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Sample records for significantly improved drug

  1. Identification of clinically significant drug-drug interactions in cardiac ...

    African Journals Online (AJOL)

    Purpose: To identify clinically significant potential drug-drug interactions in cardiac intensive care units of two tertiary care ... hypertension, hyperlipidemia, diabetes or other diseases .... May result in digoxin toxicity (nausea, vomiting, cardiac.

  2. IMPROVING ACCESS TO DRUGS

    Directory of Open Access Journals (Sweden)

    Max Joseph Herman

    2012-11-01

    Full Text Available Although essentially not all therapies need drug intervention, drugs is still an important components in health sector, either in preventive, curative, rehabilitative or promotion efforts. Hence the access to drugs is a main problem, either in international or national scale even to the smallest unit. The problem on access to drugs is very complicated and cannot be separated especially from pharmacy management problems; moreover in general from the overall lack of policy development and effective of health policy, and also the implementation process. With the policy development and effective health policy, rational drug uses, sufficient health service budget so a country can overcome the health problems. Besides infrastructures, regulations, distribution and cultural influences; the main obstacles for drug access is drugs affordability if the price of drugs is an important part and determined by many factors, especially the drug status whether is still patent orgenerics that significantly decrease cost of health cares and enhance the drugs affordability. The determination of essential drug prices in developing countries should based on equity principal so that poor people pay cheaper and could afford the essential drugs. WHO predicts two third of world population can not afford the essential drugs in which in developing countries, some are because of in efficient budget allocation in consequence of drug distribution management, including incorrect selection and allocation and also irrational uses. In part these could be overcome by enhancing performances on the allocation pharmacy needs, including the management of information system, inventory management, stock management and the distribution. Key words: access, drugs, essential drugs, generic drugs

  3. PolySearch2: a significantly improved text-mining system for discovering associations between human diseases, genes, drugs, metabolites, toxins and more.

    Science.gov (United States)

    Liu, Yifeng; Liang, Yongjie; Wishart, David

    2015-07-01

    PolySearch2 (http://polysearch.ca) is an online text-mining system for identifying relationships between biomedical entities such as human diseases, genes, SNPs, proteins, drugs, metabolites, toxins, metabolic pathways, organs, tissues, subcellular organelles, positive health effects, negative health effects, drug actions, Gene Ontology terms, MeSH terms, ICD-10 medical codes, biological taxonomies and chemical taxonomies. PolySearch2 supports a generalized 'Given X, find all associated Ys' query, where X and Y can be selected from the aforementioned biomedical entities. An example query might be: 'Find all diseases associated with Bisphenol A'. To find its answers, PolySearch2 searches for associations against comprehensive collections of free-text collections, including local versions of MEDLINE abstracts, PubMed Central full-text articles, Wikipedia full-text articles and US Patent application abstracts. PolySearch2 also searches 14 widely used, text-rich biological databases such as UniProt, DrugBank and Human Metabolome Database to improve its accuracy and coverage. PolySearch2 maintains an extensive thesaurus of biological terms and exploits the latest search engine technology to rapidly retrieve relevant articles and databases records. PolySearch2 also generates, ranks and annotates associative candidates and present results with relevancy statistics and highlighted key sentences to facilitate user interpretation. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  4. Transdermal drug delivery: approaches and significance

    OpenAIRE

    Murthy, SATHYANARAYANA

    2012-01-01

    S Narasimha MurthyDepartment of Pharmaceutics, The University of Mississippi, USATransdermal drug delivery systems deliver drugs through the skin as an alternative to oral, intravascular, subcutaneous, and transmucosal routes. Potential advantages of transdermal delivery include, but are not limited to, elimination of first-pass metabolism, steady delivery/blood levels, better patient compliance, reduced systemic drug interactions, possible dose intervention, avoidance of medically assisted d...

  5. Pharmacokinetics of Anti-Epileptic Drugs and their Clinical Significance

    Directory of Open Access Journals (Sweden)

    Svein I. Johannessen

    1990-01-01

    Full Text Available The serum concentration achieved and maintained following the administration of a fixed drug dosage is a direct consequence of the interactions of a wide variety of interrelated processes, including drug absorption, distribution, metabolism, and excretion, and the physiological status of the patient. These interrelationships are reviewed with specific reference to the major anti-epileptic drugs, phenobarbitone, phenytoin, sodium valproate, and carbamazepine, as well as a new first-line antiepileptic, oxcarbazepine. Both older drugs, such as phenobarbitone and phenytoin, and newer drugs, such as carbamazepine (CBZ and sodium valproate, have been studied extensively over the past years giving valuable information for drug treatment. An important feature of oxcarbazepine (OXC , which was developed through minimal changes in the structure of CBZ in order to improve on the tolerability of CBZ without sacrificing efficacy, is that its metabolites do not include the 11-epoxide which has been implicated in the side-effects of CBZ. In man, OXC is metabolized to a monohydroxy derivative which has independent anti-epileptic properties. OXC seems to lack several disadavantageous pharmacokinetic properties common to other major anti-epileptic drugs. OXC does not influence its own metabolism after repeated administration, in contrast to the auto-induction displayed by CBZ. The metabolism of OXC is not influenced by anti-epileptic co-medication and does not influence the kinetics of other anti-epileptic drugs – or if it does, then to a lesser extent than CBZ.

  6. Significance and challenges of stereoselectivity assessing methods in drug metabolism

    Directory of Open Access Journals (Sweden)

    Zhuowei Shen

    2016-02-01

    Full Text Available Stereoselectivity in drug metabolism can not only influence the pharmacological activities, tolerability, safety, and bioavailability of drugs directly, but also cause different kinds of drug–drug interactions. Thus, assessing stereoselectivity in drug metabolism is of great significance for pharmaceutical research and development (R&D and rational use in clinic. Although there are various methods available for assessing stereoselectivity in drug metabolism, many of them have shortcomings. The indirect method of chromatographic methods can only be applicable to specific samples with functional groups to be derivatized or form complex with a chiral selector, while the direct method achieved by chiral stationary phases (CSPs is expensive. As a detector of chromatographic methods, mass spectrometry (MS is highly sensitive and specific, whereas the matrix interference is still a challenge to overcome. In addition, the use of nuclear magnetic resonance (NMR and immunoassay in chiral analysis are worth noting. This review presents several typical examples of drug stereoselective metabolism and provides a literature-based evaluation on current chiral analytical techniques to show the significance and challenges of stereoselectivity assessing methods in drug metabolism.

  7. Carotid endarterectomy significantly improves postoperative laryngeal sensitivity.

    Science.gov (United States)

    Hammer, Georg Philipp; Tomazic, Peter Valentin; Vasicek, Sarah; Graupp, Matthias; Gugatschka, Markus; Baumann, Anneliese; Konstantiniuk, Peter; Koter, Stephan Herwig

    2016-11-01

    sensory threshold on the operated-on side (6.08 ± 2.02 mm Hg) decreased significantly at the 6-week follow-up, even in relation to the preoperative measure (P = .022). With the exception of one patient with permanent unilateral vocal fold immobility, no signs of nerve injury were detected. In accordance with previous reports, injuries to the recurrent laryngeal nerve during CEA seem to be rare. In most patients, postoperative symptoms (globus, dysphagia, dysphonia) and signs fade within a few weeks without any specific therapeutic intervention. This study shows an improved long-term postoperative superior laryngeal nerve function with regard to laryngopharyngeal sensitivity. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Significant role of cationic polymers in drug delivery systems.

    Science.gov (United States)

    Farshbaf, Masoud; Davaran, Soodabeh; Zarebkohan, Amir; Annabi, Nasim; Akbarzadeh, Abolfazl; Salehi, Roya

    2017-11-06

    Cationic polymers are characterized as the macromolecules that possess positive charges, which can be either inherently in the polymer side chains and/or its backbone. Based on their origins, cationic polymers are divided in two category including natural and synthetic, in which the possessed positive charges are as result of primary, secondary or tertiary amine functional groups that could be protonated in particular situations. Cationic polymers have been employed commonly as drug delivery agents due to their superior encapsulation efficacy, enhanced bioavailability, low toxicity and improved release profile. In this paper, we focus on the most prominent examples of cationic polymers which have been revealed to be applicable in drug delivery systems and we also discuss their general synthesis and surface modification methods as well as their controlled release profile in drug delivery.

  9. Drug and Alcohol Use -- A Significant Risk Factor for HIV

    Science.gov (United States)

    ... Alcohol Club Drugs Cocaine Fentanyl Hallucinogens Inhalants Heroin Marijuana MDMA (Ecstasy/Molly) Methamphetamine Opioids Over-the-Counter Medicines Prescription Medicines Steroids (Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/ ...

  10. Inhaler Reminders Significantly Improve Asthma Patients' Use of Controller Medications

    Science.gov (United States)

    ... controller medications Share | Inhaler reminders significantly improve asthma patients’ use of controller medications Published Online: July 22, ... the burden and risk of asthma, but many patients do not use them regularly. This poor adherence ...

  11. Significant improvement in the thermal annealing process of optical resonators

    Science.gov (United States)

    Salzenstein, Patrice; Zarubin, Mikhail

    2017-05-01

    Thermal annealing performed during process improves the quality of the roughness of optical resonators reducing stresses at the periphery of their surface thus allowing higher Q-factors. After a preliminary realization, the design of the oven and the electronic method were significantly improved thanks to nichrome resistant alloy wires and chopped basalt fibers for thermal isolation during the annealing process. Q-factors can then be improved.

  12. Improving drug treatment in general practice

    NARCIS (Netherlands)

    Veninga, CCM; Denig, P; Zwaagstra, R; Haaijer-Ruskamp, FM

    In the international Drug Education Project, an educational program involving auditing and feedback in peer groups to improve the treatment of asthma and urinary tract infections (UTI) was developed and tested in primary care. Individualized feedback was provided and discussed in 24 Dutch peer

  13. Broken home or drug using peers : "Significant relations"?

    NARCIS (Netherlands)

    Quensel, S; McArdle, P; Brinkley, A; Wiegersma, A; Blom, M; Fitzgerald, M; Johnson, R; Kolte, B; Michels, [No Value; Pierolini, A; Pos, R; Stoeckel, [No Value

    2002-01-01

    This study reports the results of a comparative survey with representative samples of 3,386 school attending youths, most of whom were 15 years of age and residing in five European cities. We found significant but low correlations between the type of family structure (intact family, model family,

  14. Mutagenicity in drug development: interpretation and significance of test results.

    Science.gov (United States)

    Clive, D

    1985-03-01

    , methapyrilene). In vivo mutagenicity assays are more physiological but appear to be relatively insensitive due to the inability to achieve sufficiently high acute plasma levels to mimic cumulative long-term effects. Examination of the mutagenicity of naturally occurring analogs may indicate the irrelevance of a test compound's mutagenicity (e.g., deoxyguanosine and the structurally related antiviral drug, acyclovir, have identical mutagenicity patterns). Life-threatening or severe debilitating diseases (e.g., cancer, severe psychoses, severe crippling arthritis, sight-threatening diseases) may justify treatment with mutagenic or even carcinogenic therapeutic agents (benefit/risk considerations).(ABSTRACT TRUNCATED AT 400 WORDS)

  15. Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

    Science.gov (United States)

    Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

    2017-11-01

    Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

  16. Training directionally selective motion pathways can significantly improve reading efficiency

    Science.gov (United States)

    Lawton, Teri

    2004-06-01

    This study examined whether perceptual learning at early levels of visual processing would facilitate learning at higher levels of processing. This was examined by determining whether training the motion pathways by practicing leftright movement discrimination, as found previously, would improve the reading skills of inefficient readers significantly more than another computer game, a word discrimination game, or the reading program offered by the school. This controlled validation study found that practicing left-right movement discrimination 5-10 minutes twice a week (rapidly) for 15 weeks doubled reading fluency, and significantly improved all reading skills by more than one grade level, whereas inefficient readers in the control groups barely improved on these reading skills. In contrast to previous studies of perceptual learning, these experiments show that perceptual learning of direction discrimination significantly improved reading skills determined at higher levels of cognitive processing, thereby being generalized to a new task. The deficits in reading performance and attentional focus experienced by the person who struggles when reading are suggested to result from an information overload, resulting from timing deficits in the direction-selectivity network proposed by Russell De Valois et al. (2000), that following practice on direction discrimination goes away. This study found that practicing direction discrimination rapidly transitions the inefficient 7-year-old reader to an efficient reader.

