette; Wichmann, H.-Erich; Ingram, Christiana; Bradford, Yuki; Carter, Shannon; Norris, Kris; Ritchie, Marylyn D.; George, Alfred L.; Roden, Dan M.

    2012-01-01

    Background-Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS. Methods and Results-In a

  20. United States Food and Drug Administration and Department of Defense shelf-life extension program of pharmaceutical products: progress and promise.

    Science.gov (United States)

    Khan, Saeed R; Kona, Ravikanth; Faustino, Patrick J; Gupta, Abhay; Taylor, Jeb S; Porter, Donna A; Khan, Mansoor

    2014-05-01

    The Department of Defense (DoD)-United States Food and Drug Administration (FDA) shelf-life extension program (SLEP) was established in 1986 through an intra-agency agreement between the DoD and the FDA to extend the shelf life of product nearing expiry. During the early stages of development, special attention was paid to program operation, labeling requirements, and the cost benefits associated with this program. In addition to the substantial cost benefits, the program also provides the FDA's Center for Drug Evaluation and Research with significant scientific understanding and pharmaceutical resource. As a result of this unique resource, numerous regulatory research opportunities to improve public health present themselves from this distinctive scientific database, which includes examples of products shelf life, their long-term stability issues, and various physical and chemical tests to identify such failures. The database also serves as a scientific resource for mechanistic understanding and identification of test failures leading to the development of new formulations or more robust packaging. It has been recognized that SLEP is very important in maintaining both national security and public welfare by confirming that the stockpiled pharmaceutical products meet quality standards after the "expiration date" assigned by the sponsor. SLEP research is an example of regulatory science that is needed to best ensure product performance past the original shelf life. The objective of this article is to provide a brief history and background and most importantly the public health benefits of the SLEP. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  1. Walleye Autochthonous Bacteria as Promising Probiotic Candidates against Flavobacterium columnare

    Directory of Open Access Journals (Sweden)

    Hamza Seghouani

    2017-07-01

    Full Text Available Walleye (Sander vitreus is the second most fished freshwater species in Canada. While much sought by anglers, walleye also supports substantial commercial fisheries. To cope with the recent decline of wild walleye populations, fish farmers produce juveniles for lake stocking. However, walleye breeding is particularly tedious, mostly due to high disease susceptibility at larval and juvenile developmental stages. The main threat is the columnaris disease, which is caused by Flavobacterium columnare, an opportunistic bacteria. As F. columnare strains exhibit increasing antibiotic resistance, there is a strong need to develop efficient and sustainable alternative strategies to control columnaris disease. Bacterial probiotics have been shown to mitigate infections either by enhancing host immune response or by inhibiting pathogen growth. Being successfully assessed in many fish/pathogen combinations, we developed a tailored probiotic strategy for walleye to prevent and treat columnaris disease. Thirty-seven endogenous bacterial strains were isolated from healthy walleye’s skin and gut, were tested in vitro against F. columnare. Significant antagonistic effect against F. columnare was measured for 2 out of 37 endogenous strains. These two probiotic strains were identified as Pseudomonas fluorescens. The antagonistic effect of these two successful probiotics was further validated in vivo during a 2-month stress trial: groups receiving probiotic treatments showed on average 53.74% survival improvement.

  2. Phosphorene nanoribbon as a promising candidate for thermoelectric applications

    Science.gov (United States)

    Zhang, J.; Liu, H. J.; Cheng, L.; Wei, J.; Liang, J. H.; Fan, D. D.; Shi, J.; Tang, X. F.; Zhang, Q. J.

    2014-01-01

    In this work, the electronic properties of phosphorene nanoribbons with different width and edge configurations are studied by using density functional theory. It is found that the armchair phosphorene nanoribbons are semiconducting while the zigzag nanoribbons are metallic. The band gaps of armchair nanoribbons decrease monotonically with increasing ribbon width. By passivating the edge phosphorus atoms with hydrogen, the zigzag series also become semiconducting, while the armchair series exhibit a larger band gap than their pristine counterpart. The electronic transport properties of these phosphorene nanoribbons are then investigated using Boltzmann theory and relaxation time approximation. We find that all the semiconducting nanoribbons exhibit very large values of Seebeck coefficient and can be further enhanced by hydrogen passivation at the edge. Taking pristine armchair nanoribbons and hydrogen-passivated zigzag naoribbons with width N = 7, 8, 9 as examples, we calculate the lattice thermal conductivity with the help of phonon Boltzmann transport equation and evaluate the width-dependent thermoelectric performance. Due to significantly enhanced Seebeck coefficient and decreased thermal conductivity, we find that at least one type of phosphorene nanoribbons can be optimized to exhibit very high figure of merit (ZT values) at room temperature, which suggests their appealing thermoelectric applications. PMID:25245326

  3. Amorphous drugs and dosage forms

    DEFF Research Database (Denmark)

    Grohganz, Holger; Löbmann, K.; Priemel, P.

    2013-01-01

    The transformation to an amorphous form is one of the most promising approaches to address the low solubility of drug compounds, the latter being an increasing challenge in the development of new drug candidates. However, amorphous forms are high energy solids and tend to recry stallize. New...... formulation principles are needed to ensure the stability of amorphous drug forms. The formation of solid dispersions is still the most investigated approach, but additional approaches are desirable to overcome the shortcomings of solid dispersions. Spatial separation by either coating or the use of micro-containers...... before single molecules are available for the formation of crystal nuclei, thus stabilizing the amorphous form....

  4. Discovery of a Potent, Selective T-type Calcium Channel Blocker as a Drug Candidate for the Treatment of Generalized Epilepsies.

    Science.gov (United States)

    Bezençon, Olivier; Heidmann, Bibia; Siegrist, Romain; Stamm, Simon; Richard, Sylvia; Pozzi, Davide; Corminboeuf, Olivier; Roch, Catherine; Kessler, Melanie; Ertel, Eric A; Reymond, Isabelle; Pfeifer, Thomas; de Kanter, Ruben; Toeroek-Schafroth, Michael; Moccia, Luca G; Mawet, Jacques; Moon, Richard; Rey, Markus; Capeleto, Bruno; Fournier, Elvire

    2017-12-14

    We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.

  5. Semantic Web Ontology and Data Integration: a Case Study in Aiding Psychiatric Drug Repurposing.

    Science.gov (United States)

    Liang, Chen; Sun, Jingchun; Tao, Cui

    2015-01-01

    There remain significant difficulties selecting probable candidate drugs from existing databases. We describe an ontology-oriented approach to represent the nexus between genes, drugs, phenotypes, symptoms, and diseases from multiple information sources. We also report a case study in which we attempted to explore candidate drugs effective for bipolar disorder and epilepsy. We constructed an ontology incorporating knowledge between the two diseases and performed semantic reasoning tasks with the ontology. The results suggested 48 candidate drugs that hold promise for further breakthrough. The evaluation demonstrated the validity our approach. Our approach prioritizes the candidate drugs that have potential associations among genes, phenotypes and symptoms, and thus facilitates the data integration and drug repurposing in psychiatric disorders.

  6. Elicited vs. voluntary promises

    NARCIS (Netherlands)

    Ismayilov, H.; Potters, Jan

    2017-01-01

    We set up an experiment with pre-play communication to study the impact of promise elicitation by trustors from trustees on trust and trustworthiness. When given the opportunity a majority of trustors solicits a promise from the trustee. This drives up the promise making rate by trustees to almost

  7. Antimicrobial Peptides: A Promising Therapeutic Strategy in Tackling Antimicrobial Resistance.

    Science.gov (United States)

    Nuti, Ramya; Goud, Nerella S; Saraswati, A Prasanth; Alvala, Ravi; Alvala, Mallika

    2017-01-01

    Antimicrobial resistance (AMR) has posed a serious threat to global public health and it requires immediate action, preferably long term. Current drug therapies have failed to curb this menace due to the ability of microbes to circumvent the mechanisms through which the drugs act. From the drug discovery point of view, the majority of drugs currently employed for antimicrobial therapy are small molecules. Recent trends reveal a surge in the use of peptides as drug candidates as they offer remarkable advantages over small molecules. Newer synthetic strategies like organometalic complexes, Peptide-polymer conjugates, solid phase, liquid phase and recombinant DNA technology encouraging the use of peptides as therapeutic agents with a host of chemical functions, and tailored for specific applications. In the last decade, many peptide based drugs have been successfully approved by the Food and Drug Administration (FDA). This success can be attributed to their high specificity, selectivity and efficacy, high penetrability into the tissues, less immunogenicity and less tissue accumulation. Considering the enormity of AMR, the use of Antimicrobial Peptides (AMPs) can be a viable alternative to current therapeutics strategies. AMPs are naturally abundant allowing synthetic chemists to develop semi-synthetics peptide molecules. AMPs have a broad spectrum of activity towards microbes and they possess the ability to bypass the resistance induction mechanisms of microbes. The present review focuses on the potential applications of AMPs against various microbial disorders and their future prospects. Several resistance mechanisms and their strategies have also been discussed to highlight the importance in the current scenario. Breakthroughs in AMP designing, peptide synthesis and biotechnology have shown promise in tackling this challenge and has revived the interest of using AMPs as an important weapon in fighting AMR. Copyright© Bentham Science Publishers; For any queries

  8. The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates.

    Science.gov (United States)

    Buccafusco, Jerry J; Terry, Alvin V; Webster, Scott J; Martin, Daniel; Hohnadel, Elizabeth J; Bouchard, Kristy A; Warner, Samantha E

    2008-08-01

    The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 microg/kg in the DMTS task. The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.

  9. Computational design of drug candidates for influenza A virus subtype H1N1 by inhibiting the viral neuraminidase-1 enzyme

    Directory of Open Access Journals (Sweden)

    Tambunan Usman Sumo Friend

    2014-06-01

    Full Text Available It is critical to seek potential alternative treatments for H1N1 infections by inhibiting neuraminidase-1 enzyme. One of the viable options for inhibiting the activity of neuraminidase- 1 is peptide drug design. In order to increase peptide stability, cyclization is necessary to prevent its digestion by protease enzyme. Cyclization of peptide ligands by formation of disulfide bridges is preferable for designing inhibitors of neuraminidase-1 because of their high activity and specificity. Here we designed ligands by using molecular docking, drug scan and dynamics computational methods. Based on our docking results, short polypeptides of cystein-arginine-methionine-tyrosine- -proline-cysteine (CRMYPC and cysteine-arginine-aspargine- phenylalanine-proline-cysteine (CRNFPC have good residual interactions with the target and the binding energy ΔGbinding of -31.7402 and -31.0144 kcal mol-1, respectively. These values are much lower than those of the standards, and it means that both ligands are more accessible to ligand-receptor binding. Based on drug scan results, both of these ligands are neither mutagenic nor carcinogenic. They also show good oral bioavailability. Moreover, both ligands show relatively stable molecular dynamics progression of RMSD vs. time plot. However, based on our metods, the CRMYPC ligand has sufficient hydrogen bonding interactions with residues of the active side of neuraminidase-1 and can be therefore proposed as a potential inhibitor of neuraminidase-1

  10. Virtual Dual inhibition of COX-2 / 5-LOX enzymes based on binding properties of alpha-amyrins, the anti-inflammatory compound as a promising anti-cancer drug

    Science.gov (United States)

    Ranjbar, Mohammad Mehdi; Assadolahi, Vahideh; Yazdani, Mohsen; Nikaein, Donya; Rashidieh, Behnam

    2016-01-01

    ) that are known as cancer preventive agents, since it is free of side effects on human body and it can be a promising drug for cancer therapeutics. PMID:27231478

  11. The Promise of Neuroprotective Agents in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Judith ePotashkin

    2011-11-01

    Full Text Available Parkinson’s Disease is characterized by loss of dopamine neurons in the substantia nigra of the brain. Since there are limited treatment options for PD, neuroprotective agents are currently being tested as a means to slow disease progression. Agents targeting oxidative stress, mitochondrial dysfunction and inflammation are prime candidates for neuroprotection. This review identifies Rasagiline, Minocycline and creatine, as the most promising neuroprotective agents for PD, and they are all currently in phase III trials. Other agents possessing protective characteristics in delaying PD include stimulants, vitamins, supplements, and other drugs. Additionally, combination therapies also show benefits in slowing PD progression. The identification of neuroprotective agents for PD provides us with therapeutic opportunities for modifying the course of disease progression and, perhaps, reducing the risk of onset when preclinical biomarkers become available.

  12. Keeping the Promise

    Science.gov (United States)

    Whissemore, Tabitha

    2016-01-01

    Since its launch in September 2015, Heads Up America has collected information on nearly 125 promise programs across the country, many of which were instituted long before President Barack Obama announced the America's College Promise (ACP) plan in 2015. At least 27 new free community college programs have launched in states, communities, and at…

  13. Candidate DNA Barcode Tags Combined With High Resolution Melting (Bar-HRM Curve Analysis for Authentication of Senna alexandrina Mill. With Validation in Crude Drugs

    Directory of Open Access Journals (Sweden)

    Priyanka Mishra

    2018-03-01

    Full Text Available Senna alexandrina (Fabaceae is a globally recognized medicinal plant for its laxative properties as well as the only source of sennosides, and is highly exported bulk herb from India. Its major procurement is exclusively from limited cultivation, which leads to risks of deliberate or unintended adulteration. The market raw materials are in powdered or finished product form, which lead to difficulties in authentication. Here, DNA barcode tags based on chloroplast genes (rbcL and matK and intergenic spacers (psbA-trnH and ITS were developed for S. alexandrina along with the allied species. The ability and performance of the ITS1 region to discriminate among the Senna species resulted in the present proposal of the ITS1 tags as successful barcode. Further, these tags were coupled with high-resolution melting (HRM curve analysis in a real-time PCR genotyping method to derive Bar-HRM (Barcoding-HRM assays. Suitable HRM primer sets were designed through SNP detection and mutation scanning in genomic signatures of Senna species. The melting profiles of S. alexandrina and S. italica subsp. micrantha were almost identical and the remaining five species were clearly separated so that they can be differentiated by HRM method. The sensitivity of the method was utilized to authenticate market samples [Herbal Sample Assays (HSAs]. HSA01 (S. alexandrina crude drug sample from Bangalore and HSA06 (S. alexandrina crude drug sample from Tuticorin, Tamil Nadu, India were found to be highly contaminated with S. italica subsp. micrantha. Species admixture samples mixed in varying percentage was identified sensitively with detection of contamination as low as 1%. The melting profiles of PCR amplicons are clearly distinct, which enables the authentic differentiation of species by the HRM method. This study reveals that DNA barcoding coupled with HRM is an efficient molecular tool to authenticate Senna herbal products in the market for quality control in the drug

  14. Candidate DNA Barcode Tags Combined With High Resolution Melting (Bar-HRM) Curve Analysis for Authentication of Senna alexandrina Mill. With Validation in Crude Drugs.

    Science.gov (United States)

    Mishra, Priyanka; Shukla, Ashutosh K; Sundaresan, Velusamy

    2018-01-01

    Senna alexandrina (Fabaceae) is a globally recognized medicinal plant for its laxative properties as well as the only source of sennosides, and is highly exported bulk herb from India. Its major procurement is exclusively from limited cultivation, which leads to risks of deliberate or unintended adulteration. The market raw materials are in powdered or finished product form, which lead to difficulties in authentication. Here, DNA barcode tags based on chloroplast genes ( rbcL and matK ) and intergenic spacers ( psbA-trnH and ITS ) were developed for S. alexandrina along with the allied species. The ability and performance of the ITS1 region to discriminate among the Senna species resulted in the present proposal of the ITS1 tags as successful barcode. Further, these tags were coupled with high-resolution melting (HRM) curve analysis in a real-time PCR genotyping method to derive Bar-HRM (Barcoding-HRM) assays. Suitable HRM primer sets were designed through SNP detection and mutation scanning in genomic signatures of Senna species. The melting profiles of S. alexandrina and S . italica subsp. micrantha were almost identical and the remaining five species were clearly separated so that they can be differentiated by HRM method. The sensitivity of the method was utilized to authenticate market samples [Herbal Sample Assays (HSAs)]. HSA01 ( S. alexandrina crude drug sample from Bangalore) and HSA06 ( S. alexandrina crude drug sample from Tuticorin, Tamil Nadu, India) were found to be highly contaminated with S . italica subsp. micrantha . Species admixture samples mixed in varying percentage was identified sensitively with detection of contamination as low as 1%. The melting profiles of PCR amplicons are clearly distinct, which enables the authentic differentiation of species by the HRM method. This study reveals that DNA barcoding coupled with HRM is an efficient molecular tool to authenticate Senna herbal products in the market for quality control in the drug supply

  15. Topical delivery of low-cost protein drug candidates made in chloroplasts for biofilm disruption and uptake by oral epithelial cells.

    Science.gov (United States)

    Liu, Yuan; Kamesh, Aditya C; Xiao, Yuhong; Sun, Victor; Hayes, Michael; Daniell, Henry; Koo, Hyun

    2016-10-01

    Protein drugs (PD) are minimally utilized in dental medicine due to high cost and invasive surgical delivery. There is limited clinical advancement in disrupting virulent oral biofilms, despite their high prevalence in causing dental caries. Poor efficacy of antimicrobials following topical treatments or to penetrate and disrupt formed biofilms is a major challenge. We report an exciting low-cost approach using plant-made antimicrobial peptides (PMAMPs) retrocyclin or protegrin with complex secondary structures (cyclic/hairpin) for topical use to control biofilms. The PMAMPs rapidly killed the pathogen Streptococcus mutans and impaired biofilm formation following a single topical application of tooth-mimetic surface. Furthermore, we developed a synergistic approach using PMAMPs combined with matrix-degrading enzymes to facilitate their access into biofilms and kill the embedded bacteria. In addition, we identified a novel role for PMAMPs in delivering drugs to periodontal and gingival cells, 13-48 folds more efficiently than any other tested cell penetrating peptides. Therefore, PDs fused with protegrin expressed in plant cells could potentially play a dual role in delivering therapeutic proteins to gum tissues while killing pathogenic bacteria when delivered as topical oral formulations or in chewing gums. Recent FDA approval of plant-produced PDs augurs well for clinical advancement of this novel concept. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. "Heart-cut" bidimensional achiral-chiral liquid chromatography applied to the evaluation of stereoselective metabolism, in vivo biological activity and brain response to chiral drug candidates targeting the central nervous system.

    Science.gov (United States)

    Battisti, Umberto M; Citti, Cinzia; Larini, Martina; Ciccarella, Giuseppe; Stasiak, Natalia; Troisi, Luigino; Braghiroli, Daniela; Parenti, Carlo; Zoli, Michele; Cannazza, Giuseppe

    2016-04-22

    A "heart-cut" two-dimensional achiral-chiral liquid chromatography triple-quadrupole mass spectrometry method (LC-LC-MS/MS) was developed and coupled to in vivo cerebral microdialysis to evaluate the brain response to the chiral compound (±)-7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide ((±)-1), a potent positive allosteric modulator (PAM) of AMPA receptor. The method was successfully employed to evaluate also its stereoselective metabolism and in vitro biological activity. In particular, the LC achiral method developed, employs a pentafluorinated silica based column (Discovery HS-F5) to separate dopamine, acetylcholine, serotonin, (±)-1 and its two hepatic metabolites. In the "heart-cut" two-dimension achiral-chiral configuration, (±)-1 and (±)-1-d4 eluted from the achiral column (1st dimension), were transferred to a polysaccharide-based chiral column (2nd dimension, Chiralcel OD-RH) by using an automatic six-port valve. Single enantiomers of (±)-1 were separated and detected using electrospray positive ionization mode and quantified in selected reaction monitoring mode. The method was validated and showed good performance in terms of linearity, accuracy and precision. The new method employed showed several possible applications in the evaluation of: (a) brain response to neuroactive compounds by measuring variations in the brain extracellular levels of selected neurotransmitters and other biomarkers; (b) blood brain barrier penetration of drug candidates by measuring the free concentration of the drug in selected brain areas; (c) the presence of drug metabolites in the brain extracellular fluid that could prove very useful during drug discovery; (d) a possible stereoselective metabolization or blood brain barrier stereoselective crossing of chiral drugs. Finally, compared to the methods reported in the literature, this technique avoids the necessity of euthanizing an animal at each time point to measure drug

  17. Safety Lead Optimization and Candidate Identification: Integrating New Technologies into Decision-Making.

    Science.gov (United States)

    Dambach, Donna M; Misner, Dinah; Brock, Mathew; Fullerton, Aaron; Proctor, William; Maher, Jonathan; Lee, Dong; Ford, Kevin; Diaz, Dolores

    2016-04-18

    Discovery toxicology focuses on the identification of the most promising drug candidates through the development and implementation of lead optimization strategies and hypothesis-driven investigation of issues that enable rational and informed decision-making. The major goals are to [a] identify and progress the drug candidate with the best overall drug safety profile for a therapeutic area, [b] remove the most toxic drugs from the portfolio prior to entry into humans to reduce clinical attrition due to toxicity, and [c] establish a well-characterized hazard and translational risk profile to enable clinical trial designs. This is accomplished through a framework that balances the multiple considerations to identify a drug candidate with the overall best drug characteristics and provides a cogent understanding of mechanisms of toxicity. The framework components include establishing a target candidate profile for each program that defines the qualities of a successful candidate based on the intended therapeutic area, including the risk tolerance for liabilities; evaluating potential liabilities that may result from engaging the therapeutic target (pharmacology-mediated or on-target) and that are chemical structure-mediated (off-target); and characterizing identified liabilities. Lead optimization and investigation relies upon the integrated use of a variety of technologies and models (in silico, in vitro, and in vivo) that have achieved a sufficient level of qualification or validation to provide confidence in their use. We describe the strategic applications of various nonclinical models (established and new) for a holistic and integrated risk assessment that is used for rational decision-making. While this review focuses on strategies for small molecules, the overall concepts, approaches, and technologies are generally applicable to biotherapeutics.

  18. Promise Zones for Applicants

    Data.gov (United States)

    Department of Housing and Urban Development — This tool assists applicants to HUD's Promise Zone initiative prepare data to submit with their application by allowing applicants to draw the exact location of the...

  19. Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females.

    Science.gov (United States)

    Rahikainen, Anna-Liina; Palo, Jukka U; Haukka, Jari; Sajantila, Antti

    2018-04-01

    Genetic variation in efflux transporter, permeability glycoprotein (P-gp), has recently been associated with completed violent suicides and also violent suicide attempts. As depression is known to be a risk factor for suicide and many antidepressants are P-gp substrates, it has been speculated that inadequate antidepressant treatment response or adverse side effects could be involved. The aim of this study was to investigate whether there is an association between the P-gp coding ABCB1 gene and completed suicides in citalopram users. Also, the effect of sex and suicide method used (violent vs. non-violent) was evaluated. All cases included in the study population, 349 completed suicide victims and 284 controls, were shown to be positive for antidepressant citalopram in a post-mortem toxicological drug screen. ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were determined by TaqMan genotyping assays. Haplotypes were constructed from genotype data using the PHASE software. The association between the manner of death and the ABCB1 haplotype was tested with logistic regression analysis. No statistically significant differences were observed in the ABCB1 allele or genotype frequencies between the suicide and control groups. However, the ABCB1 1236T-2677T-3435T haplotype was associated with completed suicides of female citalopram users (odds ratio: 2.23; 95% confidence interval: 1.22-4.07; P=0.009). After stratification by the method used for suicide, the association emerged in fatal intoxications (odds ratio: 2.51; 95% confidence interval: 1.29-4.87; P=0.007). In other groups, no statistically significant associations were observed. Our results suggest that female citalopram users with ABCB1 1236T-2677T-3435T are more vulnerable to adverse effects of the drugs as this haplotype was enriched in non-violent suicides of female citalopram users. Even though the biological mechanism behind this observation is unknown, the results provide another example of the importance

  20. Promising More Information

    Science.gov (United States)

    2003-01-01

    When NASA needed a real-time, online database system capable of tracking documentation changes in its propulsion test facilities, engineers at Stennis Space Center joined with ECT International, of Brookfield, Wisconsin, to create a solution. Through NASA's Dual-Use Program, ECT developed Exdata, a software program that works within the company's existing Promise software. Exdata not only satisfied NASA s requirements, but also expanded ECT s commercial product line. Promise, ECT s primary product, is an intelligent software program with specialized functions for designing and documenting electrical control systems. An addon to AutoCAD software, Promis e generates control system schematics, panel layouts, bills of material, wire lists, and terminal plans. The drawing functions include symbol libraries, macros, and automatic line breaking. Primary Promise customers include manufacturing companies, utilities, and other organizations with complex processes to control.

  1. G-Protein-coupled receptors as potential drug candidates in preeclampsia: targeting the relaxin/insulin-like family peptide receptor 1 for treatment and prevention.

    Science.gov (United States)

    Conrad, Kirk P

    2016-09-01

    Important roles for G-protein-coupled receptors (GPCRs) have been identified in the maternal physiological adaptations to pregnancy and in the pathogenesis of preeclampsia. On this basis, GPCRs are potential therapeutic targets for preeclampsia. In this review, vasopressin and apelin are initially considered in this context before the focus on the hormone relaxin and its cognate receptor, the relaxin/insulin-like family peptide receptor 1 (RXFP1). Based on both compelling scientific rationale and a promising safety profile, the relaxin ligand-receptor system is comprehensively evaluated as a potential therapeutic endpoint in preeclampsia. The published literature relating to the topic was searched through January 2016 using PubMed. Relaxin is a peptide hormone secreted by the corpus luteum; it circulates in the luteal phase and during pregnancy. Activation of RXFP1 is vasodilatory; thus, relaxin supplementation is expected to at least partly restore the fundamental vasodilatory changes of normal pregnancy, thereby alleviating maternal organ hypoperfusion, which is a major pathogenic manifestation of severe preeclampsia. Specifically, by exploiting its pleiotropic hemodynamic attributes in preeclampsia, relaxin administration is predicted to (i) reverse robust arterial myogenic constriction; (ii) blunt systemic and renal vasoconstriction in response to activation of the angiotensin II receptor, type 1; (iii) mollify the action of endogenous vasoconstrictors on uterine spiral arteries with failed remodeling and retained smooth muscle; (iv) increase arterial compliance; (v) enhance insulin-mediated glucose disposal by promoting skeletal muscle vasodilation and (vi) mobilize and activate bone marrow-derived angiogenic progenitor cells, thereby repairing injured endothelium and improving maternal vascularity in organs such as breast, uterus, pancreas, skin and fat. By exploiting its pleiotropic molecular attributes in preeclampsia, relaxin supplementation is

  2. Mass spectrometric characterization of the hypoxia-inducible factor (HIF) stabilizer drug candidate BAY 85-3934 (molidustat) and its glucuronidated metabolite BAY-348, and their implementation into routine doping controls.

    Science.gov (United States)

    Dib, Josef; Mongongu, Cynthia; Buisson, Corinne; Molina, Adeline; Schänzer, Wilhelm; Thuss, Uwe; Thevis, Mario

    2017-01-01

    The development of new therapeutics potentially exhibiting performance-enhancing properties implicates the risk of their misuse by athletes in amateur and elite sports. Such drugs necessitate preventive anti-doping research for consideration in sports drug testing programmes. Hypoxia-inducible factor (HIF) stabilizers represent an emerging class of therapeutics that allows for increasing erythropoiesis in patients. BAY 85-3934 is a novel HIF stabilizer, which is currently undergoing phase-2 clinical trials. Consequently, the comprehensive characterization of BAY 85-3934 and human urinary metabolites as well as the implementation of these analytes into routine doping controls is of great importance. The mass spectrometric behaviour of the HIF stabilizer drug candidate BAY 85-3934 and a glucuronidated metabolite (BAY-348) were characterized by electrospray ionization-(tandem) mass spectrometry (ESI-MS(/MS)) and multiple-stage mass spectrometry (MS n ). Subsequently, two different laboratories established different analytical approaches (one each) enabling urine sample analyses by employing either direct urine injection or solid-phase extraction. The methods were cross-validated for the metabolite BAY-348 that is expected to represent an appropriate target analyte for human urine analysis. Two test methods allowing for the detection of BAY-348 in human urine were applied and cross-validated concerning the validation parameters specificity, linearity, lower limit of detection (LLOD; 1-5 ng/mL), ion suppression/enhancement (up to 78%), intra- and inter-day precision (3-21%), recovery (29-48%), and carryover. By means of ten spiked test urine samples sent blinded to one of the participating laboratories, the fitness-for-purpose of both assays was provided as all specimens were correctly identified applying both testing methods. As no post-administration study samples were available, analyses of authentic urine specimens remain desirable. Copyright © 2016 John Wiley

  3. Candidate cave entrances on Mars

    Science.gov (United States)

    Cushing, Glen E.

    2012-01-01

    This paper presents newly discovered candidate cave entrances into Martian near-surface lava tubes, volcano-tectonic fracture systems, and pit craters and describes their characteristics and exploration possibilities. These candidates are all collapse features that occur either intermittently along laterally continuous trench-like depressions or in the floors of sheer-walled atypical pit craters. As viewed from orbit, locations of most candidates are visibly consistent with known terrestrial features such as tube-fed lava flows, volcano-tectonic fractures, and pit craters, each of which forms by mechanisms that can produce caves. Although we cannot determine subsurface extents of the Martian features discussed here, some may continue unimpeded for many kilometers if terrestrial examples are indeed analogous. The features presented here were identified in images acquired by the Mars Odyssey's Thermal Emission Imaging System visible-wavelength camera, and by the Mars Reconnaissance Orbiter's Context Camera. Select candidates have since been targeted by the High-Resolution Imaging Science Experiment. Martian caves are promising potential sites for future human habitation and astrobiology investigations; understanding their characteristics is critical for long-term mission planning and for developing the necessary exploration technologies.

  4. Properties of myelin altered peptide ligand cyclo(87-99)(Ala91,Ala96)MBP87-99 render it a promising drug lead for immunotherapy of multiple sclerosis.

    Science.gov (United States)

    Deraos, George; Rodi, Maria; Kalbacher, Hubert; Chatzantoni, Kokona; Karagiannis, Fotios; Synodinos, Loukas; Plotas, Panayiotis; Papalois, Apostolos; Dimisianos, Nikolaos; Papathanasopoulos, Panagiotis; Gatos, Dimitrios; Tselios, Theodore; Apostolopoulos, Vasso; Mouzaki, Athanasia; Matsoukas, John

    2015-08-28

    , rendering cyclo(87-99)(Ala91,Ala96)MBP87-99 an important candidate drug for MS immunotherapy. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  5. Citizen Candidates Under Uncertainty

    OpenAIRE

    Eguia, Jon X.

    2005-01-01

    In this paper we make two contributions to the growing literature on "citizen-candidate" models of representative democracy. First, we add uncertainty about the total vote count. We show that in a society with a large electorate, where the outcome of the election is uncertain and where winning candidates receive a large reward from holding office, there will be a two-candidate equilibrium and no equilibria with a single candidate. Second, we introduce a new concept of equilibrium, which we te...

  6. Systematic in-vitro evaluation of the NCI/NIH Developmental Therapeutics Program Approved Oncology Drug Set for the identification of a candidate drug repertoire for MLL-rearranged leukemia

    Directory of Open Access Journals (Sweden)

    Hoeksema KA

    2011-09-01

    Full Text Available Kimberley A Hoeksema1, Aarthi Jayanthan1, Todd Cooper2, Lia Gore3, Tanya Trippett4, Jessica Boklan6, Robert J Arceci5, Aru Narendran11Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, AB, Canada; 2Aflac Cancer Center and Blood Disorders Service, Children's Healthcare of Atlanta, Emory University, Atlanta, GA, USA; 3Center for Cancer and Blood Disorders, Children's Hospital, University of Colorado Denver, Aurora, CO, USA; 4Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 5Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA; 6Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USAAbstract: Despite significant progress made in the overall cure rate, the prognosis for relapsed and refractory malignancies in children remains extremely poor. Hence, there is an urgent need for studies that enable the timely selection of appropriate agents for Phase I clinical studies. The Pediatric Oncology Experimental Therapeutics Investigators' Consortium (POETIC is systematically evaluating libraries of known and novel compounds for activity against subsets of high-risk pediatric malignancies with defined molecular aberrations for future clinical development. In this report, we describe the in-vitro activity of a diverse panel of approved oncology drugs against MLL-rearranged pediatric leukemia cell lines. Agents in the Approved Oncology Drug Set II (National Cancer Institute/National Institutes of Health Developmental Therapeutics Program were evaluated by in-vitro cytotoxicity assays in pediatric acute lymphoblastic leukemia and acute myeloid leukemia cell lines with MLL gene rearrangements. Validation studies were carried out with patient leukemia cells in culture. Comparative analysis for toxicity against nonmalignant cells was evaluated in normal bone marrow stromal cells and normal human lymphocytes. Results from this study show that 42 of the 89 agents tested have

  7. Imaging biomarkers as surrogate endpoints for drug development

    International Nuclear Information System (INIS)

    Richter, Wolf S.

    2006-01-01

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

  8. Development of an achiral supercritical fluid chromatography method with ultraviolet absorbance and mass spectrometric detection for impurity profiling of drug candidates. Part II. Selection of an orthogonal set of stationary phases.