  17. Nanoemulsifying drug delivery system to improve the bioavailability of piroxicam.

    Science.gov (United States)

    Motawea, Amira; Borg, Thanaa; Tarshoby, Manal; Abd El-Gawad, Abd El-Gawad H

    2017-05-01

    The aim of this study is to develop and characterize self-nanoemulsifying drug delivery system (SNEDDS) of piroxicam in liquid and solid forms to improve its dissolution, absorption and therapeutic efficacy. The generation of liquid SNEDDS (L-SNEDDS) was composed of soybean or coconut oil/Tween 80/Transcutol HP (12/80/8%w/w) and it was selected as the optimized formulation based on the solubility study and pseudo-ternary phase diagram. Optimized L-SNEDDS and liquid supersaturatable SNEDDS (L-sSNEDDS) preparations were then adsorbed onto adsorbents and formulated as directly compressed tablets. The improved drug dissolution rate in the solid supersaturatable preparation (S-sSNEDDS) may be due to the formation of a nanoemulsion and the presence of drug in an amorphous state with hydrogen bond interaction between the drug and SNEDDS components. In vivo pharmacokinetic studies on eight healthy human volunteers showed a significant improvement in the oral bioavailability of piroxicam from S-sSNEDDS (F12) compared with both the pure drug (PP) and its commercial product (Feldene ® ) (commercial dosage form (CD)). The relative bioavailability of S-sSNEDDS (F12) relative to PP or CD was about 151.01 and 98.96%, respectively. The obtained results ratify that S-sSNEDDS is a promising drug delivery system to enhance the oral bioavailability of piroxicam.

  18. Significant Improvement of Catalytic Efficiencies in Ionic Liquids

    International Nuclear Information System (INIS)

    Song, Choong Eui; Yoon, Mi Young; Choi, Doo Seong

    2005-01-01

    The use of ionic liquids as reaction media can confer many advantages upon catalytic reactions over reactions in organic solvents. In ionic liquids, catalysts having polar or ionic character can easily be immobilized without additional structural modification and thus the ionic solutions containing the catalyst can easily be separated from the reagents and reaction products, and then, be reused. More interestingly, switching from an organic solvent to an ionic liquid often results in a significant improvement in catalytic performance (e.g., rate acceleration, (enantio)selectivity improvement and an increase in catalyst stability). In this review, some recent interesting results which can nicely demonstrate these positive 'ionic liquid effect' on catalysis are discussed

  19. Bedtime Blood Pressure Chronotherapy Significantly Improves Hypertension Management.

    Science.gov (United States)

    Hermida, Ramón C; Ayala, Diana E; Fernández, José R; Mojón, Artemio; Crespo, Juan J; Ríos, María T; Smolensky, Michael H

    2017-10-01

    Consistent evidence of numerous studies substantiates the asleep blood pressure (BP) mean derived from ambulatory BP monitoring (ABPM) is both an independent and a stronger predictor of cardiovascular disease (CVD) risk than are daytime clinic BP measurements or the ABPM-determined awake or 24-hour BP means. Hence, cost-effective adequate control of sleep-time BP is of marked clinical relevance. Ingestion time, according to circadian rhythms, of hypertension medications of 6 different classes and their combinations significantly improves BP control, particularly sleep-time BP, and reduces adverse effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. [Improvement of Phi bodies stain and its clinical significance].

    Science.gov (United States)

    Gong, Xu-Bo; Lu, Xing-Guo; Yan, Li-Juan; Xiao, Xi-Bin; Wu, Dong; Xu, Gen-Bo; Zhang, Xiao-Hong; Zhao, Xiao-Ying

    2009-02-01

    The aim of this study was to improve the dyeing method of hydroperoxidase (HPO), to analyze the morphologic features of Phi bodies and to evaluate the clinical application of this method. 128 bone marrow or peripheral blood smears from patients with myeloid and lymphoid malignancies were stained by improved HPO staining. The Phi bodies were observed with detection rate of Phi bodies in different leukemias. 69 acute myeloid leukemia (AML) specimens were chosen randomly, the positive rate and the number of Phi bodies between the improved HPO and POX stain based on the same substrate of 3, 3'diaminobenzidine were compared. The results showed that the shape of bundle-like Phi bodies was variable, long or short. while the nubbly Phi bodies often presented oval and smooth. Club-like Phi bodies were found in M(3). The detection rates of bundle-like Phi bodies in AML M(1)-M(5) were 42.9% (6/14), 83.3% (15/18), 92.0% (23/25), 52.3% (11/21), 33.3% (5/15) respectively, and those of nubbly Phi bodies were 28.6% (4/14), 66.7% (12/18), 11.1% (3/25), 33.3% (7/21), 20.0% (3/15) respectively. The detection rate of bundle-like Phi bodies in M(3) was significantly higher than that in (M(1) + M(2)) or (M(4) + M(5)) groups. The detection rate of nubbly Phi bodies in (M(1) + M(2)) group was higher than that in M(3) group. In conclusion, after improvement of staining method, the HPO stain becomes simple, the detection rate of Phi bodies is higher than that by the previous method, the positive granules are more obvious, and the results become stable. This improved method plays an important role in differentiating AML from ALL, subtyping AML, and evaluating the therapeutic results.

  1. Inhaler Reminders Significantly Improve Asthma Patients' Use of Controller Medications

    Science.gov (United States)

    ... Conditions Drug Guide Conditions Dictionary Just for Kids Library School Tools Videos Virtual Allergist Education & Training Careers in ... Support the AAAAI Foundation Donate Utility navigation Español Journals Annual Meeting Member Login / My Membership Search navigation ...

  2. Ceramic Composite Intermediate Temperature Stress-Rupture Properties Improved Significantly

    Science.gov (United States)

    Morscher, Gregory N.; Hurst, Janet B.

    2002-01-01

    Silicon carbide (SiC) composites are considered to be potential materials for future aircraft engine parts such as combustor liners. It is envisioned that on the hot side (inner surface) of the combustor liner, composites will have to withstand temperatures in excess of 1200 C for thousands of hours in oxidizing environments. This is a severe condition; however, an equally severe, if not more detrimental, condition exists on the cold side (outer surface) of the combustor liner. Here, the temperatures are expected to be on the order of 800 to 1000 C under high tensile stress because of thermal gradients and attachment of the combustor liner to the engine frame (the hot side will be under compressive stress, a less severe stress-state for ceramics). Since these composites are not oxides, they oxidize. The worst form of oxidation for strength reduction occurs at these intermediate temperatures, where the boron nitride (BN) interphase oxidizes first, which causes the formation of a glass layer that strongly bonds the fibers to the matrix. When the fibers strongly bond to the matrix or to one another, the composite loses toughness and strength and becomes brittle. To increase the intermediate temperature stress-rupture properties, researchers must modify the BN interphase. With the support of the Ultra-Efficient Engine Technology (UEET) Program, significant improvements were made as state-of-the-art SiC/SiC composites were developed during the Enabling Propulsion Materials (EPM) program. Three approaches were found to improve the intermediate-temperature stress-rupture properties: fiber-spreading, high-temperature silicon- (Si) doped boron nitride (BN), and outside-debonding BN.

  3. Consensus-based evaluation of clinical significance and management of anticancer drug interactions

    NARCIS (Netherlands)

    Jansman, F.G.A.; Reyners, A.K.L.; van Roon, E.N.; Smorenburg, C.H.; Helgason, H.H.; le Comte, M.; Wensveen, B.M.; van den Tweel, A.M.A.; de Blois, M.; Kwee, W.; Kerremans, A.L.; Brouwers, J.R.B.J.

    Background: Anticancer drug interactions can affect the efficacy and toxicity of anticancer treatment and that of the interacting drugs. However, information on the significance, prevention, and management of these interactions is currently lacking. Objective: The purpose of this study was to assess

  4. Significant Acute Kidney Injury Due to Non-steroidal Anti-inflammatory Drugs: Inpatient Setting

    Directory of Open Access Journals (Sweden)

    Mehul Dixit

    2010-04-01

    Full Text Available In the United States non-steroidal anti-inflammatory drugs (NSAID are freely available over-the-counter. Because of the adverse effects on the kidneys and the popularity of these drugs, unregulated use of NSAIDs is an under recognized and potentially dangerous problem. Fifteen inpatients, mean age of 15.2 ± 2.3 years (five males, 10 females, were referred to nephrology for acute kidney injury. All patients admitted to taking ibuprofen and six also consumed naproxen. None of the patients had underlying renal diseases at the time of admission. Nine patients had proteinuria and 12 had hematuria (including one with gross hematuria. One patient had nephrotic syndrome but the condition resolved spontaneously without steroids and has remained in remission for four years. Two patients required dialysis. Only one of the dialyzed patients required steroid therapy for recovery of renal function. The mean duration of hospitalization was 7.4 ± 5.5 days. The serum creatinine peaked at 4.09 ± 4.24 (range 1.2-15.3 mg/dL. All patients recovered renal function with normalization of serum creatinine to 0.71 ± 0.15 mg/dL. The estimated GFR (glomerular filtration rate at peak of renal failure was 38.2 ± 20.5 mL/min but did improve to a baseline of 134 ± 26.2 mL/min (range 89-177, p < 0.01. However, the duration from onset to normalization of serum creatinine was 37 ± 42 days indicating that majority of patients had abnormal renal function for a prolonged period. In conclusion, NSAIDs pose a significant risk of renal failure for significant duration and as an entity may be under recognized.

  5. Displacement of Drugs from Human Serum Albumin: From Molecular Interactions to Clinical Significance.

    Science.gov (United States)

    Rimac, Hrvoje; Debeljak, Željko; Bojić, Mirza; Miller, Larisa

    2017-01-01

    Human serum albumin (HSA) is the most abundant protein in human serum. It has numerous functions, one of which is transport of small hydrophobic molecules, including drugs, toxins, nutrients, hormones and metabolites. HSA has the ability to interact with a wide variety of structurally different compounds. This promiscuous, nonspecific affinity can lead to sudden changes in concentrations caused by displacement, when two or more compounds compete for binding to the same molecular site. It is important to consider drug combinations and their binding to HSA when defining dosing regimens, as this can directly influence drug's free, active concentration in blood. In present paper we review drug interactions with potential for displacement from HSA, situations in which they are likely to occur and their clinical significance. We also offer guidelines in designing drugs with decreased binding to HSA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Methylphenidate significantly improves declarative memory functioning of adults with ADHD.

    NARCIS (Netherlands)

    Verster, J.C.; Bekker, E.M.; Kooij, J.J.; Buitelaar, J.K.; Verbaten, M.N.; Volkerts, E.R.; Olivier, B.

    2010-01-01

    BACKGROUND: Declarative memory deficits are common in untreated adults with attention-deficit hyperactivity disorder (ADHD), but limited evidence exists to support improvement after treatment with methylphenidate. The objective of this study was to examine the effects of methylphenidate on memory

  7. Metabolomics has the potential to improve drug therapy

    DEFF Research Database (Denmark)

    Stage, Claus; Jürgens, Gesche; Dalhoff, Kim Peder

    2014-01-01

    Until now drug therapy has primarily been controlled by dose titration on the basis of effects and side effects. However, a lot of people being treated with a drug experience too little effect or too many side effects. Therefore it will be advantageous to improve drug therapy and make it even more...

  8. Classification and occurrence of clinically significant drug interactions with irinotecan and oxaliplatin in patients with metastatic colorectal cancer

    NARCIS (Netherlands)

    Jansman, FGA; Idzinga, FSF; Smit, WM; de Graaf, JC; Coenen, JLLM; Sleijfer, DT; Brouwers, JRBJ

    Background: Pharmacokinetic and pharmacodynamic drug interactions with cytotoxic drugs may significantly influence the efficacy and toxicity of chemotherapy. Objective: The purpose of this study was to identify drug interactions with irinotecan and oxaliplatin reported in the literature, to assess

  9. Creating a Middle Grades Environment that Significantly Improves Student Achievement

    Science.gov (United States)

    L'Esperance, Mark E.; Lenker, Ethan; Bullock, Ann; Lockamy, Becky; Mason, Cathy

    2013-01-01

    This article offers an overview of the framework that Sampson County Public Schools (North Carolina) used to critically reflect on the current state of their middle grades schools. The article also highlights the changes that resulted from the district-wide analysis and the ways in which these changes led to a significant increase in the academic…

  10. Adaptive Programming Improves Outcomes in Drug Court: An Experimental Trial.

    Science.gov (United States)

    Marlowe, Douglas B; Festinger, David S; Dugosh, Karen L; Benasutti, Kathleen M; Fox, Gloria; Croft, Jason R

    2012-04-01

    Prior studies in Drug Courts reported improved outcomes when participants were matched to schedules of judicial status hearings based on their criminological risk level. The current experiment determined whether incremental efficacy could be gained by periodically adjusting the schedule of status hearings and clinical case-management sessions in response to participants' ensuing performance in the program. The adjustments were made pursuant to a priori criteria specified in an adaptive algorithm. Results confirmed that participants in the full adaptive condition (n = 62) were more than twice as likely as those assigned to baseline-matching only (n = 63) to be drug-abstinent during the first 18 weeks of the program; however, graduation rates and the average time to case resolution were not significantly different. The positive effects of the adaptive program appear to have stemmed from holding noncompliant participants more accountable for meeting their attendance obligations in the program. Directions for future research and practice implications are discussed.

  11. Thermodynamic study of three pharmacologically significant drugs: Density, viscosity, and refractive index measurements at different temperatures

    International Nuclear Information System (INIS)

    Iqbal, Muhammad Javed; Chaudhry, Mansoora Ahmed

    2009-01-01

    Measurements of density, viscosity, and refractive index of three pharmacologically significant drugs, i.e. diclofenac sodium, cetrizine, and doxycycline have been carried in aqueous medium at T = (293.15 to 313.15) K. An automated vibrating-tube densimeter, viscometer, and refractometer are used in a concentration range from (7.5) . 10 -3 to 25 . 10 -3 ) mol . kg -1 . The precise density results are used to evaluate the apparent molar volume, partial molar volume, thermal expansion coefficient, partial molar expansivity, and the Hepler's constant. Viscosity results are used to calculate the Jones-Dole viscosity B-coefficient, free energy of activation of the solute and solvent, activation enthalpy, and activation entropy. The molar refractive indices of the drug solutions can be employed to calculate molar refraction. It is inferred from these results that the above mentioned drugs act as structure-making compounds due to hydrophobic hydration of the molecules in the drugs

  12. Low-dose vaporized cannabis significantly improves neuropathic pain.

    Science.gov (United States)

    Wilsey, Barth; Marcotte, Thomas; Deutsch, Reena; Gouaux, Ben; Sakai, Staci; Donaghe, Haylee

    2013-02-01

    We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning. Published by Elsevier Inc.

  13. 7 Strategies for Improving Drug Utilization.

    Science.gov (United States)

    Schlosser, Michael; Chamberlain, Ronald; Dortch, Marcus

    2017-06-01

    When new pharmaceutical products enter the market, the lack of real-world experience with these drugs creates quandaries for payers and providers alike. Often, all there is to go on is the minimum required for FDA approval-non-inferiority to a comparator product in terms of efficacy and safety. Here are a few promising strategies to end this ambiguity.

  14. Low Dose Vaporized Cannabis Significantly Improves Neuropathic Pain

    Science.gov (United States)

    Wilsey, Barth; Marcotte, Thomas D.; Deutsch, Reena; Gouaux, Ben; Sakai, Staci; Donaghe, Haylee

    2013-01-01

    We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling either medium dose (3.53%), low dose (1.29%), or placebo cannabis with the primary outcome being VAS pain intensity. Psychoactive side-effects, and neuropsychological performance were also evaluated. Mixed effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the two active dose groups’ results (p>0.7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo vs. low dose, 2.9 for placebo vs. medium dose, and 25 for medium vs. low dose. As these NNT are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being, for all intents and purposes, as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well-tolerated, and neuropsychological effects were of limited duration and readily reversible within 1–2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. PMID:23237736

  15. A significant association between BDNF promoter methylation and the risk of drug addiction.

    Science.gov (United States)

    Xu, Xuting; Ji, Huihui; Liu, Guili; Wang, Qinwen; Liu, Huifen; Shen, Wenwen; Li, Longhui; Xie, Xiaohu; Zhou, Wenhua; Duan, Shiwei

    2016-06-10

    As a member of the neurotrophic factor family, brain derived neurotrophic factor (BDNF) plays an important role in the survival and differentiation of neurons. The aim of our work was to evaluate the role of BDNF promoter methylation in drug addiction. A total of 60 drug abusers (30 heroin and 30 methylamphetamine addicts) and 52 healthy age- and gender-matched controls were recruited for the current case control study. Bisulfite pyrosequencing technology was used to determine the methylation levels of five CpGs (CpG1-5) on the BDNF promoter. Among the five CpGs, CpG5 methylation was significantly lower in drug abusers than controls. Moreover, significant associations were found between CpG5 methylation and addictive phenotypes including tension-anxiety, anger-hostility, fatigue-inertia, and depression-dejection. In addition, luciferase assay showed that the DNA fragment of BDNF promoter played a key role in the regulation of gene expression. Our results suggest that BDNF promoter methylation is associated with drug addiction, although further studies are needed to understand the mechanisms by which BDNF promoter methylation contributes to the pathophysiology of drug addiction. Copyright © 2016. Published by Elsevier B.V.

  16. Improving Alcohol/Drug Education in Illinois Schools.

    Science.gov (United States)

    Illinois State Board of Education, Springfield.

    This paper lists guidelines approved by the Illinois State Board of Education for improving alcohol and drug education in the schools. Statistics point out the seriousness of alcohol and drug abuse in terms of human costs to the victim, his/her family, and associates, and the economic costs of health care, accident losses, crime, social programs,…

  17. Drug Improves Birth Rates for Women with Ovary Disorder

    Science.gov (United States)

    ... NIH Research Matters July 21, 2014 Drug Improves Birth Rates for Women with Ovary Disorder At a ... more effective than standard therapy in increasing live births for women with polycystic ovary syndrome. Letrozole could ...

  18. Thermodynamic study of three pharmacologically significant drugs: Density, viscosity, and refractive index measurements at different temperatures

    Energy Technology Data Exchange (ETDEWEB)

    Iqbal, Muhammad Javed [Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan)], E-mail: mjiqauchem@yahoo.com; Chaudhry, Mansoora Ahmed [Department of Chemistry, Quaid-i-Azam University, Islamabad 45320 (Pakistan)

    2009-02-15

    Measurements of density, viscosity, and refractive index of three pharmacologically significant drugs, i.e. diclofenac sodium, cetrizine, and doxycycline have been carried in aqueous medium at T = (293.15 to 313.15) K. An automated vibrating-tube densimeter, viscometer, and refractometer are used in a concentration range from (7.5) . 10{sup -3} to 25 . 10{sup -3}) mol . kg{sup -1}. The precise density results are used to evaluate the apparent molar volume, partial molar volume, thermal expansion coefficient, partial molar expansivity, and the Hepler's constant. Viscosity results are used to calculate the Jones-Dole viscosity B-coefficient, free energy of activation of the solute and solvent, activation enthalpy, and activation entropy. The molar refractive indices of the drug solutions can be employed to calculate molar refraction. It is inferred from these results that the above mentioned drugs act as structure-making compounds due to hydrophobic hydration of the molecules in the drugs.

  19. Functional alterations of astrocytes in mental disorders: pharmacological significance as a drug target

    Directory of Open Access Journals (Sweden)

    Yutaka eKoyama

    2015-07-01

    Full Text Available Astrocytes play an essential role in supporting brain functions in physiological and pathological states. Modulation of their pathophysiological responses have beneficial actions on nerve tissue injured by brain insults and neurodegenerative diseases, therefore astrocytes are recognized as promising targets for neuroprotective drugs. Recent investigations have identified several astrocytic mechanisms for modulating synaptic transmission and neural plasticity. These include altered expression of transporters for neurotransmitters, release of gliotransmitters and neurotrophic factors, and intercellular communication through gap junctions. Investigation of patients with mental disorders shows morphological and functional alterations in astrocytes. According to these observations, manipulation of astrocytic function by gene mutation and pharmacological tools reproduce mental disorder-like behavior in experimental animals. Some drugs clinically used for mental disorders affect astrocyte function. As experimental evidence shows their role in the pathogenesis of mental disorders, astrocytes have gained much attention as drug targets for mental disorders. In this article, I review functional alterations of astrocytes in several mental disorders including schizophrenia, mood disorder, drug dependence, and neurodevelopmental disorders. The pharmacological significance of astrocytes in mental disorders is also discussed.

  20. Improving drug manufacturing with process analytical technology.

    Science.gov (United States)

    Rodrigues, Licinia O; Alves, Teresa P; Cardoso, Joaquim P; Menezes, José C

    2006-01-01

    Within the process analytical technology (PAT) framework, as presented in the US Food and Drug Administration guidelines, the aim is to design, develop and operate processes consistently to ensure a pre-defined level of quality at the end of the manufacturing process. Three PAT implementation scenarios can be envisaged. Firstly, PAT could be used in its most modest version (in an almost non-PAT manner) to simply replace an existing quality control protocol (eg, using near-infrared spectroscopy for an in-process quality control, such as moisture content). Secondly, the use of in-process monitoring and process analysis could be integrated to enhance process understanding and operation for an existing industrial process. Thirdly, PAT could be used extensively and exclusively throughout development, scale-up and full-scale production of a new product and process. Although the first type of implementations are well known, reports of the second and third types remain scarce. Herein, results obtained from PAT implementations of the second and third types are described for two industrial processes for preparing bulk active pharmaceutical ingredients, demonstrating the benefits in terms of increased process understanding and process control.

  1. General Beliefs and Stigma Regarding Illicit Drug Use: Perspectives of Family Members and Significant Others of Drug Users in an Inner City in Brazil.

    Science.gov (United States)

    Ventura, Carla Aparecida Arena; Carrara, Bruna Sordi; Bobbili, Sireesha; Vedana, Kelly Graziani Giacchero; Khenti, Akwatu; Hayashida, Miyeko; Ferreira, Paulo Sergio

    2017-09-01

    People who use drugs are continuously subjected to harsh stigmatization through a process of relational and social degradation, which limits their possibility for recovery. This quantitative study explores the perspectives of family members or significant others of illicit drug users, regarding general beliefs about illicit drug use and their stigma. Respondents agree that most people do not trust people who use drugs, disregard individuals who have been hospitalized due to drug problems and do not think people who use drugs are as intelligent as the general population. These findings reveal a high level of public stigma regarding illicit drug use.

  2. A novel multi-drug metronomic chemotherapy significantly delays tumor growth in mice.

    Science.gov (United States)

    Tagliamonte, Maria; Petrizzo, Annacarmen; Napolitano, Maria; Luciano, Antonio; Rea, Domenica; Barbieri, Antonio; Arra, Claudio; Maiolino, Piera; Tornesello, Marialina; Ciliberto, Gennaro; Buonaguro, Franco M; Buonaguro, Luigi

    2016-02-24

    The tumor immunosuppressive microenvironment represents a major obstacle to an effective tumor-specific cellular immune response. In the present study, the counterbalance effect of a novel metronomic chemotherapy protocol on such an immunosuppressive microenvironment was evaluated in a mouse model upon sub-cutaneous ectopic implantation of B16 melanoma cells. The chemotherapy consisted of a novel multi-drug cocktail including taxanes and alkylating agents, administered in a daily metronomic fashion. The newly designed strategy was shown to be safe, well tolerated and significantly efficacious. Treated animals showed a remarkable delay in tumor growth and prolonged survival as compared to control group. Such an effect was directly correlated with CD4(+) T cell reduction and CD8(+) T cell increase. Furthermore, a significant reduction in the percentage of both CD25(+)FoxP3(+) and CD25(+)CD127(low) regulatory T cell population was found both in the spleens and in the tumor lesions. Finally, the metronomic chemotherapy induced an intrinsic CD8(+) T cell response specific to B16 naturally expressed Trp2 TAA. The novel multi-drug daily metronomic chemotherapy evaluated in the present study was very effective in counterbalancing the immunosuppressive tumor microenvironment. Consequently, the intrinsic anti-tumor T cell immunity could exert its function, targeting specific TAA and significantly containing tumor growth. Overall, the results show that this represents a promising adjuvant approach to significantly enhance efficacy of intrinsic or vaccine-elicited tumor-specific cellular immunity.

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

    Science.gov (United States)

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

    2015-09-01

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

  4. Improving clinical drug development regulatory procedures for anticonvulsants

    Directory of Open Access Journals (Sweden)

    Janković Slobodan

    2015-01-01

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

  5. The Prodrug Approach: A Successful Tool for Improving Drug Solubility

    Directory of Open Access Journals (Sweden)

    Daniela Hartmann Jornada

    2015-12-01

    Full Text Available Prodrug design is a widely known molecular modification strategy that aims to optimize the physicochemical and pharmacological properties of drugs to improve their solubility and pharmacokinetic features and decrease their toxicity. A lack of solubility is one of the main obstacles to drug development. This review aims to describe recent advances in the improvement of solubility via the prodrug approach. The main chemical carriers and examples of successful strategies will be discussed, highlighting the advances of this field in the last ten years.

  6. Student nurses need more than maths to improve their drug calculating skills.

    Science.gov (United States)

    Wright, Kerri

    2007-05-01

    Nurses need to be able to calculate accurate drug calculations in order to safely administer drugs to their patients (NMC, 2002). Studies have shown however that nurses do not always have the necessary skills to calculate accurate drug dosages and are potentially administering incorrect dosages of drugs to their patients (Hutton, M. 1998. Nursing Mathematics: the importance of application. Nursing Standard 13(11), 35-38; Kapborg, I. 1994. Calculation and administration of drug dosage by Swedish nurses, Student Nurses and Physicians. International Journal for Quality in Health Care 6(4), 389-395; O'Shea, E. 1999. Factors contributing to medication errors: a literature review. Journal of Advanced Nursing 8, 496-504; Wilson, A. 2003. Nurses maths: researching a practical approach. Nursing Standard 17(47), 33-36). The literature indicates that in order to improve drug calculations strategies need to focus on both the mathematical skills and conceptual skills of student nurses so they can interpret clinical data into drug calculations to be solved. A study was undertaken to investigate the effectiveness of implementing several strategies which focussed on developing the mathematical and conceptual skills of student nurses to improve their drug calculation skills. The study found that implementing a range of strategies which addressed these two developmental areas significantly improved the drug calculation skills of nurses. The study also indicates that a range of strategies has the potential ensuring that the skills taught are retained by the student nurses. Although the strategies significantly improved the drug calculation skills of student nurses, the fact that only 2 students were able to achieve 100% in their drug calculation test indicates a need for further research into this area.