    Science.gov (United States)

    Lemasson, Elise; Bertin, Sophie; Hennig, Philippe; Boiteux, Hélène; Lesellier, Eric; West, Caroline

    2015-08-21

    Impurity profiling of organic products that are synthesized as possible drug candidates requires complementary analytical methods to ensure that all impurities are identified. Supercritical fluid chromatography (SFC) is a very useful tool to achieve this objective, as an adequate selection of stationary phases can provide orthogonal separations so as to maximize the chances to see all impurities. In this series of papers, we have developed a method for achiral SFC-MS profiling of drug candidates, based on a selection of 160 analytes issued from Servier Research Laboratories. In the first part of this study, focusing on mobile phase selection, a gradient elution with carbon dioxide and methanol comprising 2% water and 20mM ammonium acetate proved to be the best in terms of chromatographic performance, while also providing good MS response [1]. The objective of this second part was the selection of an orthogonal set of ultra-high performance stationary phases, that was carried out in two steps. Firstly, a reduced set of analytes (20) was used to screen 23 columns. The columns selected were all 1.7-2.5μm fully porous or 2.6-2.7μm superficially porous particles, with a variety of stationary phase chemistries. Derringer desirability functions were used to rank the columns according to retention window, column efficiency evaluated with peak width of selected analytes, and the proportion of analytes successfully eluted with good peak shapes. The columns providing the worst performances were thus eliminated and a shorter selection of columns (11) was obtained. Secondly, based on 160 tested analytes, the 11 columns were ranked again. The retention data obtained on these columns were then compared to define a reduced set of the best columns providing the greatest orthogonality, to maximize the chances to see all impurities within a limited number of runs. Two high-performance columns were thus selected: ACQUITY UPC(2) HSS C18 SB and Nucleoshell HILIC. Copyright © 2015

  9. Drug Repositioning for Effective Prostate Cancer Treatment.

    Science.gov (United States)

    Turanli, Beste; Grøtli, Morten; Boren, Jan; Nielsen, Jens; Uhlen, Mathias; Arga, Kazim Y; Mardinoglu, Adil

    2018-01-01

    Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-κB inhibition, Wnt/β-Catenin pathway inhibition, DNMT1 inhibition, and GSK-3β inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.

  10. "Smart Pills" Promising, Problematic

    Science.gov (United States)

    Sparks, Sarah D.

    2012-01-01

    An explosion in the variety and availability of cognitive-enhancing drugs, from prescriptions like Ritalin to commercial drinks like NeuroFuel, raises concerns for scientists and educators alike--not just over the potential for abuse, but also over what educators and researchers consider, and how they approach, normal achievement. Evidence is…

  11. Vaccines: an ongoing promise?

    Science.gov (United States)

    Alsahli, M; Farrell, R J; Michetti, P

    2001-01-01

    Over the past decade, intensive research has focused on developing a vaccine therapy for Helicobacter pylori. Substantial unresolved questions cloud the current approach, and the development of a vaccine against this unique organism has proved very challenging. Many candidate vaccines have been tested in animal models. The immunogenicity and the safety of some vaccine formulations have been recently evaluated through clinical trials, and the efficacy of these vaccine therapies in humans will be determined in the near future. This article will provide an overview of the current knowledge of natural and vaccine-induced immune responses to H. pylori infection. It will also review past vaccine successes and failures in animal models and the limited experience to date in using vaccine therapy in humans. Several obstacles to H. pylori vaccine development efforts along with the future direction of these efforts will be discussed. Copyright 2001 S. Karger AG, Basel

  12. Curcumin, a potential therapeutic candidate for retinal diseases.

    Science.gov (United States)

    Wang, Lei-Lei; Sun, Yue; Huang, Kun; Zheng, Ling

    2013-09-01

    Curcumin, the major extraction of turmeric, has been widely used in many countries for centuries both as a spice and as a medicine. In the last decade, researchers have found the beneficial effects of curcumin on multiple disorders are due to its antioxidative, anti-inflammatory, and antiproliferative properties, as well as its novel function as an inhibitor of histone aectyltransferases. In this review, we summarize the recent progress made on studying the beneficial effects of curcumin on multiple retinal diseases, including diabetic retinopathy, glaucoma, and age-related macular degeneration. Recent clinical trials on the effectiveness of phosphatidylcholine formulated curcumin in treating eye diseases have also shown promising results, making curcumin a potent therapeutic drug candidate for inflammatory and degenerative retinal and eye diseases. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Promising change, delivering continuity

    DEFF Research Database (Denmark)

    Lund, Jens Friis; Sungusia, Eliezeri; Mabele, Mathew Bukhi

    2017-01-01

    REDD+ is an ambition to reduce carbon emissions from deforestation and forest degradation in the Global South. This ambition has generated unprecedented commitment of political support and financial funds for the forest-development sector. Many academics and people-centered advocacy organizations...... have conceptualized REDD+ as an example of ‘‘green grabbing” and have voiced fears of a potential global rush for land and trees. In this paper we argue that, in practice and up until now, REDD+ resembles longstanding dynamics of the development and conservation industry, where the promise of change...... becomes a discursive commodity that is constantly reproduced and used to generate value and appropriate financial resources. We thus argue for a re-conceptualization of REDD+ as a conservation fad within the broader political economy of development and conservation. We derive this argument from a study...

  14. Update on the Clinical Development of Candidate Malaria Vaccines

    National Research Council Canada - National Science Library

    Ballou, W. R; Arevalo-Herrera, Myriam; Carucci, Daniel; Richie, Thomas L; Corradin, Giampietro; Diggs, Carter; Druilhe, Pierre; Giersing, Birgitte K; Saul, Allan; Heppner, D. G

    2004-01-01

    ... powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure...

  15. Promising ion-sensitive in situ ocular nanoemulsion gels of terbinafine hydrochloride: design, in vitro characterization and in vivo estimation of the ocular irritation and drug pharmacokinetics in the aqueous humor of rabbits.

    Science.gov (United States)

    Tayel, Saadia Ahmed; El-Nabarawi, Mohamed Ahmed; Tadros, Mina Ibrahim; Abd-Elsalam, Wessam Hamdy

    2013-02-25

    Terbinafine hydrochloride (T-HCl) is recommended for the management of fungal keratitis. To maintain effective aqueous humor concentrations, frequent instillation of T-HCl drops is necessary. This work aimed to develop alternative controlled-release in situ ocular drug-loaded nanoemulsion (NE) gels. Twelve pseudoternary-phase diagrams were constructed using oils (isopropyl myristate/Miglyol 812), surfactants (Tween 80/Cremophor EL), a co-surfactant (polyethylene glycol 400) and water. Eight drug-loaded (0.5%, w/v) NEs were evaluated for thermodynamic stability, morphology, droplet size and drug release in simulated tear fluid (pH 7.4). Following dispersion in gellan gum solution (0.2%, w/w), the in situ NE gels were characterized for transparency, rheological behavior, mucoadhesive force, drug release and histopathological assessment of ocular irritation. Drug pharmacokinetics of sterilized F31 [Miglyol 812, Cremophor EL: polyethylene glycol 400 (1:2) and water (5, 55 and 40%, w/w, respectively)] in situ NE gel and oily drug solution were evaluated in rabbit aqueous humor. The NEs were thermodynamically stable and have spherical droplets (<30 nm). The gels were transparent, pseudoplastic, mucoadhesive and showed more retarded zero-order drug release rates. F31 in situ NE gel showed the least ocular irritation potential and significantly (P<0.01) higher C(max), delayed T(max), prolonged mean residence time and increased bioavailability. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Polymer brush hexadecyltrimethylammonium bromide (CTAB) modified poly (propylene-g-styrene sulphonic acid) fiber (ZB-1): CTAB/ZB-1 as a promising strategy for improving the dissolution and physical stability of poorly water-soluble drugs.

    Science.gov (United States)

    Cao, Jinxu; Yang, Baixue; Wang, Yumei; Wei, Chen; Wang, Hongyu; Li, Sanming

    2017-11-01

    The feasibility of polymer brush as drug delivery vehicle was demonstrated with the goal of improving the dissolution and physical stability of poorly water-soluble drugs. Polymer brush CTAB/ZB-1 was synthesized by electrostatic interaction using a physical modification method with anionic poly (propylene-g-styrene sulphonic acid) fiber (ZB-1) as the substrate and cationic hexadecyltrimethylammonium bromide (CTAB) as the modifier. The polymer brush structure of CTAB/ZB-1 was validated by atomic force microscopy (AFM) and the channels of brush provided the drug loading sites. Flurbiprofen (FP), a BCS class II representative drug, was selected as the model poorly water-soluble drug to be loaded into this polymer brush. Then the drug loading and release were systematically investigated. Besides, the transformation from crystalline FP to amorphous state was observed by differential scanning calorimeter (DSC). In vitro dissolution in pure water and pH1.2 HCl media with/without 0.1% sodium dodecyl sulfate (SDS) was tested. Moreover, the optimal formulations (namely carrier/drug ratios) were determined. The results demonstrated prominent improvement of dissolution when FP was released from CTAB/ZB-1. After a long time storage, FP remained amorphous in CTAB/ZB-1 according to DSC determinations and performed an approximately equivalent dissolution compared with fresh samples, suggesting the advantage of CTAB/ZB-1 as carrier in enhancing the physical stability of drugs. The study introduced the versatile easily formulated polymer brush CTAB/ZB-1 and demonstrated the potential of polymer brush as an alternative approach for improving the dissolution and physical stability of poorly water-soluble drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.

    Science.gov (United States)

    Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H

    2018-02-01

    More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  18. The promise of N-acetylcysteine in neuropsychiatry.

    Science.gov (United States)

    Berk, Michael; Malhi, Gin S; Gray, Laura J; Dean, Olivia M

    2013-03-01

    N-Acetylcysteine (NAC) targets a diverse array of factors germane to the pathophysiology of multiple neuropsychiatric disorders including glutamatergic transmission, the antioxidant glutathione, neurotrophins, apoptosis, mitochondrial function, and inflammatory pathways. This review summarises the areas where the mechanisms of action of NAC overlap with known pathophysiological elements, and offers a précis of current literature regarding the use of NAC in disorders including cocaine, cannabis, and smoking addictions, Alzheimer's and Parkinson's diseases, autism, compulsive and grooming disorders, schizophrenia, depression, and bipolar disorder. There are positive trials of NAC in all these disorders, and although many of these require replication and are methodologically preliminary, this makes it one of the most promising drug candidates in neuropsychiatric disorders. The efficacy pattern of NAC interestingly shows little respect for the current diagnostic systems. Its benign tolerability profile, its action on multiple operative pathways, and the emergence of positive trial data make it an important target to investigate. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. The Promises of Biology and the Biology of Promises

    DEFF Research Database (Denmark)

    Lee, Jieun

    2015-01-01

    commitments with differently imagined futures. I argue that promises are constitutive of the stem cell biology, rather than being derivative of it. Since the biological concept of stem cells is predicated on the future that they promise, the biological life of stem cells is inextricably intertwined...... patients’ bodies in anticipation of materializing the promises of stem cell biology, they are produced as a new form of biovaluable. The promises of biology move beyond the closed circuit of scientific knowledge production, and proliferate in the speculative marketplaces of promises. Part II looks at how...... of technologized biology and biological time can appear promising with the backdrop of the imagined intransigence of social, political, and economic order in the Korean society....

  20. Buckyballs meet Viral Nanoparticles – Candidates for Biomedicine

    Science.gov (United States)

    Steinmetz, Nicole F.; Hong, Vu; Spoerke, Erik D.; Lu, Ping; Breitenkamp, Kurt; Finn, M.G.; Manchester, Marianne

    2009-01-01

    Fullerenes such as C60 show promise as functional components in several emerging technologies. For biomedical applications, C60 has been used in gene- and drug-delivery vectors, as imaging agents, and as photosensitizers in cancer therapy. A major drawback of C60 for bioapplications is its insolubility in water. To overcome this limitation, we covalently attached C60 derivatives to Cowpea mosaic virus and bacteriophage Qβ virus-like particles, as examples of naturally occurring viral nanoparticle (VNP) structures that have been shown to be promising candidates for biomedicine. Two different labeling strategies were employed, giving rise to water-soluble and stable VNP-C60 and VNP-PEG-C60 conjugates. Samples were characterized using a combination of transmission electron microscopy, scanning transmission electron microscopy (STEM), gel electrophoresis, size-exclusion chromatography, dynamic light scattering, and western blotting. “Click” chemistry bioconjugation using a PEG-modified propargyl-O-PEG-C60 derivative gave rise to high loadings of fullerene on the VNP surface, indicated by the imaging of individual C60 units by STEM. The cellular uptake of dye-labeled VNP-PEG-C60 complexes in a human cancer cell line was found by confocal microscopy to be robust, showing that cell internalization was not inhibited by the attached C60 units. These results open the door for the development of novel therapeutic devices with potential applications in photo-activated tumor therapy. PMID:19904938

  1. Repurposing drugs for the treatment and control of helminth infections

    Directory of Open Access Journals (Sweden)

    Gordana Panic

    2014-12-01

    Full Text Available Helminth infections are responsible for a considerable public health burden, yet the current drug armamentarium is small. Given the high cost of drug discovery and development, the high failure rates and the long duration to develop novel treatments, drug repurposing circumvents these obstacles by finding new uses for compounds other than those they were initially intended to treat. In the present review, we summarize in vivo and clinical trial findings testing clinical candidates and marketed drugs against schistosomes, food-borne trematodes, soil-transmitted helminths, Strongyloides stercoralis, the major human filariases lymphatic filariasis and onchocerciasis, taeniasis, neurocysticercosis and echinococcosis. While expanding the applications of broad-spectrum or veterinary anthelmintics continues to fuel alternative treatment options, antimalarials, antibiotics, antiprotozoals and anticancer agents appear to be producing fruitful results as well. The trematodes and nematodes continue to be most investigated, while cestodal drug discovery will need to be accelerated. The most clinically advanced drug candidates include the artemisinins and mefloquine against schistosomiasis, tribendimidine against liver flukes, oxantel pamoate against trichuriasis, and doxycycline against filariasis. Preclinical studies indicate a handful of promising future candidates, and are beginning to elucidate the broad-spectrum activity of some currently used anthelmintics. Challenges and opportunities are further discussed.

  2. Dark matter candidates

    International Nuclear Information System (INIS)

    Turner, M.S.

    1989-01-01

    One of the simplest, yet most profound, questions we can ask about the Universe is, how much stuff is in it, and further what is that stuff composed of? Needless to say, the answer to this question has very important implications for the evolution of the Universe, determining both the ultimate fate and the course of structure formation. Remarkably, at this late date in the history of the Universe we still do not have a definitive answer to this simplest of questions---although we have some very intriguing clues. It is known with certainty that most of the material in the Universe is dark, and we have the strong suspicion that the dominant component of material in the Cosmos is not baryons, but rather is exotic relic elementary particles left over from the earliest, very hot epoch of the Universe. If true, the Dark Matter question is a most fundamental one facing both particle physics and cosmology. The leading particle dark matter candidates are: the axion, the neutralino, and a light neutrino species. All three candidates are accessible to experimental tests, and experiments are now in progress. In addition, there are several dark horse, long shot, candidates, including the superheavy magnetic monopole and soliton stars. 13 refs

  3. Plasticity of the Leishmania genome leading to gene copy number variations and drug resistance [version 1; referees: 5 approved

    Directory of Open Access Journals (Sweden)

    Marie-Claude N. Laffitte

    2016-09-01

    Full Text Available Leishmania has a plastic genome, and drug pressure can select for gene copy number variation (CNV. CNVs can apply either to whole chromosomes, leading to aneuploidy, or to specific genomic regions. For the latter, the amplification of chromosomal regions occurs at the level of homologous direct or inverted repeated sequences leading to extrachromosomal circular or linear amplified DNAs. This ability of Leishmania to respond to drug pressure by CNVs has led to the development of genomic screens such as Cos-Seq, which has the potential of expediting the discovery of drug targets for novel promising drug candidates.

  4. Microfluidic cell culture systems for drug research.

    Science.gov (United States)

    Wu, Min-Hsien; Huang, Song-Bin; Lee, Gwo-Bin

    2010-04-21

    In pharmaceutical research, an adequate cell-based assay scheme to efficiently screen and to validate potential drug candidates in the initial stage of drug discovery is crucial. In order to better predict the clinical response to drug compounds, a cell culture model that is faithful to in vivo behavior is required. With the recent advances in microfluidic technology, the utilization of a microfluidic-based cell culture has several advantages, making it a promising alternative to the conventional cell culture methods. This review starts with a comprehensive discussion on the general process for drug discovery and development, the role of cell culture in drug research, and the characteristics of the cell culture formats commonly used in current microfluidic-based, cell-culture practices. Due to the significant differences in several physical phenomena between microscale and macroscale devices, microfluidic technology provides unique functionality, which is not previously possible by using traditional techniques. In a subsequent section, the niches for using microfluidic-based cell culture systems for drug research are discussed. Moreover, some critical issues such as cell immobilization, medium pumping or gradient generation in microfluidic-based, cell-culture systems are also reviewed. Finally, some practical applications of microfluidic-based, cell-culture systems in drug research particularly those pertaining to drug toxicity testing and those with a high-throughput capability are highlighted.

  5. Optimized candidal biofilm microtiter assay

    NARCIS (Netherlands)

    Krom, Bastiaan P.; Cohen, Jesse B.; Feser, Gail E. McElhaney; Cihlar, Ronald L.

    Microtiter based candidal biofilm formation is commonly being used. Here we describe the analysis of factors influencing the development of candidal biofilms such as the coating with serum, growth medium and pH. The data reported here show that optimal candidal biofilm formation is obtained when

  6. Anti-Aging Drugs - Prospect of Longer Life?

    Science.gov (United States)

    Klimova, Blanka; Novotny, Michal; Kuca, Kamil

    2017-11-29

    Aging is a natural part of human life. However, recent discoveries indicate that pharmacological approaches used for the improvement and possibly, for the delay of the aging process, might shed a new light on this topic. This might obviously contribute to the extension of the active life of older people and maintenance of their quality of life, which could consequently reduce both social and economic burden of each country, especially the developed ones. The purpose of this study is to explore pharmacological discoveries which may help to the delay or improvement of the aging process. More specifically, the authors focus on three anti-aging drugs candidates: metformin, rapamycin and resveratrol and one anti-aging component NAD+ precursors whose randomized control trials on animals have appeared to provide some efficacy in this respect and they seem to be promising in the aging process of human beings. This was done by conducting a literature review of available sources describing the issue of aging process with special focus on those anti-aging drug candidates. The results of this study indicate that promising anti-aging candidates seem to be metformin, especially as far as cardiovascular or cancer mortality is concerned, and NAD+ precursors since they appear to promote better organ function, increased physical resistance, disease resistance and prolonged life expectancy. There is a call for more longitudinal clinical trials, which would prove the efficacy of the promising anti-aging drugs candidates in humans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Mastering JavaScript promises

    CERN Document Server

    Hussain, Muzzamil

    2015-01-01

    This book is for all the software and web engineers wanting to apply the promises paradigm to their next project and get the best outcome from it. This book also acts as a reference for the engineers who are already using promises in their projects and want to improve their current knowledge to reach the next level. To get the most benefit from this book, you should know basic programming concepts, have a familiarity with JavaScript, and a good understanding of HTML.

  8. Has molecular imaging delivered to drug development?

    Science.gov (United States)

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

    2017-10-01

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

  9. Candida Biofilms: Threats, Challenges, and Promising Strategies

    Science.gov (United States)

    Cavalheiro, Mafalda; Teixeira, Miguel Cacho

    2018-01-01

    Candida species are fungal pathogens known for their ability to cause superficial and systemic infections in the human host. These pathogens are able to persist inside the host due to the development of pathogenicity and multidrug resistance traits, often leading to the failure of therapeutic strategies. One specific feature of Candida species pathogenicity is their ability to form biofilms, which protects them from external factors such as host immune system defenses and antifungal drugs. This review focuses on the current threats and challenges when dealing with biofilms formed by Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis, highlighting the differences between the four species. Biofilm characteristics depend on the ability of each species to produce extracellular polymeric substances (EPS) and display dimorphic growth, but also on the biofilm substratum, carbon source availability and other factors. Additionally, the transcriptional control over processes like adhesion, biofilm formation, filamentation, and EPS production displays great complexity and diversity within pathogenic yeasts of the Candida genus. These differences not only have implications in the persistence of colonization and infections but also on antifungal resistance typically found in Candida biofilm cells, potentiated by EPS, that functions as a barrier to drug diffusion, and by the overexpression of drug resistance transporters. The ability to interact with different species in in vivo Candida biofilms is also a key factor to consider when dealing with this problem. Despite many challenges, the most promising strategies that are currently available or under development to limit biofilm formation or to eradicate mature biofilms are discussed. PMID:29487851

  10. Candida Biofilms: Threats, Challenges, and Promising Strategies.

    Science.gov (United States)

    Cavalheiro, Mafalda; Teixeira, Miguel Cacho

    2018-01-01

    Candida species are fungal pathogens known for their ability to cause superficial and systemic infections in the human host. These pathogens are able to persist inside the host due to the development of pathogenicity and multidrug resistance traits, often leading to the failure of therapeutic strategies. One specific feature of Candida species pathogenicity is their ability to form biofilms, which protects them from external factors such as host immune system defenses and antifungal drugs. This review focuses on the current threats and challenges when dealing with biofilms formed by Candida albicans, Candida glabrata, Candida tropicalis , and Candida parapsilosis , highlighting the differences between the four species. Biofilm characteristics depend on the ability of each species to produce extracellular polymeric substances (EPS) and display dimorphic growth, but also on the biofilm substratum, carbon source availability and other factors. Additionally, the transcriptional control over processes like adhesion, biofilm formation, filamentation, and EPS production displays great complexity and diversity within pathogenic yeasts of the Candida genus. These differences not only have implications in the persistence of colonization and infections but also on antifungal resistance typically found in Candida biofilm cells, potentiated by EPS, that functions as a barrier to drug diffusion, and by the overexpression of drug resistance transporters. The ability to interact with different species in in vivo Candida biofilms is also a key factor to consider when dealing with this problem. Despite many challenges, the most promising strategies that are currently available or under development to limit biofilm formation or to eradicate mature biofilms are discussed.

  11. Using Metabolomics to Investigate Biomarkers of Drug Addiction.

    Science.gov (United States)

    Ghanbari, Reza; Sumner, Susan

    2018-02-01

    Drug addiction has been associated with an increased risk for cancer, psychological complications, heart, liver, and lung disease, as well as infection. While genes have been identified that can mark individuals at risk for substance abuse, the initiation step of addiction is attributed to persistent metabolic disruptions occurring following the first instance of narcotic drug use. Advances in analytical technologies can enable the detection of thousands of signals in body fluids and excreta that can be used to define biochemical profiles of addiction. Today, these approaches hold promise for determining how exposure to drugs, in the absence or presence of other environmentally relevant factors, can impact human metabolism. We posit that these can lead to candidate biomarkers of drug dependence, treatment, withdrawal, or relapse. Copyright © 2017. Published by Elsevier Ltd.

  12. West Nile Virus Drug Discovery

    Directory of Open Access Journals (Sweden)

    Siew Pheng Lim

    2013-12-01

    Full Text Available The outbreak of West Nile virus (WNV in 1999 in the USA, and its continued spread throughout the Americas, parts of Europe, the Middle East and Africa, underscored the need for WNV antiviral development. Here, we review the current status of WNV drug discovery. A number of approaches have been used to search for inhibitors of WNV, including viral infection-based screening, enzyme-based screening, structure-based virtual screening, structure-based rationale design, and antibody-based therapy. These efforts have yielded inhibitors of viral or cellular factors that are critical for viral replication. For small molecule inhibitors, no promising preclinical candidate has been developed; most of the inhibitors could not even be advanced to the stage of hit-to-lead optimization due to their poor drug-like properties. However, several inhibitors developed for related members of the family Flaviviridae, such as dengue virus and hepatitis C virus, exhibited cross-inhibition of WNV, suggesting the possibility to re-purpose these antivirals for WNV treatment. Most promisingly, therapeutic antibodies have shown excellent efficacy in mouse model; one of such antibodies has been advanced into clinical trial. The knowledge accumulated during the past fifteen years has provided better rationale for the ongoing WNV and other flavivirus antiviral development.

  13. Nuclear energy: obstacles and promises

    International Nuclear Information System (INIS)

    Bacher, P.

    2003-01-01

    Nuclear energy has distinctive merits (sustainable resources, low costs, no greenhouse gases) but its development must overcome serious hurdles (fear of accidents, radio-phobia, waste management). The large unit size of present-day reactors is compatible only with large electrical grids, and involves a high capital cost. Taking into account these different factors, the paper outlines how nuclear energy may contribute to the reduction of greenhouse gases, and which are the most promising developments. (author)

  14. The promise of cyborg intelligence.

    Science.gov (United States)

    Brown, Michael F; Brown, Alexander A

    2017-03-01

    Yu et al. (2016) demonstrated that algorithms designed to find efficient routes in standard mazes can be integrated with the natural processes controlling rat navigation and spatial choices, and they pointed out the promise of such "cyborg intelligence" for biorobotic applications. Here, we briefly describe Yu et al.'s work, explore its relevance to the study of comparative cognition, and indicate how work involving cyborg intelligence would benefit from interdisciplinary collaboration between behavioral scientists and engineers.

  15. Freedom: A Promise of Possibility.

    Science.gov (United States)

    Bunkers, Sandra Schmidt

    2015-10-01

    The idea of freedom as a promise of possibility is explored in this column. The core concepts from a research study on considering tomorrow (Bunkers, 1998) coupled with humanbecoming community change processes (Parse, 2003) are used to illuminate this notion. The importance of intentionality in human freedom is discussed from both a human science and a natural science perspective. © The Author(s) 2015.

  16. Silicon homo-heterojunction solar cells: A promising candidate to realize high performance more stably

    Directory of Open Access Journals (Sweden)

    Miao Tan

    2017-08-01

    Full Text Available We have investigated the influences of diverse physical parameters on the performances of a silicon homo-heterojunction (H-H solar cell, which encompasses both homojunction and heterojunction, together with their underlying mechanisms by the aid of AFORS-HET simulation. It is found that the performances of H-H solar cell are less sensitive to (i the work function of the transparent conductive oxide layer, (ii the interfacial density of states at the front hydrogenated amorphous silicon/crystalline silicon (a-Si:H/c-Si interface, (iii the peak dangling bond defect densities within the p-type a-Si:H (p-a-Si:H layer, and (iv the doping concentration of the p-a-Si:H layer, when compared to that of the conventional heterojunction with intrinsic thin layer (HIT counterparts. These advantages are due to the fact that the interfacial recombination and the recombination within the a-Si:H region are less affected by all the above parameters, which fundamentally benefit from the field-effect passivation of the homojunction. Therefore, the design of H-H structure can provide an opportunity to produce high-efficiency solar cells more stably.

  17. Betula pendula: A Promising Candidate for Phytoremediation of TCE in Northern Climates.

    Science.gov (United States)

    Lewis, Jeffrey; Qvarfort, Ulf; Sjöström, Jan

    2015-01-01

    Betula pendula (Silver birch) trees growing on two contaminated sites were evaluated to assess their capacity to phytoscreen and phytoremediate chlorinated aliphatic compounds and heavy metals. Both locations are industrially-contaminated properties in central Sweden. The first was the site of a trichloroethylene (TCE) spill in the 1980s while the second was polluted with heavy metals by burning industrial wastes. In both cases, sap and sapwood from Silver birch trees were collected and analyzed for either chlorinated aliphatic compounds or heavy metals. These results were compared to analyses of the surface soil, vadose zone pore air and groundwater. Silver birch demonstrated the potential to phytoscreen and possibly phytoremediate TCE and related compounds, but it did not demonstrate the ability to effectively phytoextract heavy metals when compared with hyperaccumulator plants. The capacity of Silver birch to phytoremediate TCE appears comparable to tree species that have been employed in field-scale TCE phytoremediation efforts, such as Populus spp. and Eucalyptus sideroxylon rosea.

  18. Pyrolytic carbon coating for cytocompatibility of titanium oxide nanoparticles: a promising candidate for medical applications

    International Nuclear Information System (INIS)

    Behzadi, Shahed; Simchi, Abdolreza; Imani, Mohammad; Yousefi, Mohammad; Galinetto, Pietro; Amiri, Houshang; Stroeve, Pieter; Mahmoudi, Morteza

    2012-01-01

    Nanoparticles for biomedical use must be cytocompatible with the biological environment that they are exposed to. Current research has focused on the surface functionalization of nanoparticles by using proteins, polymers, thiols and other organic compounds. Here we show that inorganic nanoparticles such as titanium oxide can be coated by pyrolytic carbon (PyC) and that the coating has cytocompatible properties. Pyrolization and condensation of methane formed a thin layer of pyrolytic carbon on the titanium oxide core. The formation of the PyC shell retards coalescence and sintering of the ceramic phase. Our MTT assay shows that the PyC-coated particles are cytocompatible at employed doses. (paper)

  19. Bionomics of Neolasioptera aculeatae (Diptera: Cecidomyiidae, a promising biological control candidate against Parkinsonia aculeata (Fabaceae

    Directory of Open Access Journals (Sweden)

    Fernando Mc KAY

    2014-01-01

    Full Text Available Inspecciones de campo realizadas sobre Parkinsonia aculeata L. en el Norte-centro de Argentina entre 2008 y 2011 revelaron la presencia del mosquito agallícola Neolasioptera aculeatae Gagné (Diptera: Cecidomyiidae. La presencia de las agallas de N. aculeatae está restringida a la distribución norte de P. aculeata. La disección de agallas recolectadas a lo largo del año, reveló la presencia de larvas y/o pupas en distintos estados fenológicos de P. aculeata. La emergencia de adultos de N. aculeatae tuvo lugar 13 a 34 días desde la recolección en el campo y se extendió por un período promedio de 22 días. Entre once especies de leguminosas inspeccionadas en el campo, adultos de N. aculeatae emergieron únicamente de agallas recolectadas sobre P. aculeata. Los atributos biológicos y el restringido conjunto de plantas hospederas utilizadas en el campo, hacen de N. aculeatae un agente promisorio para el control biológico de P. aculeata.

  20. Bacillus pumilus BpCRI 6, a promising candidate for cellulase ...

    African Journals Online (AJOL)

    Cellulose degrading organisms have been used for the conversion of cellulolytic materials into soluble sugars or solvents in several biotechnological and industrial applications. In this report, a mutant of Bacillus pumilus was obtained after chemical mutagenesis and screened for cellulase production. This mutant named ...

  1. Coalitional game theory as a promising approach to identify candidate autism genes.

    Science.gov (United States)

    Gupta, Anika; Sun, Min Woo; Paskov, Kelley Marie; Stockham, Nate Tyler; Jung, Jae-Yoon; Wall, Dennis Paul

    2018-01-01

    Despite mounting evidence for the strong role of genetics in the phenotypic manifestation of Autism Spectrum Disorder (ASD), the specific genes responsible for the variable forms of ASD remain undefined. ASD may be best explained by a combinatorial genetic model with varying epistatic interactions across many small effect mutations. Coalitional or cooperative game theory is a technique that studies the combined effects of groups of players, known as coalitions, seeking to identify players who tend to improve the performance--the relationship to a specific disease phenotype--of any coalition they join. This method has been previously shown to boost biologically informative signal in gene expression data but to-date has not been applied to the search for cooperative mutations among putative ASD genes. We describe our approach to highlight genes relevant to ASD using coalitional game theory on alteration data of 1,965 fully sequenced genomes from 756 multiplex families. Alterations were encoded into binary matrices for ASD (case) and unaffected (control) samples, indicating likely gene-disrupting, inherited mutations in altered genes. To determine individual gene contributions given an ASD phenotype, a "player" metric, referred to as the Shapley value, was calculated for each gene in the case and control cohorts. Sixty seven genes were found to have significantly elevated player scores and likely represent significant contributors to the genetic coordination underlying ASD. Using network and cross-study analysis, we found that these genes are involved in biological pathways known to be affected in the autism cases and that a subset directly interact with several genes known to have strong associations to autism. These findings suggest that coalitional game theory can be applied to large-scale genomic data to identify hidden yet influential players in complex polygenic disorders such as autism.

  2. A Highly Luminescent Hexanuclear Molybdenum Cluster - A Promising Candidate toward Photoactive Materials

    Czech Academy of Sciences Publication Activity Database

    Kirakci, Kaplan; Kubát, Pavel; Dušek, Michal; Fejfarová, Karla; Šícha, Václav; Mosinger, Jiří; Lang, Kamil

    2012-01-01

    Roč. 2012, č. 19 (2012), s. 3107-3111 ISSN 1434-1948 R&D Projects: GA ČR(CZ) GAP204/11/0809; GA ČR GAP208/10/1678 Institutional support: RVO:61388980 ; RVO:61388955 ; RVO:68378271 Keywords : cluster compounds * luminescence * molybdenum * organic-inorganic hybrid composites * singlet oxygen Subject RIV: CA - Inorganic Chemistry Impact factor: 3.120, year: 2012

  3. Trisoctahedral gold nanocrystal: A promising candidate for the study of plasmonics using cathodoluminescence

    International Nuclear Information System (INIS)

    Maity, Achyut; Maiti, Arpan; Satpati, Biswarup; Chini, Tapas Kumar

    2016-01-01

    We study plasmon assisted luminescence from an isolated single trisoctahedral (TOH) gold (Au) nanocrystal using cathodoluminescence (CL) spectroscopy and imaging in a field emission scanning electron microscope (FESEM). The site specific e-beam excitation reveals a double peaked spectrum with the localized surface plasmon resonance (LSPR) at 540 nm and 660 nm and a single resonant peaked spectrum at 560 nm. The spatial variation of the plasmon assisted luminescence was strongest at the apex points as well as at the edges and corners.