  7. Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

    Science.gov (United States)

    Bruun, Emmi; Virta, Lauri J; Kälviäinen, Reetta; Keränen, Tapani

    2017-08-01

    A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic

  8. Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment

    Directory of Open Access Journals (Sweden)

    Giovanni Sotgiu

    2015-03-01

    Full Text Available In this article we describe the key role of tuberculosis (TB treatment, the challenges (mainly the emergence of drug resistance, and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM is discussed in detail. Treatment success in multidrug-resistant (MDR TB cases is low (62%, with 7% failing or relapsing and 9% dying and in extensively drug-resistant (XDR TB cases is even lower (40%, with 22% failing or relapsing and 15% dying. The treatment of drug-resistant TB is also more expensive (exceeding €50 000 for MDR-TB and €160 000 for XDR-TB and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The ‘dried blood spot’ technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world.

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

    Science.gov (United States)

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

    2016-03-01

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

  10. Systems biology-embedded target validation: improving efficacy in drug discovery.

    Science.gov (United States)

    Vandamme, Drieke; Minke, Benedikt A; Fitzmaurice, William; Kholodenko, Boris N; Kolch, Walter

    2014-01-01

    The pharmaceutical industry is faced with a range of challenges with the ever-escalating costs of drug development and a drying out of drug pipelines. By harnessing advances in -omics technologies and moving away from the standard, reductionist model of drug discovery, there is significant potential to reduce costs and improve efficacy. Embedding systems biology approaches in drug discovery, which seek to investigate underlying molecular mechanisms of potential drug targets in a network context, will reduce attrition rates by earlier target validation and the introduction of novel targets into the currently stagnant market. Systems biology approaches also have the potential to assist in the design of multidrug treatments and repositioning of existing drugs, while stratifying patients to give a greater personalization of medical treatment. © 2013 Wiley Periodicals, Inc.

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

    Science.gov (United States)

    Gao, Yue; Ma, Zengchun; Zhang, Boli

    2012-01-01

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

  12. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Directory of Open Access Journals (Sweden)

    Raphaël Millière

    2017-05-01

    Full Text Available There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR. While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves

  13. Looking for the Self: Phenomenology, Neurophysiology and Philosophical Significance of Drug-induced Ego Dissolution

    Science.gov (United States)

    Millière, Raphaël

    2017-01-01

    There is converging evidence that high doses of hallucinogenic drugs can produce significant alterations of self-experience, described as the dissolution of the sense of self and the loss of boundaries between self and world. This article discusses the relevance of this phenomenon, known as “drug-induced ego dissolution (DIED)”, for cognitive neuroscience, psychology and philosophy of mind. Data from self-report questionnaires suggest that three neuropharmacological classes of drugs can induce ego dissolution: classical psychedelics, dissociative anesthetics and agonists of the kappa opioid receptor (KOR). While these substances act on different neurotransmitter receptors, they all produce strong subjective effects that can be compared to the symptoms of acute psychosis, including ego dissolution. It has been suggested that neuroimaging of DIED can indirectly shed light on the neural correlates of the self. While this line of inquiry is promising, its results must be interpreted with caution. First, neural correlates of ego dissolution might reveal the necessary neurophysiological conditions for the maintenance of the sense of self, but it is more doubtful that this method can reveal its minimally sufficient conditions. Second, it is necessary to define the relevant notion of self at play in the phenomenon of DIED. This article suggests that DIED consists in the disruption of subpersonal processes underlying the “minimal” or “embodied” self, i.e., the basic experience of being a self rooted in multimodal integration of self-related stimuli. This hypothesis is consistent with Bayesian models of phenomenal selfhood, according to which the subjective structure of conscious experience ultimately results from the optimization of predictions in perception and action. Finally, it is argued that DIED is also of particular interest for philosophy of mind. On the one hand, it challenges theories according to which consciousness always involves self-awareness. On

  14. Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers

    Directory of Open Access Journals (Sweden)

    Stefano Salmaso

    2013-01-01

    Full Text Available Over the last few decades, nanocarriers for drug delivery have emerged as powerful tools with unquestionable potential to improve the therapeutic efficacy of anticancer drugs. Many colloidal drug delivery systems are underdevelopment to ameliorate the site specificity of drug action and reduce the systemic side effects. By virtue of their small size they can be injected intravenously and disposed into the target tissues where they release the drug. Nanocarriers interact massively with the surrounding environment, namely, endothelium vessels as well as cells and blood proteins. Consequently, they are rapidly removed from the circulation mostly by the mononuclear phagocyte system. In order to endow nanosystems with long circulation properties, new technologies aimed at the surface modification of their physicochemical features have been developed. In particular, stealth nanocarriers can be obtained by polymeric coating. In this paper, the basic concept underlining the “stealth” properties of drug nanocarriers, the parameters influencing the polymer coating performance in terms of opsonins/macrophages interaction with the colloid surface, the most commonly used materials for the coating process and the outcomes of this peculiar procedure are thoroughly discussed.

  15. 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.

  16. [Predictive factors of clinically significant drug-drug interactions among regimens based on protease inhibitors, non-nucleoside reverse transcriptase inhibitors and raltegravir].

    Science.gov (United States)

    Cervero, Miguel; Torres, Rafael; Jusdado, Juan José; Pastor, Susana; Agud, Jose Luis

    2016-04-15

    To determine the prevalence and types of clinically significant drug-drug interactions (CSDI) in the drug regimens of HIV-infected patients receiving antiretroviral treatment. retrospective review of database. Centre: Hospital Universitario Severo Ochoa, Infectious Unit. one hundred and forty-two participants followed by one of the authors were selected from January 1985 to December 2014. from their outpatient medical records we reviewed information from the last available visit of the participants, in relation to HIV infection, comorbidities, demographics and the drugs that they were receiving; both antiretroviral drugs and drugs not related to HIV infection. We defined CSDI from the information sheet and/or database on antiretroviral drug interactions of the University of Liverpool (http://www.hiv-druginteractions.org) and we developed a diagnostic tool to predict the possibility of CSDI. By multivariate logistic regression analysis and by estimating the diagnostic performance curve obtained, we identified a quick tool to predict the existence of drug interactions. Of 142 patients, 39 (29.11%) had some type of CSDI and in 11.2% 2 or more interactions were detected. In only one patient the combination of drugs was contraindicated (this patient was receiving darunavir/r and quetiapine). In multivariate analyses, predictors of CSDI were regimen type (PI or NNRTI) and the use of 3 or more non-antiretroviral drugs (AUC 0.886, 95% CI 0.828 to 0.944; P=.0001). The risk was 18.55 times in those receiving NNRTI and 27,95 times in those receiving IP compared to those taking raltegravir. Drug interactions, including those defined as clinically significant, are common in HIV-infected patients treated with antiretroviral drugs, and the risk is greater in IP-based regimens. Raltegravir-based prescribing, especially in patients who receive at least 3 non-HIV drugs could avoid interactions. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  17. 21 CFR 201.303 - Labeling of drug preparations containing significant proportions of wintergreen oil.

    Science.gov (United States)

    2010-04-01

    ... proportions of wintergreen oil. (a) Because methyl salicylate (wintergreen oil) manifests no toxicity in the... poisoning. (c) This statement of interpretation in no way exempts methyl salicylate (wintergreen oil) or its... provisions of the Federal Food, Drug, and Cosmetic Act any drug containing more than 5 percent methyl...

  18. National Emergency Preparedness and Response: Improving for Incidents of National Significance

    National Research Council Canada - National Science Library

    Clayton, Christopher M

    2006-01-01

    The national emergency management system has need of significant improvement in its contingency planning and early consolidation of effort and coordination between federal, state, and local agencies...

  19. Factors Related to Significant Improvement of Estimated Glomerular Filtration Rates in Chronic Hepatitis B Patients Receiving Telbivudine Therapy

    Directory of Open Access Journals (Sweden)

    Te-Fu Lin

    2017-01-01

    Full Text Available Background and Aim. The improvement of estimated glomerular filtration rates (eGFRs in chronic hepatitis B (CHB patients receiving telbivudine therapy is well known. The aim of this study was to clarify the kinetics of eGFRs and to identify the significant factors related to the improvement of eGFRs in telbivudine-treated CHB patients in a real-world setting. Methods. Serial eGFRs were calculated every 3 months using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI equation. The patients were classified as CKD-1, -2, or -3 according to a baseline eGFR of ≥90, 60–89, or <60 mL/min/1.73 m2, respectively. A significant improvement of eGFR was defined as a more than 10% increase from the baseline. Results. A total of 129 patients were enrolled, of whom 36% had significantly improved eGFRs. According to a multivariate analysis, diabetes mellitus (DM (p=0.028 and CKD-3 (p=0.043 were both significantly related to such improvement. The rates of significant improvement of eGFR were about 73% and 77% in patients with DM and CKD-3, respectively. Conclusions. Telbivudine is an alternative drug of choice for the treatment of hepatitis B patients for whom renal safety is a concern, especially patients with DM and CKD-3.

  20. Overcoming cellular and tissue barriers to improve liposomal drug delivery

    Science.gov (United States)

    Kohli, Aditya G.

    Forty years of liposome research have demonstrated that the anti-tumor efficacy of liposomal therapies is, in part, driven by three parameters: 1) liposome formulation and lipid biophysics, 2) accumulation and distribution in the tumor, and 3) release of the payload at the site of interest. This thesis outlines three studies that improve on each of these delivery steps. In the first study, we engineer a novel class of zwitterlipids with an inverted headgroup architecture that have remarkable biophysical properties and may be useful for drug delivery applications. After intravenous administration, liposomes accumulate in the tumor by the enhanced permeability and retention effect. However, the tumor stroma often limits liposome efficacy by preventing distribution into the tumor. In the second study, we demonstrate that depletion of hyaluronan in the tumor stroma improves the distribution and efficacy of DoxilRTM in murine 4T1 tumors. Once a liposome has distributed to the therapeutic site, it must release its payload over the correct timescale. Few facile methods exist to quantify the release of liposome therapeutics in vivo. In the third study, we outline and validate a simple, robust, and quantitative method for tracking the rate and extent of release of liposome contents in vivo. This tool should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals. This work highlights aspects of liposome behavior that have prevented successful clinical translation and proposes alternative approaches to improve liposome drug delivery.

  1. Renal myoglobin in drug addicts: occurrence and significance in a postmortem study

    DEFF Research Database (Denmark)

    Kock, Kirsten Friis; Simonsen, Kirsten Wiese

    1994-01-01

    In a 3-year period (1989–1991) a non-selected, consecutive series of 62 deaths in drug addicts was autopsied at the Forensic Institute in Odense. The kidney sections from these addicts were examined for the presence of renal myoglobin using immunohistochemical methods. A reference group consisting......, immobilization, hypovolemia). In sufficient amounts, renal myoglobin may be of importance as a cause of death or a contributing factor to death in both drug addicts and non-addicts....

  2. Significance of MDR1 and multiple drug resistance in refractory human epileptic brain

    Directory of Open Access Journals (Sweden)

    Dini Gabriele

    2004-10-01

    Full Text Available Abstract Background The multiple drug resistance protein (MDR1/P-glycoprotein is overexpressed in glia and blood-brain barrier (BBB endothelium in drug refractory human epileptic tissue. Since various antiepileptic drugs (AEDs can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs. Methods Human drug resistant epileptic brain tissues were collected after surgical resection. Astrocyte cell cultures were established from these tissues, and commercially available normal human astrocytes were used as controls. Uptake of fluorescent doxorubicin and radioactive-labeled Phenytoin was measured in the two cell populations, and the effect of MDR1 blockers was evaluated. Frozen human epileptic brain tissue slices were double immunostained to locate MDR1 in neurons and glia. Other slices were exposed to toxic concentrations of Phenytoin to study cell viability in the presence or absence of a specific MDR1 blocker. Results MDR1 was overexpressed in blood vessels, astrocytes and neurons in human epileptic drug-resistant brain. In addition, MDR1-mediated cellular drug extrusion was increased in human 'epileptic' astrocytes compared to 'normal' ones. Concomitantly, cell viability in the presence of cytotoxic compounds was increased. Conclusions Overexpression of MDR1 in different cell types in drug-resistant epileptic human brain leads to functional alterations, not all of which are linked to drug pharmacokinetics. In particular, the modulation of glioneuronal MDR1 function in epileptic brain in the presence of toxic concentrations of xenobiotics may constitute a novel cytoprotective mechanism.

  3. Frameworks for improvement: clinical audit, the plan-do-study-act cycle and significant event audit.

    Science.gov (United States)

    Gillam, Steve; Siriwardena, A Niroshan

    2013-01-01

    This is the first in a series of articles about quality improvement tools and techniques. We explore common frameworks for improvement, including the model for improvement and its application to clinical audit, plan-do-study-act (PDSA) cycles and significant event analysis (SEA), examining the similarities and differences between these and providing examples of each.

  4. Improving drug policy: The potential of broader democratic participation.

    Science.gov (United States)

    Ritter, Alison; Lancaster, Kari; Diprose, Rosalyn

    2018-05-01

    Policies concerned with illicit drugs vex governments. While the 'evidence-based policy' paradigm argues that governments should be informed by 'what works', in practice policy makers rarely operate this way. Moreover the evidence-based policy paradigm fails to account for democratic participatory processes, particularly how community members and people who use drugs might be included. The aim of this paper is to explore the political science thinking about democratic participation and the potential afforded in 'deliberative democracy' approaches, such as Citizens Juries and other mini-publics for improved drug policy processes. Deliberative democracy, through its focus on inclusion, equality and reasoned discussion, shows potential for drug policy reform and shifts the focus from reliance on and privileging of experts and scientific evidence. But the very nature of this kind of 'deliberation' may delimit participation, notably through its insistence on authorised modes of communication. Other forms of participation beyond reasoned deliberation aligned with the ontological view that participatory processes themselves are constitutive of subject positions and policy problems, may generate opportunities for considering how the deleterious effects of authorised modes of communication might be overcome. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. The toxicological significance of post-mortem drug concentrations in bile.

    Science.gov (United States)

    Ferner, Robin E; Aronson, Jeffrey K

    2018-01-01

    Some authors have proposed that post-mortem drug concentrations in bile are useful in estimating concentrations in blood. Both The International Association of Forensic Toxicologists (TIAFT) and the US Federal Aviation Administration recommend that samples of bile should be obtained in some circumstances. Furthermore, standard toxicological texts compare blood and bile concentrations, implying that concentrations in bile are of forensic value. To review the evidence on simultaneous measurements of blood and bile drug concentrations reported in the medical literature. We made a systematic search of EMBASE 1980-2016 using the search terms ("bile/" OR "exp drug bile level/concentration/") AND "drug blood level/concentration/", PubMed 1975-2017 for ("bile[tw]" OR "biliary[tw]") AND ("concentration[tw]" OR "concentrations[tw]" OR "level[tw]" OR "levels[tw]") AND "post-mortem[tw]" and also MEDLINE 1990-2016 for information on drugs whose biliary concentrations were mentioned in standard textbooks. The search was limited to human studies without language restrictions. We also examined recent reviews, indexes of relevant journals and citations in Web of Science and Google Scholar. We calculated the bile:blood concentration ratio. The searches together yielded 1031 titles with abstracts. We scanned titles and abstracts for relevance and retrieved 230, of which 161 were considered further. We excluded 49 papers because: the paper reported only one case (30 references); the data referred only to a metabolite (1); the work was published before 1980 (3); the information concerned only samples taken during life (10); or the paper referred to a toxin or unusual recreational drug (5). The remaining 112 papers provided data for analysis, with at least two observations for each of 58 drugs. Bile:blood concentration ratios: Median bile:blood concentration ratios varied from 0.18 (range 0.058-0.32) for dextromoramide to 520 (range 0.62-43,000) for buprenorphine. Median bile

  6. Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers

    International Nuclear Information System (INIS)

    Hu Jun; Dong Yuancai; Pastorin, Giorgia; Ng, Wai Kiong; Tan, Reginald B. H.

    2013-01-01

    The aim of this study was to produce micron-sized spherical agglomerates of pure drug nanoparticles to achieve improved aerosol performance in dry powder inhalers (DPIs). Sodium cromoglicate was chosen as the model drug. Pure drug nanoparticles were prepared through a bottom-up particle formation process, liquid antisolvent precipitation, and then rapidly agglomerated into porous spherical microparticles by immediate (on-line) spray drying. Nonporous spherical drug microparticles with similar geometric size distribution were prepared by conventional spray drying of the aqueous drug solution, which together with the mechanically micronized drug particles were used as the control samples. The three samples were characterized by field emission scanning electron microscopy, laser diffraction, Brunauer–Emmett–Teller analysis, density measurement, powder X-ray diffraction, and in vitro aerosol deposition measurement with a multistage liquid impinger. It was found that drug nanoparticles with a diameter of ∼100 nm were precipitated and agglomerated into highly porous spherical microparticles with a volume median diameter (D 50% ) of 2.25 ± 0.08 μm and a specific surface area of 158.63 ± 3.27 m 2 /g. In vitro aerosol deposition studies showed the fine particle fraction of such spherical agglomerates of drug nanoparticles was increased by more than 50 % in comparison with the control samples, demonstrating significant improvements in aerosol performance. The results of this study indicated the potential of the combined particle engineering process of liquid antisolvent precipitation followed by immediate (on-line) spray drying in the development of novel DPI drug products with improved aerosol performance.

  7. Spherical agglomerates of pure drug nanoparticles for improved pulmonary delivery in dry powder inhalers

    Energy Technology Data Exchange (ETDEWEB)

    Hu Jun; Dong Yuancai [Institute of Chemical and Engineering Sciences (Singapore); Pastorin, Giorgia, E-mail: phapg@nus.edu.sg [National University of Singapore, Department of Pharmacy (Singapore); Ng, Wai Kiong, E-mail: ng_wai_kiong@ices.a-star.edu.sg; Tan, Reginald B. H. [Institute of Chemical and Engineering Sciences (Singapore)

    2013-04-15

    The aim of this study was to produce micron-sized spherical agglomerates of pure drug nanoparticles to achieve improved aerosol performance in dry powder inhalers (DPIs). Sodium cromoglicate was chosen as the model drug. Pure drug nanoparticles were prepared through a bottom-up particle formation process, liquid antisolvent precipitation, and then rapidly agglomerated into porous spherical microparticles by immediate (on-line) spray drying. Nonporous spherical drug microparticles with similar geometric size distribution were prepared by conventional spray drying of the aqueous drug solution, which together with the mechanically micronized drug particles were used as the control samples. The three samples were characterized by field emission scanning electron microscopy, laser diffraction, Brunauer-Emmett-Teller analysis, density measurement, powder X-ray diffraction, and in vitro aerosol deposition measurement with a multistage liquid impinger. It was found that drug nanoparticles with a diameter of {approx}100 nm were precipitated and agglomerated into highly porous spherical microparticles with a volume median diameter (D{sub 50%}) of 2.25 {+-} 0.08 {mu}m and a specific surface area of 158.63 {+-} 3.27 m{sup 2}/g. In vitro aerosol deposition studies showed the fine particle fraction of such spherical agglomerates of drug nanoparticles was increased by more than 50 % in comparison with the control samples, demonstrating significant improvements in aerosol performance. The results of this study indicated the potential of the combined particle engineering process of liquid antisolvent precipitation followed by immediate (on-line) spray drying in the development of novel DPI drug products with improved aerosol performance.

  8. Random Forest Segregation of Drug Responses May define Regions of Biological Significance

    Directory of Open Access Journals (Sweden)

    Qasim eBukhari

    2016-03-01

    Full Text Available The ability to assess brain responses in unsupervised manner based on fMRI measure has remained a challenge. Here we have applied the Random Forest (RF method to detect differences in the pharmacological MRI (phMRI response in rats to treatment with an analgesic drug (buprenorphine as compared to control (saline. Three groups of animals were studied: two groups treated with different doses of the opioid buprenorphine, low (LD and high dose (HD, and one receiving saline. PhMRI responses were evaluated in 45 brain regions and RF analysis was applied to allocate rats to the individual treatment groups. RF analysis was able to identify drug effects based on differential phMRI responses in the hippocampus, amygdala, nucleus accumbens, superior colliculus and the lateral and posterior thalamus for drug vs. saline. These structures have high levels of mu opioid receptors. In addition these regions are involved in aversive signaling, which is inhibited by mu opioids. The results demonstrate that buprenorphine mediated phMRI responses comprise characteristic features that allow an unsupervised differentiation from placebo treated rats as well as the proper allocation to the respective drug dose group using the RF method, a method that has been successfully applied in clinical studies.

  9. Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

    Directory of Open Access Journals (Sweden)

    Claire Jackson

    2013-01-01

    Full Text Available Overexpression of human epidermal growth factor receptor (HER-2 occurs in 20–30% of breast cancers and confers survival and proliferative advantages on the tumour cells making HER-2 an ideal therapeutic target for drugs like Herceptin. Continued delineation of tumour biology has identified splice variants of HER-2, with contrasting roles in tumour cell biology. For example, the splice variant 16HER-2 (results from exon 16 skipping increases transformation of cancer cells and is associated with treatment resistance; conversely, Herstatin (results from intron 8 retention and p100 (results from intron 15 retention inhibit tumour cell proliferation. This review focuses on the potential clinical implications of the expression and coexistence of HER-2 splice variants in cancer cells in relation to breast cancer progression and drug resistance. “Individualised” strategies currently guide breast cancer management; in accordance, HER-2 splice variants may prove valuable as future prognostic and predictive factors, as well as potential therapeutic targets.

  10. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs

    DEFF Research Database (Denmark)

    Prahl, Julie B; Johansen, Isik S; Cohen, Arieh S

    2014-01-01

    OBJECTIVES: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. METHODS: After 6......-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed...... failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). CONCLUSIONS: At 2 h, plasma concentrations of isoniazid...

  11. [Clinical significance of drug resistance-associated mutations in treatment of hepatitis C with direct-acting antiviral agents].

    Science.gov (United States)

    Li, Z; Chen, Z W; Ren, H; Hu, P

    2017-03-20

    Direct-acting antiviral agents (DAAs) achieve a high sustained virologic response rate in the treatment of chronic hepatitis C virus infection. However, drug resistance-associated mutations play an important role in treatment failure and have attracted more and more attention. This article elaborates on the clinical significance of drug resistance-associated mutations from the aspects of their definition, association with genotype, known drug resistance-associated mutations and their prevalence rates, the impact of drug resistance-associated mutations on treatment naive and treatment-experienced patients, and the role of clinical detection, in order to provide a reference for clinical regimens with DAAs and help to achieve higher sustained virologic response rates.

  12. The significance of sampling time in therapeutic drug monitoring of clozapine

    DEFF Research Database (Denmark)

    Jakobsen, M I; Larsen, J R; Svensson, C K

    2017-01-01

    OBJECTIVE: Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite...... N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose. METHOD: Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose. RESULTS: Minor changes in median percentage values were...

  13. Ethnopharmacological Approaches for Dementia Therapy and Significance of Natural Products and Herbal Drugs

    Directory of Open Access Journals (Sweden)

    Devesh Tewari

    2018-02-01

    Full Text Available Dementia is a clinical syndrome wherein gradual decline of mental and cognitive capabilities of an afflicted person takes place. Dementia is associated with various risk factors and conditions such as insufficient cerebral blood supply, toxin exposure, mitochondrial dysfunction, oxidative damage, and often coexisting with some neurodegenerative disorders such as Alzheimer's disease (AD, Huntington's disease (HD, and Parkinson's disease (PD. Although there are well-established (semi-synthetic drugs currently used for the management of AD and AD-associated dementia, most of them have several adverse effects. Thus, traditional medicine provides various plant-derived lead molecules that may be useful for further medical research. Herein we review the worldwide use of ethnomedicinal plants in dementia treatment. We have explored a number of recognized databases by using keywords and phrases such as “dementia”, “Alzheimer's,” “traditional medicine,” “ethnopharmacology,” “ethnobotany,” “herbs,” “medicinal plants” or other relevant terms, and summarized 90 medicinal plants that are traditionally used to treat dementia. Moreover, we highlight five medicinal plants or plant genera of prime importance and discuss the physiological effects, as well as the mechanism of action of their major bioactive compounds. Furthermore, the link between mitochondrial dysfunction and dementia is also discussed. We conclude that several drugs of plant origin may serve as promising therapeutics for the treatment of dementia, however, pivotal evidence for their therapeutic efficacy in advanced clinical studies is still lacking.

  14. Improving maraviroc oral bioavailability by formation of solid drug nanoparticles.

    Science.gov (United States)

    Savage, Alison C; Tatham, Lee M; Siccardi, Marco; Scott, Trevor; Vourvahis, Manoli; Clark, Andrew; Rannard, Steve P; Owen, Andrew

    2018-05-17

    Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70 wt% MVC solid drug nanoparticle (SDN) formulations (containing 30 wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients ( MVC SDN PVA/AOT ), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728 nm and polydispersity index of 0.3. In vitro and in vivo studies of MVC SDN PVA/AOT showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71 ng h ml -1 ). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for MVC SDN PVA/AOT . These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product. Copyright © 2018. Published by Elsevier B.V.

  15. [Improve the accessibility of essential drugs for the populations of one medical region in Burkina Faso].