  4. Silicon homo-heterojunction solar cells: A promising candidate to realize high performance more stably

    Science.gov (United States)

    Tan, Miao; Zhong, Sihua; Wang, Wenjie; Shen, Wenzhong

    2017-08-01

    We have investigated the influences of diverse physical parameters on the performances of a silicon homo-heterojunction (H-H) solar cell, which encompasses both homojunction and heterojunction, together with their underlying mechanisms by the aid of AFORS-HET simulation. It is found that the performances of H-H solar cell are less sensitive to (i) the work function of the transparent conductive oxide layer, (ii) the interfacial density of states at the front hydrogenated amorphous silicon/crystalline silicon (a-Si:H/c-Si) interface, (iii) the peak dangling bond defect densities within the p-type a-Si:H (p-a-Si:H) layer, and (iv) the doping concentration of the p-a-Si:H layer, when compared to that of the conventional heterojunction with intrinsic thin layer (HIT) counterparts. These advantages are due to the fact that the interfacial recombination and the recombination within the a-Si:H region are less affected by all the above parameters, which fundamentally benefit from the field-effect passivation of the homojunction. Therefore, the design of H-H structure can provide an opportunity to produce high-efficiency solar cells more stably.

  5. Pyrolytic carbon coating for cytocompatibility of titanium oxide nanoparticles: a promising candidate for medical applications.

    NARCIS (Netherlands)

    Behzadi, S.; Imani, M.; Yousefi, M.; Galinetto, P.; Simchi, A.; Amiri, H.; Stroeve, P.; Mahmoudi, M.

    2012-01-01

    Nanoparticles for biomedical use must be cytocompatible with the biological environment that they are exposed to. Current research has focused on the surface functionalization of nanoparticles by using proteins, polymers, thiols and other organic compounds. Here we show that inorganic nanoparticles

  6. 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.

  7. P-glycoprotein targeted nanoscale drug carriers

    KAUST Repository

    Li, Wengang

    2013-02-01

    Multi-drug resistance (MDR) is a trend whereby tumor cells exposed to one cytotoxic agent develop cross-resistance to a range of structurally and functionally unrelated compounds. P -glycoprotein (P -gp) efflux pump is one of the mostly studied drug carrying processes that shuttle the drugs out of tumor cells. Thus, P -gp inhibitors have attracted a lot of attention as they can stop cancer drugs from being pumped out of target cells with the consumption of ATP. Using quantitive structure activity relationship (QSAR), we have successfully synthesized a series of novel P -gp inhibitors. The obtained dihydropyrroloquinoxalines series were fully characterized and then tested against bacterial and tumor assays with over-expressed P -gps. All compounds were bioactive especially compound 1c that had enhanced antibacterial activity. Furthermore, these compounds were utilized as targeting vectors to direct drug delivery vehicles such as silica nanoparticles (SNPs) to cancerous Hela cells with over expressed P -gps. Cell uptake studies showed a successful accumulation of these decorated SNPs in tumor cells compared to undecorated SNPs. The results obtained show that dihydropyrroloquinoxalines constitute a promising drug candidate for targeting cancers with MDR. Copyright © 2013 American Scientific Publishers All rights reserved.

  8. Indolcarboxamide is a preclinical candidate for treating multidrug-resistant tuberculosis.

    Science.gov (United States)

    Rao, Srinivasa P S; Lakshminarayana, Suresh B; Kondreddi, Ravinder R; Herve, Maxime; Camacho, Luis R; Bifani, Pablo; Kalapala, Sarath K; Jiricek, Jan; Ma, Ng L; Tan, Bee H; Ng, Seow H; Nanjundappa, Mahesh; Ravindran, Sindhu; Seah, Peck G; Thayalan, Pamela; Lim, Siao H; Lee, Boon H; Goh, Anne; Barnes, Whitney S; Chen, Zhong; Gagaring, Kerstin; Chatterjee, Arnab K; Pethe, Kevin; Kuhen, Kelli; Walker, John; Feng, Gu; Babu, Sreehari; Zhang, Lijun; Blasco, Francesca; Beer, David; Weaver, Margaret; Dartois, Veronique; Glynne, Richard; Dick, Thomas; Smith, Paul W; Diagana, Thierry T; Manjunatha, Ujjini H

    2013-12-04

    New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.

  9. Novel amidines and analogues as promising agents against intracellular parasites: a systematic review.

    Science.gov (United States)

    Soeiro, M N C; Werbovetz, K; Boykin, D W; Wilson, W D; Wang, M Z; Hemphill, A

    2013-07-01

    Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

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

    Science.gov (United States)

    Beesetti, Hemalatha; Khanna, Navin; Swaminathan, Sathyamangalam

    2016-09-01

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

  11. Produtos naturais como candidatos a fármacos úteis no tratamento do Mal de Alzheimer Natural products as candidates for useful drugs in the treatment of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Cláudio Viegas Junior

    2004-08-01

    Full Text Available Alzheimer's disease (AD is a progressive neurodegenerative pathology with severe economic and social impact. There is currently no cure, although cholinesterase inhibitors provide effective temporary relief of symptoms in some patients. Nowadays drug research and development are based on the cholinergic hypothesis that supports the cognition improvement by regulation of the synthesis and release of acetylcholine in the brain. There are only four commercial medicines approved for treatment of AD and natural products have played an important role in the research for new acetylcholinesterase inhibitors.

  12. Large-scale computational drug repositioning to find treatments for rare diseases.

    Science.gov (United States)

    Govindaraj, Rajiv Gandhi; Naderi, Misagh; Singha, Manali; Lemoine, Jeffrey; Brylinski, Michal

    2018-01-01

    Rare, or orphan, diseases are conditions afflicting a small subset of people in a population. Although these disorders collectively pose significant health care problems, drug companies require government incentives to develop drugs for rare diseases due to extremely limited individual markets. Computer-aided drug repositioning, i.e., finding new indications for existing drugs, is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Structure-based matching of drug-binding pockets is among the most promising computational techniques to inform drug repositioning. In order to find new targets for known drugs ultimately leading to drug repositioning, we recently developed e MatchSite, a new computer program to compare drug-binding sites. In this study, e MatchSite is combined with virtual screening to systematically explore opportunities to reposition known drugs to proteins associated with rare diseases. The effectiveness of this integrated approach is demonstrated for a kinase inhibitor, which is a confirmed candidate for repositioning to synapsin Ia. The resulting dataset comprises 31,142 putative drug-target complexes linked to 980 orphan diseases. The modeling accuracy is evaluated against the structural data recently released for tyrosine-protein kinase HCK. To illustrate how potential therapeutics for rare diseases can be identified, we discuss a possibility to repurpose a steroidal aromatase inhibitor to treat Niemann-Pick disease type C. Overall, the exhaustive exploration of the drug repositioning space exposes new opportunities to combat orphan diseases with existing drugs. DrugBank/Orphanet repositioning data are freely available to research community at https://osf.io/qdjup/.

  13. Chitin fulfilling a biomaterials promise

    CERN Document Server

    Khor, Eugene

    2001-01-01

    The second edition of Chitin underscores the important factors for standardizing chitin processing and characterization. It captures the essential interplay between chitin's assets and limitations as a biomaterial, placing the past promises of chitin in perspective, addressing its present realities and offering insight into what is required to realize chitin's destiny (including its derivative, chitosan) as a biomaterial of the twenty-first century. This book is an ideal guide for both industrialists and researchers with a vested interest in commercializing chitin.An upd

  14. Candida Biofilms: Threats, Challenges, and Promising Strategies

    Directory of Open Access Journals (Sweden)

    Mafalda Cavalheiro

    2018-02-01

    Full Text Available Candida species are fungal pathogens known for their ability to cause superficial and systemic infections in the human host. These pathogens are able to persist inside the host due to the development of pathogenicity and multidrug resistance traits, often leading to the failure of therapeutic strategies. One specific feature of Candida species pathogenicity is their ability to form biofilms, which protects them from external factors such as host immune system defenses and antifungal drugs. This review focuses on the current threats and challenges when dealing with biofilms formed by Candida albicans, Candida glabrata, Candida tropicalis, and Candida parapsilosis, highlighting the differences between the four species. Biofilm characteristics depend on the ability of each species to produce extracellular polymeric substances (EPS and display dimorphic growth, but also on the biofilm substratum, carbon source availability and other factors. Additionally, the transcriptional control over processes like adhesion, biofilm formation, filamentation, and EPS production displays great complexity and diversity within pathogenic yeasts of the Candida genus. These differences not only have implications in the persistence of colonization and infections but also on antifungal resistance typically found in Candida biofilm cells, potentiated by EPS, that functions as a barrier to drug diffusion, and by the overexpression of drug resistance transporters. The ability to interact with different species in in vivo Candida biofilms is also a key factor to consider when dealing with this problem. Despite many challenges, the most promising strategies that are currently available or under development to limit biofilm formation or to eradicate mature biofilms are discussed.

  15. MFTF-progress and promise

    International Nuclear Information System (INIS)

    Thomassen, K.I.

    1980-01-01

    The Mirror Fusion Test Facility (MFTF) has been in construction at Lawrence Livermore National Laboratory (LLNL) for 3 years, and most of the major subsystems are nearing completion. Recently, the scope of this project was expanded to meet new objectives, principally to reach plasma conditions corresponding to energy break-even. To fulfill this promise, the single-cell minimum-B mirror configuration will be replaced with a tandem mirror configuration (MFTF-B). The facility must accordingly be expanded to accomodate the new geometry. This paper briefly discusses the status of the major MFTF subsystems and describes how most of the technological objectives of MFTF will be demonstrated before we install the additional systems necessary to make the tandem. It also summarizes the major features of the expanded facility

  16. The promising opportunity of dismantlement

    International Nuclear Information System (INIS)

    Anon.

    2009-01-01

    Civil engineering, mechanics and waste conditioning companies are thriving around the market of nuclear facilities dismantlement which is promised to a huge development in the coming decade. This paper presents a map of the opportunities of the dismantlement market throughout Europe (research and power reactors, fuel fabrication plants, spent fuel reprocessing plants) and a cost estimation of a given dismantling work with respect to the different steps of the work. In France a small core of about twenty companies is involved in nuclear dismantlement but the French market is also looking towards foreign specialists of this activity. The British market is also targeted by the French companies but for all the actors the technological or commercial advance gained today will be determining for the future markets. (J.S.)

  17. A physarum-inspired prize-collecting steiner tree approach to identify subnetworks for drug repositioning.

    Science.gov (United States)

    Sun, Yahui; Hameed, Pathima Nusrath; Verspoor, Karin; Halgamuge, Saman

    2016-12-05

    Drug repositioning can reduce the time, costs and risks of drug development by identifying new therapeutic effects for known drugs. It is challenging to reposition drugs as pharmacological data is large and complex. Subnetwork identification has already been used to simplify the visualization and interpretation of biological data, but it has not been applied to drug repositioning so far. In this paper, we fill this gap by proposing a new Physarum-inspired Prize-Collecting Steiner Tree algorithm to identify subnetworks for drug repositioning. Drug Similarity Networks (DSN) are generated using the chemical, therapeutic, protein, and phenotype features of drugs. In DSNs, vertex prizes and edge costs represent the similarities and dissimilarities between drugs respectively, and terminals represent drugs in the cardiovascular class, as defined in the Anatomical Therapeutic Chemical classification system. A new Physarum-inspired Prize-Collecting Steiner Tree algorithm is proposed in this paper to identify subnetworks. We apply both the proposed algorithm and the widely-used GW algorithm to identify subnetworks in our 18 generated DSNs. In these DSNs, our proposed algorithm identifies subnetworks with an average Rand Index of 81.1%, while the GW algorithm can only identify subnetworks with an average Rand Index of 64.1%. We select 9 subnetworks with high Rand Index to find drug repositioning opportunities. 10 frequently occurring drugs in these subnetworks are identified as candidates to be repositioned for cardiovascular diseases. We find evidence to support previous discoveries that nitroglycerin, theophylline and acarbose may be able to be repositioned for cardiovascular diseases. Moreover, we identify seven previously unknown drug candidates that also may interact with the biological cardiovascular system. These discoveries show our proposed Prize-Collecting Steiner Tree approach as a promising strategy for drug repositioning.

  18. Monoclonal antibody form and function: manufacturing the right antibodies for treating drug abuse.

    Science.gov (United States)

    Peterson, Eric; Owens, S Michael; Henry, Ralph L

    2006-05-26

    Drug abuse continues to be a major national and worldwide problem, and effective treatment strategies are badly needed. Antibodies are promising therapies for the treatment of medical problems caused by drug abuse, with several candidates in preclinical and early clinical trials. Monoclonal antibodies can be designed that have customized affinity and specificity against drugs of abuse, and because antibodies can be designed in various forms, in vivo pharmacokinetic characteristics can be tailored to suit specific clinical applications (eg, long-acting for relapse prevention, or short-acting for overdose). Passive immunization with antibodies against drugs of abuse has several advantages over active immunization, but because large doses of monoclonal antibodies may be needed for each patient, efficient antibody production technology is essential. In this minireview we discuss some of the antibody forms that may be effective clinical treatments for drug abuse, as well as several current and emerging production systems that could bridge the gap from discovery to patient use.

  19. Drug Repositioning: An Opportunity to Develop Novel Treatments for Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Clive Ballard

    2013-10-01

    Full Text Available Alzheimer’s Disease (AD is the most common cause of dementia, affecting approximately two thirds of the 35 million people worldwide with the condition. Despite this, effective treatments are lacking, and there are no drugs that elicit disease modifying effects to improve outcome. There is an urgent need to develop and evaluate more effective pharmacological treatments. Drug repositioning offers an exciting opportunity to repurpose existing licensed treatments for use in AD, with the benefit of providing a far more rapid route to the clinic than through novel drug discovery approaches. This review outlines the current most promising candidates for repositioning in AD, their supporting evidence and their progress through trials to date. Furthermore, it begins to explore the potential of new transcriptomic and microarray techniques to consider the future of drug repositioning as a viable approach to drug discovery.

  20. Magnetic nanoparticles for local drug delivery using magnetic implants

    International Nuclear Information System (INIS)

    Fernandez-Pacheco, Rodrigo; Marquina, Clara; Gabriel Valdivia, J.

    2007-01-01

    Magnetic nanoparticles are good candidates used for the targeted delivery of anti-tumor agents. They can be concentrated on a desired region, reducing collateral effects and improving the efficiency of the chemotherapy. We propose a method in which permanent magnets are implanted by laparoscopic technique directly in the affected organ. This method proposes the use of FeC nanoparticles, which are loaded with doxorubicin and injected intravenously. The particles, once attracted to the magnet, release the drug at the tumor region. This method seems to be more promising and effective than that based on the application of external magnetic fields

  1. Magnetic nanoparticles for local drug delivery using magnetic implants

    Energy Technology Data Exchange (ETDEWEB)

    Fernandez-Pacheco, Rodrigo [Instituto Universitario de Investigacion en Nanociencia de Aragon (INA), Universidad de Zaragoza, Edif. Inter. II, 50009 Zaragoza (Spain); Marquina, Clara [Instituto de Ciencia de Materiales de Aragon (ICMA), CSIC-Universidad de Zaragoza, Facultad de Ciencias, 50009 Zaragoza (Spain); Gabriel Valdivia, J. [Instituto Universitario de Investigacion en Nanociencia de Aragon (INA), Universidad de Zaragoza, Edif. Inter. II, 50009 Zaragoza (Spain); Hospital Clinico Universitario ' Lozano Blesa' , Avda Gomez Laguna, 50009 Zaragoza (Spain)] (and others)

    2007-04-15

    Magnetic nanoparticles are good candidates used for the targeted delivery of anti-tumor agents. They can be concentrated on a desired region, reducing collateral effects and improving the efficiency of the chemotherapy. We propose a method in which permanent magnets are implanted by laparoscopic technique directly in the affected organ. This method proposes the use of FeC nanoparticles, which are loaded with doxorubicin and injected intravenously. The particles, once attracted to the magnet, release the drug at the tumor region. This method seems to be more promising and effective than that based on the application of external magnetic fields.

  2. Twenty years on: the impact of fragments on drug discovery.

    Science.gov (United States)

    Erlanson, Daniel A; Fesik, Stephen W; Hubbard, Roderick E; Jahnke, Wolfgang; Jhoti, Harren

    2016-09-01

    After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.

  3. Prediction of Drug-Plasma Protein Binding Using Artificial Intelligence Based Algorithms.

    Science.gov (United States)

    Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

    2018-01-01

    Plasma protein binding (PPB) has vital importance in the characterization of drug distribution in the systemic circulation. Unfavorable PPB can pose a negative effect on clinical development of promising drug candidates. The drug distribution properties should be considered at the initial phases of the drug design and development. Therefore, PPB prediction models are receiving an increased attention. In the current study, we present a systematic approach using Support vector machine, Artificial neural network, k- nearest neighbor, Probabilistic neural network, Partial least square and Linear discriminant analysis to relate various in vitro and in silico molecular descriptors to a diverse dataset of 736 drugs/drug-like compounds. The overall accuracy of Support vector machine with Radial basis function kernel came out to be comparatively better than the rest of the applied algorithms. The training set accuracy, validation set accuracy, precision, sensitivity, specificity and F1 score for the Suprort vector machine was found to be 89.73%, 89.97%, 92.56%, 87.26%, 91.97% and 0.898, respectively. This model can potentially be useful in screening of relevant drug candidates at the preliminary stages of drug design and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. In Silico Chemogenomics Drug Repositioning Strategies for Neglected Tropical Diseases.

    Science.gov (United States)

    Andrade, Carolina Horta; Neves, Bruno Junior; Melo-Filho, Cleber Camilo; Rodrigues, Juliana; Silva, Diego Cabral; Braga, Rodolpho Campos; Cravo, Pedro Vitor Lemos

    2018-03-08

    Only ~1% of all drug candidates against Neglected Tropical Diseases (NTDs) have reached clinical trials in the last decades, underscoring the need for new, safe and effective treatments. In such context, drug repositioning, which allows finding novel indications for approved drugs whose pharmacokinetic and safety profiles are already known, is emerging as a promising strategy for tackling NTDs. Chemogenomics is a direct descendent of the typical drug discovery process that involves the systematic screening of chemical compounds against drug targets in high-throughput screening (HTS) efforts, for the identification of lead compounds. However, different to the one-drug-one-target paradigm, chemogenomics attempts to identify all potential ligands for all possible targets and diseases. In this review, we summarize current methodological development efforts in drug repositioning that use state-of-the-art computational ligand- and structure-based chemogenomics approaches. Furthermore, we highlighted the recent progress in computational drug repositioning for some NTDs, based on curation and modeling of genomic, biological, and chemical data. Additionally, we also present in-house and other successful examples and suggest possible solutions to existing pitfalls. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Assessment of potential solder candidates for high temperature applications

    DEFF Research Database (Denmark)

    pressure to eliminate lead containing materials despite the fact that materials for high Pb containing alloys are currently not affected by any legislations. A tentative assessment was carried out to determine the potential solder candidates for high temperature applications based on the solidification...... criterion, phases predicted in the bulk solder and the thermodynamic stability of chlorides. These promising solder candidates were precisely produced using the hot stage microscope and its respective anodic and cathodic polarization curves were investigated using a micro-electrochemical set up...

  6. Generating Genome-Scale Candidate Gene Lists for Pharmacogenomics

    DEFF Research Database (Denmark)

    Hansen, Niclas Tue; Brunak, Søren; Altman, R. B.

    2009-01-01

    A critical task in pharmacogenomics is identifying genes that may be important modulators of drug response. High-throughput experimental methods are often plagued by false positives and do not take advantage of existing knowledge. Candidate gene lists can usefully summarize existing knowledge...

  7. MXene: a potential candidate for yarn supercapacitors.

    Science.gov (United States)

    Zhang, Jizhen; Seyedin, Shayan; Gu, Zhoujie; Yang, Wenrong; Wang, Xungai; Razal, Joselito M

    2017-12-07

    The increasing developments in wearable electronics demand compatible power sources such as yarn supercapacitors (YSCs) that can effectively perform in a limited footprint. MXene nanosheets, which have been recently shown in the literature to possess ultra-high volumetric capacitance, were used in this study for the fabrication of YSCs in order to identify their potential merit and performance in YSCs. With the aid of a conductive binder (PEDOT-PSS), YSCs with high mass loading of MXene are demonstrated. These MXene-based YSCs exhibit excellent device performance and stability even under bending and twisting. This study demonstrates that MXene is a promising candidate for YSCs and its further development can lead to flexible power sources with sufficient performance for powering miniaturized and/or wearable electronics.

  8. Drug resistance of yeasts isolated from oropharyngeal candidiasis in aids patients Resistência à drogas de leveduras isoladas de candidíase orofaríngea em pacientes com Aids

    Directory of Open Access Journals (Sweden)

    Maria do Rosário Rodrigues Silva

    1998-10-01

    Full Text Available Candida spp was isolated from 59 (68.60% out of eighty six samples of oral mucosa of AIDS patients. The identification, based or the production of a germ tube and chlamydospores, and on the assimilation and fermentation of carbohydrates, revealed 52 strains (88.13% of C. albicans, 4 (6.77% of C. tropicalis and 3 (5.08% of C. krusei. The susceptibility of these strains to amphotericin B, flucytosine, itraconazole, fluconazole and ketoconazole was determined using the agar dilution method. Comparing the minimum inhibitory concentration values found in the susceptibility test with the serum levels achieved by these drugs, only 8.47% and 5.08% of the yeasts strains proved to be resistant to amphotericin B and flucitosyne, respectively. A high frequency of strains resistant to azole derivatives (25.42%, to itraconazole, 45.76%, to ketoconazole and 66.10% to fluconazole was observed.Entre oitenta e seis amostras da mucosa oral de pacientes com AIDS, 59 (68,60% foram positivas para leveduras do gênero Candida. A identificação, feita pela produção de tubo germinativo e clamidósporos e através de assimilação e fermentação de hidratos de carbono, revelou 52 cepas (88,13% de C.albicans, 4 (6,77% de C. tropicalis e 3 (5,08% de C.krusei. Avaliação destas leveduras para susceptibilidade in vitro frente a anfotericina B, flucitosina, itraconazol, fluconazol e cetoconazol, foi realizada pelo método de diluição em ágar. Comparando-se os valores de concentração inibitória mínima encontrados com os níveis séricos alcançados por estes antifúngicos verificou-se que apenas 8,47% e 5,08% das 59 leveduras foram resistentes a anfotericina B e flucitosina, respectivamente. Foi registrada uma percentagem de cepas resistentes aos derivados azólicos, sendo 25,42% ao itraconazol, 45,76% ao cetoconazol e 66,10% ao fluconazol.

  9. Identifying problematic drugs based on the characteristics of their targets.

    Science.gov (United States)

    Lopes, Tiago J S; Shoemaker, Jason E; Matsuoka, Yukiko; Kawaoka, Yoshihiro; Kitano, Hiroaki

    2015-01-01

    Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60-70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  10. Identifying problematic drugs based on the characteristics of their targets

    Directory of Open Access Journals (Sweden)

    Tiago Jose eDa Silva Lopes

    2015-09-01

    Full Text Available Identifying promising compounds during the early stages of drug development is a major challenge for both academia and the pharmaceutical industry. The difficulties are even more pronounced when we consider multi-target pharmacology, where the compounds often target more than one protein, or multiple compounds are used together. Here, we address this problem by using machine learning and network analysis to process sequence and interaction data from human proteins to identify promising compounds. We used this strategy to identify properties that make certain proteins more likely to cause harmful effects when targeted; such proteins usually have domains commonly found throughout the human proteome. Additionally, since currently marketed drugs hit multiple targets simultaneously, we combined the information from individual proteins to devise a score that quantifies the likelihood of a compound being harmful to humans. This approach enabled us to distinguish between approved and problematic drugs with an accuracy of 60%¬–70%. Moreover, our approach can be applied as soon as candidate drugs are available, as demonstrated with predictions for more than 5000 experimental drugs. These resources are available at http://sourceforge.net/projects/psin/.

  11. Advanced Vaccine Candidates for Lassa Fever

    Directory of Open Access Journals (Sweden)

    Igor S. Lukashevich

    2012-10-01

    Full Text Available Lassa virus (LASV is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF. LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever with an estimated several hundred thousand infections annually, resulting in thousands of deaths in Western Africa. The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently, several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this manuscript is to review the LASV pathogenesis and immune mechanisms involved in protection. The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered.

  12. Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles.

    Science.gov (United States)

    Dangol, Manita; Yang, Huisuk; Li, Cheng Guo; Lahiji, Shayan Fakhraei; Kim, Suyong; Ma, Yonghao; Jung, Hyungil

    2016-02-10

    Lipophilic drugs are potential drug candidates during drug development. However, due to the need for hazardous organic solvents for their solubilization, these drugs often fail to reach the pharmaceutical market, and in doing so highlight the importance of solvent free systems. Although transdermal drug delivery systems (TDDSs) are considered prospective safe drug delivery routes, a system involving lipophilic drugs in solvent free or powder form has not yet been described. Here, we report, for the first time, a novel approach for the delivery of every kind of lipophilic drug in powder form based on an innovative polymeric system (IPS). The phase transition of powder form of lipophilic drugs due to interior chemical bonds between drugs and biodegradable polymers and formation of nano-sized colloidal structures allowed the fabrication of dissolving microneedles (DMNs) to generate a powerful TDDS. We showed that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Drug repurposing to target Ebola virus replication and virulence using structural systems pharmacology.

    Science.gov (United States)

    Zhao, Zheng; Martin, Che; Fan, Raymond; Bourne, Philip E; Xie, Lei

    2016-02-18

    The recent outbreak of Ebola has been cited as the largest in history. Despite this global health crisis, few drugs are available to efficiently treat Ebola infections. Drug repurposing provides a potentially efficient solution to accelerating the development of therapeutic approaches in response to Ebola outbreak. To identify such candidates, we use an integrated structural systems pharmacology pipeline which combines proteome-scale ligand binding site comparison, protein-ligand docking, and Molecular Dynamics (MD) simulation. One thousand seven hundred and sixty-six FDA-approved drugs and 259 experimental drugs were screened to identify those with the potential to inhibit the replication and virulence of Ebola, and to determine the binding modes with their respective targets. Initial screening has identified a number of promising hits. Notably, Indinavir; an HIV protease inhibitor, may be effective in reducing the virulence of Ebola. Additionally, an antifungal (Sinefungin) and several anti-viral drugs (e.g. Maraviroc, Abacavir, Telbivudine, and Cidofovir) may inhibit Ebola RNA-directed RNA polymerase through targeting the MTase domain. Identification of safe drug candidates is a crucial first step toward the determination of timely and effective therapeutic approaches to address and mitigate the impact of the Ebola global crisis and future outbreaks of pathogenic diseases. Further in vitro and in vivo testing to evaluate the anti-Ebola activity of these drugs is warranted.

  14. Filled carbon nanotubes in biomedical imaging and drug delivery.

    Science.gov (United States)

    Martincic, Markus; Tobias, Gerard

    2015-04-01

    Carbon nanotubes have been advocated as promising candidates in the biomedical field in the areas of diagnosis and therapy. In terms of drug delivery, the use of carbon nanotubes can overcome some limitations of 'free' drugs by improving the formulation of poorly water-soluble drugs, allowing targeted delivery and even enabling the co-delivery of two or more drugs for combination therapy. Two different approaches are currently being explored for the delivery of diagnostic and therapeutic agents by carbon nanotubes, namely attachment of the payload to the external sidewalls or encapsulation into the inner cavities. Although less explored, the latter confers additional stability to the chosen diagnostic or therapeutic agents, and leaves the backbone structure of the nanotubes available for its functionalization with dispersing and targeting moieties. Several drug delivery systems and diagnostic agents have been developed in the last years employing the inner tubular cavities of carbon nanotubes. The research discussed in this review focuses on the use of carbon nanotubes that contain in their interior drug molecules and diagnosis-related compounds. The approaches employed for the development of such nanoscale vehicles along with targeting and releasing strategies are discussed. The encapsulation of both biomedical contrast agents and drugs inside carbon nanotubes is further expanding the possibilities to allow an early diagnosis and treatment of diseases.

  15. Glycogen synthase kinase-3: A promising therapeutic target for Fragile X Syndrome

    Directory of Open Access Journals (Sweden)

    Marjelo M. Mines

    2011-11-01

    Full Text Available Recent advances in understanding the pathophysiological mechanisms contributing to Fragile X Syndrome (FXS have increased optimism that drug interventions can provide significant therapeutic benefits. FXS results from inadequate expression of functional fragile X mental retardation protein (FMRP. FMRP may have several functions, but it is most well-established as an RNA-binding protein that regulates translation, and it is by this mechanism that FMRP is capable of affecting numerous cellular processes by selectively regulating protein levels. The multiple cellular functions regulated by FMRP suggest that multiple interventions may be required for reversing the effects of deficient FMRP. Evidence that inhibitors of glycogen synthase kinase-3 (GSK3 may contribute to the therapeutic treatment of FXS is reviewed here. In the mouse model of FXS, which lacks FMRP expression (FX mice, GSK3 is hyperactive in several brain regions. Furthermore, significant improvements in several FX-related phenotypes have been obtained in FX mice following the administration of lithium, and in some case other GSK3 inhibitors. These responses include normalization of heightened audiogenic seizure susceptibility and of hyperactive locomotor behavior, enhancement of passive avoidance learning retention and of sociability behaviors, and corrections of macroorchidism, neuronal spine density, and neural plasticity measured electrophysiologically as long term depression. A pilot clinical trial of lithium in FXS patients also found improvements in several measures of behavior. Taken together, these findings indicate that lithium and other inhibitors of GSK3 are promising candidate therapeutic agents for treating FXS.

  16. Teacher Candidate Selection and Evaluation.

    Science.gov (United States)

    Collins, Mary Lynn; And Others

    Summaries are presented of three papers presented at a summer workshop on Quality Assurance in Teacher Education conducted by the Association of Teacher Educators. The general topic covered by these presentations was teacher candidate selection and evaluation. Papers focused upon the following questions: (1) What entry level criteria should be…

  17. Candidate Prediction Models and Methods

    DEFF Research Database (Denmark)

    Nielsen, Henrik Aalborg; Nielsen, Torben Skov; Madsen, Henrik

    2005-01-01

    This document lists candidate prediction models for Work Package 3 (WP3) of the PSO-project called ``Intelligent wind power prediction systems'' (FU4101). The main focus is on the models transforming numerical weather predictions into predictions of power production. The document also outlines...... the possibilities w.r.t. different numerical weather predictions actually available to the project....

  18. Drug Delivery to CNS: Challenges and Opportunities with Emphasis on Biomaterials Based Drug Delivery Strategies.

    Science.gov (United States)

    Khambhla, Ekta; Shah, Viral; Baviskar, Kalpesh

    2016-01-01

    The current epoch has witnessed a lifestyle impregnated with stress, which is a major cause of several neurological disorders. High morbidity and mortality rate due to neurological diseases and disorders have generated a huge social impact. Despite voluminous research, patients suffering from fatal and/or debilitating CNS diseases such as brain tumors, HIV, encephalopathy, Alzheimer's, epilepsy, Parkinson's, migraine and multiple sclerosis outnumbered those suffering from systemic cancer or heart diseases. The brain being a highly sensitive neuronal organ, has evolved with vasculature barriers, which regulates the efflux and influx of substances to CNS. Treatment of CNS diseases/disorders is challenging because of physiologic, metabolic and biochemical obstacles created by these barriers which comprise mainly of BBB and BCFB. The inability of achieving therapeutically active concentration has become the bottleneck level difficulty, hampering the therapeutic efficiency of several promising drug candidates for CNS related disorders. Parallel maturation of an effective CNS drug delivery strategy with CNS drug discovery is the need of the hour. Recently, the focus of the pharmaceutical community has aggravated in the direction of developing novel and more efficient drug delivery systems, giving the potential of more effective and safer CNS therapies. The present review outlines several hurdles in drug delivery to the CNS along with ideal physicochemical properties desired in drug substance/formulation for CNS delivery. The review also focuses on different conventional and novel strategies for drug delivery to the CNS. The article also assesses and emphasizes on possible benefits of biomaterial based formulations for drug delivery to the CNS.

  19. Predicting drug?drug interactions through drug structural similarities and interaction networks incorporating pharmacokinetics and pharmacodynamics knowledge

    OpenAIRE

    Takeda, Takako; Hao, Ming; Cheng, Tiejun; Bryant, Stephen H.; Wang, Yanli

    2017-01-01

    Drug?drug interactions (DDIs) may lead to adverse effects and potentially result in drug withdrawal from the market. Predicting DDIs during drug development would help reduce development costs and time by rigorous evaluation of drug candidates. The primary mechanisms of DDIs are based on pharmacokinetics (PK) and pharmacodynamics (PD). This study examines the effects of 2D structural similarities of drugs on DDI prediction through interaction networks including both PD and PK knowledge. Our a...

  20. Drug Facts

    Medline Plus

    Full Text Available ... Why Is It So Hard to Quit Drugs? Effects of Drugs Drug Use and Other People Drug ... Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug ...

  1. Promising Practices in Higher Education: Art Education and Human Rights Using Information, Communication Technologies (ICT)

    Science.gov (United States)

    Black, Joanna; Cap, Orest

    2014-01-01

    Promising pedagogical practices is described in relation to incorporating ICT (Information, Communication and Technologies) with the study of Human Rights issues in Visual Arts Education for teacher candidates. As part of a course, "Senior Years Art," students at the Faculty of Education, University of Manitoba during 2013-2014…

  2. Enantioselectivity of mass spectrometry: challenges and promises.

    Science.gov (United States)

    Awad, Hanan; El-Aneed, Anas

    2013-01-01

    With the fast growing market of pure enantiomer drugs and bioactive molecules, new chiral-selective analytical tools have been instigated including the use of mass spectrometry (MS). Even though MS is one of the best analytical tools that has efficiently been used in several pharmaceutical and biological applications, traditionally MS is considered as a "chiral-blind" technique. This limitation is due to the MS inability to differentiate between two enantiomers of a chiral molecule based merely on their masses. Several approaches have been explored to assess the potential role of MS in chiral analysis. The first approach depends on the use of MS-hyphenated techniques utilizing fast and sensitive chiral separation tools such as liquid chromatography (LC), gas chromatography (GC), and capillary electrophoresis (CE) coupled to MS detector. More recently, several alternative separation techniques have been evaluated such as supercritical fluid chromatography (SFC) and capillary electrochromatography (CEC); the latter being a hybrid technique that combines the efficiency of CE with the selectivity of LC. The second approach is based on using the MS instrument solely for the chiral recognition. This method depends on the behavioral differences between enantiomers towards a foreign molecule and the ability of MS to monitor such differences. These behavioral differences can be divided into three types: (i) differences in the enantiomeric affinity for association with the chiral selector, (ii) differences of the enantiomeric exchange rate with a foreign reagent, and (iii) differences in the complex MS dissociation behaviors of the enantiomers. Most recently, ion mobility spectrometry was introduced to qualitatively and quantitatively evaluate chiral compounds. This article provides an overview of MS role in chiral analysis by discussing MS based methodologies and presenting the challenges and promises associated with each approach. © 2013 Wiley Periodicals, Inc.

  3. Bacteriophages show promise as antimicrobial agents.

    Science.gov (United States)

    Alisky, J; Iczkowski, K; Rapoport, A; Troitsky, N

    1998-01-01

    The emergence of antibiotic-resistant bacteria has prompted interest in alternatives to conventional drugs. One possible option is to use bacteriophages (phage) as antimicrobial agents. We have conducted a literature review of all Medline citations from 1966-1996 that dealt with the therapeutic use of phage. There were 27 papers from Poland, the Soviet Union, Britain and the U.S.A. The Polish and Soviets administered phage orally, topically or systemically to treat a wide variety of antibiotic-resistant pathogens in both adults and children. Infections included suppurative wound infections, gastroenteritis, sepsis, osteomyelitis, dermatitis, empyemas and pneumonia; pathogens included Staphylococcus, Streptococcus, Klebsiella, Escherichia, Proteus, Pseudomonas, Shigella and Salmonella spp. Overall, the Polish and Soviets reported success rates of 80-95% for phage therapy, with rare, reversible gastrointestinal or allergic side effects. However, efficacy of phage was determined almost exclusively by qualitative clinical assessment of patients, and details of dosages and clinical criteria were very sketchy. There were also six British reports describing controlled trials of phage in animal models (mice, guinea pigs and livestock), measuring survival rates and other objective criteria. All of the British studies raised phage against specific pathogens then used to create experimental infections. Demonstrable efficacy against Escherichia, Acinetobacter, Pseudomonas and Staphylococcus spp. was noted in these model systems. Two U.S. papers dealt with improving the bioavailability of phage. Phage is sequestered in the spleen and removed from circulation. This can be overcome by serial passage of phage through mice to isolate mutants that resist sequestration. In conclusion, bacteriophages may show promise for treating antibiotic resistant pathogens. To facilitate further progress, directions for future research are discussed and a directory of authors from the reviewed

  4. Bioactive compounds fractionated from endophyte Streptomyces SUK 08 with promising ex-vivo antimalarial activity

    Directory of Open Access Journals (Sweden)

    Noraziah Mohamad Zin

    2017-12-01

    Full Text Available Objective: To determine ex vivo antimalarial activity and cytotoxicity of endophytic Streptomyces SUK 08 as well as the main core structure fractionated from its crude extract. Methods: The activities of SUK 08 crude extract were evaluated by using the Plasmodium lactate dehydrogenase assay and synchronization test against rodent malaria parasite Plasmodium berghei, instead of human malarial parasite Plasmodium falciparum. The cytotoxicity of the crude extract was determined by MTT assay. The crude extract was analyzed by thin-layer chromatography and gas chromatography–mass spectrophotometry. Results: The ethyl acetate crude extract showed very promising antimalarial activity with IC50 of 1.25 mg/mL. The synchronization tests showed that ethyl acetate extraction could inhibit all stages of the Plasmodium life cycle, but it was most effective at the Plasmodium ring stage. On the basis of a MTT assay on Chang Liver cells, ethyl acetate and ethanol demonstrated IC50 values of >1.0 mg/mL. The IC50 of parasitemia at 5% and 30% for this extract was lower than chloroquine. Thin-layer chromatography, with 1: 9 ratio of ethyl acetate: hexane, was used to isolate several distinct compounds. Based on gas chromatography–mass spectrophotometry analysis, three core structures were identified as cyclohexane, butyl propyl ester, and 2,3-heptanedione. Structurally, these compounds were similar to currently available antimalarial drugs. Conclusions: The results suggest that compounds isolated from Streptomyces SUK 08 are viable antimalarial drug candidates that require further investigations. Keywords: Butyl–propyl–ester, Cyclohexane, 2,3-Heptanedione, Endophyte, Streptomyces, Antimalarial

  5. USING STELLAR DENSITIES TO EVALUATE TRANSITING EXOPLANETARY CANDIDATES

    International Nuclear Information System (INIS)

    Tingley, B.; Deeg, H. J.; Bonomo, A. S.

    2011-01-01

    One of the persistent complications in searches for transiting exoplanets is the low percentage of the detected candidates that ultimately prove to be planets, which significantly increases the load on the telescopes used for the follow-up observations to confirm or reject candidates. Several attempts have been made at creating techniques that can pare down candidate lists without the need of additional observations. Some of these techniques involve a detailed analysis of light curve characteristics; others estimate the stellar density or some proxy thereof. In this paper, we extend upon this second approach, exploring the use of independently calculated stellar densities to identify the most promising transiting exoplanet candidates. We use a set of CoRoT candidates and the set of known transiting exoplanets to examine the potential of this approach. In particular, we note the possibilities inherent in the high-precision photometry from space missions, which can detect stellar asteroseismic pulsations from which accurate stellar densities can be extracted without additional observations.

  6. Evaluation of Candidate Anti-Aids Drugs In Vitro

    Science.gov (United States)

    1991-05-31

    numba by 50% (ED5) was calulatad using a regression aa-ysis program for semi-log curve fit’tig and was exnpresed a* ."g/Tn- The eapic index ,) wa dvte b y...czztairng 1.25 pg of poly (rA). p(c!T)12.11, 200 pM d= (400 kLCi of •’H,’•nle of ’- dT’P). 1mM S apo-rne•’ý • ol, 120 mM KCI, 0.6 mM MnC½, 0. 10 mM EDTA...Appendix B). The Mrst aýtive compounds (i.e. confirrnme activity with Selectivity Index (SI) of >10) are listed in Table !. During our overall experience

  7. The future of drug discovery: enabling technologies for enhancing lead characterization and profiling therapeutic potential.

    Science.gov (United States)

    Janero, David R

    2014-08-01

    Technology often serves as a handmaiden and catalyst of invention. The discovery of safe, effective medications depends critically upon experimental approaches capable of providing high-impact information on the biological effects of drug candidates early in the discovery pipeline. This information can enable reliable lead identification, pharmacological compound differentiation and successful translation of research output into clinically useful therapeutics. The shallow preclinical profiling of candidate compounds promulgates a minimalistic understanding of their biological effects and undermines the level of value creation necessary for finding quality leads worth moving forward within the development pipeline with efficiency and prognostic reliability sufficient to help remediate the current pharma-industry productivity drought. Three specific technologies discussed herein, in addition to experimental areas intimately associated with contemporary drug discovery, appear to hold particular promise for strengthening the preclinical valuation of drug candidates by deepening lead characterization. These are: i) hydrogen-deuterium exchange mass spectrometry for characterizing structural and ligand-interaction dynamics of disease-relevant proteins; ii) activity-based chemoproteomics for profiling the functional diversity of mammalian proteomes; and iii) nuclease-mediated precision gene editing for developing more translatable cellular and in vivo models of human diseases. When applied in an informed manner congruent with the clinical understanding of disease processes, technologies such as these that span levels of biological organization can serve as valuable enablers of drug discovery and potentially contribute to reducing the current, unacceptably high rates of compound clinical failure.

  8. Campaigning on behalf of the party? Party constraints on candidate campaign personalisation

    DEFF Research Database (Denmark)

    Bøggild, Troels; Pedersen, Helene Helboe

    2017-01-01

    This article analyses what makes political candidates run a party-focused or personalised election campaign. Prior work shows that candidates face incentives from voters and the media to personalise their campaign rhetoric and promises at the expense of party policy. This has raised concerns about...... that party control over the candidate nomination process and campaign financing constrains most political candidates in following electoral incentives for campaign personalisation. Using candidate survey data from the 2009 EP election campaign in 27 countries, we show how candidates from parties in which...... party officials exerted greater control over the nomination process and campaign finances were less likely to engage in personalised campaigning at the expense of the party programme. The findings imply that most parties, as central gatekeepers and resource suppliers, hold important control mechanisms...

  9. The effect of network biology on drug toxicology

    DEFF Research Database (Denmark)

    Gautier, Laurent; Taboureau, Olivier; Audouze, Karine Marie Laure

    2013-01-01

    Introduction: The high failure rate of drug candidates due to toxicity, during clinical trials, is a critical issue in drug discovery. Network biology has become a promising approach, in this regard, using the increasingly large amount of biological and chemical data available and combining...... it with bioinformatics. With this approach, the assessment of chemical safety can be done across multiple scales of complexity from molecular to cellular and system levels in human health. Network biology can be used at several levels of complexity. Areas covered: This review describes the strengths and limitations...... of network biology. The authors specifically assess this approach across different biological scales when it is applied to toxicity. Expert opinion: There has been much progress made with the amount of data that is generated by various omics technologies. With this large amount of useful data, network...

  10. Peptide drugs to target G protein-coupled receptors.

    Science.gov (United States)

    Bellmann-Sickert, Kathrin; Beck-Sickinger, Annette G

    2010-09-01

    Major indications for use of peptide-based therapeutics include endocrine functions (especially diabetes mellitus and obesity), infectious diseases, and cancer. Whereas some peptide pharmaceuticals are drugs, acting as agonists or antagonists to directly treat cancer, others (including peptide diagnostics and tumour-targeting pharmaceuticals) use peptides to 'shuttle' a chemotherapeutic agent or a tracer to the tumour and allow sensitive imaging or targeted therapy. Significant progress has been made in the last few years to overcome disadvantages in peptide design such as short half-life, fast proteolytic cleavage, and low oral bioavailability. These advances include peptide PEGylation, lipidisation or multimerisation; the introduction of peptidomimetic elements into the sequences; and innovative uptake strategies such as liposomal, capsule or subcutaneous formulations. This review focuses on peptides targeting G protein-coupled receptors that are promising drug candidates or that have recently entered the pharmaceutical market. Copyright 2010 Elsevier Ltd. All rights reserved.

  11. Candidate genes in panic disorder

    DEFF Research Database (Denmark)

    Howe, A. S.; Buttenschön, Henriette N; Bani-Fatemi, A.

    2016-01-01

    The utilization of molecular genetics approaches in examination of panic disorder (PD) has implicated several variants as potential susceptibility factors for panicogenesis. However, the identification of robust PD susceptibility genes has been complicated by phenotypic diversity, underpowered...... association studies and ancestry-specific effects. In the present study, we performed a succinct review of case-control association studies published prior to April 2015. Meta-analyses were performed for candidate gene variants examined in at least three studies using the Cochrane Mantel-Haenszel fixed......-effect model. Secondary analyses were also performed to assess the influences of sex, agoraphobia co-morbidity and ancestry-specific effects on panicogenesis. Meta-analyses were performed on 23 variants in 20 PD candidate genes. Significant associations after correction for multiple testing were observed...

  12. In silico design of fragment-based drug targeting host processing α-glucosidase i for dengue fever

    Science.gov (United States)

    Toepak, E. P.; Tambunan, U. S. F.

    2017-02-01

    Dengue is a major health problem in the tropical and sub-tropical regions. The development of antiviral that targeting dengue’s host enzyme can be more effective and efficient treatment than the viral enzyme. Host enzyme processing α-glucosidase I has an important role in the maturation process of dengue virus envelope glycoprotein. The inhibition of processing α-glucosidase I can become a promising target for dengue fever treatment. The antiviral approach using in silico fragment-based drug design can generate drug candidates with high binding affinity. In this research, 198.621 compounds were obtained from ZINC15 Biogenic Database. These compounds were screened to find the favorable fragments according to Rules of Three and pharmacological properties. The screening fragments were docked into the active site of processing α-glucosidase I. The potential fragment candidates from the molecular docking simulation were linked with castanospermine (CAST) to generate ligands with a better binding affinity. The Analysis of ligand - enzyme interaction showed ligands with code LRS 22, 28, and 47 have the better binding free energy than the standard ligand. Ligand LRS 28 (N-2-4-methyl-5-((1S,3S,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxyoctahydroindolizin-3-yl) pentyl) indolin-1-yl) propionamide) itself among the other ligands has the lowest binding free energy. Pharmacological properties prediction also showed the ligands LRS 22, 28, and 47 can be promising as the dengue fever drug candidates.

  13. Drug-resistant tuberculosis: emerging treatment options

    Directory of Open Access Journals (Sweden)

    Adhvaryu MR

    2011-12-01

    Full Text Available Meghna Adhvaryu1, Bhasker Vakharia21Department of Biotechnology, SRK Institute of Computer Education and Applied Sciences, 2R&D, Bhuma Research in Ayurvedic and Herbal Medicine, Surat, Gujarat, IndiaAbstract: Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug–drug interactions in patients coinfected with human immunodeficiency virus (HIV, inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drug-susceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and

  14. Antiprotozoal Activity of α,β-Unsaturated δ-Lactones: Promising ...

    African Journals Online (AJOL)

    The parasite resistance and side effects of drugs used to treat protozoal diseases have led to the search for new therapies, both natural and synthetic. Studies have shown that various α,β-unsaturated δ-lactones displayed high antiprotozoal activity and thus are promising compounds for new drug discovery and ...

  15. Novel catalytic micromotor of porous zeolitic imidazolate framework-67 for precise drug delivery.

    Science.gov (United States)

    Wang, Linlin; Zhu, Hongli; Shi, Ying; Ge, You; Feng, Xiaomiao; Liu, Ruiqing; Li, Yi; Ma, Yanwen; Wang, Lianhui

    2018-06-07

    Micromotors hold promise as drug carriers for targeted drug delivery owing to the characteristics of self-propulsion and directional navigation. However, several defects still exist, including high cost, short movement life, low drug loading and slow release rate. Herein, a novel catalytic micromotor based on porous zeolitic imidazolate framework-67 (ZIF-67) synthesized by a greatly simplified wet chemical method assisted with ultrasonication is described as an efficient anticancer drug carrier. These porous micromotors display effective autonomous motion in hydrogen peroxide and long durable movement life of up to 90 min. Moreover, the multifunctional micromotor ZIF-67/Fe3O4/DOX exhibits excellent performance in precise drug delivery under external magnetic field with high drug loading capacity of fluorescent anticancer drug DOX up to 682 μg mg-1 owing to its porous nature, high surface area and rapid drug release based on dual stimulus of catalytic reaction and solvent effects. Therefore, these porous ZIF-67-based catalytic micromotors combine the domains of metal-organic frameworks (MOFs) and micomotors, thus developing potential resources for micromotors and holding great potential as label-free and precisely controlled high-quality candidates of drug delivery systems for biomedical applications.

  16. The prediction of candidate genes for cervix related cancer through gene ontology and graph theoretical approach.

    Science.gov (United States)

    Hindumathi, V; Kranthi, T; Rao, S B; Manimaran, P

    2014-06-01

    With rapidly changing technology, prediction of candidate genes has become an indispensable task in recent years mainly in the field of biological research. The empirical methods for candidate gene prioritization that succors to explore the potential pathway between genetic determinants and complex diseases are highly cumbersome and labor intensive. In such a scenario predicting potential targets for a disease state through in silico approaches are of researcher's interest. The prodigious availability of protein interaction data coupled with gene annotation renders an ease in the accurate determination of disease specific candidate genes. In our work we have prioritized the cervix related cancer candidate genes by employing Csaba Ortutay and his co-workers approach of identifying the candidate genes through graph theoretical centrality measures and gene ontology. With the advantage of the human protein interaction data, cervical cancer gene sets and the ontological terms, we were able to predict 15 novel candidates for cervical carcinogenesis. The disease relevance of the anticipated candidate genes was corroborated through a literature survey. Also the presence of the drugs for these candidates was detected through Therapeutic Target Database (TTD) and DrugMap Central (DMC) which affirms that they may be endowed as potential drug targets for cervical cancer.

  17. Drug Facts

    Medline Plus

    Full Text Available ... Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use and Other People Drug Use and Families Drug Use and Kids Drug Use and Unborn ...

  18. Drug Facts

    Medline Plus

    Full Text Available ... Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, ... Drugs? Effects of Drugs Drug Use and Other People Drug Use and Families Drug Use and Kids ...

  19. Drug Facts

    Medline Plus

    Full Text Available ... People Drug Use and Families Drug Use and Kids Drug Use and Unborn Children Drug Use and ... Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used ...

  20. Realizing the promises of marine biotechnology

    NARCIS (Netherlands)

    Luiten, EEM; Akkerman, [No Value; Koulman, A; Kamermans, P; Reith, H; Barbosa, MJ; Sipkema, D; Wijffels, RH

    High-quality research in the field of marine biotechnology is one of the key-factors for successful innovation in exploiting the vast diversity of marine life. However, fascinating scientific research with promising results and claims on promising potential applications (e.g. for pharmaceuticals,

  1. Realizing the promises of marine biotechnology

    NARCIS (Netherlands)

    Luiten, E.E.M.; Akkerman, I.; Koulman, A.; Kamermans, P.; Reith, H.; Barbosa, M.J.; Sipkema, D.; Wijffels, R.H.

    2003-01-01

    High-quality research in the field of marine biotechnology is one of the key-factors for successful innovation in exploiting the vast diversity of marine life. However, fascinating scientific research with promising results and claims on promising potential applications (e.g. for pharmaceuticals,

  2. Tennessee Promise: A Response to Organizational Change

    Science.gov (United States)

    Littlepage, Ben; Clark, Teresa; Wilson, Randal; Stout, Logan

    2018-01-01

    Community colleges in Tennessee, either directly or indirectly, experienced unprecedented change as a result of Tennessee Promise. The present study explored how student support service administrators at three community colleges responded to organizational change as a result of the Tennessee Promise legislation. Investigators selected community…

  3. SEARCHES FOR MILLISECOND PULSAR CANDIDATES AMONG THE UNIDENTIFIED FERMI OBJECTS

    Energy Technology Data Exchange (ETDEWEB)

    Hui, C. Y.; Park, S. M. [Department of Astronomy and Space Science, Chungnam National University, Daejeon (Korea, Republic of); Hu, C. P. [Graduate Institute of Astronomy, National Central University, Jhongli 32001, Taiwan (China); Lin, L. C. C. [Institute of Astronomy and Astrophysics, Academia Sinica, Taiwan (China); Li, K. L.; Kong, A. K. H.; Jin, Ruolan; Yen, T.-C. [Institute of Astronomy and Department of Physics, National Tsing Hua University, Hsinchu, Taiwan (China); Tam, P. H. T. [Institute of Astronomy and Space Science, Sun Yat-Sen University, Guangzhou 510275 (China); Takata, J.; Cheng, K. S. [Department of Physics, University of Hong Kong, Pokfulam Road, Hong Kong (China); Kim, Chunglee, E-mail: cyhui@cnu.ac.kr [Yonsei University Observatory, Yonsei University, Seoul (Korea, Republic of)

    2015-08-10

    Here we report the results of searching millisecond pulsar (MSP) candidates from the Fermi LAT second source catalog (2FGL). Seven unassociated γ-ray sources in this catalog are identified as promising MSP candidates based on their γ-ray properties. Through the X-ray analysis, we have detected possible X-ray counterparts, localized to an arcsecond accuracy. We have systematically estimated their X-ray fluxes and compared them with the corresponding γ-ray fluxes. The X-ray to γ-ray flux ratios for 2FGL J1653.6-0159 and 2FGL J1946.4-5402 are comparable with the typical value for pulsars. For 2FGL J1625.2-0020, 2FGL J1653.6-0159, and 2FGL J1946.4-5402, their candidate X-ray counterparts are bright enough to perform a detailed spectral and temporal analysis to discriminate their thermal/non-thermal nature and search for the periodic signal. We have also searched for possible optical/IR counterparts at the X-ray positions. For the optical/IR source coincident with the brightest X-ray object associated with 2FGL J1120.0-2204, its spectral energy distribution is comparable with a late-type star. Evidence for the variability has also been found by examining its optical light curve. All the aforementioned 2FGL sources resemble a pulsar in one or more aspects, making them promising targets for follow-up investigations.

  4. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    International Nuclear Information System (INIS)

    Taylor, David J; Parsons, Christine E; Han, Haiyong; Jayaraman, Arul; Rege, Kaushal

    2011-01-01

    Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells

  5. Parallel screening of FDA-approved antineoplastic drugs for identifying sensitizers of TRAIL-induced apoptosis in cancer cells

    Directory of Open Access Journals (Sweden)

    Taylor David J

    2011-11-01

    Full Text Available Abstract Background Tumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis. Methods FDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis. Results Fourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward

  6. Alternative dark matter candidates. Axions

    International Nuclear Information System (INIS)

    Ringwald, Andreas

    2017-01-01

    The axion is arguably one of the best motivated candidates for dark matter. For a decay constant >or similar 10 9 GeV, axions are dominantly produced non-thermally in the early universe and hence are ''cold'', their velocity dispersion being small enough to fit to large scale structure. Moreover, such a large decay constant ensures the stability at cosmological time scales and its behaviour as a collisionless fluid at cosmological length scales. Here, we review the state of the art of axion dark matter predictions and of experimental efforts to search for axion dark matter in laboratory experiments.

  7. Alternative dark matter candidates. Axions

    Energy Technology Data Exchange (ETDEWEB)

    Ringwald, Andreas

    2017-01-15

    The axion is arguably one of the best motivated candidates for dark matter. For a decay constant >or similar 10{sup 9} GeV, axions are dominantly produced non-thermally in the early universe and hence are ''cold'', their velocity dispersion being small enough to fit to large scale structure. Moreover, such a large decay constant ensures the stability at cosmological time scales and its behaviour as a collisionless fluid at cosmological length scales. Here, we review the state of the art of axion dark matter predictions and of experimental efforts to search for axion dark matter in laboratory experiments.

  8. Glutamatergic substrates of drug addiction and alcoholism1

    Science.gov (United States)

    Gass, Justin T.; Foster Olive, M.

    2008-01-01

    The past two decades have witnessed a dramatic accumulation of evidence indicating that the excitatory amino acid glutamate plays an important role in drug addiction and alcoholism. The purpose of this review is to summarize findings on glutamatergic substrates of addiction, surveying data from both human and animal studies. The effects of various drugs of abuse on glutamatergic neurotransmission are discussed, as are the effects of pharmacological or genetic manipulation of various components of glutamate transmission on drug reinforcement, conditioned reward, extinction, and relapse-like behavior. In addition, glutamatergic agents that are currently in use or are undergoing testing in clinical trials for the treatment of addiction are discussed, including acamprosate, N-acetylcysteine, modafinil, topiramate, lamotrigine, gabapentin and mematine. All drugs of abuse appear to modulate glutamatergic transmission, albeit by different mechanisms, and this modulation of glutamate transmission is believed to result in long-lasting neuroplastic changes in the brain that may contribute to the perseveration of drug-seeking behavior and drug-associated memories. In general, attenuation of glutamatergic transmission reduces drug reward, reinforcement, and relapse-like behavior. On the other hand, potentiation of glutamatergic transmission appears to facilitate the extinction of drug-seeking behavior. However, attempts at identifying genetic polymorphisms in components of glutamate transmission in humans have yielded only a limited number of candidate genes that may serve as risk factors for the development of addiction. Nonetheless, manipulation of glutamatergic neurotransmission appears to be a promising avenue of research in developing improved therapeutic agents for the treatment of drug addiction and alcoholism. PMID:17706608

  9. Hybrid nanostructured drug carrier with tunable and controlled drug release

    International Nuclear Information System (INIS)

    Depan, D.; Misra, R.D.K.

    2012-01-01

    We describe here a transformative approach to synthesize a hybrid nanostructured drug carrier that exhibits the characteristics of controlled drug release. The synthesis of the nanohybrid architecture involved two steps. The first step involved direct crystallization of biocompatible copolymer along the long axis of the carbon nanotubes (CNTs), followed by the second step of attachment of drug molecule to the polymer via hydrogen bonding. The extraordinary inorganic–organic hybrid architecture exhibited high drug loading ability and is physically stable even under extreme conditions of acidic media and ultrasonic irradiation. The temperature and pH sensitive characteristics of the hybrid drug carrier and high drug loading ability merit its consideration as a promising carrier and utilization of the fundamental aspects used for synthesis of other promising drug carriers. The higher drug release response during the application of ultrasonic frequency is ascribed to a cavitation-type process in which the acoustic bubbles nucleate and collapse releasing the drug. Furthermore, the study underscores the potential of uniquely combining CNTs and biopolymers for drug delivery. - Graphical abstract: Block-copolymer crystallized on carbon nanotubes (CNTs). Nanohybrid drug carrier synthesized by attaching doxorubicin (DOX) to polymer crystallized CNTs. Crystallized polymer on CNTs provide mechanical stability. Triggered release of DOX. Highlights: ► The novel synthesis of a hybrid nanostructured drug carrier is described. ► The drug carrier exhibits high drug loading ability and is physically stable. ► The high drug release is ascribed to a cavitation-type process.

  10. Multiomics Data Triangulation for Asthma Candidate Biomarkers and Precision Medicine.

    Science.gov (United States)

    Pecak, Matija; Korošec, Peter; Kunej, Tanja

    2018-06-01

    Asthma is a common complex disorder and has been subject to intensive omics research for disease susceptibility and therapeutic innovation. Candidate biomarkers of asthma and its precision treatment demand that they stand the test of multiomics data triangulation before they can be prioritized for clinical applications. We classified the biomarkers of asthma after a search of the literature and based on whether or not a given biomarker candidate is reported in multiple omics platforms and methodologies, using PubMed and Web of Science, we identified omics studies of asthma conducted on diverse platforms using keywords, such as asthma, genomics, metabolomics, and epigenomics. We extracted data about asthma candidate biomarkers from 73 articles and developed a catalog of 190 potential asthma biomarkers (167 human, 23 animal data), comprising DNA loci, transcripts, proteins, metabolites, epimutations, and noncoding RNAs. The data were sorted according to 13 omics types: genomics, epigenomics, transcriptomics, proteomics, interactomics, metabolomics, ncRNAomics, glycomics, lipidomics, environmental omics, pharmacogenomics, phenomics, and integrative omics. Importantly, we found that 10 candidate biomarkers were apparent in at least two or more omics levels, thus promising potential for further biomarker research and development and precision medicine applications. This multiomics catalog reported herein for the first time contributes to future decision-making on prioritization of biomarkers and validation efforts for precision medicine in asthma. The findings may also facilitate meta-analyses and integrative omics studies in the future.

  11. Design of colon targeting drug delivery systems using natural polymeric carriers and their evaluation by gamma scintigraphy technique

    International Nuclear Information System (INIS)

    Soni, P.S.; Sawarkar, S.P.; Deshpande, S.G.; Bajaj, A.N.

    2004-01-01

    Of late, there has been a great awareness in the concept of drug targeting and delivery to a specific site (organ, tissue or cell) in the body to maximize therapeutic effect and reduce toxicity. The various approaches of site-specific drug delivery are implantable pumps, adhesive patches impregnated with drugs, vesicle enclosed drugs and drug carriers. Colonic drug delivery is intended for local and systemic treatment in the diseases of colon like inflammatory bowel conditions. Several approaches using viz. pro-drugs, biodegradable polymers and pH sensitive polymer coatings have been used to achieve colonic delivery. Natural polysaccarides like guar gum and pectin are promising candidates because they are susceptible to degradation by colonic bacteria and thus can release the entrapped drug in the colonic region. These indigenous natural polymers are cheaply and readily available. They comprise of polygalactouronic acid and refractory to host enzymes present in the upper gastrointestinal tract and are degraded by the enzymes produced by the colonic microflora. They were evaluated as a colonic carrier using 5-amino salicylic acid (5-ASA) as a model drug. After successful in vitro testing, gamma scintigraphy technique was used to assess in-vivo behavior of the colon specific drug delivery after a coat of Guar gum and Pectin

  12. Alphavirus capsid proteins self-assemble into core-like particles in insect cells: A promising platform for nanoparticle vaccine development

    NARCIS (Netherlands)

    Hikke, M.C.; Geertsema, C.; Wu, V.; Metz, Stefan; Lent, van J.W.M.; Vlak, J.M.; Pijlman, G.P.

    2016-01-01

    The mosquito-borne chikungunya virus (CHIKV) causes arthritic diseases in humans, whereas the aquatic salmonid alphavirus (SAV) is associated with high mortality in aquaculture of salmon and trout. Using modern biotechnological approaches, promising vaccine candidates based upon highly immunogenic,

  13. Drug repurposing for aging research using model organisms.

    Science.gov (United States)

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

    2017-10-01

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

  14. Financial Technology: The Promise of Blockchain

    OpenAIRE

    Demary, Markus; Demary, Vera

    2017-01-01

    Digitization affects all sectors of the economy. A new and possibly disruptive digital technology is the blockchain, a decentralized ledger, which seems to offer great promise for many financial and business applications.

  15. 11 CFR 100.154 - Candidate debates.

    Science.gov (United States)

    2010-01-01

    ... 11 Federal Elections 1 2010-01-01 2010-01-01 false Candidate debates. 100.154 Section 100.154 Federal Elections FEDERAL ELECTION COMMISSION GENERAL SCOPE AND DEFINITIONS (2 U.S.C. 431) Exceptions to Expenditures § 100.154 Candidate debates. Funds used to defray costs incurred in staging candidate debates in...

  16. 11 CFR 100.92 - Candidate debates.

    Science.gov (United States)

    2010-01-01

    ... 11 Federal Elections 1 2010-01-01 2010-01-01 false Candidate debates. 100.92 Section 100.92 Federal Elections FEDERAL ELECTION COMMISSION GENERAL SCOPE AND DEFINITIONS (2 U.S.C. 431) Exceptions to Contributions § 100.92 Candidate debates. Funds provided to defray costs incurred in staging candidate debates...

  17. eRepo-ORP: Exploring the Opportunity Space to Combat Orphan Diseases with Existing Drugs.

    Science.gov (United States)

    Brylinski, Michal; Naderi, Misagh; Govindaraj, Rajiv Gandhi; Lemoine, Jeffrey

    2017-12-10

    About 7000 rare, or orphan, diseases affect more than 350 million people worldwide. Although these conditions collectively pose significant health care problems, drug companies seldom develop drugs for orphan diseases due to extremely limited individual markets. Consequently, developing new treatments for often life-threatening orphan diseases is primarily contingent on financial incentives from governments, special research grants, and private philanthropy. Computer-aided drug repositioning is a cheaper and faster alternative to traditional drug discovery offering a promising venue for orphan drug research. Here, we present eRepo-ORP, a comprehensive resource constructed by a large-scale repositioning of existing drugs to orphan diseases with a collection of structural bioinformatics tools, including eThread, eFindSite, and eMatchSite. Specifically, a systematic exploration of 320,856 possible links between known drugs in DrugBank and orphan proteins obtained from Orphanet reveals as many as 18,145 candidates for repurposing. In order to illustrate how potential therapeutics for rare diseases can be identified with eRepo-ORP, we discuss the repositioning of a kinase inhibitor for Ras-associated autoimmune leukoproliferative disease. The eRepo-ORP data set is available through the Open Science Framework at https://osf.io/qdjup/. Copyright © 2017. Published by Elsevier Ltd.

  18. 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.

  19. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... groups of young people, guiding the use of technology, the discussion between friends, and the importance of ... between drug misuse and HIV/AIDS and the discovery of promising treatment interventions for breaking the harmful ...

  20. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... of people infected with HIV, drug misuse can interfere with an individual's likelihood of adhering to the ... HIV/AIDS and the discovery of promising treatment interventions for breaking the harmful links between them, we ...

  1. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... between drug misuse and HIV/AIDS and the discovery of promising treatment interventions for breaking the harmful ... requires the free Adobe Flash Player . NIH...Turning Discovery Into Health ®

  2. Drug Facts

    Medline Plus

    Full Text Available ... Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You Used Drugs in the Past Drug Use ... Videos Information About Drugs Alcohol ...

  3. Drug Allergy

    Science.gov (United States)

    ... Loss of consciousness Other conditions resulting from drug allergy Less common drug allergy reactions occur days or ... you take the drug. Drugs commonly linked to allergies Although any drug can cause an allergic reaction, ...

  4. Survey of Swedish buffer material candidates and methods for characterization

    International Nuclear Information System (INIS)

    Erlstroem, M.; Pusch, R.