    Science.gov (United States)

    Ridde, Valéry; Nitièma, Abdoulaye P; Dadjoari, Moussa

    2005-01-01

    Despite the formulation of the Bamako initiative in 1992 in Burkina Faso, not until 2001 and the launching of a project by a nongovernmental organization was the policy really implemented in a region of the country. One of the goals of this policy is to improve access to health care by using generic essential drugs. The objective of this article is to summarize the results of the evaluation of the project's ability to improve the population's access to drugs. The project lasted three years (2001-2003) and the interventions took place in 41 basic health centres of three districts. According to WHO, improving access to drugs requires consideration of four essential factors: rational use, affordable prices, financial viability, and effectiveness of the distribution. The average number of drugs prescribed per prescription sheet (n = 1061) was 2.4; 93% of the drugs were prescribed by their generic name (international non-proprietary names); 44% of infant diarrheas were treated with oral rehydration salt. National drug prices were respected but not the directives aiming at exempting from payment or subsidizing certain population sub-groups (children, indigents). The average annual cash flow of the basic health centres was 1.2 million F CFA and it increased by 854% compared to the beginning of the project. The cost-recovery scheme for administrative expenses was 106%. The average annual availability of the 10 essential drugs was 89%. Utilization rates increased (0.13 in 1999 to 0.21 in 2003) but not significantly differently than in other basic health centres of the area not supported by the project (p = 0.084). The project succeeded in improving access to these drugs for the overall population but not for the worst-off. The drugs are now geographically available for all and financially accessible for those who can afford to pay. The intervention strategy supported the sustainability of the project's activities but much remains to be done to provide the poorest with

  16. Comparison of 5 health care professionals’ratings of the clinical significance of drug related problems

    DEFF Research Database (Denmark)

    Villesen, Christine; Hojsted, Jette; Kjeldsen, Lene Juel

    2014-01-01

    to a mutual agreement on the level of clinical significance. However, to what degree does the panel agree?Purpose To compare the agreement between different health care professionals who have evaluated the clinical significance of DRPs.Materials and methods DRPs were identified in 30 comprehensive medicines...... reviews conducted by a clinical pharmacist. Two hospital pharmacists, a general practitioner and two specialists in pain management from hospital care (the Panel) evaluated each DRP considering the potential clinical outcome for the patient. The DRPs were rated either nil, low, minor, moderate or highly...... clinically significant. Agreement was analysed using Kappa statistics. A Kappa value of 0.8 to 1.0 indicated nearly perfect agreement between ratings of the Panel members.Results The Panel rated 45 percent of the total 162 DRPs as of moderate clinical significance. However, the overall kappa score was 0...

  17. Measuring improvement in knowledge of drug policy reforms following a police education program in Tijuana, Mexico.

    Science.gov (United States)

    Arredondo, J; Strathdee, S A; Cepeda, J; Abramovitz, D; Artamonova, I; Clairgue, E; Bustamante, E; Mittal, M L; Rocha, T; Bañuelos, A; Olivarria, H O; Morales, M; Rangel, G; Magis, C; Beletsky, L

    2017-11-08

    Mexico's 2009 "narcomenudeo reform" decriminalized small amounts of drugs, shifting some drug law enforcement to the states and mandating drug treatment diversion instead of incarceration. Data from Tijuana suggested limited implementation of this harm reduction-oriented policy. We studied whether a police education program (PEP) improved officers' drug and syringe policy knowledge, and aimed to identify participant characteristics associated with improvement of drug policy knowledge. Pre- and post-training surveys were self-administered by municipal police officers to measure legal knowledge. Training impact was assessed through matched paired nominal data using McNemar's tests. Multivariable logistic regression was used to identify predictors of improved legal knowledge, as measured by officers' ability to identify conceptual legal provisions related to syringe possession and thresholds of drugs covered under the reform. Of 1750 respondents comparing pre- versus post training, officers reported significant improvement (p < 0.001) in their technical understanding of syringe possession (56 to 91%) and drug amounts decriminalized, including marijuana (9 to 52%), heroin (8 to 71%), and methamphetamine (7 to 70%). The training was associated with even greater success in improving conceptual legal knowledge for syringe possession (67 to 96%) (p < 0.001), marijuana (16 to 91%), heroin (11 to 91%), and methamphetamine (11 to 89%). In multivariable modeling, those with at least a high school education were more likely to exhibit improvement of conceptual legal knowledge of syringe possession (adjusted odds ratio [aOR] 2.6, 95% CI 1.4-3.2) and decriminalization for heroin (aOR 2.7, 95% CI 1.3-4.3), methamphetamine (aOR 2.2, 95% CI 1.4-3.2), and marijuana (aOR 2.5, 95% CI 1.6-4). Drug policy reform is often necessary, but not sufficient to achieve public health goals because of gaps in translating formal laws to policing practice. To close such gaps, PEP initiatives

  18. Measuring improvement in knowledge of drug policy reforms following a police education program in Tijuana, Mexico

    Directory of Open Access Journals (Sweden)

    J. Arredondo

    2017-11-01

    Full Text Available Abstract Background Mexico’s 2009 “narcomenudeo reform” decriminalized small amounts of drugs, shifting some drug law enforcement to the states and mandating drug treatment diversion instead of incarceration. Data from Tijuana suggested limited implementation of this harm reduction-oriented policy. We studied whether a police education program (PEP improved officers’ drug and syringe policy knowledge, and aimed to identify participant characteristics associated with improvement of drug policy knowledge. Methods Pre- and post-training surveys were self-administered by municipal police officers to measure legal knowledge. Training impact was assessed through matched paired nominal data using McNemar’s tests. Multivariable logistic regression was used to identify predictors of improved legal knowledge, as measured by officers’ ability to identify conceptual legal provisions related to syringe possession and thresholds of drugs covered under the reform. Results Of 1750 respondents comparing pre- versus post training, officers reported significant improvement (p < 0.001 in their technical understanding of syringe possession (56 to 91% and drug amounts decriminalized, including marijuana (9 to 52%, heroin (8 to 71%, and methamphetamine (7 to 70%. The training was associated with even greater success in improving conceptual legal knowledge for syringe possession (67 to 96% (p < 0.001, marijuana (16 to 91%, heroin (11 to 91%, and methamphetamine (11 to 89%. In multivariable modeling, those with at least a high school education were more likely to exhibit improvement of conceptual legal knowledge of syringe possession (adjusted odds ratio [aOR] 2.6, 95% CI 1.4–3.2 and decriminalization for heroin (aOR 2.7, 95% CI 1.3–4.3, methamphetamine (aOR 2.2, 95% CI 1.4–3.2, and marijuana (aOR 2.5, 95% CI 1.6–4. Conclusions Drug policy reform is often necessary, but not sufficient to achieve public health goals because of gaps in translating

  19. Neuro-Linguistic Programming: Improving Rapport between Track/Cross Country Coaches and Significant Others

    Science.gov (United States)

    Helm, David Jay

    2017-01-01

    This study examines the background information and the components of N.L.P., being eye movements, use of predicates, and posturing, as they apply to improving rapport and empathy between track/cross country coaches and their significant others in the arena of competition to help alleviate the inherent stressors.

  20. 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

  1. A comparative study on the nanoparticles for improved drug delivery systems.

    Science.gov (United States)

    Mahmoodi, Nosrat O; Ghavidast, Atefeh; Amirmahani, Najmeh

    2016-09-01

    Nanoparticles have attracted considerable recent interest for diverse biomedical applications because of the unique properties of the nanomaterials. It is already known that one of the major advances in the relative application of nanoparticles is the recognition of the steric stabilization which can increase the particle stability in the biological environment and provide the opportunities of the application of nanoparticles in the development of drug delivery systems (DDSs) for achieving drug targeting and controlled drug release. To facilitate their use in such applications, the appropriate design of surface ligands on these nanoparticles is necessary. In view of these, functionalized nanoparticles through surface modification can be utilized to specifically interact with the target molecules on the cell membrane or intracellular ones. This review briefly presents self-assembled nanoparticles with molecules of therapeutic significance with two strategies. The first strategy attempts to improve the placement of the drugs using conjugating the appropriate ligands or adding targeting moieties to the DDS. The second strategy utilizes trigger-controlled drug-release, which restricts drug release at the targeted site to kill cancer cells by externally controlled mechanisms. Among external stimulations, conveniently light has attracted much interest because it, as an orthogonal external stimulus, gives spatiotemporal control of payload release. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. EMUDRA: Ensemble of Multiple Drug Repositioning Approaches to Improve Prediction Accuracy.

    Science.gov (United States)

    Zhou, Xianxiao; Wang, Minghui; Katsyv, Igor; Irie, Hanna; Zhang, Bin

    2018-04-24

    Availability of large-scale genomic, epigenetic and proteomic data in complex diseases makes it possible to objectively and comprehensively identify therapeutic targets that can lead to new therapies. The Connectivity Map has been widely used to explore novel indications of existing drugs. However, the prediction accuracy of the existing methods, such as Kolmogorov-Smirnov statistic remains low. Here we present a novel high-performance drug repositioning approach that improves over the state-of-the-art methods. We first designed an expression weighted cosine method (EWCos) to minimize the influence of the uninformative expression changes and then developed an ensemble approach termed EMUDRA (Ensemble of Multiple Drug Repositioning Approaches) to integrate EWCos and three existing state-of-the-art methods. EMUDRA significantly outperformed individual drug repositioning methods when applied to simulated and independent evaluation datasets. We predicted using EMUDRA and experimentally validated an antibiotic rifabutin as an inhibitor of cell growth in triple negative breast cancer. EMUDRA can identify drugs that more effectively target disease gene signatures and will thus be a useful tool for identifying novel therapies for complex diseases and predicting new indications for existing drugs. The EMUDRA R package is available at doi:10.7303/syn11510888. bin.zhang@mssm.edu or zhangb@hotmail.com. Supplementary data are available at Bioinformatics online.

  3. Clinically significant drug–drug interactions involving opioid analgesics used for pain treatment in patients with cancer: a systematic review

    Directory of Open Access Journals (Sweden)

    Kotlinska-Lemieszek A

    2015-09-01

    Full Text Available Aleksandra Kotlinska-Lemieszek,1 Pål Klepstad,2,3,6 Dagny Faksvåg Haugen2,4,5 1Palliative Medicine Chair and Department, University Hospital of the Lord’s Transfiguration, Karol Marcinkowski University of Medical Sciences, Poznan, Poland; 2European Palliative Care Research Centre, Faculty of Medicine, Norwegian University of Science and Technology,Trondheim, Norway; 3Department of Anaesthesiology and Intensive Care Medicine, St Olavs Hospital, Trondheim, Norway; 4Regional Centre of Excellence for Palliative Care, Haukeland University Hospital, Bergen, Norway; 5Department of Clinical Medicine K1, University of Bergen, Bergen, Norway; 6Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway Background: Opioids are the most frequently used drugs to treat pain in cancer patients. In some patients, however, opioids can cause adverse effects and drug–drug interactions. No advice concerning the combination of opioids and other drugs is given in the current European guidelines. Objective: To identify studies that report clinically significant drug–drug interactions involving opioids used for pain treatment in adult cancer patients. Design and data sources: Systematic review with searches in Embase, MEDLINE, and Cochrane Central Register of Controlled Trials from the start of the databases (Embase from 1980 through January 2014. In addition, reference lists of relevant full-text papers were hand-searched. Results: Of 901 retrieved papers, 112 were considered as potentially eligible. After full-text reading, 17 were included in the final analysis, together with 15 papers identified through hand-searching of reference lists. All of the 32 included publications were case reports or case series. Clinical manifestations of drug–drug interactions involving opioids were grouped as follows: 1 sedation and respiratory depression, 2 other central nervous system symptoms, 3 impairment of pain

  4. Rehearsal significantly improves immediate and delayed recall on the Rey Auditory Verbal Learning Test.

    Science.gov (United States)

    Hessen, Erik

    2011-10-01

    A repeated observation during memory assessment with the Rey Auditory Verbal Learning Test (RAVLT) is that patients who spontaneously employ a memory rehearsal strategy by repeating the word list more than once achieve better scores than patients who only repeat the word list once. This observation led to concern about the ability of the standard test procedure of RAVLT and similar tests in eliciting the best possible recall scores. The purpose of the present study was to test the hypothesis that a rehearsal recall strategy of repeating the word list more than once would result in improved scores of recall on the RAVLT. We report on differences in outcome after standard administration and after experimental administration on Immediate and Delayed Recall measures from the RAVLT of 50 patients. The experimental administration resulted in significantly improved scores for all the variables employed. Additionally, it was found that patients who failed effort screening showed significantly poorer improvement on Delayed Recall compared with those who passed the effort screening. The general clear improvement both in raw scores and T-scores demonstrates that recall performance can be significantly influenced by the strategy of the patient or by small variations in instructions by the examiner.