    1987-12-01

    The study has given a good overview of potential clay buffer candidates in the part of Sweden that offers the best possibilities to find large accessible quantities of smectitic materials. The most promising Scanian materials are those in the Kaageroed and Vallaakra (Margreteberg) areas since they represent the most smectitic ones, which may serve as raw material for the production of canister embedment. The moraine clays in the Lund-Landskrona region seem to be useful for backfilling purposes. A refined version of Reynolds technique is suggested as an SKB standard for prospecting and characterization of buffer materials. (orig./DG)

  5. [Obesity studies in candidate genes].

    Science.gov (United States)

    Ochoa, María del Carmen; Martí, Amelia; Martínez, J Alfredo

    2004-04-17

    There are more than 430 chromosomic regions with gene variants involved in body weight regulation and obesity development. Polymorphisms in genes related to energy expenditure--uncoupling proteins (UCPs), related to adipogenesis and insulin resistance--hormone-sensitive lipase (HLS), peroxisome proliferator-activated receptor gamma (PPAR gamma), beta adrenergic receptors (ADRB2,3), and alfa tumor necrosis factor (TNF-alpha), and related to food intake--ghrelin (GHRL)--appear to be associated with obesity phenotypes. Obesity risk depends on two factors: a) genetic variants in candidate genes, and b) biographical exposure to environmental risk factors. It is necessary to perform new studies, with appropriate control groups and designs, in order to reach relevant conclusions with regard to gene/environmental (diet, lifestyle) interactions.

  6. A kernel for open source drug discovery in tropical diseases.

    Science.gov (United States)

    Ortí, Leticia; Carbajo, Rodrigo J; Pieper, Ursula; Eswar, Narayanan; Maurer, Stephen M; Rai, Arti K; Taylor, Ginger; Todd, Matthew H; Pineda-Lucena, Antonio; Sali, Andrej; Marti-Renom, Marc A

    2009-01-01

    Conventional patent-based drug development incentives work badly for the developing world, where commercial markets are usually small to non-existent. For this reason, the past decade has seen extensive experimentation with alternative R&D institutions ranging from private-public partnerships to development prizes. Despite extensive discussion, however, one of the most promising avenues-open source drug discovery-has remained elusive. We argue that the stumbling block has been the absence of a critical mass of preexisting work that volunteers can improve through a series of granular contributions. Historically, open source software collaborations have almost never succeeded without such "kernels". HERE, WE USE A COMPUTATIONAL PIPELINE FOR: (i) comparative structure modeling of target proteins, (ii) predicting the localization of ligand binding sites on their surfaces, and (iii) assessing the similarity of the predicted ligands to known drugs. Our kernel currently contains 143 and 297 protein targets from ten pathogen genomes that are predicted to bind a known drug or a molecule similar to a known drug, respectively. The kernel provides a source of potential drug targets and drug candidates around which an online open source community can nucleate. Using NMR spectroscopy, we have experimentally tested our predictions for two of these targets, confirming one and invalidating the other. The TDI kernel, which is being offered under the Creative Commons attribution share-alike license for free and unrestricted use, can be accessed on the World Wide Web at http://www.tropicaldisease.org. We hope that the kernel will facilitate collaborative efforts towards the discovery of new drugs against parasites that cause tropical diseases.

  7. [Absorbable coronary stents. New promising technology].

    Science.gov (United States)

    Erbel, Raimund; Böse, Dirk; Haude, Michael; Kordish, Igor; Churzidze, Sofia; Malyar, Nasser; Konorza, Thomas; Sack, Stefan

    2007-06-01

    Coronary stent implantation started in Germany 20 years ago. In the beginning, the progress was very slow and accelerated 10 years later. Meanwhile, coronary stent implantation is a standard procedure in interventional cardiology. From the beginning of permanent stent implantation, research started to provide temporary stenting of coronary arteries, first with catheter-based systems, later with stent-alone technology. Stents were produced from polymers or metal. The first polymer stent implantation failed except the Igaki-Tamai stent in Japan. Newly developed absorbable polymer stents seem to be very promising, as intravascular ultrasound (IVUS) and optical coherence tomography have demonstrated. Temporary metal stents were developed based on iron and magnesium. Currently, the iron stent is tested in peripheral arteries. The absorbable magnesium stent (Biotronik, Berlin, Germany) was tested in peripheral arteries below the knee and meanwhile in the multicenter international PROGRESS-AMS (Clinical Performance and Angiographic Results of Coronary Stenting with Absorbable Metal Stents) study. The first magnesium stent implantation was performed on July 30, 2004 after extended experimental testing in Essen. The magnesium stent behaved like a bare-metal stent with low recoil of 5-7%. The stent struts were absorbed when tested with IVUS. Stent struts were not visible by fluoroscopy or computed tomography (CT) as well as magnetic resonance imaging (MRI). That means, that the magnesium stent is invisible and therefore CT and MRI can be used for imaging of interventions. Only using micro-CT the stent struts were visible. The absorption process could be demonstrated in a patient 18 days after implantation due to suspected acute coronary syndrome, which was excluded. IVUS showed a nice open lumen. Stent struts were no longer visible, but replaced by tissue indicating the previous stent location. Coronary angiography after 4 months showed an ischemia-driven target lesion

  8. Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys.

    Science.gov (United States)

    Kapetanovic, Izet M; Muzzio, Miguel; Hu, Shu-Chieh; Crowell, James A; Rajewski, Roger A; Haslam, John L; Jong, Ling; McCormick, David L

    2010-05-01

    SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent under development. It was designed using computational modeling based on a naturally occurring indole-3-carbinol and its in vivo condensation products. It showed promising anti-cancer activity and its preclinical toxicology profile (genotoxicity battery and subchronic rat and dog studies) was unremarkable. However, it exhibited a very poor oral bioavailability (Solutol, were tested in dogs and monkeys. Levels of SR13668 were measured in plasma and blood using a high-performance liquid chromatograph-tandem mass spectrometer system. Non-compartmental analysis was used to derive pharmacokinetic parameters including the bioavailability. The Solutol formulation yielded better bioavailability reaching a maximum of about 14.6 and 7.3% in dogs and monkeys, respectively, following nominal oral dose of ca. 90 mg SR13668/m(2). Blood levels of SR13668 were consistently about threefold higher than those in plasma in both species. SR13668 did not cause untoward hematology, clinical chemistry, or coagulation effects in dogs or monkeys with the exception of a modest, reversible increase in liver function enzymes in monkeys. The lipid-based surfactant/emulsifiers, especially Solutol, markedly enhanced the oral bioavailability of SR13668 over that previously seen in preclinical studies. These formulations are being evaluated in a Phase 0 clinical study prior to further clinical development of this drug.

  9. Promising Themes for Antismoking Campaigns Targeting Youth and Young Adults.

    Science.gov (United States)

    Brennan, Emily; Gibson, Laura A; Kybert-Momjian, Ani; Liu, Jiaying; Hornik, Robert C

    2017-01-01

    Behavior change campaigns typically try to change beliefs that influence behaviors, with targeted beliefs comprising the campaign theme. We present an empirical approach for choosing among a large number of potential themes, and results from the implementation of this approach for campaigns aimed at 4 behavioral targets: (1) preventing smoking initiation among youth, and (2) preventing initiation, (3) stopping progression to daily smoking and (4) encouraging cessation among young adults. An online survey of 13- to 17-year-olds and 18- to 25-year-olds in the United States (US), in which 20 potential campaign themes were represented by 154 beliefs. For each behavioral target, themes were ranked based on the strength of belief-intention and belief-behavior associations and size of the population not already endorsing the beliefs. The most promising themes varied across behavioral targets but 3 were consistently promising: consequences of smoking for mood, social acceptance and social popularity. Using a robust and systematic approach, this study provides campaign developers with empirical data to inform their selection of promising themes. Findings related to the campaign to prevent initiation among youth informed the development of the US Food and Drug Administration's "The Real Cost" campaign.

  10. Nanocarrier mediated retinal drug delivery: overcoming ocular barriers to treat posterior eye diseases.

    Science.gov (United States)

    Bisht, Rohit; Mandal, Abhirup; Jaiswal, Jagdish K; Rupenthal, Ilva D

    2018-03-01

    Effective drug delivery to the retina still remains a challenge due to ocular elimination mechanisms and complex barriers that selectively limit the entry of drugs into the eye. To overcome these barriers, frequent intravitreal injections are currently used to achieve high drug concentrations in vitreous and retina. However, these repetitive injections may result in several side effects. Recent advancements in the field of nanoparticle-based drug delivery could overcome some of these unmet needs and various preclinical studies conducted to date have demonstrated promising results of nanotherapies in the treatment of retinal diseases. Compared to the majority of commercially available ocular implants, the biodegradable nature of most nanoparticles (NPs) avoids the need for surgical implantation and removal after the release of the payload. In addition, the sustained drug release from NPs over an extended period of time reduces the need for frequent intravitreal injections and the risk of associated side effects. The nanometer size and highly modifiable surface properties make NPs excellent candidates for targeted ocular drug delivery. Studies have shown that nanocarriers enhance the intravitreal half-life and thus bioavailability of a number of drugs including proteins and peptides. In addition, they have shown promising results in delivering genetic material to the retinal tissues by protecting it from possible intravitreal degradation. This review covers the various challenges associated with drug delivery to the posterior segment of the eye, particularly the retina, and highlights the application of nanocarriers to overcome these challenges in context with recent advances in preclinical studies. WIREs Nanomed Nanobiotechnol 2018, 10:e1473. doi: 10.1002/wnan.1473 This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Implantable Materials and Surgical Technologies > Nanomaterials and Implants. © 2017 Wiley Periodicals

  11. Design, challenge, and promise of stimuli-responsive nanoantibiotics

    Science.gov (United States)

    Edson, Julius A.; Kwon, Young Jik

    2016-10-01

    Over the past few years, there have been calls for novel antimicrobials to combat the rise of drug-resistant bacteria. While some promising new discoveries have met this call, it is not nearly enough. The major problem is that although these new promising antimicrobials serve as a short-term solution, they lack the potential to provide a long-term solution. The conventional method of creating new antibiotics relies heavily on the discovery of an antimicrobial compound from another microbe. This paradigm of development is flawed due to the fact that microbes can easily transfer a resistant mechanism if faced with an environmental pressure. Furthermore, there has been some evidence to indicate that the environment of the microbe can provide a hint as to their virulence. Because of this, the use of materials with antimicrobial properties has been garnering interest. Nanoantibiotics, (nAbts), provide a new way to circumvent the current paradigm of antimicrobial discovery and presents a novel mechanism of attack not found in microbes yet; which may lead to a longer-term solution against drug-resistance formation. This allows for environment-specific activation and efficacy of the nAbts but may also open up and create new design methods for various applications. These nAbts provide promise, but there is still ample work to be done in their development. This review looks at possible ways of improving and optimizing nAbts by making them stimuli-responsive, then consider the challenges ahead, and industrial applications.[Figure not available: see fulltext.

  12. Do promises matter? An exploration of the role of promises in psychological contract breach.

    Science.gov (United States)

    Montes, Samantha D; Zweig, David

    2009-09-01

    Promises are positioned centrally in the study of psychological contract breach and are argued to distinguish psychological contracts from related constructs, such as employee expectations. However, because the effects of promises and delivered inducements are confounded in most research, the role of promises in perceptions of, and reactions to, breach remains unclear. If promises are not an important determinant of employee perceptions, emotions, and behavioral intentions, this would suggest that the psychological contract breach construct might lack utility. To assess the unique role of promises, the authors manipulated promises and delivered inducements separately in hypothetical scenarios in Studies 1 (558 undergraduates) and 2 (441 employees), and they measured them separately (longitudinally) in Study 3 (383 employees). The authors' results indicate that breach perceptions do not represent a discrepancy between what employees believe they were promised and were given. In fact, breach perceptions can exist in the absence of promises. Further, promises play a negligible role in predicting feelings of violation and behavioral intentions. Contrary to the extant literature, the authors' findings suggest that promises may matter little; employees are concerned primarily with what the organization delivers.

  13. Ferritic/martensitic steels: Promises and problems

    International Nuclear Information System (INIS)

    Klueh, R.L.; Ehrlich, K.; Abe, F.

    1992-01-01

    Ferritic/martensitic steels are candidate structural materials for fusion reactors because of their higher swelling resistance, higher thermal conductivity, lower thermal expansion, and better liquid-metal compatibility than austenitic steels. Irradiation effects will ultimately determine the applicability of these steels, and the effects of irradiation on microstructure and swelling, and on the tensile, fatigue, and impact properties of the ferritic/martensitic steels are discussed. Most irradiation studies have been carried out in fast reactors, where little transmutation helium forms. Helium has been shown to enhance swelling and affect tensile and fracture behavior, making helium a critical issue, since high helium concentrations will be generated in conjunction with displacement damage in a fusion reactor. These issues are reviewed to evaluate the status of ferritic/martensitic steels and to assess the research required to insure that such steels are viable candidates for fusion applications

  14. The path to fulfilling the promise

    Energy Technology Data Exchange (ETDEWEB)

    Barrett, J. [Canadian Nuclear Association, Ottawa, ON (Canada)

    2014-07-01

    'Full text:'Countries work together to develop effective governance and regulation. Canada has made big investments in these areas and it carries a premium for us. The rapid build-out of nuclear technology around the Pacific Rim holds vast promise for our populations in better climate, better air, affordable and reliable electricity, and longer lives. The biggest risk is not another accident: rather, it is the risk of failing to fulfill that promise to our people. Every country that wants the benefits of nuclear must also want to be sure that those benefits are realized and sustained by good governance and regulation. Canada has the people, laws, organizations, public institutions, and relationships that can help our partners fulfill the whole and lasting promise of nuclear technology. (author)

  15. Promising Compilation to ARMv8 POP

    OpenAIRE

    Podkopaev, Anton; Lahav, Ori; Vafeiadis, Viktor

    2017-01-01

    We prove the correctness of compilation of relaxed memory accesses and release-acquire fences from the "promising" semantics of [Kang et al. POPL'17] to the ARMv8 POP machine of [Flur et al. POPL'16]. The proof is highly non-trivial because both the ARMv8 POP and the promising semantics provide some extremely weak consistency guarantees for normal memory accesses; however, they do so in rather different ways. Our proof of compilation correctness to ARMv8 POP strengthens the results of the Kan...

  16. Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer

    OpenAIRE

    Papademetriou, Iason T; Porter, Tyrone

    2015-01-01

    Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood–brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers non...

  17. Candidate immune biomarkers for radioimmunotherapy.

    Science.gov (United States)

    Levy, Antonin; Nigro, Giulia; Sansonetti, Philippe J; Deutsch, Eric

    2017-08-01

    Newly available immune checkpoint blockers (ICBs), capable to revert tumor immune tolerance, are revolutionizing the anticancer armamentarium. Recent evidence also established that ionizing radiation (IR) could produce antitumor immune responses, and may as well synergize with ICBs. Multiple radioimmunotherapy combinations are thenceforth currently assessed in early clinical trials. Past examples have highlighted the need for treatment personalization, and there is an unmet need to decipher immunological biomarkers that could allow selecting patients who could benefit from these promising but expensive associations. Recent studies have identified potential predictive and prognostic immune assays at the cellular (tumor microenvironment composition), genomic (mutational/neoantigen load), and peripheral blood levels. Within this review, we collected the available evidence regarding potential personalized immune biomarker-directed radiation therapy strategies that might be used for patient selection in the era of radioimmunotherapy. Copyright © 2017. Published by Elsevier B.V.

  18. BEEF CATTLE MUSCULARITY CANDIDATE GENES

    Directory of Open Access Journals (Sweden)

    Irida Novianti

    2010-04-01

    Full Text Available Muscularity is a potential indicator for the selection of more productive cattle. Mapping quantitative trait loci (QTL for traits related to muscularity is useful to identify the genomic regions where the genes affecting muscularity reside. QTL analysis from a Limousin-Jersey double backcross herd was conducted using QTL Express software with cohort and breed as the fixed effects. Nine QTL suggested to have an association with muscularity were identified on cattle chromosomes BTA 1, 2, 3, 4, 5, 8, 12, 14 and 17. The myostatin gene is located at the centromeric end of chromosome 2 and not surprisingly, the Limousin myostatin F94L variant accounted for the QTL on BTA2. However, when the myostatin F94L genotype was included as an additional fixed effect, the QTL on BTA17 was also no longer significant. This result suggests that there may be gene(s that have epistatic effects with myostatin located on cattle chromosome 17. Based on the position of the QTL in base pairs, all the genes that reside in the region were determined using the Ensembl data base (www.ensembl.org. There were two potential candidate genes residing within these QTL regions were selected. They were Smad nuclear interacting protein 1 (SNIP1 and similar to follistatin-like 5 (FSTL5. (JIIPB 2010 Vol 20 No 1: 1-10

  19. A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications.

    Science.gov (United States)

    Pillay, Viness; Tsai, Tong-Sheng; Choonara, Yahya E; du Toit, Lisa C; Kumar, Pradeep; Modi, Girish; Naidoo, Dinesh; Tomar, Lomas K; Tyagi, Charu; Ndesendo, Valence M K

    2014-06-01

    Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an "on-off" drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The "on-off" drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. Copyright © 2013 Wiley Periodicals, Inc.

  20. Injectable, in situ forming poly(propylene fumarate)-based ocular drug delivery systems.

    Science.gov (United States)

    Ueda, H; Hacker, M C; Haesslein, A; Jo, S; Ammon, D M; Borazjani, R N; Kunzler, J F; Salamone, J C; Mikos, A G

    2007-12-01

    This study sought to develop an injectable formulation for long-term ocular delivery of fluocinolone acetonide (FA) by dissolving the anti-inflammatory drug and the biodegradable polymer poly(propylene fumarate) (PPF) in the biocompatible, water-miscible, organic solvent N-methyl-2-pyrrolidone (NMP). Upon injection of the solution into an aqueous environment, a FA-loaded PPF matrix is precipitated in situ through the diffusion/extraction of NMP into surrounding aqueous fluids. Fabrication of the matrices and in vitro release studies were performed in phosphate buffered saline at 37 degrees C. Drug loadings up to 5% were achieved. High performance liquid chromatography was employed to determine the released amount of FA. The effects of drug loading, PPF content of the injectable formulation, and additional photo-crosslinking of the matrix surface were investigated. Overall, FA release was sustained in vitro over up to 400 days. After an initial burst release of 22 to 68% of initial FA loading, controlled drug release driven by diffusion and bulk erosion was observed. Drug release rates in a therapeutic range were demonstrated. Release kinetics were found to be dependent on drug loading, formulation PPF content, and extent of surface crosslinking. The results suggest that injectable, in situ formed PPF matrices are promising candidates for the formulation of long-term, controlled delivery devices for intraocular drug delivery. Copyright 2007 Wiley Periodicals, Inc.

  1. The Promise of Zoomable User Interfaces

    Science.gov (United States)

    Bederson, Benjamin B.

    2011-01-01

    Zoomable user interfaces (ZUIs) have received a significant amount of attention in the 18 years since they were introduced. They have enjoyed some success, and elements of ZUIs are widely used in computers today, although the grand vision of a zoomable desktop has not materialised. This paper describes the premise and promise of ZUIs along with…

  2. Promising carbons for supercapacitors derived from fungi

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hui; Wang, Xiaolei; Yang, Fan; Yang, Xiurong [State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022 (China)

    2011-06-24

    Activated carbons with promising performance in capacitors are produced from fungi via a hydrothermal assistant pyrolysis approach. This study introduces a facile strategy to discover carbonaceous materials and triggers interest in exploring fungi for material science applications. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  3. Seaweed: Promising plant of the millennium

    Digital Repository Service at National Institute of Oceanography (India)

    Dhargalkar, V.K.; Pereira, N.

    Seaweeds, one of the important marine living resources could be termed as the futuristically promising plants. These plants have been a source of food, feed and medicine in the orient as well as in the west, since ancient times. Although, seaweeds...

  4. Complexity of Propositional Proofs Under a Promise

    Czech Academy of Sciences Publication Activity Database

    Dershowitz, N.; Tzameret, Iddo

    2010-01-01

    Roč. 11, č. 3 (2010), s. 1-29 ISSN 1529-3785 Institutional research plan: CEZ:AV0Z10190503 Keywords : theory * promise problems * propositional proof complexity * random 3CNF * resolution Subject RIV: BA - General Mathematics Impact factor: 1.391, year: 2010 http://dl.acm.org/ citation .cfm?doid=1740582.1740586

  5. Complexity of Propositional Proofs Under a Promise

    Czech Academy of Sciences Publication Activity Database

    Dershowitz, N.; Tzameret, Iddo

    2010-01-01

    Roč. 11, č. 3 (2010), s. 1-29 ISSN 1529-3785 Institutional research plan: CEZ:AV0Z10190503 Keywords : theory * promise problems * propositional proof complexity * random 3CNF * resolution Subject RIV: BA - General Mathematics Impact factor: 1.391, year: 2010 http://dl.acm.org/citation.cfm?doid=1740582.1740586

  6. 76 FR 13152 - Promise Neighborhoods Program

    Science.gov (United States)

    2011-03-10

    ... comprehensive education reforms that are linked to improved educational outcomes for children and youth in... parents or family members who report talking with their child about the importance of college and career... DEPARTMENT OF EDUCATION RIN 1855-ZA07 Promise Neighborhoods Program Catalog of Federal Domestic...

  7. Drugs from the Sea - Opportunities and Obstacles

    Directory of Open Access Journals (Sweden)

    Rainer Ebel

    2003-11-01

    Full Text Available Abstract: The supply problem with regard to drug development and sustainable production lies in the limited amounts of biomass of most marine invertebrates available from wild stocks. Thus, most pharmacologically active marine natural products can only be isolated in minute yields. Total synthesis of pharmacologically active natural products has been successfully established but is in many cases economically not feasible due to the complexity of the molecular structures and the low yields. To solve the pressing supply issue in marine drug discovery, other strategies appear to be more promising. One of these is mariculture which has successfully been established with the bryozoan Bugula neritina (the source of the bryostatins and the tunicate Ecteinascidia turbinata (the source of ET-743. Another strategy involves partial synthesis from precursors which are biotechnologically available. An example is ET-743 that can be partially synthesized from safracin B which is a metabolite of Pseudomonas fluorescens. There have been many examples of striking structural similarities between natural products obtained from marine invertebrates and those of microbial origin which suggests that microorganisms living in their invertebrate hosts could be the actual producers of these secondary metabolites. With regard to sustainable biotechnological production of pharmacologically important metabolites from marine invertebrates and their “endosymbionts”, a more advanced strategy is to focus on cloning and expression of the respective key biosynthetic gene clusters. This molecular biological approach will open up new avenues for biotechnological production of drugs or drug candidates from the sea.

  8. Tasty THC: Promises and Challenges of Cannabis Edibles

    Science.gov (United States)

    Barrus, Daniel G.; Capogrossi, Kristen L.; Cates, Sheryl C.; Gourdet, Camille K.; Peiper, Nicholas C.; Novak, Scott P.; Lefever, Timothy W.; Wiley, Jenny L.

    2016-01-01

    Food products containing cannabis extract (edibles) have emerged as a popular and lucrative facet of the legalized market for both recreational and medicinal cannabis. The many formulations of cannabis extracts used in edibles present a unique regulatory challenge for policy makers. Though edibles are often considered a safe, discreet, and effective means of attaining the therapeutic and/or intoxicating effects of cannabis without exposure to the potentially harmful risks of cannabis smoking, little research has evaluated how ingestion differs from other methods of cannabis administration in terms of therapeutic efficacy, subjective effects, and safety. The most prominent difference between ingestion and inhalation of cannabis extracts is the delayed onset of drug effect with ingestion. Consumers often do not understand this aspect of edible use and may consume a greater than intended amount of drug before the drug has taken effect, often resulting in profoundly adverse effects. Written for the educated layperson and for policy makers, this paper explores the current state of research regarding edibles, highlighting the promises and challenges that edibles present to both users and policy makers, and describes the approaches that four states in which recreational cannabis use is legal have taken regarding regulating edibles. PMID:28127591

  9. Microfluidics Enables Small-Scale Tissue-Based Drug Metabolism Studies With Scarce Human Tissue

    NARCIS (Netherlands)

    van Midwoud, Paul M.; Verpoorte, Elisabeth; Groothuis, Geny M. M.; Merema, M.T.

    2011-01-01

    Early information on the metabolism and toxicity properties of new drug candidates is crucial for selecting the right candidates for further development. Preclinical trials rely on cell-based in vitro tests and animal studies to characterize the in vivo behavior of drug candidates, although neither

  10. Perspectives on Advances in Tuberculosis Diagnostics, Drugs, and Vaccines.

    Science.gov (United States)

    Schito, Marco; Migliori, Giovanni Battista; Fletcher, Helen A; McNerney, Ruth; Centis, Rosella; D'Ambrosio, Lia; Bates, Matthew; Kibiki, Gibson; Kapata, Nathan; Corrah, Tumena; Bomanji, Jamshed; Vilaplana, Cris; Johnson, Daniel; Mwaba, Peter; Maeurer, Markus; Zumla, Alimuddin

    2015-10-15

    Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with expanding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise of better point-of-care rapid tests for tuberculosis including nucleic acid-based amplification tests, imaging, and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multidrug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several new drug regimens and their evaluation in clinical trials and now influence World Health Organization guidelines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candidates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immunodeficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder commitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and prevention are urgently required. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Flavonoids as modulators of metabolic enzymes and drug transporters.

    Science.gov (United States)

    Miron, Anca; Aprotosoaie, Ana Clara; Trifan, Adriana; Xiao, Jianbo

    2017-06-01

    Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR. © 2017 New York Academy of Sciences.

  12. Probiotic Candidates from Fish Pond Water in Central Java Indonesia

    Science.gov (United States)

    Harjuno Condro Haditomo, Alfabetian; Desrina; Sarjito; Budi Prayitno, S.

    2018-02-01

    Aeromonas hydrophilla is a major bacterial pathogen of intensive fresh water fish culture in Indonesia. An alternative method to control the pathogen is using probiotics. Probiotics is usually consist of live microorganisms which when administered in adequate amounts confer a health benefits on host. The aim of this research was to determine the probiotic candidates against A. hydrophilla which identified based on the 16S rDNA gene sequences. This research was started with field survey to obtained the probiotic candidate and continue with laboratory experiment. Probiotic candidates were isolated from fish pond water located in Boyolali, and Banjarnegara Regency, Central Java, Indonesia. A total of 133 isolates bacteria were isolated and cultured on to TSA, TSB and GSP medium. Out of 133 isolates only 30 isolates showed inhibition to A.hydrophilla activity. Three promising isolates were identified with PCR using primer for 16S rDNA. Based on 16S rDNA sequence analysis, all three isolates were belong to Bacillus genus. Isolate CKlA21, CKlA28, and CBA14 respectively were closely related to Bacillus sp. 13843 (GenBank accession no. JN874760.1 -100% homology), Bacillus subtilis strain H13 (GenBank accession no.KT907045.1 -- 99% homology), and Bacillus sp. strain 22-4 (GenBank accession no. KX816417.1 -- 97% homology).

  13. Drug Safety

    Science.gov (United States)

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  14. Drug Abuse

    Science.gov (United States)

    ... Cocaine Heroin Inhalants Marijuana Prescription drugs, including opioids Drug abuse also plays a role in many major social problems, such as drugged driving, violence, stress, and child abuse. Drug abuse can lead to ...

  15. Drug Facts

    Medline Plus

    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  16. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Kids Drug Use and Unborn Children Drug Use and Your Health Other Effects on ... Someone Find Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids ...

  17. Club Drugs

    Science.gov (United States)

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  18. Exploring drug-target interaction networks of illicit drugs

    OpenAIRE

    Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

    2013-01-01

    Background Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit dru...

  19. Stages of Drug Use Acquisition among College Students: Implications for the Prevention of Drug Abuse.

    Science.gov (United States)

    Werch, Chudley E.; And Others

    1993-01-01

    Examined stages of drug use acquisition among college students (n=669) and relationship between stage status and motivation to avoid drugs and frequency of drug use. College students differed with regard to their stage of habit acquisition across five drugs. Findings suggest that acquisition stage heuristic holds promise in increasing…

  20. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    Science.gov (United States)

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353

  1. Exploring drug-target interaction networks of illicit drugs.

    Science.gov (United States)

    Atreya, Ravi V; Sun, Jingchun; Zhao, Zhongming

    2013-01-01

    Drug addiction is a complex and chronic mental disease, which places a large burden on the American healthcare system due to its negative effects on patients and their families. Recently, network pharmacology is emerging as a promising approach to drug discovery by integrating network biology and polypharmacology, allowing for a deeper understanding of molecular mechanisms of drug actions at the systems level. This study seeks to apply this approach for investigation of illicit drugs and their targets in order to elucidate their interaction patterns and potential secondary drugs that can aid future research and clinical care. In this study, we extracted 188 illicit substances and their related information from the DrugBank database. The data process revealed 86 illicit drugs targeting a total of 73 unique human genes, which forms an illicit drug-target network. Compared to the full drug-target network from DrugBank, illicit drugs and their target genes tend to cluster together and form four subnetworks, corresponding to four major medication categories: depressants, stimulants, analgesics, and steroids. External analysis of Anatomical Therapeutic Chemical (ATC) second sublevel classifications confirmed that the illicit drugs have neurological functions or act via mechanisms of stimulants, opioids, and steroids. To further explore other drugs potentially having associations with illicit drugs, we constructed an illicit-extended drug-target network by adding the drugs that have the same target(s) as illicit drugs to the illicit drug-target network. After analyzing the degree and betweenness of the network, we identified hubs and bridge nodes, which might play important roles in the development and treatment of drug addiction. Among them, 49 non-illicit drugs might have potential to be used to treat addiction or have addictive effects, including some results that are supported by previous studies. This study presents the first systematic review of the network

  2. Service Users perspectives in PROMISE and research.

    Science.gov (United States)

    Rae, Sarah

    2017-09-01

    Since its inception in 2013, PROMISE (PROactive Management of Integrated Services and Environments) has been supporting service users and staff at the Cambridgeshire and Peterborough NHS Foundation Trust (CPFT) on a journey to reduce reliance on force. The author's own personal experiences led to the founding of PROMISE and illustrates how individual experiences can influence a patient to lead change. Coproduction is actively embedded in PROMISE. Patients have been meaningfully involved because they are innovators and problem solvers who bring an alternative viewpoint by the very nature of their condition. A patient is more than just a person who needs to be 'fixed' they are individuals with untapped skills and added insight. There have been 2 separate Patient Advisory Groups (PAGs) since the project was first established. The first Patient Advisory Group was recruited to work with the PROMISE researchers on a study which used a participatory qualitative approach. Drawing on their lived experience and different perspectives the PAG was instrumental in shaping the qualitative study, including the research questions. Their active involvement helped to ensure that that the study was sensitively designed, methodologically robust and ethically sound. The 2 nd PAG was formed in 2016 to give the project an overall steer. Patients in this group contributed to the work on the 'No' Audit and reviewed several CPFT policies such as the Seclusion and Segregation policy which has impacted on frontline practice. They also made a significant contribution to the study design for a funding application that was submitted by the PROMISE team to the National Institute for Health Research (NIHR). Both PAGs were supported by funding from East of England Collaboration for Leadership in Applied Health Research and Care (CLAHRC EoE) and were influential in different ways. An evaluation of the 2 nd PAG which was conducted in June 2017 showed very high satisfaction levels. The free text

  3. Application of CaCu3Ti4O12 based quadruple perovskites as a promising candidate for optoelectronic devices

    Science.gov (United States)

    Pal, Kamalesh; Jana, Rajkumar; Dey, Arka; Ray, Partha P.; Seikh, Md Motin; Gayen, Arup

    2018-05-01

    We report the synthesis of nanosized (40-50 nm) CaCu3-xMnxTi4-xMnxO12 (x = 0, 0.5 and 1) quadruple perovskite (QP) semiconductor via a modified combustion method for use as Schottky barrier diode (SBD) at the Al/QP junction. The fabricated SBD is analysed on the basis of thermionic emission theory to observe its quality and some important diode parameters. For insight analysis of charge transport mechanism through metal-semiconductor junction, theory of space charge limited currents is applied and discussed in the light of parameters like carrier concentration, mobility-lifetime product and diffusion length. The Mn-doped exhibit better device performance compared to parent material.

  4. Arsenene as a promising candidate for NO and NO{sub 2} sensor: A first-principles study

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Can [School of Electronic Science and Engineering, Nanjing University of Posts and Telecommunications, Nanjing 210023 (China); Key Laboratory of Radio Frequency and Micro-Nano Electronics of Jiangsu Province, Nanjing 210023, Jiangsu (China); Liu, Chun-Sheng, E-mail: csliu@njupt.edu.cn [School of Electronic Science and Engineering, Nanjing University of Posts and Telecommunications, Nanjing 210023 (China); Key Laboratory of Radio Frequency and Micro-Nano Electronics of Jiangsu Province, Nanjing 210023, Jiangsu (China); Yan, Xiaohong [School of Electronic Science and Engineering, Nanjing University of Posts and Telecommunications, Nanjing 210023 (China); Key Laboratory of Radio Frequency and Micro-Nano Electronics of Jiangsu Province, Nanjing 210023, Jiangsu (China); College of Science, Nanjing University of Aeronautics and Astronautics, Nanjing 211106 (China)

    2017-03-26

    Based on first-principles calculations, we have studied the adsorption of CO, CO{sub 2}, N{sub 2}, NH{sub 3}, NO and NO{sub 2} molecules on the pristine arsenene monolayer. These gas molecules are held by an interaction that is intermediate between the physisorbed and chemisorbed states. Furthermore, the adsorption of NO and NO{sub 2} can produce a noticeable modifications of the density of states near the Fermi level. Interestingly, only the adsorption of NO and NO{sub 2} can lead to a magnetic moment of 1 μB. Therefore, our results can provide a theoretical basis for the potential applications of arsenene monolayer in gas sensing with electrical and magnetic methods. - Highlights: • A new type of two-dimensional single element semiconductor. • Investigated by first-principles calculations. • Easy desorption and good reversibility. • Gas sensing with electrical and magnetic methods.