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

    Science.gov (United States)

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

    2016-01-01

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

  6. Reimbursed Price of Orphan Drugs: Current Strategies and Potential Improvements.

    Science.gov (United States)

    Mincarone, Pierpaolo; Leo, Carlo Giacomo; Sabina, Saverio; Sarriá-Santamera, Antonio; Taruscio, Domenica; Serrano-Aguilar, Pedro Guillermo; Kanavos, Panos

    2017-01-01

    The pricing and reimbursement policies for pharmaceuticals are relevant to balance timely and equitable access for all patients, financial sustainability, and reward for valuable innovation. The proliferation of high-cost specialty medicines is particularly true in rare diseases (RDs) where the pricing mechanism is characterised by a lack of transparency. This work provides an overall picture of current strategies for the definition of the reimbursed prices of orphan drugs (ODs) and highlights some potential improvements. Current strategies and suggestions are presented along 4 dimensions: (1) comprehensive value assessment, (2) early dialogs among relevant stakeholders, (3) innovative reimbursement approaches, and (4) societal participation in producing ODs. Comprehensive value assessment could be achieved by clarifying the approach of distributive justice to adopt, ensuring a representative participation of stakeholders, and with a broad consideration of value-bearing factors. With respect to early dialogs, cross-border cooperation can be determinant to companies and agencies. The cost-benefit ratio of early dialogs needs to be demonstrated and the "regulatory capture" effect should be monitored. Innovative reimbursement approaches were developed to balance the need for evidence-based decisions with the timely access to innovative drugs. The societal participation in producing ODs needs to be recognised in a collaborating framework where adaptive agreements can be developed with mutual satisfaction. Such agreements could also impact on coverage and reimbursement decisions as additional elements for the determination of a comprehensive societal value of ODs. Further research is needed to investigate the highlighted open challenges so that RDs will not remain, in practical terms, orphan diseases. © 2017 S. Karger AG, Basel.

  7. Mindfulness meditation improves emotion regulation and reduces drug abuse.

    Science.gov (United States)

    Tang, Yi-Yuan; Tang, Rongxiang; Posner, Michael I

    2016-06-01

    The core clinical symptoms of addiction include an enhanced incentive for drug taking (craving), impaired self-control (impulsivity and compulsivity), emotional dysregulation (negative mood) and increased stress reactivity. Symptoms related to impaired self-control involve reduced activity in anterior cingulate cortex (ACC), adjacent prefrontal cortex (mPFC) and other brain areas. Behavioral training such as mindfulness meditation can increase the function of control networks including those leading to improved emotion regulation and thus may be a promising approach for the treatment of addiction. In a series of randomized controlled trials (RCTs), we tested whether increased ACC/mPFC activity is related to better self-control abilities in executive functions, emotion regulation and stress response in healthy and addicted populations. After a brief mindfulness training (Integrative Body-Mind Training, IBMT), we used the Positive and Negative Affect Schedule (PANAS) and Profile of Mood States (POMS) to measure emotion regulation, salivary cortisol for the stress response and fMRI for brain functional and DTI structural changes. Relaxation training was used to serve as an active control. In both smokers and nonsmokers, improved self-control abilities in emotion regulation and stress reduction were found after training and these changes were related to increased ACC/mPFC activity following training. Compared with nonsmokers, smokers showed reduced ACC/mPFC activity in the self-control network before training, and these deficits were ameliorated after training. These results indicate that promoting emotion regulation and improving ACC/mPFC brain activity can help for addiction prevention and treatment. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

  8. Costello Syndrome with Severe Nodulocystic Acne: Unexpected Significant Improvement of Acanthosis Nigricans after Oral Isotretinoin Treatment

    Directory of Open Access Journals (Sweden)

    Leelawadee Sriboonnark

    2015-01-01

    Full Text Available We report the case of 17-year-old female diagnosed with Costello syndrome. Genetic testing provided a proof with G12S mutation in the HRAS gene since 3 years of age with a presentation of severe nodulocystic acne on her face. After 2 months of oral isotretinoin treatment, improvement in her acne was observed. Interestingly, an unexpected significant improvement of acanthosis nigricans on her neck and dorsum of her hands was found as well. We present this case as a successful treatment option by using oral isotretinoin for the treatment of acanthosis nigricans in Costello syndrome patients.

  9. Determination of significance in Ecological Impact Assessment: Past change, current practice and future improvements

    Energy Technology Data Exchange (ETDEWEB)

    Briggs, Sam; Hudson, Malcolm D., E-mail: mdh@soton.ac.uk

    2013-01-15

    Ecological Impact Assessment (EcIA) is an important tool for conservation and achieving sustainable development. 'Significant' impacts are those which disturb or alter the environment to a measurable degree. Significance is a crucial part of EcIA, our understanding of the concept in practice is vital if it is to be effective as a tool. This study employed three methods to assess how the determination of significance has changed through time, what current practice is, and what would lead to future improvements. Three data streams were collected: interviews with expert stakeholders, a review of 30 Environmental Statements and a broad-scale survey of the United Kingdom Institute of Ecology and Environmental Management (IEEM) members. The approach taken in the determination of significance has become more standardised and subjectivity has become constrained through a transparent framework. This has largely been driven by a set of guidelines produced by IEEM in 2006. The significance of impacts is now more clearly justified and the accuracy with which it is determined has improved. However, there are limitations to accuracy and effectiveness of the determination of significance. These are the quality of baseline survey data, our scientific understanding of ecological processes and the lack of monitoring and feedback of results. These in turn are restricted by the limited resources available in consultancies. The most notable recommendations for future practice are the implementation of monitoring and the publication of feedback, the creation of a central database for baseline survey data and the streamlining of guidance. - Highlights: Black-Right-Pointing-Pointer The assessment of significance has changed markedly through time. Black-Right-Pointing-Pointer The IEEM guidelines have driven a standardisation of practice. Black-Right-Pointing-Pointer Currently limited by quality of baseline data and scientific understanding. Black-Right-Pointing-Pointer Monitoring

  10. Histone deacetylase inhibitor significantly improved the cloning efficiency of porcine somatic cell nuclear transfer embryos.

    Science.gov (United States)

    Huang, Yongye; Tang, Xiaochun; Xie, Wanhua; Zhou, Yan; Li, Dong; Yao, Chaogang; Zhou, Yang; Zhu, Jianguo; Lai, Liangxue; Ouyang, Hongsheng; Pang, Daxin

    2011-12-01

    Valproic acid (VPA), a histone deacetylase inbibitor, has been shown to generate inducible pluripotent stem (iPS) cells from mouse and human fibroblasts with a significant higher efficiency. Because successful cloning by somatic cell nuclear transfer (SCNT) undergoes a full reprogramming process in which the epigenetic state of a differentiated donor nuclear is converted into an embryonic totipotent state, we speculated that VPA would be useful in promoting cloning efficiency. Therefore, in the present study, we examined whether VPA can promote the developmental competence of SCNT embryos by improving the reprogramming state of donor nucleus. Here we report that 1 mM VPA for 14 to 16 h following activation significantly increased the rate of blastocyst formation of porcine SCNT embryos constructed from Landrace fetal fibroblast cells compared to the control (31.8 vs. 11.4%). However, we found that the acetylation level of Histone H3 lysine 14 and Histone H4 lysine 5 and expression level of Oct4, Sox2, and Klf4 was not significantly changed between VPA-treated and -untreated groups at the blastocyst stage. The SCNT embryos were transferred to 38 surrogates, and the cloning efficiency in the treated group was significantly improved compared with the control group. Taken together, we have demonstrated that VPA can improve both in vitro and in vivo development competence of porcine SCNT embryos.

  11. Communication: Proper treatment of classically forbidden electronic transitions significantly improves detailed balance in surface hopping

    Energy Technology Data Exchange (ETDEWEB)

    Sifain, Andrew E. [Department of Physics and Astronomy, University of Southern California, Los Angeles, California 90089-0485 (United States); Wang, Linjun [Department of Chemistry, Zhejiang University, Hangzhou 310027 (China); Prezhdo, Oleg V. [Department of Physics and Astronomy, University of Southern California, Los Angeles, California 90089-0485 (United States); Department of Chemistry, University of Southern California, Los Angeles, California 90089-1062 (United States)

    2016-06-07

    Surface hopping is the most popular method for nonadiabatic molecular dynamics. Many have reported that it does not rigorously attain detailed balance at thermal equilibrium, but does so approximately. We show that convergence to the Boltzmann populations is significantly improved when the nuclear velocity is reversed after a classically forbidden hop. The proposed prescription significantly reduces the total number of classically forbidden hops encountered along a trajectory, suggesting that some randomization in nuclear velocity is needed when classically forbidden hops constitute a large fraction of attempted hops. Our results are verified computationally using two- and three-level quantum subsystems, coupled to a classical bath undergoing Langevin dynamics.

  12. The challenges of ESRD care in developing economies: sub-Saharan African opportunities for significant improvement.

    Science.gov (United States)

    Bamgboye, Ebun Ladipo

    Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in sub-Saharan Africa. This, along with other noncommunicable diseases like hypertension, diabetes, and heart diseases, poses a double burden on a region that is still struggling to cope with the scourge of communicable diseases like malaria, tuberculosis, HIV, and more recently Ebola. Causes of CKD in the region are predominantly glomerulonephritis and hypertension, although type 2 diabetes is also becoming a significant cause as is the retroviral disease. Patients are generally younger than in the developed world, and there is a significant male preponderance. Most patients are managed by hemodialysis, with peritoneal dialysis and kidney transplantation being available in only few countries in the region. Government funding and support for dialysis is often unavailable, and when available, often with restrictions. There is a dearth of trained manpower to treat the disease, and many countries have a limited number of units, which are often ill-equipped to deal adequately with the number of patients who require end-stage renal disease (ESRD) care in the region. Although there has been a significant improvement when compared with the situation, even as recently as 10 years ago, there is also the potential for further improvement, which would significantly improve the outcomes in patients with ESRD in the region. The information in this review was obtained from a combination of renal registry reports (published and unpublished), published articles, responses to a questionnaire sent to nephrologists prior to the World Congress of Nephrology (WCN) in Cape Town, and from nephrologists attending the WCN in Cape Town (March 13 - 17, 2015).

  13. Survival prediction algorithms miss significant opportunities for improvement if used for case selection in trauma quality improvement programs.

    Science.gov (United States)

    Heim, Catherine; Cole, Elaine; West, Anita; Tai, Nigel; Brohi, Karim

    2016-09-01

    Quality improvement (QI) programs have shown to reduce preventable mortality in trauma care. Detailed review of all trauma deaths is a time and resource consuming process and calculated probability of survival (Ps) has been proposed as audit filter. Review is limited on deaths that were 'expected to survive'. However no Ps-based algorithm has been validated and no study has examined elements of preventability associated with deaths classified as 'expected'. The objective of this study was to examine whether trauma performance review can be streamlined using existing mortality prediction tools without missing important areas for improvement. We conducted a retrospective study of all trauma deaths reviewed by our trauma QI program. Deaths were classified into non-preventable, possibly preventable, probably preventable or preventable. Opportunities for improvement (OPIs) involve failure in the process of care and were classified into clinical and system deviations from standards of care. TRISS and PS were used for calculation of probability of survival. Peer-review charts were reviewed by a single investigator. Over 8 years, 626 patients were included. One third showed elements of preventability and 4% were preventable. Preventability occurred across the entire range of the calculated Ps band. Limiting review to unexpected deaths would have missed over 50% of all preventability issues and a third of preventable deaths. 37% of patients showed opportunities for improvement (OPIs). Neither TRISS nor PS allowed for reliable identification of OPIs and limiting peer-review to patients with unexpected deaths would have missed close to 60% of all issues in care. TRISS and PS fail to identify a significant proportion of avoidable deaths and miss important opportunities for process and system improvement. Based on this, all trauma deaths should be subjected to expert panel review in order to aim at a maximal output of performance improvement programs. Copyright © 2016 Elsevier

  14. Nanomedicine for improved efficacy of tuberculosis drugs – Pharmacokinetic importance

    CSIR Research Space (South Africa)

    Hayeshi, R

    2012-10-01

    Full Text Available Efficacy of Tuberculosis Drugs ? Pharmacokinetic importance Emerging Researcher Symposium Dr. Rose Hayeshi 10 October 2012 Outline ? Challenges in TB treatment ? Nanomedicine as proposed solution ? Results ? Conclusions ? CSIR 2012 Slide 2... ? 1 x 106 cfu/lung 3 x 103 cfu/spleen Effects of the Nanodrug on Mycobacaterium tuberculosis replication ? Nanodrug once a week vs conventional drug daily ? Treatment with nanoencapsulated TB drugs once a week, comparable to daily treatment...

  15. Inulin significantly improves serum magnesium levels in proton pump inhibitor-induced hypomagnesaemia.

    Science.gov (United States)

    Hess, M W; de Baaij, J H F; Broekman, M; Bisseling, T M; Haarhuis, B; Tan, A; Te Morsche, R; Hoenderop, J G J; Bindels, R J M; Drenth, J P H

    2016-06-01

    Proton pump inhibitors (PPI) are among the most widely prescribed drugs to treat gastric acid-related disorders. PPI-induced hypomagnesaemia, a defect in intestinal absorption of Mg(2+) , can be a severe side effect of chronic PPI use. To restore serum Mg(2+) concentrations in PPI-induced hypomagnesaemia patients by dietary supplementation with inulin fibres. Eleven patients with PPI-induced hypomagnesaemia and 10 controls were treated with inulin (20 g/day). Each trial consisted of two cycles of 14-day inulin treatment followed by a washout period of 14 days. Patients continued to use their PPI. Serum Mg(2+) levels served as the primary endpoint. Inulin significantly enhanced serum Mg(2+) levels from 0.60 to 0.68 mmol/L in PPI-induced hypomagnesaemia patients, and from 0.84 to 0.93 mmol/L in controls. As a consequence 24 h urinary Mg(2+) excretion was significantly increased in patients with PPI-induced hypomagnesaemia (0.3-2.2 mmol/day). Symptoms related to hypomagnesaemia, including muscle cramps and paraesthesia, were reduced during intervention with inulin. Inulin increases serum Mg(2+) concentrations under PPI maintenance in patients with PPI-induced hypomagnesaemia. © 2016 John Wiley & Sons Ltd.