  5. Silver oxide nanocrystals anchored on titanate nanotubes and nanofibers: promising candidates for entrapment of radioactive iodine anions.

    Science.gov (United States)

    Yang, Dongjiang; Liu, Hongwei; Liu, Long; Sarina, Sarina; Zheng, Zhanfeng; Zhu, Huaiyong

    2013-11-21

    Iodine radioisotopes are released into the environment by the nuclear industry and medical research institutions using radioactive materials. The (129)I(-) anion is one of the more mobile radioactive species due to a long half-life, and it is a great challenge to design long-term management solutions for such radioactive waste. In this study, a new adsorbent structure with the potential to efficiently remove radioactive iodine anions (I(-)) from water is devised: silver oxide (Ag2O) nanocrystals firmly anchored on the surface of titanate nanotubes and nanofibers via coherent interfaces between Ag2O and titanate phases. I(-) anions in fluids can easily access the Ag2O nanocrystals and be efficiently trapped by forming AgI precipitate that firmly attaches to the adsorbent. Due to their one-dimensional morphology, the new adsorbents can be readily dispersed in liquids and easily separated after purification; and the adsorption beds loaded with the adsorbents can permit high flux. This significantly enhances the adsorption efficiency and reduces the separation costs. The proposed structure reveals a new direction in developing efficient adsorbents for the removal of radioactive anions from wastewater.

  6. Evaluation of solution and rheological properties for hydrophobically associated polyacrylamide copolymer as a promised enhanced oil recovery candidate

    Directory of Open Access Journals (Sweden)

    A.N. El-hoshoudy

    2017-09-01

    Full Text Available Crude oil is the most critical energy source in the world, especially for transportation, provision of heat and light as there has not been a sufficient energy source to replace crude oil has broadly integrated, so there is an urgent need to maximize the extraction of the original oil in-place for every reservoir, and accelerating the development of enhanced oil recovery (EOR technologies. Polymer flooding by hydrophobically associated polyacrylamides (HAPAM is a widely used technique through EOR technology. For successful application of these polymers, one should evaluate rheological and solution properties at simulated reservoir conditions as a function of polymer concentration, salinity, temperature and shear rate. The results showed that these copolymers exhibit favorable salt tolerance, temperature resistance, and recoverable viscosity after shearing, reasonable thickening behavior and improved viscosity enhancement properties due to presence of hydrophobic association in the copolymer main chains. Moreover, its capacity for oil production improvement was evaluated during flooding experiments through one dimensional sandstone model at simulated reservoir conditions.

  7. Nanometer size 3d–4d and 3d–5d substitutional clusters: Promising candidates for magnetic storageapplications

    KAUST Repository

    Mokkath, Junais Habeeb

    2013-05-01

    Spin-polarized density-functional calculations including spin-orbit coupling (SOC) have been performed for FemRhn and FemPtn clusters having N=m+n,N≤19 atoms. The spin magnetic moments, orbital magnetic moments, and the magnetic anisotropy energies have been determined. A significant enhancement of magnetic anisotropy energies is found by the substitutional nanoalloying of Fe with Rh and Pt atoms. We obtained a remarkable non-monotonous dependence of the MAE as a function of Fe content, i.e., upon going from pure Fe to pure Rh and Pt. The substitutional nanoalloying boost the magnetic anisotropy energies by creating significant cluster symmetry lowerings. © 2013 Elsevier B.V.

  8. Nanometer size 3d–4d and 3d–5d substitutional clusters: Promising candidates for magnetic storageapplications

    KAUST Repository

    Mokkath, Junais Habeeb

    2013-01-01

    Spin-polarized density-functional calculations including spin-orbit coupling (SOC) have been performed for FemRhn and FemPtn clusters having N=m+n,N≤19 atoms. The spin magnetic moments, orbital magnetic moments, and the magnetic anisotropy energies

  9. Ceramic/polymer nanocomposites with tunable drug delivery capability at specific disease sites.

    Science.gov (United States)

    Liu, Huinan; Webster, Thomas J

    2010-06-01

    placed in rat calvaria, this study continued to demonstrate that ceramic/polymer nanocomposites are promising candidates as novel orthopedic materials to promote bone regeneration.

  10. The impact of assay technology as applied to safety assessment in reducing compound attrition in drug discovery.

    Science.gov (United States)

    Thomas, Craig E; Will, Yvonne

    2012-02-01

    Attrition in the drug industry due to safety findings remains high and requires a shift in the current safety testing paradigm. Many companies are now positioning safety assessment at each stage of the drug development process, including discovery, where an early perspective on potential safety issues is sought, often at chemical scaffold level, using a variety of emerging technologies. Given the lengthy development time frames of drugs in the pharmaceutical industry, the authors believe that the impact of new technologies on attrition is best measured as a function of the quality and timeliness of candidate compounds entering development. The authors provide an overview of in silico and in vitro models, as well as more complex approaches such as 'omics,' and where they are best positioned within the drug discovery process. It is important to take away that not all technologies should be applied to all projects. Technologies vary widely in their validation state, throughput and cost. A thoughtful combination of validated and emerging technologies is crucial in identifying the most promising candidates to move to proof-of-concept testing in humans. In spite of the challenges inherent in applying new technologies to drug discovery, the successes and recognition that we cannot continue to rely on safety assessment practices used for decades have led to rather dramatic strategy shifts and fostered partnerships across government agencies and industry. We are optimistic that these efforts will ultimately benefit patients by delivering effective and safe medications in a timely fashion.

  11. Perpendicular recording: the promise and the problems

    International Nuclear Information System (INIS)

    Wood, Roger; Sonobe, Yoshiaki; Jin Zhen; Wilson, Bruce

    2001-01-01

    Perpendicular recording has long been advocated as a means of achieving the highest areal densities. In particular, in the context of the 'superparamagnetic limit', perpendicular recording with a soft underlayer promises several key advantages. These advantages include a higher coercivity, thicker media that should permit smaller diameter grains and higher signal-to-noise ratio. Also, the sharper edge-writing will facilitate recording at very high track densities (lower bit aspect ratio). Recent demonstrations of the technology have shown densities comparable with the highest densities reported for longitudinal recording. This paper further examines the promise that perpendicular recording will deliver an increase in areal density two to eight times higher than that achievable with longitudinal recording. There are a number of outstanding issues but the key challenge is to create a low-noise medium with a coercivity that is high and is much larger than the remanent magnetization

  12. The deepwater Gulf of Mexico : promises delivered?

    International Nuclear Information System (INIS)

    Pickering, D.R.

    1999-01-01

    A summary review of deepwater Gulf of Mexico (GOM) oil production was presented for the years 1989 to 1998. Trends and prospects in deepwater GOM production and leasing were assessed. Promises and forecasts made in the early 1990s were compared with what actually happened since then. Forecasts in the early 1990s promised deeper, faster and cheaper developments in the deepwater Gulf. Results of the comparison showed that the prognosticators were correct on all three counts. Regarding the future of the Gulf, one can be justified in being optimistic in so far as more experience, robust economics, more and cheaper rigs can be taken as reliable indicators of optimism. In contrast, there are certain negatives to consider, such as low commodity prices, budget constraints, lease expirations, technical challenges and increased competition. . 12 figs

  13. A REVIEW ON OSMOTIC DRUG DELIVERY SYSTEM

    OpenAIRE

    Harnish Patel; Upendra Patel; Hiren Kadikar; Bhavin Bhimani; Dhiren Daslaniya; Ghanshyam Patel

    2012-01-01

    Conventional oral drug delivery systems supply an instantaneous release of drug, which cannot control the release of the drug and effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis. Osmotic devices are the most promising strategy based systems for controlled drug delivery. They are the most reliable con...

  14. Promising Products for Printing and Publishing Market

    Directory of Open Access Journals (Sweden)

    Renata Činčikaitė

    2011-04-01

    Full Text Available The article surveys printing and publishing market and its strong and weak aspects. The concept of a new product is described as well as its lifetime and the necessity of its introduction to the market. The enterprise X operating on the market is analyzed, its strong and weak characteristics are presented. The segmentation of the company consumers is performed. On the basis of the performed analysis the potential promising company products are defined.Article in Lithuanian

  15. Melanoma Vaccines: Mixed Past, Promising Future

    Science.gov (United States)

    Ozao-Choy, Junko; Lee, Delphine J.; Faries, Mark B.

    2014-01-01

    Synopsis Cancer vaccines were one of the earliest forms of immunotherapy to be investigated. Past attempts to vaccinate against cancer, including melanoma, have mixed results, revealing the complexity of what was thought to be a simple concept. However, several recent successes and the combination of improved knowledge of tumor immunology and the advent of new immunomodulators make vaccination a promising strategy for the future. PMID:25245965

  16. 11 CFR 110.13 - Candidate debates.

    Science.gov (United States)

    2010-01-01

    ... debates include at least two candidates; and (2) The staging organization(s) does not structure the... PROHIBITIONS § 110.13 Candidate debates. (a) Staging organizations. (1) Nonprofit organizations described in 26..., subparts D and E. (b) Debate structure. The structure of debates staged in accordance with this section and...

  17. A possible candidate for cold dark matter

    Indian Academy of Sciences (India)

    This additional scalar can be a viable candidate of cold dark matter (CDM) since the stability of is achieved by the application of Z 2 symmetry on . Considering as a possible candidate of CDM, Boltzmann's equation is solved to find the freeze-out temperature and relic density of for Higgs mass 120 GeV in the scalar ...

  18. 76 FR 36130 - Call for Candidates

    Science.gov (United States)

    2011-06-21

    ... financial information in decision-making. The Board meets in Washington, DC, for two days every other month... FEDERAL ACCOUNTING STANDARDS ADVISORY BOARD Call for Candidates AGENCY: Federal Accounting... candidates. Any applicant who provided the Federal Accounting Standards Advisory Board (FASAB or the Board...

  19. Evaluating historical candidate genes for schizophrenia

    DEFF Research Database (Denmark)

    Farrell, M S; Werge, T; Sklar, P

    2015-01-01

    Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of thes...

  20. 11 CFR 9003.2 - Candidate certifications.

    Science.gov (United States)

    2010-01-01

    ... funds under 11 CFR 9003.2(c)(3) shall not count against such candidate's $50,000 expenditure limitation... expenditures. (8) Expenditures made using a credit card for which the candidate is jointly or solely liable will count against the limits of this section to the extent that the full amount due, including any...

  1. Nanomedicine: Perspective and promises with ligand-directed molecular imaging

    Energy Technology Data Exchange (ETDEWEB)

    Pan Dipanjan [Department of Medicine, Washington University Medical School, St. Louis, MO (United States)], E-mail: dipanjan@wustl.edu; Lanza, Gregory M.; Wickline, Samuel A. [Department of Medicine, Washington University Medical School, St. Louis, MO (United States); Caruthers, Shelton D. [Department of Medicine, Washington University Medical School, St. Louis, MO (United States); Philips Healthcare, Andover, MA (United States)], E-mail: scaruthers@cmrl.wustl.edu

    2009-05-15

    Molecular imaging and targeted drug delivery play an important role toward personalized medicine, which is the future of patient management. Of late, nanoparticle-based molecular imaging has emerged as an interdisciplinary area, which shows promises to understand the components, processes, dynamics and therapies of a disease at a molecular level. The unprecedented potential of nanoplatforms for early detection, diagnosis and personalized treatment of diseases, have found application in every biomedical imaging modality. Biological and biophysical barriers are overcome by the integration of targeting ligands, imaging agents and therapeutics into the nanoplatform which allow for theranostic applications. In this article, we have discussed the opportunities and potential of targeted molecular imaging with various modalities putting a particular emphasis on perfluorocarbon nanoemulsion-based platform technology.

  2. Nanomedicine: Perspective and promises with ligand-directed molecular imaging

    International Nuclear Information System (INIS)

    Pan Dipanjan; Lanza, Gregory M.; Wickline, Samuel A.; Caruthers, Shelton D.

    2009-01-01

    Molecular imaging and targeted drug delivery play an important role toward personalized medicine, which is the future of patient management. Of late, nanoparticle-based molecular imaging has emerged as an interdisciplinary area, which shows promises to understand the components, processes, dynamics and therapies of a disease at a molecular level. The unprecedented potential of nanoplatforms for early detection, diagnosis and personalized treatment of diseases, have found application in every biomedical imaging modality. Biological and biophysical barriers are overcome by the integration of targeting ligands, imaging agents and therapeutics into the nanoplatform which allow for theranostic applications. In this article, we have discussed the opportunities and potential of targeted molecular imaging with various modalities putting a particular emphasis on perfluorocarbon nanoemulsion-based platform technology.

  3. Systematic evaluation of candidate blood markers for detecting ovarian cancer.

    Directory of Open Access Journals (Sweden)

    Chana Palmer

    2008-07-01

    Full Text Available Epithelial ovarian cancer is a significant cause of mortality both in the United States and worldwide, due largely to the high proportion of cases that present at a late stage, when survival is extremely poor. Early detection of epithelial ovarian cancer, and of the serous subtype in particular, is a promising strategy for saving lives. The low prevalence of ovarian cancer makes the development of an adequately sensitive and specific test based on blood markers very challenging. We evaluated the performance of a set of candidate blood markers and combinations of these markers in detecting serous ovarian cancer.We selected 14 candidate blood markers of serous ovarian cancer for which assays were available to measure their levels in serum or plasma, based on our analysis of global gene expression data and on literature searches. We evaluated the performance of these candidate markers individually and in combination by measuring them in overlapping sets of serum (or plasma samples from women with clinically detectable ovarian cancer and women without ovarian cancer. Based on sensitivity at high specificity, we determined that 4 of the 14 candidate markers--MUC16, WFDC2, MSLN and MMP7--warrant further evaluation in precious serum specimens collected months to years prior to clinical diagnosis to assess their utility in early detection. We also reported differences in the performance of these candidate blood markers across histological types of epithelial ovarian cancer.By systematically analyzing the performance of candidate blood markers of ovarian cancer in distinguishing women with clinically apparent ovarian cancer from women without ovarian cancer, we identified a set of serum markers with adequate performance to warrant testing for their ability to identify ovarian cancer months to years prior to clinical diagnosis. We argued for the importance of sensitivity at high specificity and of magnitude of difference in marker levels between cases and

  4. Repurposing of Copper(II)-chelating Drugs for the Treatment of Neurodegenerative Diseases.

    Science.gov (United States)

    Lanza, Valeria; Milardi, Danilo; Di Natale, Giuseppe; Pappalardo, Giuseppe

    2018-02-12

    repositioned drugs had already passed the safety and toxicity tests. Promising drug candidates in neurodegenerative diseases may be represented by copper chelating classes of drugs, provided that sufficient details on their mechanism of action are available to encourage further investigations and clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Transforming fragments into candidates: small becomes big in medicinal chemistry.

    Science.gov (United States)

    de Kloe, Gerdien E; Bailey, David; Leurs, Rob; de Esch, Iwan J P

    2009-07-01

    Fragment-based drug discovery (FBDD) represents a logical and efficient approach to lead discovery and optimisation. It can draw on structural, biophysical and biochemical data, incorporating a wide range of inputs, from precise mode-of-binding information on specific fragments to wider ranging pharmacophoric screening surveys using traditional HTS approaches. It is truly an enabling technology for the imaginative medicinal chemist. In this review, we analyse a representative set of 23 published FBDD studies that describe how low molecular weight fragments are being identified and efficiently transformed into higher molecular weight drug candidates. FBDD is now becoming warmly endorsed by industry as well as academia and the focus on small interacting molecules is making a big scientific impact.

  6. Candidate genes for COPD: current evidence and research

    Directory of Open Access Journals (Sweden)

    Kim WJ

    2015-10-01

    Full Text Available Woo Jin Kim,1 Sang Do Lee2 1Department of Internal Medicine and Environmental Health Center, Kangwon National University, Chuncheon, 2Department of Pulmonary and Critical Care Medicine, Clinical Research Center for Chronic Obstructive Airway Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Abstract: COPD is a common complex disease characterized by progressive airflow limitation. Several genome-wide association studies (GWASs have discovered genes that are associated with COPD. Recently, candidate genes for COPD identified by GWASs include CHRNA3/5 (cholinergic nicotine receptor alpha 3/5, IREB2 (iron regulatory binding protein 2, HHIP (hedgehog-interacting protein, FAM13A (family with sequence similarity 13, member A, and AGER (advanced glycosylation end product–specific receptor. Their association with COPD susceptibility has been replicated in multiple populations. Since these candidate genes have not been considered in COPD, their pathological roles are still largely unknown. Herein, we review some evidences that they can be effective drug targets or serve as biomarkers for diagnosis or subtyping. However, more study is required to understand the functional roles of these candidate genes. Future research is needed to characterize the effect of genetic variants, validate gene function in humans and model systems, and elucidate the genes’ transcriptional and posttranscriptional regulatory mechanisms. Keywords: chronic obstructive pulmonary disease, genetics, genome-wide association study

  7. Crowd Sourcing a New Paradigm for Interactome Driven Drug Target Identification in Mycobacterium tuberculosis

    Science.gov (United States)

    Rohira, Harsha; Bhat, Ashwini G.; Passi, Anurag; Mukherjee, Keya; Choudhary, Kumari Sonal; Kumar, Vikas; Arora, Anshula; Munusamy, Prabhakaran; Subramanian, Ahalyaa; Venkatachalam, Aparna; S, Gayathri; Raj, Sweety; Chitra, Vijaya; Verma, Kaveri; Zaheer, Salman; J, Balaganesh; Gurusamy, Malarvizhi; Razeeth, Mohammed; Raja, Ilamathi; Thandapani, Madhumohan; Mevada, Vishal; Soni, Raviraj; Rana, Shruti; Ramanna, Girish Muthagadhalli; Raghavan, Swetha; Subramanya, Sunil N.; Kholia, Trupti; Patel, Rajesh; Bhavnani, Varsha; Chiranjeevi, Lakavath; Sengupta, Soumi; Singh, Pankaj Kumar; Atray, Naresh; Gandhi, Swati; Avasthi, Tiruvayipati Suma; Nisthar, Shefin; Anurag, Meenakshi; Sharma, Pratibha; Hasija, Yasha; Dash, Debasis; Sharma, Arun; Scaria, Vinod; Thomas, Zakir; Chandra, Nagasuma; Brahmachari, Samir K.; Bhardwaj, Anshu

    2012-01-01

    A decade since the availability of Mycobacterium tuberculosis (Mtb) genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative ‘Connect to Decode’ (C2D) to generate the first and largest manually curated interactome of Mtb termed ‘interactome pathway’ (IPW), encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach. PMID:22808064

  8. Crowd sourcing a new paradigm for interactome driven drug target identification in Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Rohit Vashisht

    Full Text Available A decade since the availability of Mycobacterium tuberculosis (Mtb genome sequence, no promising drug has seen the light of the day. This not only indicates the challenges in discovering new drugs but also suggests a gap in our current understanding of Mtb biology. We attempt to bridge this gap by carrying out extensive re-annotation and constructing a systems level protein interaction map of Mtb with an objective of finding novel drug target candidates. Towards this, we synergized crowd sourcing and social networking methods through an initiative 'Connect to Decode' (C2D to generate the first and largest manually curated interactome of Mtb termed 'interactome pathway' (IPW, encompassing a total of 1434 proteins connected through 2575 functional relationships. Interactions leading to gene regulation, signal transduction, metabolism, structural complex formation have been catalogued. In the process, we have functionally annotated 87% of the Mtb genome in context of gene products. We further combine IPW with STRING based network to report central proteins, which may be assessed as potential drug targets for development of drugs with least possible side effects. The fact that five of the 17 predicted drug targets are already experimentally validated either genetically or biochemically lends credence to our unique approach.

  9. Construction and characterization of a pure protein hydrogel for drug delivery application.

    Science.gov (United States)

    Xu, Xu; Xu, ZhaoKang; Yang, XiaoFeng; He, YanHao; Lin, Rong

    2017-02-01

    Injectable hydrogels have a variety of applications, including regenerative medicine, tissue engineering and controlled drug delivery. In this paper, we reported on a pure protein hydrogel based on tetrameric recombinant proteins for the potential drug delivery application. This protein hydrogel was formed instantly by simply mixing two recombinant proteins (ULD-TIP1 and ULD-GGGWRESAI) through the specific protein-peptide interaction. The protein hydrogel was characterized by rheology and scanning electron microscopy (SEM). In vitro cytotoxicity test indicated that the developed protein hydrogel had no apparent cytotoxicity against L-929 cells and HCEC cells after 48h incubation. The formed protein hydrogels was gradually degraded after incubation in phosphate buffered solution (PBS, pH=7.4) for a period of 144h study, as indicated by in vitro degradation test. Encapsulation of model drug (sodium diclofenac; DIC) were achieved by simple mixing of drugs with hydrogelator and the entrapped drugs was almost completely released from hydrogels within 24h via a diffusion manner. As a conclusion, the simple and mild preparation procedure and good biocompatibility of protein hydrogel would render its good promising candidate for drug delivery applications. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Extensively Drug-Resistant TB

    Centers for Disease Control (CDC) Podcasts

    2016-12-16

    Dr. Charlotte Kvasnovsky, a surgery resident and Ph.D. candidate in biostatistics, discusses various types of drug resistance in TB patients in South Africa.  Created: 12/16/2016 by National Center for Emerging and Zoonotic Infectious Diseases (NCEZID).   Date Released: 12/16/2016.

  11. The life cycles of six multi-center adaptive clinical trials focused on neurological emergencies developed for the Advancing Regulatory Science initiative of the National Institutes of Health and US Food and Drug Administration: Case studies from the Adaptive Designs Accelerating Promising Treatments Into Trials Project.

    Science.gov (United States)

    Guetterman, Timothy C; Fetters, Michael D; Mawocha, Samkeliso; Legocki, Laurie J; Barsan, William G; Lewis, Roger J; Berry, Donald A; Meurer, William J

    2017-01-01

    Clinical trials are complicated, expensive, time-consuming, and frequently do not lead to discoveries that improve the health of patients with disease. Adaptive clinical trials have emerged as a methodology to provide more flexibility in design elements to better answer scientific questions regarding whether new treatments are efficacious. Limited observational data exist that describe the complex process of designing adaptive clinical trials. To address these issues, the Adaptive Designs Accelerating Promising Treatments Into Trials project developed six, tailored, flexible, adaptive, phase-III clinical trials for neurological emergencies, and investigators prospectively monitored and observed the processes. The objective of this work is to describe the adaptive design development process, the final design, and the current status of the adaptive trial designs that were developed. To observe and reflect upon the trial development process, we employed a rich, mixed methods evaluation that combined quantitative data from visual analog scale to assess attitudes about adaptive trials, along with in-depth qualitative data about the development process gathered from observations. The Adaptive Designs Accelerating Promising Treatments Into Trials team developed six adaptive clinical trial designs. Across the six designs, 53 attitude surveys were completed at baseline and after the trial planning process completed. Compared to baseline, the participants believed significantly more strongly that the adaptive designs would be accepted by National Institutes of Health review panels and non-researcher clinicians. In addition, after the trial planning process, the participants more strongly believed that the adaptive design would meet the scientific and medical goals of the studies. Introducing the adaptive design at early conceptualization proved critical to successful adoption and implementation of that trial. Involving key stakeholders from several scientific domains early

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

    Directory of Open Access Journals (Sweden)

    Hyeong-Min Lee

    2016-01-01

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

  13. Does environmental archaeology need an ethical promise?

    DEFF Research Database (Denmark)

    Riede, Felix; Andersen, Per; Price, Neil

    2016-01-01

    formalized ethical codes or promises that not only guide the dissemination of data but oblige scientists to relate to fundamentally political issues. This article couples a survey of the recent environmental ethics literature with two case studies of how past natural hazards have affected vulnerable...... societies in Europe?s prehistory. We ask whether cases of past calamities and their societal effects should play a greater role in public debates and whether archaeologists working with past environmental hazards should be more outspoken in their ethical considerations. We offer no firm answers, but suggest...... that archaeologists engage with debates in human?environment relations at this interface between politics, public affairs and science....

  14. Assessing pharmacologic and nonpharmacologic risks in candidates for kidney transplantation.

    Science.gov (United States)

    Maldonado, Angela Q; Tichy, Eric M; Rogers, Christin C; Campara, Maya; Ensor, Christopher; Doligalski, Christina T; Gabardi, Steven; Descourouez, Jillian L; Doyle, Ian C; Trofe-Clark, Jennifer

    2015-05-15

    Pharmacotherapy concerns and other factors with a bearing on patient selection for kidney transplantation are discussed. The process of selecting appropriate candidates for kidney transplantation involves multidisciplinary assessment to evaluate a patient's mental, social, physical, financial, and medical readiness for successful surgery and good posttransplantation outcomes. Transplantation pharmacists can play important roles in the recognition and stratification of pharmacologic and nonpharmacologic risks in prospective kidney transplant recipients and the identification of issues that require a mitigation strategy. Key pharmacotherapy-related issues and considerations during the risk assessment process include (1) anticoagulation concerns, (2) cytochrome P-450 isoenzyme-mediated drug interactions, (3) mental health-related medication use, (4) chronic pain-related medication use, (5) medication allergies, (6) use of hormonal contraception and replacement therapy, (7) prior or current use of immunosuppressants, (8) issues with drug absorption, (9) alcohol use, (10) tobacco use, (11) active use of illicit substances, and (12) use of herbal supplements. Important areas of nonpharmacologic risk include vaccine delivery, infection prophylaxis and treatment, and socially related factors such as nonadherent behavior, communication barriers, and financial, insurance, or transportation challenges that can compromise posttransplantation outcomes. Consensus opinions of practitioners in transplantation pharmacy regarding the pharmacologic and nonpharmacologic factors that should be considered in assessing candidates for kidney transplantation are presented. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

  15. Neuroimaging in psychiatric pharmacogenetics research: the promise and pitfalls.

    Science.gov (United States)

    Falcone, Mary; Smith, Ryan M; Chenoweth, Meghan J; Bhattacharjee, Abesh Kumar; Kelsoe, John R; Tyndale, Rachel F; Lerman, Caryn

    2013-11-01

    The integration of research on neuroimaging and pharmacogenetics holds promise for improving treatment for neuropsychiatric conditions. Neuroimaging may provide a more sensitive early measure of treatment response in genetically defined patient groups, and could facilitate development of novel therapies based on an improved understanding of pathogenic mechanisms underlying pharmacogenetic associations. This review summarizes progress in efforts to incorporate neuroimaging into genetics and treatment research on major psychiatric disorders, such as schizophrenia, major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, and addiction. Methodological challenges include: performing genetic analyses in small study populations used in imaging studies; inclusion of patients with psychiatric comorbidities; and the extensive variability across studies in neuroimaging protocols, neurobehavioral task probes, and analytic strategies. Moreover, few studies use pharmacogenetic designs that permit testing of genotype × drug effects. As a result of these limitations, few findings have been fully replicated. Future studies that pre-screen participants for genetic variants selected a priori based on drug metabolism and targets have the greatest potential to advance the science and practice of psychiatric treatment.

  16. Albendazole as a promising molecule for tumor control.

    Science.gov (United States)

    Castro, L S E P W; Kviecinski, M R; Ourique, F; Parisotto, E B; Grinevicius, V M A S; Correia, J F G; Wilhelm Filho, D; Pedrosa, R C

    2016-12-01

    This work evaluated the antitumor effects of albendazole (ABZ) and its relationship with modulation of oxidative stress and induction of DNA damage. The present results showed that ABZ causes oxidative cleavage on calf-thymus DNA suggesting that this compound can break DNA. ABZ treatment decreased MCF-7 cell viability (EC 50 =44.9 for 24h) and inhibited MCF-7 colony formation (~67.5% at 5μM). Intracellular ROS levels increased with ABZ treatment (~123%). The antioxidant NAC is able to revert the cytotoxic effects, ROS generation and loss of mitochondrial membrane potential of MCF-7 cells treated with ABZ. Ehrlich carcinoma growth was inhibited (~32%) and survival time was elongated (~50%) in animals treated with ABZ. Oxidative biomarkers (TBARS and protein carbonyl levels) and activity of antioxidant enzymes (CAT, SOD and GR) increased, and reduced glutathione (GSH) was depleted in animals treated with ABZ, indicating an oxidative stress condition, leading to a DNA damage causing phosphorylation of histone H2A variant, H2AX, and triggering apoptosis signaling, which was confirmed by increasing Bax/Bcl-xL rate, p53 and Bax expression. We propose that ABZ induces oxidative stress promoting DNA fragmentation and triggering apoptosis and inducing cell death, making this drug a promising leader molecule for development of new antitumor drugs. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Interleukin-11 Receptor Is a Candidate Target for Ligand-Directed Therapy in Lung Cancer: Analysis of Clinical Samples and BMTP-11 Preclinical Activity.

    Science.gov (United States)

    Cardó-Vila, Marina; Marchiò, Serena; Sato, Masanori; Staquicini, Fernanda I; Smith, Tracey L; Bronk, Julianna K; Yin, Guosheng; Zurita, Amado J; Sun, Menghong; Behrens, Carmen; Sidman, Richard L; Lee, J Jack; Hong, Waun K; Wistuba, Ignacio I; Arap, Wadih; Pasqualini, Renata

    2016-08-01

    We previously isolated an IL-11-mimic motif (CGRRAGGSC) that binds to IL-11 receptor (IL-11R) in vitro and accumulates in IL-11R-expressing tumors in vivo. This synthetic peptide ligand was used as a tumor-targeting moiety in the rational design of BMTP-11, which is a drug candidate in clinical trials. Here, we investigated the specificity and accessibility of IL-11R as a target and the efficacy of BMTP-11 as a ligand-targeted drug in lung cancer. We observed high IL-11R expression levels in a large cohort of patients (n = 368). In matching surgical specimens (i.e., paired tumors and nonmalignant tissues), the cytoplasmic levels of IL-11R in tumor areas were significantly higher than in nonmalignant tissues (n = 36; P = 0.003). Notably, marked overexpression of IL-11R was observed in both tumor epithelial and vascular endothelial cell membranes (n = 301; P < 0.0001). BMTP-11 induced in vitro cell death in a representative panel of human lung cancer cell lines. BMTP-11 treatment attenuated the growth of subcutaneous xenografts and reduced the number of pulmonary tumors after tail vein injection of human lung cancer cells in mice. Our findings validate BMTP-11 as a pharmacologic candidate drug in preclinical models of lung cancer and patient-derived tumors. Moreover, the high expression level in patients with non-small cell lung cancer is a promising feature for potential translational applications. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  18. Triple Reuptake Inhibitors: A Premise and Promise

    OpenAIRE

    Marks, David M.; Pae, Chi-Un; Patkar, Ashwin A.

    2008-01-01

    On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant...

  19. Quantitative decisions in drug development

    CERN Document Server

    Chuang-Stein, Christy

    2017-01-01

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

  20. Status and promise of fuel cell technology

    Energy Technology Data Exchange (ETDEWEB)

    Williams, M.C. [National Energy Technology Lab., Pittsburgh, PA (United States). Dept. of Energy

    2001-09-01

    The niche or early entry market penetration by ONSI and its phosphoric acid fuel cell technology has proven that fuel cells are reliable and suitable for premium power and other opportunity fuel niche market applications. Now, new fuel cell technologies - solid oxide fuel cells, molten carbonate fuel cells, and polymer electrolyte fuel cells - are being developed for near-term distributed generation shortly after 2003. Some of the evolving fuel cell systems are incorporating gas turbines in hybrid configurations. The combination of the gas turbine with the fuel cell promises to lower system costs and increase efficiency to enhance market penetration. Market estimates indicate that significant early entry markets exist to sustain the initially high cost of some distributed generation technologies. However, distributed generation technologies must have low introductory first cost, low installation cost, and high system reliability to be viable options in competitive commercial and industrial markets. In the long-term, solid state fuel cell technology with stack costs under $100/kilowatt (kW) promises deeper and wider market penetration in a range of applications including a residential, auxillary power, and the mature distributed generation markets. The solid state energy conversion alliance (SECA) with its vision for fuel cells in 2010 was recently formed to commercialize solid state fuel cells and realize the full potential of the fuel cell technology. Ultimately, the SECA concept could lead to megawatt-size fuel-cell systems for commercial and industrial applications and Vision 21 fuel cell turbine hybrid energy plants in 2015. (orig.)

  1. Promises in intelligent plant control systems

    International Nuclear Information System (INIS)

    Otaduy, P.J.

    1987-01-01

    The control system is the brain of a power plant. The traditional goal of control systems has been productivity. However, in nuclear power plants the potential for disaster requires safety to be the dominant concern, and the worldwide political climate demands trustworthiness for nuclear power plants. To keep nuclear generation as a viable option for power in the future, trust is the essential critical goal which encompasses all others. In most of today's nuclear plants the control system is a hybrid of analog, digital, and human components that focuses on productivity and operates under the protective umbrella of an independent engineered safety system. Operation of the plant is complex, and frequent challenges to the safety system occur which impact on their trustworthiness. Advances in nuclear reactor design, computer sciences, and control theory, and in related technological areas such as electronics and communications as well as in data storage, retrieval, display, and analysis have opened a promise for control systems with more acceptable human brain-like capabilities to pursue the required goals. This paper elaborates on the promise of futuristic nuclear power plants with intelligent control systems and addresses design requirements and implementation approaches

  2. New Zealand’s Drug Development Industry

    Directory of Open Access Journals (Sweden)

    Christopher Carswell

    2013-09-01

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

  3. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The first time ...

  4. Study Drugs

    Science.gov (United States)

    ... to quit, they may have withdrawal symptoms like depression, thoughts of suicide, intense drug cravings, sleep problems, and fatigue. The health risks aren't the only downside to study drugs. Students caught with illegal prescription drugs may get suspended ...

  5. Drug Facts

    Medline Plus

    Full Text Available ... symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to ...

  6. Drug Facts

    Medline Plus

    Full Text Available ... Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen ... to prescription drugs. The addiction slowly took over his life. I need different people around me. To ...

  7. Drug Reactions

    Science.gov (United States)

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as ginkgo and blood thinners ...

  8. Drug Facts

    Science.gov (United States)

    ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  9. 76 FR 4896 - Call for Candidates

    Science.gov (United States)

    2011-01-27

    ... designated to establish generally accepted accounting principles for federal government entities. Generally, non-federal Board members are selected from the general financial community, the accounting and... FEDERAL ACCOUNTING STANDARDS ADVISORY BOARD Call for Candidates AGENCY: Federal Accounting...

  10. Updated candidate list for engineered barrier materials

    International Nuclear Information System (INIS)

    McCright, R.D.

    1995-10-01

    This report describes candidate materials to be evaluated over the next several years during advanced design phases for the waste package to be used for the underground disposal of high-level radioactive wastes at the Yucca Mountain facility

  11. Characterization of nanoparticles as candidate reference materials

    International Nuclear Information System (INIS)

    Martins Ferreira, E.H.; Robertis, E. de; Landi, S.M.; Gouvea, C.P.; Archanjo, B.S.; Almeida, C.A.; Araujo, J.R. de; Kuznetsov, O.; Achete, C.A.

    2013-01-01

    We report the characterization of three different nanoparticles (silica, silver and multi-walled carbon nanotubes) as candidate reference material. We focus our analysis on the size distribution of those particles as measured by different microscopy techniques. (author)

  12. Indico CONFERENCE: Candidate participant's registration/application

    CERN Multimedia

    CERN. Geneva; Ferreira, Pedro

    2017-01-01

    In this tutorial you are going to learn how to apply as a candidate participant (if the event requires approval from the event manager) or to register (if participation to the event doesn't require approval from an event manager) to the conference using the registration form for the event. You are also going to learn how to approve a candidate participant's application as an event manager.

  13. Do People 'Like' Candidates on Facebook?

    DEFF Research Database (Denmark)

    Nielsen, Rasmus Kleis

    The online popularity of a few exceptional candidates has led many to suggest that social media have given politicians powerful ways of communicating directly with voters. In this paper, we examine whether this is happening on a significant scale and show, based on analysis of 224 candidates....... We therefore suggest that the political implications of social media are generally better understood in terms of facilitating indirect communication and institutional change than in terms of direct communication....

  14. PEG-based degradable networks for drug delivery applications

    Science.gov (United States)

    Ostroha, Jamie L.

    The controlled delivery of therapeutic agents by biodegradable hydrogels has become a popular mechanism for drug administration in recent years. Hydrogels are three-dimensional networks of polymer chains held together by crosslinks. Although the changes which the hydrogel undergoes in solution are important to a wide range of experimental studies, they have not been investigated systematically and the factors which influence the degree of swelling have not been adequately described. Hydrogels made of poly(ethylene glycol) (PEG) will generally resist degradation in aqueous conditions, while a hydrogel made from a copolymer of poly(lactic acid) (PLA) and PEG will degrade via hydrolysis of the lactic acid group. This ability to degrade makes these hydrogels promising candidates for controlled release drug delivery systems. The goal of this research was to characterize the swelling and degradation of both degradable and non-degradable gels and to evaluate the release of different drugs from these hydrogels, where the key variable is the molecular weight of the PEG segment. These hydrogels were formed by the addition and subsequent chemically crosslinking of methacrylate end groups. During crosslinking, both PEG and LA-PEG-LA hydrogels of varied PEG molecular weight were loaded with Vitamin B12, Insulin, Haloperidol, and Dextran. It was shown that increasing PEG molecular weight produces a hydrogel with larger pores, thus increasing water uptake and degradation rate. While many environmental factors do not affect the swelling behavior, they do significantly impact the degradation of the hydrogel, and thus the release of incorporated therapeutic agents.

  15. Drug gastrointestinal absorption in rat: Strain and gender differences.

    Science.gov (United States)

    Oltra-Noguera, Davinia; Mangas-Sanjuan, Victor; González-Álvarez, Isabel; Colon-Useche, Sarin; González-Álvarez, Marta; Bermejo, Marival

    2015-10-12

    Predictive animal models of intestinal drug absorption are essential tools in drug development to identify compounds with promising biopharmaceutical properties. In situ perfusion absorption studies are routinely used in the preclinical setting to screen drug candidates. The objective of this work is to explore the differences in magnitude and variability on intestinal absorption associated with rat strain and gender. Metoprolol and Verapamil absorption rate coefficients were determined using the in situ closed loop perfusion model in four strains of rats and in both genders. Strains used were Sprague-Dawley, Wistar-Han, Wistar-Unilever, Long-Evans and CD∗IGS. In the case of Metoprolol only CD∗IGS and Wistar Unilever showed differences between males and females. For Verapamil, Wistar Han and Sprague-Dawley strains do not show differences between male and female rats. That means that in these strains permeability data from male and female could be combined. In male rats, which are commonly used for permeability estimation, there were differences for Metoprolol permeability between Sprague-Dawley (with lower permeability values) and the other strains, while for Verapamil Sprague-Dawley and Wistar-Han showed the lower permeability values. In conclusion, the selection of rat's strain and gender for intestinal absorption experiments is a relevant element during study design and data from different strains may not be always comparable. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Antiherpetic Drugs in Equine Medicine.

    Science.gov (United States)

    Maxwell, Lara K

    2017-04-01

    Since vaccination may not prevent disease, antiherpetic drugs have been investigated for the therapy of several equine herpesviruses. Drug efficacy has been assessed in horses with disease, but most evidence is in vitro, in other species, or empirical. Oral valacyclovir is most often administered in the therapy of equine herpesvirus type-1 (EHV-1) to protect adult horses from equine herpesvirus myeloencephalopathy, while oral acyclovir is frequently administered for EHV-5 infection in the therapy of equine multinodular pulmonary fibrosis. Other antiherpetic drugs are promising but require further investigation. Several topical drugs are also empirically used in the therapy of equine viral keratitis. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Cyanobacteria: Promising biocatalysts for sustainable chemical production.

    Science.gov (United States)

    Knoot, Cory J; Ungerer, Justin; Wangikar, Pramod P; Pakrasi, Himadri B

    2018-04-06

    Cyanobacteria are photosynthetic prokaryotes showing great promise as biocatalysts for the direct conversion of CO 2 into fuels, chemicals, and other value-added products. Introduction of just a few heterologous genes can endow cyanobacteria with the ability to transform specific central metabolites into many end products. Recent engineering efforts have centered around harnessing the potential of these microbial biofactories for sustainable production of chemicals conventionally produced from fossil fuels. Here, we present an overview of the unique chemistry that cyanobacteria have been co-opted to perform. We highlight key lessons learned from these engineering efforts and discuss advantages and disadvantages of various approaches. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  18. Analysis of promising sustainable renovation concepts

    DEFF Research Database (Denmark)

    Vanhoutteghem, Lies; Tommerup, Henrik M.; Svendsen, Svend

    This report focuses on analyses of the most promising existing sustainable renovation concepts, i.e. full-service concepts and technical concepts, for single-family houses. As a basis for the analyses a detailed building stock analysis was carried out. Furthermore, as a basis a general working...... method for proposals on package solutions for sustainable renovation was described. The method consists of four steps, going from investigation of the house to proposal for sustainable renovation, detailed planning and commissioning after renovation. It could be used by teams of consultants...... of the building envelope and the electricity required to run the system. Positive impact on the indoor environment can be expected. Thermal comfort will be improved by insulation and air-tightness measures that will increase surface temperatures and reduce draught from e.g. badly insulated windows. A ventilation...

  19. Biomolecular simulations on petascale: promises and challenges

    International Nuclear Information System (INIS)

    Agarwal, Pratul K; Alam, Sadaf R

    2006-01-01

    Proteins work as highly efficient machines at the molecular level and are responsible for a variety of processes in all living cells. There is wide interest in understanding these machines for implications in biochemical/biotechnology industries as well as in health related fields. Over the last century, investigations of proteins based on a variety of experimental techniques have provided a wealth of information. More recently, theoretical and computational modeling using large scale simulations is providing novel insights into the functioning of these machines. The next generation supercomputers with petascale computing power, hold great promises as well as challenges for the biomolecular simulation scientists. We briefly discuss the progress being made in this area

  20. Underexploited tropical plants with promising economic value

    Energy Technology Data Exchange (ETDEWEB)

    1975-01-01

    The apparent advantages of staple plants over the minor tropical plants often result only from the disproportionate research attention they have been given. A world-wide inquiry resulted in a list of 400 promising but neglected species. The 36 most important species are described in compact monographs and concern cereals (Echinochloa turnerana, grain amaranths, quinua and Zosterea mazina), roots and tubers (Arrachacha, cocoyams and taro), vegetables (chaya, hearts of palms, wax gourd, winged bean), fruits (durian, mangosteen, naranjilla, pejibaye, pummelo, soursop, uvilla), oilseeds (babassu palm, buffalo gourd, Caryocar species, Hessenia polycarpa and jojoba), forage (Acacia albida, Brosimum alicastrum Cassia sturtii, saltbushes and tamarugo) and other crops (buriti palm, Calathea lutea, candelilla, guar, guayule, Paspalum vaginatum, ramie and Spirulina).

  1. Nanomedicine delivers promising treatments for rheumatoid arthritis.

    Science.gov (United States)

    Prasad, Leena Kumari; O'Mary, Hannah; Cui, Zhengrong

    2015-01-01

    An increased understanding in the pathophysiology of chronic inflammatory diseases, such as rheumatoid arthritis, reveals that the diseased tissue and the increased presence of macrophages and other overexpressed molecules within the tissue can be exploited to enhance the delivery of nanomedicine. Nanomedicine can passively accumulate into chronic inflammatory tissues via the enhanced permeability and retention phenomenon, or be surface conjugated with a ligand to actively bind to receptors overexpressed by cells within chronic inflammatory tissues, leading to increased efficacy and reduced systemic side-effects. This review highlights the research conducted over the past decade on using nanomedicine for potential treatment of rheumatoid arthritis and summarizes some of the major findings and promising opportunities on using nanomedicine to treat this prevalent and chronic disease.

  2. Stable Higgs Bosons - new candidate for cold dark matter

    International Nuclear Information System (INIS)

    Hosotani, Yutaka

    2010-01-01

    The Higgs boson is in the backbone of the standard model of electroweak interactions. It must exist in some form for achieving unification of interactions. In the gauge-Higgs unification scenario the Higgs boson becomes a part of the extra-dimensional component of gauge fields. The Higgs boson becomes absolutely stable in a class of the gauge-Higgs unification models, serving as a promising candidate for cold dark matter in the universe. The observed relic abundance of cold dark matter is obtained with the Higgs mass around 70 GeV. The Higgs-nucleon scattering cross section is found to be close to the recent CDMS II XENON10 bounds in the direct detection of dark matter. In collider experiments stable Higgs bosons are produced in a pair, appearing as missing energies momenta so that the way of detecting Higgs bosons must be altered.

  3. Dark Matter candidates in a baryogenesis inspired scenario

    International Nuclear Information System (INIS)

    Provenza, A; Quiros, M; Ullio, P

    2006-01-01

    It has recently been shown that the electroweak baryogenesis mechanism is feasible in Standard Model extensions containing extra fermions with large Yukawa couplings. We show that the lightest of these fermionic fields can naturally be a good candidate for cold dark matter. We find regions in the parameter space where the thermal relic abundance of this particle is compatible with the dark matter density of the Universe as determined by the WMAP experiment. We study direct and indirect dark matter detection for this model and compare with current experimental limits and prospects for upcoming experiments. We find, contrary to the standard lore, that indirect detection searches are more promising than direct ones, and they already exclude part of the parameter space

  4. Tetomilast: new promise for phosphodiesterase-4 inhibitors?

    Science.gov (United States)

    Bickston, Stephen J; Snider, Kenneth R; Kappus, Matthew R

    2012-12-01

    Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD. Peer-reviewed publications, including Phase I and II clinical trials, all other formats included. Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

  5. Triple Reuptake Inhibitors: A Premise and Promise

    Science.gov (United States)

    Marks, David M.; Patkar, Ashwin A.

    2008-01-01

    On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant to possible clinical uses for this class of medications. PMID:20046357

  6. A New Way to Confirm Planet Candidates

    Science.gov (United States)

    Kohler, Susanna

    2016-05-01

    What was the big deal behind the Kepler news conference yesterday? Its not just that the number of confirmed planets found by Kepler has more than doubled (though thats certainly exciting news!). Whats especially interesting is the way in which these new planets were confirmed.Number of planet discoveries by year since 1995, including previous non-Kepler discoveries (blue), previous Kepler discoveries (light blue) and the newly validated Kepler planets (orange). [NASA Ames/W. Stenzel; Princeton University/T. Morton]No Need for Follow-UpBefore Kepler, the way we confirmed planet candidates was with follow-up observations. The candidate could be validated either by directly imaging (which is rare) or obtaining a large number radial-velocity measurements of the wobble of the planets host star due to the planets orbit. But once Kepler started producing planet candidates, these approaches to validation became less feasible. A lot of Kepler candidates are small and orbit faint stars, making follow-up observations difficult or impossible.This problem is what inspired the development of whats known as probabilistic validation, an analysis technique that involves assessing the likelihood that the candidates signal is caused by various false-positive scenarios. Using this technique allows astronomers to estimate the likelihood of a candidate signal being a true planet detection; if that likelihood is high enough, the planet candidate can be confirmed without the need for follow-up observations.A breakdown of the catalog of Kepler Objects of Interest. Just over half had previously been identified as false positives or confirmed as candidates. 1284 are newly validated, and another 455 have FPP of1090%. [Morton et al. 2016]Probabilistic validation has been used in the past to confirm individual planet candidates in Kepler data, but now Timothy Morton (Princeton University) and collaborators have taken this to a new level: they developed the first code thats designed to do fully

  7. NHI economic analysis of candidate nuclear hydrogen processes

    International Nuclear Information System (INIS)

    Allen, D.; Pickard, P.; Patterson, M.; Sink, C.

    2010-01-01

    The DOE Nuclear Hydrogen Initiative (NHI) is investigating candidate technologies for large scale hydrogen production using high temperature gas-cooled reactors (HTGR) in concert with the Next Generation Nuclear Plant (NGNP) programme. The candidate processes include high temperature thermochemical and high temperature electrolytic processes which are being investigated in a sequence of experimental and analytic studies to establish the most promising and cost effective means of hydrogen production with nuclear energy. Although these advanced processes are in an early development stage, it is important that the projected economic potential of these processes be evaluated to assist in the prioritisation of research activities, and ultimately in the selection of the most promising processes for demonstration and deployment. The projected cost of hydrogen produced is the most comprehensive metric in comparing candidate processes. Since these advanced processes are in the early stages of development and much of the technology is still unproven, the estimated production costs are also significantly uncertain. The programme approach has been to estimate the cost of hydrogen production from each process periodically, based on the best available data at that time, with the intent of increasing fidelity and reducing uncertainty as the research programme and system definition studies progress. These updated cost estimates establish comparative costs at that stage of development but are also used as inputs to the evaluation of research priorities, and identify the key cost and risk (uncertainty) drivers for each process. The economic methodology used to assess the candidate processes are based on the H2A ground rules and modelling tool (discounted cash flow) developed by the DOE Office of Energy Efficiency and Renewable Energy (EERE). The figure of merit output from the calculation is the necessary selling price for hydrogen in dollars per kilogram that satisfies the cost

  8. Modelling of potentially promising SARS protease inhibitors

    International Nuclear Information System (INIS)

    Plewczynski, Dariusz; Hoffmann, Marcin; Grotthuss, Marcin von; Knizewski, Lukasz; Rychewski, Leszek; Eitner, Krystian; Ginalski, Krzysztof

    2007-01-01

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation

  9. Modelling of potentially promising SARS protease inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Plewczynski, Dariusz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Hoffmann, Marcin [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Grotthuss, Marcin von [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Knizewski, Lukasz [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland); Rychewski, Leszek [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Eitner, Krystian [BioInfoBank Institute, Limanowskiego 24A/16, 60-744 Poznan (Poland); Ginalski, Krzysztof [Interdisciplinary Centre for Mathematical and Computational Modelling, ICM, Warsaw University, Pawinskiego 5a Street, 02-106 Warsaw (Poland)

    2007-07-18

    In many cases, at the beginning of a high throughput screening experiment some information about active molecules is already available. Active compounds (such as substrate analogues, natural products and inhibitors of related proteins) are often identified in low throughput validation studies on a biochemical target. Sometimes the additional structural information is also available from crystallographic studies on protein and ligand complexes. In addition, the structural or sequence similarity of various protein targets yields a novel possibility for drug discovery. Co-crystallized compounds from homologous proteins can be used to design leads for a new target without co-crystallized ligands. In this paper we evaluate how far such an approach can be used in a real drug campaign, with severe acute respiratory syndrome (SARS) coronavirus providing an example. Our method is able to construct small molecules as plausible inhibitors solely on the basis of the set of ligands from crystallized complexes of a protein target, and other proteins from its structurally homologous family. The accuracy and sensitivity of the method are estimated here by the subsequent use of an electronic high throughput screening flexible docking algorithm. The best performing ligands are then used for a very restrictive similarity search for potential inhibitors of the SARS protease within the million compounds from the Ligand.Info small molecule meta-database. The selected molecules can be passed on for further experimental validation.

  10. A computer vision based candidate for functional balance test.

    Science.gov (United States)

    Nalci, Alican; Khodamoradi, Alireza; Balkan, Ozgur; Nahab, Fatta; Garudadri, Harinath

    2015-08-01

    Balance in humans is a motor skill based on complex multimodal sensing, processing and control. Ability to maintain balance in activities of daily living (ADL) is compromised due to aging, diseases, injuries and environmental factors. Center for Disease Control and Prevention (CDC) estimate of the costs of falls among older adults was $34 billion in 2013 and is expected to reach $54.9 billion in 2020. In this paper, we present a brief review of balance impairments followed by subjective and objective tools currently used in clinical settings for human balance assessment. We propose a novel computer vision (CV) based approach as a candidate for functional balance test. The test will take less than a minute to administer and expected to be objective, repeatable and highly discriminative in quantifying ability to maintain posture and balance. We present an informal study with preliminary data from 10 healthy volunteers, and compare performance with a balance assessment system called BTrackS Balance Assessment Board. Our results show high degree of correlation with BTrackS. The proposed system promises to be a good candidate for objective functional balance tests and warrants further investigations to assess validity in clinical settings, including acute care, long term care and assisted living care facilities. Our long term goals include non-intrusive approaches to assess balance competence during ADL in independent living environments.

  11. Hydrogen permeation through Flinabe fluoride molten salts for blanket candidates

    Energy Technology Data Exchange (ETDEWEB)

    Nishiumi, Ryosuke, E-mail: r.nishiumi@aees.kyushu-u.ac.jp; Fukada, Satoshi; Nakamura, Akira; Katayama, Kazunari

    2016-11-01

    Highlights: • H{sub 2} diffusivity, solubility and permeability in Flinabe as T breeder are determined. • Effects in composition differences among Flibe, Fnabe and Flinabe are compared. • Changes of pressure dependence of Flinabe permeation rate are clarified. - Abstract: Fluoride molten salt Flibe (2LiF + BeF{sub 2}) is a promising candidate for the liquid blanket of a nuclear fusion reactor, because of its large advantages of tritium breeding ratio and heat-transfer fluid. Since its melting point is higher than other liquid candidates, another new fluoride molten salt Flinabe (LiF + NaF + BeF{sub 2}) is recently focused on because of its lower melting point while holding proper breeding properties. In this experiment, hydrogen permeation behavior through the three molten salts of Flibe (2LiF + BeF{sub 2}), Fnabe (NaF + BeF{sub 2}) and Flinabe are investigated in order to clarify the effects of their compositions on hydrogen transfer properties. After making up any of the three molten salts and purifying it using HF, hydrogen permeability, diffusivity and solubility of the molten salts are determined experimentally by using a system composed of tertiary cylindrical tubes. Close agreement is obtained between experimental data and analytical solutions. H{sub 2} permeability, diffusivity and solubility are correlated as a function of temperature and are compared among the three molten salts.

  12. Stimuli-Responsive Liposomes for Controlled Drug Delivery

    KAUST Repository

    Li, Wengang

    2014-01-01

    Liposomes are promising drug delivery vesicles due to their biodegradibility, large volume and biocompatibility towards both hydrophilic and hydrophobic drugs. They suffer, however, from poor stability which limits their use in controlled delivery

  13. Theoretical design and discovery of the most-promising, previously overlooked hybrid perovskite compounds

    Energy Technology Data Exchange (ETDEWEB)

    Zunger, Alex [University of Colorado Boulder; Kazmerski, Lawrence [University of Colorado Boulder; Dalpian, Gustavo [University of Colorado Boulder

    2018-03-14

    The material class of hybrid organic-inorganic perovskites (AMX3) has risen rapidly from a virtually unknown material in photovoltaic applications a short 8-years ago into 20-23% efficient thin-film solar cell devices. As promising as this class of materials is, however, there are limitations associated with its poor long-term stability, non-optimal band gap, and the presence of toxic Pb atom on the metalloid site. An Edisonian laboratory exploration (i.e., growth + characterization) via trial-and-error processes of all other candidate materials, is unpractical. Our approach uses high speed computational design and discovery to screen the ‘best of class” candidates based upon optimal functionalities.

  14. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  15. Drug Facts

    Medline Plus

    Full Text Available ... 4357) at any time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. She wants her daughter to stay away from drugs. But she's afraid ...

  16. Nanosuspension Technology for Solubilizing Poorly Soluble Drugs

    OpenAIRE

    Deoli Mukesh

    2012-01-01

    Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. It is estimated that around 40% of drugs in the pipeline cannot be delivered through the preferred route or in some cases, at all owing to poor water solubility. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor1 EL). To date, nanoscale systems f...

  17. Nanoformulations and Clinical Trial Candidates as Probably ...

    African Journals Online (AJOL)

    Encapsulation of existing anti-TB drugs into nano-delivery systems and introduction of new drugs in combination treatment for all forms of tuberculosis have resulted in novel treatments with more effectiveness and reduced side effects. Keywords: Tuberculosis, Nanotechnology, Anti-tuberculosis drugs, Nano carriers, ...

  18. JELLYFISH GALAXY CANDIDATES AT LOW REDSHIFT

    Energy Technology Data Exchange (ETDEWEB)

    Poggianti, B. M.; Fasano, G.; Omizzolo, A.; Gullieuszik, M.; Bettoni, D.; Paccagnella, A. [INAF-Astronomical Observatory of Padova (Italy); Moretti, A.; D’Onofrio, M. [Physics and Astronomy Department, University of Padova (Italy); Jaffé, Y. L. [Department of Astronomy, Universidad de Concepción, Concepción (Chile); Vulcani, B. [Kavli Institute for the Physics and Mathematics of the universe (WPI), The University of Tokyo Institutes for Advanced Study (UTIAS), the University of Tokyo, Kashiwa, 277-8582 (Japan); Fritz, J. [Centro de Radioastronomía y Astrofísica, CRyA, UNAM, Michoacán (Mexico); Couch, W. [Australian Astronomical Observatory, North Ryde, NSW 1670 (Australia)

    2016-03-15

    Galaxies that are being stripped of their gas can sometimes be recognized from their optical appearance. Extreme examples of stripped galaxies are the so-called “jellyfish galaxies” that exhibit tentacles of debris material with a characteristic jellyfish morphology. We have conducted the first systematic search for galaxies that are being stripped of their gas at low-z (z = 0.04−0.07) in different environments, selecting galaxies with varying degrees of morphological evidence for stripping. We have visually inspected B- and V-band images and identified 344 candidates in 71 galaxy clusters of the OMEGAWINGS+WINGS sample and 75 candidates in groups and lower mass structures in the PM2GC sample. We present the atlas of stripping candidates and a first analysis of their environment and their basic properties, such as morphologies, star formation rates and galaxy stellar masses. Candidates are found in all clusters and at all clustercentric radii, and their number does not correlate with the cluster velocity dispersion σ or X-ray luminosity L{sub X}. Interestingly, convincing cases of candidates are also found in groups and lower mass halos (10{sup 11}−10{sup 14}M{sub ⊙}), although the physical mechanism at work needs to be securely identified. All the candidates are disky, have stellar masses ranging from log M/M{sub ⊙} < 9 to > 11.5 and the majority of them form stars at a rate that is on average a factor of 2 higher (2.5σ) compared to non-stripped galaxies of similar mass. The few post-starburst and passive candidates have weak stripping evidence. We conclude that disturbed morphologies suggestive of stripping phenomena are ubiquitous in clusters and could be present even in groups and low mass halos. Further studies will reveal the physics of the gas stripping and clarify the mechanisms at work.

  19. Modified local diatomite as potential functional drug carrier--A model study for diclofenac sodium.

    Science.gov (United States)

    Janićijević, Jelena; Krajišnik, Danina; Čalija, Bojan; Vasiljević, Bojana Nedić; Dobričić, Vladimir; Daković, Aleksandra; Antonijević, Milan D; Milić, Jela

    2015-12-30

    Diatomite makes a promising candidate for a drug carrier because of its high porosity, large surface area, modifiable surface chemistry and biocompatibility. Herein, refined diatomite from Kolubara coal basin, which complied with the pharmacopoeial requirements for heavy metals content and microbiological quality, was used as a starting material. Inorganic modification of the starting material was performed through a simple, one-step procedure. Significant increase in adsorbent loading with diclofenac sodium (DS) was achieved after the modification process (∼373mg/g) which enabled the preparation of comprimates containing therapeutic dose of the adsorbed drug. Adsorption of DS onto modified diatomite resulted in the alteration of the drug's XRD pattern and FTIR spectrum. In vitro drug release studies in phosphate buffer pH 7.5 demonstrated prolonged DS release over 8h from comprimates containing DS adsorbed on modified diatomite (up to 37% after 8h) and those containing physical mixture of the same composition (up to 45% after 8h). The results of in vivo toxicity testing on mice pointed on potential safety of both unmodified (starting) and modified diatomite. All these findings favor the application of diatomite as a potential functional drug carrier. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Biosensors a promising future in measurements

    International Nuclear Information System (INIS)

    Saleem, Muhammad

    2013-01-01

    A biosensor is an analytical device which can be used to convert the existence of a molecule or compound into a measurable and useful signal. Biosensors use stimulus to translate changes to recognisable signals and have great importance to society. Applications include diagnosis tools for diseases, security appliances, and other biomedical equipments. Biosensors can also be used in the detection of pathogens and other microbes in foodstuffs, drugs and processing industries. Enormous progress and advancement has been witnessed in this area. Research and development in micro level systems serves to interface biology with novel materials such as nanomaterial. Development of high speed and accurate electronic devices tfor use in medicine and energy storage (such as biofuel cells) is one of the target areas. This paper discusses the importance, use and current and future trend in the application of biosensors

  1. Metformin: A Hopeful Promise in Aging Research

    Science.gov (United States)

    Novelle, Marta G.; Ali, Ahmed; Diéguez, Carlos; Bernier, Michel; de Cabo, Rafael

    2016-01-01

    Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector. PMID:26931809

  2. Breath tests: principles, problems, and promise

    International Nuclear Information System (INIS)

    Lo, C.W.; Carter, E.A.; Walker, W.A.

    1982-01-01

    Breath tests rely on the measurement of gases produced in the intestine, absorbed, and expired in the breath. Carbohydrates, such as lactose and sucrose, can be administered in ysiologic doses; if malabsorbed, they will be metabolized to hydrogen by colonic bacteria. Since hydrogen is not produced by human metabolic reactions, a rise in breath hydrogen, as measured by gas chromatography, is evidence of carbohydrate malabsorption. Likewise, a rise in breath hydrogen marks the transit time of nonabsorbable carbohydrates such as lactulose through the small intestine into the colon. Simple end-expiratory interval collection into nonsiliconized vacutainer tubes has made these noninvasive tests quite convenient to perform, but various problems, including changes in stool pH intestinal motility, or metabolic rate, may influence results. Another group of breath tests uses substrates labeled with radioactive or stable isotopes of carbon. Labeled fat substrates such as trioctanoin, tripalmitin, and triolein do not produce the expected rise in labeled breath CO 2 if there is fat malabsorption. Bile acid malabsorption and small intestinal bacterial overgrowth can be measured with labeled cholylglycine or cholyltaurine. Labeled drugs such as aminopyrine, methacetin, and phenacetin can be used as an indication of drug metabolism and liver function. Radioactive substrates have been used to trace metabolic pathways and can be measured by scintillation counters. The availability of nonradioactive stable isotopes has made these ideal for use in children and pregnant women, but the cost of substrates and the mass spectrometers to measure them has so far limited their use to research centers. It is hoped that new techniques of processing and measurement will allow further realization of the exciting potential breath analysis has in a growing list of clinical applications

  3. The promise of Lean in health care.

    Science.gov (United States)

    Toussaint, John S; Berry, Leonard L

    2013-01-01

    An urgent need in American health care is improving quality and efficiency while controlling costs. One promising management approach implemented by some leading health care institutions is Lean, a quality improvement philosophy and set of principles originated by the Toyota Motor Company. Health care cases reveal that Lean is as applicable in complex knowledge work as it is in assembly-line manufacturing. When well executed, Lean transforms how an organization works and creates an insatiable quest for improvement. In this article, we define Lean and present 6 principles that constitute the essential dynamic of Lean management: attitude of continuous improvement, value creation, unity of purpose, respect for front-line workers, visual tracking, and flexible regimentation. Health care case studies illustrate each principle. The goal of this article is to provide a template for health care leaders to use in considering the implementation of the Lean management system or in assessing the current state of implementation in their organizations. Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

  4. Hyperthermia: Clinical promise and current challenges

    International Nuclear Information System (INIS)

    Kapp, D.S.

    1987-01-01

    Local-regional hyperthermia (HT) when used in conjunction with radiation therapy (XRT), has been shown in numerous clinical trials to result in considerable improvement in response rates and local tumor control rates when compared with treatment by XRT alone. Although considerable progress has been made in understanding the biological basis for hyperthermia induced cytotoxicity and radiosensitization, additional research remains in establishing the optimal treatment schedules for the clinical utilization of HT-XRT. The number of HT treatments; the sequencing of HT and XRT; the frequency of administration of HT; and the ideal temperature-time parameters all remain to be better defined for the clinical setting. The role of tumor blood flow on the thermal distributions also warrants further investigation. In addition, considerable effort is needed to improve hyperthermia equipment in order to provide more uniform therapeutic temperature distributions (temperatures ≥42.5%C). Better heating equipment is particularly needed for the treatment of deep seeted tumors. Pertinent clinical literature will be presented summarizing the clinical promise of hyperthermia and the above mentioned clinical challenges

  5. Uterine transplantation: a promising surrogate to surrogacy?

    Science.gov (United States)

    Grynberg, Michael; Ayoubi, Jean-Marc; Bulletti, Carlo; Frydman, Rene; Fanchin, Renato

    2011-03-01

    Infertility due to the inability of the uterus to carry a pregnancy ranks among the most unresolved issues in reproductive medicine. It affects millions of women worldwide who have congenital or acquired uterine affections, often requiring hysterectomy, and potentially represents a considerable fraction of the general infertile population. Patients suffering from severe uterine infertility are currently compelled to go through gestational surrogacy or adoption; both approaches, unfortunately, deprive them of the maternal experience of pregnancy and birth. Uterine transplantation represents an outstanding, yet complex, perspective to alleviating definitive uterine infertility. In the past decades, a number of scientific experiments conducted both in animals and women, focusing on uterine transplantation, have led to promising results. Collectively, these findings undoubtedly constitute a sound basis to clinically apply uterine transplantation in the near future. This paper is, however, an overview not only of the extent and limitations of accumulated scientific knowledge on uterine transplantation, but also its ethical implications, in an effort to define the actual place of such an approach among the therapeutic arsenal for alleviating infertility. © 2011 New York Academy of Sciences.

  6. Medical big data: promise and challenges

    Directory of Open Access Journals (Sweden)

    Choong Ho Lee

    2017-03-01

    Full Text Available The concept of big data, commonly characterized by volume, variety, velocity, and veracity, goes far beyond the data type and includes the aspects of data analysis, such as hypothesis-generating, rather than hypothesis-testing. Big data focuses on temporal stability of the association, rather than on causal relationship and underlying probability distribution assumptions are frequently not required. Medical big data as material to be analyzed has various features that are not only distinct from big data of other disciplines, but also distinct from traditional clinical epidemiology. Big data technology has many areas of application in healthcare, such as predictive modeling and clinical decision support, disease or safety surveillance, public health, and research. Big data analytics frequently exploits analytic methods developed in data mining, including classification, clustering, and regression. Medical big data analyses are complicated by many technical issues, such as missing values, curse of dimensionality, and bias control, and share the inherent limitations of observation study, namely the inability to test causality resulting from residual confounding and reverse causation. Recently, propensity score analysis and instrumental variable analysis have been introduced to overcome these limitations, and they have accomplished a great deal. Many challenges, such as the absence of evidence of practical benefits of big data, methodological issues including legal and ethical issues, and clinical integration and utility issues, must be overcome to realize the promise of medical big data as the fuel of a continuous learning healthcare system that will improve patient outcome and reduce waste in areas including nephrology.

  7. Artificial Intelligence in Surgery: Promises and Perils.

    Science.gov (United States)

    Hashimoto, Daniel A; Rosman, Guy; Rus, Daniela; Meireles, Ozanan R

    2018-07-01

    The aim of this review was to summarize major topics in artificial intelligence (AI), including their applications and limitations in surgery. This paper reviews the key capabilities of AI to help surgeons understand and critically evaluate new AI applications and to contribute to new developments. AI is composed of various subfields that each provide potential solutions to clinical problems. Each of the core subfields of AI reviewed in this piece has also been used in other industries such as the autonomous car, social networks, and deep learning computers. A review of AI papers across computer science, statistics, and medical sources was conducted to identify key concepts and techniques within AI that are driving innovation across industries, including surgery. Limitations and challenges of working with AI were also reviewed. Four main subfields of AI were defined: (1) machine learning, (2) artificial neural networks, (3) natural language processing, and (4) computer vision. Their current and future applications to surgical practice were introduced, including big data analytics and clinical decision support systems. The implications of AI for surgeons and the role of surgeons in advancing the technology to optimize clinical effectiveness were discussed. Surgeons are well positioned to help integrate AI into modern practice. Surgeons should partner with data scientists to capture data across phases of care and to provide clinical context, for AI has the potential to revolutionize the way surgery is taught and practiced with the promise of a future optimized for the highest quality patient care.

  8. Medical big data: promise and challenges.

    Science.gov (United States)

    Lee, Choong Ho; Yoon, Hyung-Jin

    2017-03-01

    The concept of big data, commonly characterized by volume, variety, velocity, and veracity, goes far beyond the data type and includes the aspects of data analysis, such as hypothesis-generating, rather than hypothesis-testing. Big data focuses on temporal stability of the association, rather than on causal relationship and underlying probability distribution assumptions are frequently not required. Medical big data as material to be analyzed has various features that are not only distinct from big data of other disciplines, but also distinct from traditional clinical epidemiology. Big data technology has many areas of application in healthcare, such as predictive modeling and clinical decision support, disease or safety surveillance, public health, and research. Big data analytics frequently exploits analytic methods developed in data mining, including classification, clustering, and regression. Medical big data analyses are complicated by many technical issues, such as missing values, curse of dimensionality, and bias control, and share the inherent limitations of observation study, namely the inability to test causality resulting from residual confounding and reverse causation. Recently, propensity score analysis and instrumental variable analysis have been introduced to overcome these limitations, and they have accomplished a great deal. Many challenges, such as the absence of evidence of practical benefits of big data, methodological issues including legal and ethical issues, and clinical integration and utility issues, must be overcome to realize the promise of medical big data as the fuel of a continuous learning healthcare system that will improve patient outcome and reduce waste in areas including nephrology.

  9. Bioavailability of curcumin: problems and promises.

    Science.gov (United States)

    Anand, Preetha; Kunnumakkara, Ajaikumar B; Newman, Robert A; Aggarwal, Bharat B

    2007-01-01

    Curcumin, a polyphenolic compound derived from dietary spice turmeric, possesses diverse pharmacologic effects including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic activities. Phase I clinical trials have shown that curcumin is safe even at high doses (12 g/day) in humans but exhibit poor bioavailability. Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohn's disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.

  10. Scalar tetraquark candidates on the lattice

    International Nuclear Information System (INIS)

    Berlin, Joshua

    2017-01-01

    The topic of this thesis is the investigation of scalar tetraquark candidates from lattice QCD. It is motivated by a previous study originating in the twisted mass collaboration. The initial tetraquark candidate of choice is the a 0 (980), an isovector in the nonet of light scalars (J P =0 + ). This channel is still poorly understood. It displays an inverted mass hierarchy to what is expected from the conventional quark model and the a 0 (980) and f 0 (980) feature a surprising mass degeneracy. For this reasons the a 0 (980) is a long assumed tetraquark candidate in the literature. We follow a methodological approach by studying the sensitivity of the scalar spectrum with fully dynamical quarks to a large basis of two-quark and four-quark creation operators. Ultimately, the candidate has to be identified in the direct vicinity of two two-particles states, which is understandably inevitable for a tetraquark candidate. To succeed in this difficult task two-meson creation operators are essential to employ in this channel. By localized four-quark operators we intend to probe the Hamiltonian on eigenstates with a closely bound four-quark structure.

  11. Scalar tetraquark candidates on the lattice

    Energy Technology Data Exchange (ETDEWEB)

    Berlin, Joshua

    2017-07-01

    The topic of this thesis is the investigation of scalar tetraquark candidates from lattice QCD. It is motivated by a previous study originating in the twisted mass collaboration. The initial tetraquark candidate of choice is the a{sub 0}(980), an isovector in the nonet of light scalars (J{sup P}=0{sup +}). This channel is still poorly understood. It displays an inverted mass hierarchy to what is expected from the conventional quark model and the a{sub 0}(980) and f{sub 0}(980) feature a surprising mass degeneracy. For this reasons the a{sub 0}(980) is a long assumed tetraquark candidate in the literature. We follow a methodological approach by studying the sensitivity of the scalar spectrum with fully dynamical quarks to a large basis of two-quark and four-quark creation operators. Ultimately, the candidate has to be identified in the direct vicinity of two two-particles states, which is understandably inevitable for a tetraquark candidate. To succeed in this difficult task two-meson creation operators are essential to employ in this channel. By localized four-quark operators we intend to probe the Hamiltonian on eigenstates with a closely bound four-quark structure.

  12. High drug payload curcumin nanosuspensions stabilized by mPEG-DSPE and SPC: in vitro and in vivo evaluation.

    Science.gov (United States)

    Hong, Jingyi; Liu, Yingying; Xiao, Yao; Yang, Xiaofeng; Su, Wenjing; Zhang, Mingzhu; Liao, Yonghong; Kuang, Haixue; Wang, Xiangtao

    2017-11-01

    Curcumin (CUR) is a promising drug candidate based on its broad bioactivities and good antitumor effect, but the application of CUR is potentially restricted because of its poor solubility and bioavailability. This study aims at developing a simple and effective drug delivery system for CUR to enhance its solubility and bioavailability thus to improve its antitumor efficacy. Curcumin nanosuspensions (CUR-NSps) were prepared by precipitation-ultrasonication method using mPEG2000-DSPE and soybean lecithin as a combined stabilizer. CUR-NSps with a high drug payload of 67.07% were successfully prepared. The resultant CUR-NSps had a mean particle size of 186.33 ± 2.73 nm with a zeta potential of -19.00 ± 1.31 mV. In vitro cytotoxicity assay showed that CUR-NSps exhibited enhanced cytotoxicity compared to CUR solution. The pharmacokinetics results demonstrated that CUR-NSps exhibited a significantly greater AUC 0-24 and prolonged MRT compared to CUR injections after intravenous administration. In the biodistribution study, CUR-NSps demonstrated enhanced biodistribution compared with CUR injections in liver, spleen, kidney, brain, and tumor. The CUR-NSps also showed improved antitumor therapeutic efficacy over the injections (70.34% versus 40.03%, p < 0.01). These results suggest that CUR-NSps might represent a promising drug formulation for intravenous administration of CUR for the treatment of cancer.

  13. Probing cardiac repolarization reserve in drug safety assessment

    NARCIS (Netherlands)

    Nalos, L.

    2011-01-01

    Excessive prolongation of cardiac repolarization, manifested as QT prolongation on ECG, is common unwanted side effect of many drugs and drug candidates. Prolongation of QT interval may lead to life threatening cardiac arrhythmia – Torsade de Point (TdP). Number of drugs was withdrawn from the

  14. Centrosome – a promising anti-cancer target

    Directory of Open Access Journals (Sweden)

    Rivera-Rivera Y

    2016-12-01

    Full Text Available Yainyrette Rivera-Rivera, Harold I Saavedra Department of Pharmacology, Ponce Health Sciences University-School of Medicine, Ponce Research Institute, Ponce, Puerto Rico Abstract: The centrosome, an organelle discovered >100 years ago, is the main microtubule-organizing center in mammalian organisms. The centrosome is composed of a pair of centrioles surrounded by the pericentriolar material (PMC and plays a major role in the regulation of cell cycle transitions (G1-S, G2-M, and metaphase-anaphase, ensuring the normality of cell division. Hundreds of proteins found in the centrosome exert a variety of roles, including microtubule dynamics, nucleation, and kinetochore–microtubule attachments that allow correct chromosome alignment and segregation. Errors in these processes lead to structural (shape, size, number, position, and composition, functional (abnormal microtubule nucleation and disorganized spindles, and numerical (centrosome amplification [CA] centrosome aberrations causing aneuploidy and genomic instability. Compelling data demonstrate that centrosomes are implicated in cancer, because there are important oncogenic and tumor suppressor proteins that are localized in this organelle and drive centrosome aberrations. Centrosome defects have been found in pre-neoplasias and tumors from breast, ovaries, prostate, head and neck, lung, liver, and bladder among many others. Several drugs/compounds against centrosomal proteins have shown promising results. Other drugs have higher toxicity with modest or no benefits, and there are more recently developed agents being tested in clinical trials. All of this emerging evidence suggests that targeting centrosome aberrations may be a future avenue for therapeutic intervention in cancer research. Keywords: centrosomes, cell cycle, mitosis, CA, CIN, cancer therapy

  15. Production and Potency of Local Rambutan at East Java as a Candidate Phytopharmaca

    OpenAIRE

    Lestari, Sri Rahayu; Djati, Muhammad Sasmito; Rudijanto, Ahmad; Fatchiyah, Fatchiyah

    2013-01-01

    Rambutan is a tropical fruit that grow well in Indonesia and the peel is considered as waste. Many researchers' showed that rambutan peel contains polyphenol that could be expected to avoid obesity. The objective of this study was to explore the increasing production of local rambutan and to identify the promising phytochemical compounds on its peel as phytopharmaca candidate against obesity. Survey was conducted on the production of rambutan, potential plantation area, and marketing. Sample...

  16. PRODUCTION AND POTENCY OF LOCAL RAMBUTAN AT EAST JAVA AS A CANDIDATE PHYTOPHARMACA

    OpenAIRE

    Sri Rahayu Lestari; Muhammad Sasmito Djati; Ahmad Rudijanto; Fatchiyah

    2013-01-01

    Rambutan is a tropical fruit that grow well in Indonesia and the peel is considered as waste. Many researchers’ showed that rambutan peel contains polyphenol that could be expected to avoid obesity. The objective of this study was to explore the increasing production of local rambutan and to identify the promising phytochemical compounds on its peel as phytopharmaca candidate against obesity. Survey was conducted on the production of rambutan, potential plantation area, and marketing. Sample...

  17. Developing Potential Candidates of Preclinical Preeclampsia

    Directory of Open Access Journals (Sweden)

    Sandra Founds

    2015-11-01

    Full Text Available The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs, and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia.

  18. The promise of innovation: Nuclear energy horizons

    International Nuclear Information System (INIS)

    Mourogov, V.

    2003-01-01

    The 21st century promises the most open, competitive, and globalized markets in human history, as well as the most rapid pace of technological change ever. For nuclear energy, as any other, that presents challenges. Though the atom now supplies a good share of world electricity, its share of total energy is relatively small, anywhere from four to six per cent depending on how it is calculated. And, while energy is most needed in the developing world, four of every five nuclear plants are in industrialized countries. Critical problems that need to be overcome are well known - high capital costs for new plants, and concerns over proliferation risks and safety, (including safety of waste disposal) stand high among them. The IAEA and other programmes are confronting these problems through ambitious initiatives involving both industrialized and developing countries. They include the collaborative efforts known as the Generation-IV International Forum (GIF) and the IAEA International Project on Innovative Nuclear Reactors and Fuel Cycles (INPRO). They use ideas, results and the best experiences from today's research and development tools and advanced types of nuclear energy systems to meet tomorrow's challenges. Though the market often decides the fate of new initiatives, the market is not always right for the common good. Governments, and the people that influence them, play an indispensable role in shaping progress in energy fields for rich and poor countries alike. They shoulder the main responsibilities for fundamental science, basic research, and long-term investments. For energy in particular, government investment and support will prove instrumental in the pace of innovation toward long-term options that are ready to replace limited fossil fuel supplies, and respond to the growing premium put on clean energy alternatives. Yet governments cannot go it alone. The challenges are too diverse and complex, and public concerns - about proliferation or safety - go beyond

  19. The epigenetic promise for prostate cancer diagnosis.

    Science.gov (United States)

    Van Neste, Leander; Herman, James G; Otto, Gaëtan; Bigley, Joseph W; Epstein, Jonathan I; Van Criekinge, Wim

    2012-08-01

    Prostate cancer is the most common cancer diagnosis in men and a leading cause of death. Improvements in disease management would have a significant impact and could be facilitated by the development of biomarkers, whether for diagnostic, prognostic, or predictive purposes. The blood-based prostate biomarker PSA has been part of clinical practice for over two decades, although it is surrounded by controversy. While debates of usefulness are ongoing, alternatives should be explored. Particularly with recent recommendations against routine PSA-testing, the time is ripe to explore promising biomarkers to yield a more efficient and accurate screening for detection and management of prostate cancer. Epigenetic changes, more specifically DNA methylation, are amongst the most common alterations in human cancer. These changes are associated with transcriptional silencing of genes, leading to an altered cellular biology. One gene in particular, GSTP1, has been widely studied in prostate cancer. Therefore a meta-analysis has been conducted to examine the role of this and other genes and the potential contribution to prostate cancer management and screening refinement. More than 30 independent, peer reviewed studies have reported a consistently high sensitivity and specificity of GSTP1 hypermethylation in prostatectomy or biopsy tissue. The meta-analysis combined and compared these results. GSTP1 methylation detection can serve an important role in prostate cancer managment. The meta-analysis clearly confirmed a link between tissue DNA hypermethylation of this and other genes and prostate cancer. Detection of DNA methylation in genes, including GSTP1, could serve an important role in clinical practice. Copyright © 2011 Wiley Periodicals, Inc.

  20. Substance use - prescription drugs

    Science.gov (United States)

    Substance use disorder - prescription drugs; Substance abuse - prescription drugs; Drug abuse - prescription drugs; Drug use - prescription drugs; Narcotics - substance use; Opioid - substance use; Sedative - substance ...

  1. Hydrogen storage in Mg: a most promising material

    International Nuclear Information System (INIS)

    Jain, I.P.; Jain, A.; Lal, C.

    2009-01-01

    hydrides stand as promising candidate for competitive hydrogen storage with reversible hydrogen capacity up to 7.6 wt% for on board applications. Efforts have been devoted to these materials to decrease their desorption temperature, enhance the kinetics and cycle life. The kinetics has been improved by adding an appropriate catalyst into the system as well as by ball milling that introduces defects with improved surface properties. The studies reported promising results, such as improved kinetics and lower desorption temperatures, however, the state of the art materials are still far from meeting the aimed target for their transport applications. Therefore further research work is needed to achieve the goal by improving development on hydrogenation, thermal and cyclic behavior of metal hydrides. In the present article the possibility of commercialization of Mg based alloys has been discussed. (author)

  2. Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity.

    Science.gov (United States)

    Penrod, Nadia M; Greene, Casey S; Moore, Jason H

    2014-01-01

    Molecularly targeted drugs promise a safer and more effective treatment modality than conventional chemotherapy for cancer patients. However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes. Combination therapies can overcome resistance but finding the optimal combinations efficiently presents a formidable challenge. Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets. We have developed a framework to mine high-throughput transcriptomic data, based on differential coexpression and Pareto optimization, to investigate drug-induced tumor adaptation. We use this approach to identify tumor-essential genes as druggable candidates. We apply our method to a set of ER(+) breast tumor samples, collected before (n = 58) and after (n = 60) neoadjuvant treatment with the aromatase inhibitor letrozole, to prioritize genes as targets for combination therapy with letrozole treatment. We validate letrozole-induced tumor adaptation through coexpression and pathway analyses in an independent data set (n = 18). We find pervasive differential coexpression between the untreated and letrozole-treated tumor samples as evidence of letrozole-induced tumor adaptation. Based on patterns of coexpression, we identify ten genes as potential candidates for combination therapy with letrozole including EPCAM, a letrozole-induced essential gene and a target to which drugs have already been developed as cancer therapeutics. Through replication, we validate six letrozole-induced coexpression relationships and confirm the epithelial-to-mesenchymal transition as a process that is upregulated in the residual tumor samples following letrozole treatment. To derive the greatest benefit from molecularly targeted drugs it is critical to design combination

  3. Issue-Advocacy versus Candidate Advertising: Effects on Candidate Preferences and Democratic Process.

    Science.gov (United States)

    Pfau, Michael; Holbert, R. Lance; Szabo, Erin Alison; Kaminski, Kelly

    2002-01-01

    Examines the influence of soft-money-sponsored issue-advocacy advertising in U.S. House and Senate campaigns, comparing its effects against candidate-sponsored positive advertising and contrast advertising on viewers' candidate preferences and on their attitude that reflect democratic values. Reveals no main effects for advertising approach on…

  4. Probiotics: A Promising Role in Dental Health

    Directory of Open Access Journals (Sweden)

    Sari A. Mahasneh

    2017-09-01

    Full Text Available Probiotics have a role in maintaining oral health through interaction with oral microbiome, thus contributing to healthy microbial equilibrium. The nature and composition of any individual microbiome impacts the general health, being a major contributor to oral health. The emergence of drug resistance and the side effects of available antimicrobials have restricted their use in an array of prophylactic options. Indeed, some new strategies to prevent oral diseases are based on manipulating oral microbiota, which is provided by probiotics. Currently, no sufficient substantial evidence exists to support the use of probiotics to prevent, treat or manage oral cavity diseases. At present, probiotic use did not cause adverse effects or increased risks of caries or periodontal diseases. This implicates no strong evidence against treatment using probiotics. In this review, we try to explore the use of probiotics in prevention, treatment and management of some oral cavity diseases and the possibilities of developing designer probiotics for the next generation of oral and throat complimentary healthcare.

  5. Cocrystals of acyclovir with promising physicochemical properties.

    Science.gov (United States)

    Sarkar, Anindita; Rohani, Sohrab

    2015-01-01

    Cocrystal forming ability of antiviral drug acyclovir (ACV) with different coformers was studied. Three cocrystals containing ACV with fumaric acid, malonic acid, and DL-tartaric acid were isolated. Methods of cocrystallization included grinding with dropwise solvent addition and solvent evaporation. The cocrystals were characterized by powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. The crystal structure of the cocrystal with fumaric acid as conformer was determined by single crystal X-ray diffraction. Formation of supramolecular synthon was observed in the cocrystal. Stability with respect to relative humidity for the three cocrystals was evaluated. The aqueous solubility of the ACV-cocrystal materials was significantly improved with a maximum of malonic acid cocrystal, which was about six times more soluble at 35°C compared with that of parent ACV. The dissolution profile indicates that at any particular dissolution time, the concentration of cocrystals in the solution was higher than that of the parent ACV, and malonic acid cocrystals had a maximum release of about twice than the hydrated ACV. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  6. Promising therapies for treatment of nonalcoholic steatohepatitis

    Science.gov (United States)

    Noureddin, Mazen; Zhang, Alice; Loomba, Rohit

    2018-01-01

    Introduction Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60–80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15–20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH. Areas covered We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development. Expert opinion The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients. PMID:27501374

  7. Identifying candidate driver genes by integrative ovarian cancer genomics data

    Science.gov (United States)

    Lu, Xinguo; Lu, Jibo

    2017-08-01

    Integrative analysis of molecular mechanics underlying cancer can distinguish interactions that cannot be revealed based on one kind of data for the appropriate diagnosis and treatment of cancer patients. Tumor samples exhibit heterogeneity in omics data, such as somatic mutations, Copy Number Variations CNVs), gene expression profiles and so on. In this paper we combined gene co-expression modules and mutation modulators separately in tumor patients to obtain the candidate driver genes for resistant and sensitive tumor from the heterogeneous data. The final list of modulators identified are well known in biological processes associated with ovarian cancer, such as CCL17, CACTIN, CCL16, CCL22, APOB, KDF1, CCL11, HNF1B, LRG1, MED1 and so on, which can help to facilitate the discovery of biomarkers, molecular diagnostics, and drug discovery.

  8. Magnetic hydroxyapatite: a promising multifunctional platform for nanomedicine application

    Science.gov (United States)

    Mondal, Sudip; Manivasagan, Panchanathan; Bharathiraja, Subramaniyan; Santha Moorthy, Madhappan; Kim, Hye Hyun; Seo, Hansu; Lee, Kang Dae; Oh, Junghwan

    2017-01-01

    In this review, specific attention is paid to the development of nanostructured magnetic hydroxyapatite (MHAp) and its potential application in controlled drug/gene delivery, tissue engineering, magnetic hyperthermia treatment, and the development of contrast agents for magnetic resonance imaging. Both magnetite and hydroxyapatite materials have excellent prospects in nanomedicine with multifunctional therapeutic approaches. To date, many research articles have focused on biomedical applications of nanomaterials because of which it is very difficult to focus on any particular type of nanomaterial. This study is possibly the first effort to emphasize on the comprehensive assessment of MHAp nanostructures for biomedical applications supported with very recent experimental studies. From basic concepts to the real-life applications, the relevant characteristics of magnetic biomaterials are patented which are briefly discussed. The potential therapeutic and diagnostic ability of MHAp-nanostructured materials make them an ideal platform for future nanomedicine. We hope that this advanced review will provide a better understanding of MHAp and its important features to utilize it as a promising material for multifunctional biomedical applications. PMID:29200851

  9. Hydroxychloroquine, a promising choice for coronary artery disease?

    Science.gov (United States)

    Sun, Lizhe; Liu, Mengping; Li, Ruifeng; Zhao, Qiang; Liu, Junhui; Yang, Yanjie; Zhang, Lisha; Bai, Xiaofang; Wei, Yuanyuan; Ma, Qiangqiang; Zhou, Juan; Yuan, Zuyi; Wu, Yue

    2016-08-01

    Coronary artery disease is a common disease that seriously threaten the health of more than 150 million people per year. Atherosclerosis is considered to be the main cause of coronary artery disease which begins with damage or injury to the inner layer of a coronary artery, sometimes as early as childhood. The damage may be caused by various factors, including: smoking, high blood pressure, hypercholesterolemia, sedentary lifestyle, diabetes and insulin resistance. Once a coronary artery disease has developed, all patients need to be treated with long term standard treatment, including heart-healthy lifestyle changes, medicines, and medical procedures or surgery. Hydroxychloroquine, an original antimalarial drug, prevents inflammation caused by lupus erythematosus and rheumatoid arthritis. It is relatively safe and well-tolerated during the treatment. Since atherosclerosis and rheumatoid arthritis have resemble mechanism and increasing clinical researches confirm that hydroxychloroquine has an important role in both anti-rheumatoid arthritis and cardiovascular protection (such as anti-platelet, anti-thrombotic, lipid-regulating, anti-hypertension, hypoglycemia, and so on), we hypothesize that hydroxychloroquine might be a promising choice to coronary artery disease patients for its multiple benefits. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Magnetic hydroxyapatite: a promising multifunctional platform for nanomedicine application.

    Science.gov (United States)

    Mondal, Sudip; Manivasagan, Panchanathan; Bharathiraja, Subramaniyan; Santha Moorthy, Madhappan; Kim, Hye Hyun; Seo, Hansu; Lee, Kang Dae; Oh, Junghwan

    2017-01-01

    In this review, specific attention is paid to the development of nanostructured magnetic hydroxyapatite (MHAp) and its potential application in controlled drug/gene delivery, tissue engineering, magnetic hyperthermia treatment, and the development of contrast agents for magnetic resonance imaging. Both magnetite and hydroxyapatite materials have excellent prospects in nanomedicine with multifunctional therapeutic approaches. To date, many research articles have focused on biomedical applications of nanomaterials because of which it is very difficult to focus on any particular type of nanomaterial. This study is possibly the first effort to emphasize on the comprehensive assessment of MHAp nanostructures for biomedical applications supported with very recent experimental studies. From basic concepts to the real-life applications, the relevant characteristics of magnetic biomaterials are patented which are briefly discussed. The potential therapeutic and diagnostic ability of MHAp-nanostructured materials make them an ideal platform for future nanomedicine. We hope that this advanced review will provide a better understanding of MHAp and its important features to utilize it as a promising material for multifunctional biomedical applications.

  11. Polyelectrolyte Multilayer Film Coated Silver Nanorods: An Effective Carrier System for Externally Activated Drug Delivery

    Science.gov (United States)

    Paramasivam, Gokul; Sharma, Varsha; Sundaramurthy, Anandhakumar

    2017-08-01

    Nanoparticle anisotropy offers unique functions and features in comparison with spherical nanoparticles (NPs) and makes anisotropic nanoparticles (ANPs) promising candidates in applications like drug delivery, imaging, biosensing and theranostics. Presence of surface active groups (e.g. amine, and carboxylate groups) on their surface provides binding sites for ligands or other biomolecules, and hence, this could be targeted for specific part or cells in our body. In the quest of such surface modification, functionalization of ANPs along Layer-by-Layer (LbL) coating of oppositely charged polyelectrolytes (PE) reduces cellular toxicity and promotes easy encapsulation of drugs. In this work, we report the silver nanorods (AgNRs) synthesis by adsorbate directed synthetic approach using cetyltrimethyl ammonium bromide (CTAB). The formed ANPs is investigated by scanning electron microscopy (SEM) and UV-Visible (UV-Vis) spectroscopy revealing the shaping of AgNRs of 3-16 nm aspect ratio with some presence of triangles. These NRs were further coated with bio polymers of chitosan (CH) and dextran sulphate (DS) through LbL approach and used for encapsulation of water soluble anti-bacterial drugs like ciprofloxacin hydrochloride (CFH). The encapsulation of drugs and profiles of drug release were investigated and compared to that of spherical silver nanoparticles (AgNPs). The added advantages of the proposed drug delivery system (DDS) can be externally activated to release the loaded drug and used as contrast agents for biological imaging under exposure to NIR light. Such system shows unique and attractive characteristics required for drug delivery and bioimaging thus offering the scope for further development as theranostic material.

  12. An Assessment of the Oral Bioavailability of Three Ca-Channel Blockers Using a Cassette-Microdose Study: A New Strategy for Streamlining Oral Drug Development.

    Science.gov (United States)

    Yamashita, Shinji; Kataoka, Makoto; Suzaki, Yuki; Imai, Hiromitsu; Morimoto, Takuya; Ohashi, Kyoichi; Inano, Akihiro; Togashi, Kazutaka; Mutaguchi, Kuninori; Sugiyama, Yuichi

    2015-09-01

    A cassette-microdose (MD) clinical study was performed to demonstrate its usefulness for identifying the most promising compound for oral use. Three Ca-channel blockers (nifedipine, nicardipine, and diltiazem) were chosen as model drugs. In the MD clinical study, a cassette-dose method was employed in which three model drugs were administered simultaneously. Both intravenous (i.v.) and oral (p.o.) administration studies were conducted to calculate the oral bioavailability (BA). For comparison, p.o. studies with therapeutic dose (ThD) levels were also performed. In all studies, blood concentrations of each drug were successfully determined using liquid chromatography-mass spectrometry with the lower limit of quantification of 0.2-2.0 pg/mL. Oral BA of nifedipine in the MD study was approximately 50% and in the same range with that obtained in the ThD study, whereas other two drugs showed significantly lower BA in the MD study, indicating a dose-dependent absorption. In addition, compared with the ThD study, absorption of nicardipine was delayed in the MD study. As a result, nifedipine was considered to be most promising for oral use. In conclusion, a cassette-MD clinical study is of advantage for oral drug development that enables to identify the candidate having desired properties for oral use. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  13. Green and social bonds - A promising tool

    International Nuclear Information System (INIS)

    Blanc, Dominique; Barochez, Aurelie de; Cozic, Aela

    2013-11-01

    Issues of green bonds, socially responsible bonds and climate bonds are on the rise. Novethic estimates that some Euro 5 billion in such bonds has been issued since the start of 2013 by development banks, the main issuers of this type of debt. The figure is equal to over half of their total issues since 2007. Including local authorities, corporations and banks, a total Euro 8 billion of these bonds has been issued thus far in 2013. Given the size of the bond market, which the OECD estimated at Euro 95,000 billion in 2011, green and social bonds are still something of a niche but have strong growth potential. A number of large issues, from Euro 500 million to Euro 1 billion, were announced at the end of the year. Unlike conventional bonds, green and social bonds are not intended to finance all the activities of the issuer or refinance its debt. They serve instead to finance specific projects, such as producing renewable energy or adapting to climate change, the risk of which is shouldered by the issuer. This makes them an innovative instrument, used to earmark investments in projects with a direct environmental or social benefit rather than simply on the basis of the issuer's sustainable development policy. With financing being sought for the ecological transition, green and social bonds are promising instruments, sketching out at global level the shape of tools adapted to the financing of a green economy. On the strength of these advantages, the interest of responsible investors - the main target of green and social bond issuers - is growing fast. Judging by issuer press releases and the most commonly used currencies, the main subscribers today are US investors, among them CalSTRS and fund managers like Calvert Investment Management and Trillium Asset Management. European asset owners are also starting to focus on green and social bonds. A Novethic survey shows that 13% of them have already subscribed to such an issue or plan to do so. The present study

  14. Design of lead-free candidate alloys for high-temperature soldering based on the Au–Sn system

    DEFF Research Database (Denmark)

    Chidambaram, Vivek; Hattel, Jesper Henri; Hald, John

    2010-01-01

    of the Au–Sn binary system were explored in this work. Furthermore, the effects of thermal aging on the microstructure and microhardness of these promising Au–Sn based ternary alloys were investigated. For this purpose, the candidate alloys were aged at a lower temperature, 150°C for up to 1week...

  15. Naturally acquired antibody responses to recombinant Pfs230 and Pfs48/45 transmission blocking vaccine candidates

    NARCIS (Netherlands)

    Jones, S; Grignard, L.; Nebie, I.; Chilongola, J.; Dodoo, D.; Sauerwein, R.W.; Theisen, M.; Roeffen, W.F.; Singh, S.K; Singh, R.K.; Kyei-Baafour, E.; Tetteh, K.; Drakeley, C.; Bousema, T.

    2015-01-01

    OBJECTIVES: Pfs48/45 and Pfs230 are Plasmodium falciparum sexual stage proteins and promising malaria transmission-blocking vaccine candidates. Antibody responses against these proteins may be naturally acquired and target antigens may be under selective pressure. This has consequences for the

  16. Detecting Novel and Emerging Drug Terms Using Natural Language Processing: A Social Media Corpus Study.

    Science.gov (United States)

    Simpson, Sean S; Adams, Nikki; Brugman, Claudia M; Conners, Thomas J

    2018-01-08

    therefore considered to be successful cases of uncovering novel drug terminology. Several of these novel terms appear to have been introduced as recently as 1 or 2 months before the corpus time slice used to train the word embeddings. Though the precision of the method described here is low enough as to still necessitate human review of any candidate term lists generated in such a manner, the fact that this process was able to detect 30 novel terms for the target substance based only on one month's worth of Twitter data is highly promising. We see this pilot study as an important proof of concept and a first step toward producing a fully automated drug term discovery system capable of tracking emerging NPS terms in real time. ©Sean S Simpson, Nikki Adams, Claudia M Brugman, Thomas J Conners. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 08.01.2018.

  17. Progress and Promise of Attention-Deficit Hyperactivity Disorder Pharmacogenetics

    Science.gov (United States)

    Froehlich, Tanya E.; McGough, James J.; Stein, Mark A.

    2010-01-01

    One strategy for understanding variability in attention-deficit hyperactivity disorder (ADHD) medication response, and therefore redressing the current trial-and-error approach to ADHD medication management, is to identify genetic moderators of treatment. This article summarizes ADHD pharmacogenetic investigative efforts to date, which have primarily focused on short-term response to methylphenidate and largely been limited by modest sample sizes. The most well studied genes include the dopamine transporter and dopamine D4 receptor, with additional genes that have been significantly associated with stimulant medication response including the adrenergic α2A-receptor, catechol-O-methyltransferase, D5 receptor, noradrenaline (norepinephrine) transporter protein 1 and synaptosomal-associated protein 25 kDa. Unfortunately, results of current ADHD pharmacogenetic studies have not been entirely consistent, possibly due to differences in study design, medication dosing regimens and outcome measures. Future directions for ADHD pharmacogenetics investigations may include examination of drug-metabolizing enzymes and a wider range of stimulant and non-stimulant medications. In addition, researchers are increasingly interested in going beyond the individual candidate gene approach to investigate gene-gene interactions or pathways, effect modification by additional environmental exposures and whole genome approaches. Advancements in ADHD pharmacogenetics will be facilitated by multi-site collaborations to obtain larger sample sizes using standardized protocols. Although ADHD pharmacogenetic efforts are still in a relatively early stage, their potential clinical applications may include the development of treatment efficacy and adverse effect prediction algorithms that incorporate the interplay of genetic and environmental factors, as well as the development of novel ADHD treatments. PMID:20088618

  18. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can ...

  19. Prescription Drugs

    Science.gov (United States)

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

  20. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...