  16. Hybrid Mesoporous Silica-Based Drug Carrier Nanostructures with Improved Degradability by Hydroxyapatite.

    Science.gov (United States)

    Hao, Xiaohong; Hu, Xixue; Zhang, Cuimiao; Chen, Shizhu; Li, Zhenhua; Yang, Xinjian; Liu, Huifang; Jia, Guang; Liu, Dandan; Ge, Kun; Liang, Xing-Jie; Zhang, Jinchao

    2015-10-27

    Potential bioaccumulation is one of the biggest limitations for silica nanodrug delivery systems in cancer therapy. In this study, a mesoporous silica nanoparticles/hydroxyapatite (MSNs/HAP) hybrid drug carrier, which enhanced the biodegradability of silica, was developed by a one-step method. The morphology and structure of the nanoparticles were characterized by TEM, DLS, FT-IR, XRD, N2 adsorption-desorption isotherms, and XPS, and the drug loading and release behaviors were tested. TEM and ICP-OES results indicate that the degradability of the nanoparticles has been significantly improved by Ca(2+) escape from the skeleton in an acid environment. The MSNs/HAP sample exhibits a higher drug loading content of about 5 times that of MSNs. The biological experiment results show that the MSNs/HAP not only exhibits good biocompatibility and antitumor effect but also greatly reduces the side effects of free DOX. The as-synthesized hybrid nanoparticles may act as a promising drug delivery system due to their good biocompatibility, high drug loading efficiency, pH sensitivity, and excellent biodegradability.

  17. PXD101 significantly improves nuclear reprogramming and the in vitro developmental competence of porcine SCNT embryos

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Jun-Xue; Kang, Jin-Dan; Li, Suo; Jin, Long; Zhu, Hai-Ying; Guo, Qing; Gao, Qing-Shan; Yan, Chang-Guo; Yin, Xi-Jun, E-mail: yinxj33@msn.com

    2015-01-02

    Highlights: • First explored that the effects of PXD101 on the development of SCNT embryos in vitro. • 0.5 μM PXD101 treated for 24 h improved the development of porcine SCNT embryos. • Level of AcH3K9 was significantly higher than control group at early stages. - Abstract: In this study, we investigated the effects of the histone deacetylase inhibitor PXD101 (belinostat) on the preimplantation development of porcine somatic cell nuclear transfer (SCNT) embryos and their expression of the epigenetic markers histone H3 acetylated at lysine 9 (AcH3K9). We compared the in vitro developmental competence of SCNT embryos treated with various concentrations of PXD101 for 24 h. Treatment with 0.5 μM PXD101 significantly increased the proportion of SCNT embryos that reached the blastocyst stage, in comparison to the control group (23.3% vs. 11.5%, P < 0.05). We tested the in vitro developmental competence of SCNT embryos treated with 0.5 μM PXD101 for various amounts of times following activation. Treatment for 24 h significantly improved the development of porcine SCNT embryos, with a significantly higher proportion of embryos reaching the blastocyst stage in comparison to the control group (25.7% vs. 10.6%, P < 0.05). PXD101-treated SCNT embryos were transferred into two surrogate sows, one of whom became pregnant and four fetuses developed. PXD101 treatment significantly increased the fluorescence intensity of immunostaining for AcH3K9 in embryos at the pseudo-pronuclear and 2-cell stages. At these stages, the fluorescence intensities of immunostaining for AcH3K9 were significantly higher in PXD101-treated embryos than in control untreated embryos. In conclusion, this study demonstrates that PXD101 can significantly improve the in vitro and in vivo developmental competence of porcine SCNT embryos and can enhance their nuclear reprogramming.

  18. Unified Health Gamification can significantly improve well-being in corporate environments.

    Science.gov (United States)

    Shahrestani, Arash; Van Gorp, Pieter; Le Blanc, Pascale; Greidanus, Fabrizio; de Groot, Kristel; Leermakers, Jelle

    2017-07-01

    There is a multitude of mHealth applications that aim to solve societal health problems by stimulating specific types of physical activities via gamification. However, physical health activities cover just one of the three World Health Organization (WHO) dimensions of health. This paper introduces the novel notion of Unified Health Gamification (UHG), which covers besides physical health also social and cognitive health and well-being. Instead of rewarding activities in the three WHO dimensions using different mHealth competitions, UHG combines the scores for such activities on unified leaderboards and lets people interact in social circles beyond personal interests. This approach is promising in corporate environments since UHG can connect the employees with intrinsic motivation for physical health with those who have quite different interests. In order to evaluate this approach, we realized an app prototype and we evaluated it in two corporate pilot studies. In total, eighteen pilot users participated voluntarily for six weeks. Half of the participants were recruited from an occupational health setting and the other half from a treatment setting. Our results suggest that the UHG principles are worth more investigation: various positive health effects were found based on a validated survey. The mean mental health improved significantly at one pilot location and at the level of individual pilot participants, multiple other effects were found to be significant: among others, significant mental health improvements were found for 28% of the participants. Most participants intended to use the app beyond the pilot, especially if it would be further developed.

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

    Directory of Open Access Journals (Sweden)

    Ke ZC

    2016-06-01

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

  20. Herb-drug interactions: challenges and opportunities for improved predictions.

    Science.gov (United States)

    Brantley, Scott J; Argikar, Aneesh A; Lin, Yvonne S; Nagar, Swati; Paine, Mary F

    2014-03-01

    Supported by a usage history that predates written records and the perception that "natural" ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb-drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb-drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb-drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb-drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens.

  1. Herb–Drug Interactions: Challenges and Opportunities for Improved Predictions

    Science.gov (United States)

    Brantley, Scott J.; Argikar, Aneesh A.; Lin, Yvonne S.; Nagar, Swati

    2014-01-01

    Supported by a usage history that predates written records and the perception that “natural” ensures safety, herbal products have increasingly been incorporated into Western health care. Consumers often self-administer these products concomitantly with conventional medications without informing their health care provider(s). Such herb–drug combinations can produce untoward effects when the herbal product perturbs the activity of drug metabolizing enzymes and/or transporters. Despite increasing recognition of these types of herb–drug interactions, a standard system for interaction prediction and evaluation is nonexistent. Consequently, the mechanisms underlying herb–drug interactions remain an understudied area of pharmacotherapy. Evaluation of herbal product interaction liability is challenging due to variability in herbal product composition, uncertainty of the causative constituents, and often scant knowledge of causative constituent pharmacokinetics. These limitations are confounded further by the varying perspectives concerning herbal product regulation. Systematic evaluation of herbal product drug interaction liability, as is routine for new drugs under development, necessitates identifying individual constituents from herbal products and characterizing the interaction potential of such constituents. Integration of this information into in silico models that estimate the pharmacokinetics of individual constituents should facilitate prospective identification of herb–drug interactions. These concepts are highlighted with the exemplar herbal products milk thistle and resveratrol. Implementation of this methodology should help provide definitive information to both consumers and clinicians about the risk of adding herbal products to conventional pharmacotherapeutic regimens. PMID:24335390

  2. Ethanol-drug absorption interaction: potential for a significant effect on the plasma pharmacokinetics of ethanol vulnerable formulations.

    Science.gov (United States)

    Lennernäs, Hans

    2009-01-01

    Generally, gastric emptying of a drug to the small intestine is controlled by gastric motor activity and is the main factor affecting the onset of absorption. Accordingly, the emptying rate from the stomach is mainly affected by the digestive state, the properties of the pharmaceutical formulation and the effect of drugs, posture and circadian rhythm. Variability in the gastric emptying of drugs is reflected in variability in the absorption rate and the shape of the plasma pharmacokinetic profile. When ethanol interacts with an oral controlled release product, such that the mechanism controlling drug release is impaired, the delivery of the dissolved dose into the small intestine and the consequent absorption may result in dangerously high plasma concentrations. For example, the maximal plasma concentration of hydromorphone has individually been shown to be increased as much as 16 times through in vivo testing as a result of this specific pharmacokinetic ethanol-drug formulation interaction. Thus, a pharmacokinetic ethanol-drug interaction is a very serious safety concern when substantially the entire dose from a controlled release product is rapidly emptied into the small intestine (dose dumping), having been largely dissolved in a strong alcoholic beverage in the stomach during a sufficient lag-time in gastric emptying. Based on the literature, a two hour time frame for screening the in vitro dissolution profile of a controlled release product in ethanol concentrations of up to 40% is strongly supported and may be considered as the absolute minimum standard. It is also evident that the dilution, absorption and metabolism of ethanol in the stomach are processes with a minor effect on the local ethanol concentration and that ethanol exposure will be highly dependent on the volume and ethanol concentration of the fluid ingested, together with the rate of intake and gastric emptying. When and in which patients a clinically significant dose dumping will happen is

  3. Thermosensitive Hydrogel Mask Significantly Improves Skin Moisture and Skin Tone; Bilateral Clinical Trial

    Directory of Open Access Journals (Sweden)

    Anna Quattrone

    2017-06-01

    Full Text Available Objective: A temperature-sensitive state-changing hydrogel mask was used in this study. Once it comes into contact with the skin and reaches the body temperature, it uniformly and quickly releases the active compounds, which possess moisturizing, anti-oxidant, anti-inflammatory and regenerative properties. Methods: An open label clinical trial was conducted to evaluate the effects of the test product on skin hydration, skin tone and skin ageing. Subjects applied the product to one side of their face and underwent Corneometer® and Chromameter measurements, Visual assessment of facial skin ageing and facial photography. All assessments and Self-Perception Questionnaires (SPQ were performed at baseline, after the first application of the test product and after four applications. Results: After a single treatment we observed an increase in skin moisturisation, an improvement of skin tone/luminosity and a reduction in signs of ageing, all statistically significant. After four applications a further improvement in all measured parameters was recorded. These results were confirmed by the subjects’ own perceptions, as reported in the SPQ both after one and four applications. Conclusion: The hydrogel mask tested in this study is very effective in improving skin hydration, skin radiance and luminosity, in encouraging an even skin tone and in reducing skin pigmentation.

  4. E2F5 status significantly improves malignancy diagnosis of epithelial ovarian cancer

    KAUST Repository

    Kothandaraman, Narasimhan

    2010-02-24

    Background: Ovarian epithelial cancer (OEC) usually presents in the later stages of the disease. Factors, especially those associated with cell-cycle genes, affecting the genesis and tumour progression for ovarian cancer are largely unknown. We hypothesized that over-expressed transcription factors (TFs), as well as those that are driving the expression of the OEC over-expressed genes, could be the key for OEC genesis and potentially useful tissue and serum markers for malignancy associated with OEC.Methods: Using a combination of computational (selection of candidate TF markers and malignancy prediction) and experimental approaches (tissue microarray and western blotting on patient samples) we identified and evaluated E2F5 transcription factor involved in cell proliferation, as a promising candidate regulatory target in early stage disease. Our hypothesis was supported by our tissue array experiments that showed E2F5 expression only in OEC samples but not in normal and benign tissues, and by significantly positively biased expression in serum samples done using western blotting studies.Results: Analysis of clinical cases shows that of the E2F5 status is characteristic for a different population group than one covered by CA125, a conventional OEC biomarker. E2F5 used in different combinations with CA125 for distinguishing malignant cyst from benign cyst shows that the presence of CA125 or E2F5 increases sensitivity of OEC detection to 97.9% (an increase from 87.5% if only CA125 is used) and, more importantly, the presence of both CA125 and E2F5 increases specificity of OEC to 72.5% (an increase from 55% if only CA125 is used). This significantly improved accuracy suggests possibility of an improved diagnostics of OEC. Furthermore, detection of malignancy status in 86 cases (38 benign, 48 early and late OEC) shows that the use of E2F5 status in combination with other clinical characteristics allows for an improved detection of malignant cases with sensitivity

  5. Significance of MPEG-7 textural features for improved mass detection in mammography.

    Science.gov (United States)

    Eltonsy, Nevine H; Tourassi, Georgia D; Fadeev, Aleksey; Elmaghraby, Adel S

    2006-01-01

    The purpose of the study is to investigate the significance of MPEG-7 textural features for improving the detection of masses in screening mammograms. The detection scheme was originally based on morphological directional neighborhood features extracted from mammographic regions of interest (ROIs). Receiver Operating Characteristics (ROC) was performed to evaluate the performance of each set of features independently and merged into a back-propagation artificial neural network (BPANN) using the leave-one-out sampling scheme (LOOSS). The study was based on a database of 668 mammographic ROIs (340 depicting cancer regions and 328 depicting normal parenchyma). Overall, the ROC area index of the BPANN using the directional morphological features was Az=0.85+/-0.01. The MPEG-7 edge histogram descriptor-based BPNN showed an ROC area index of Az=0.71+/-0.01 while homogeneous textural descriptors using 30 and 120 channels helped the BPNN achieve similar ROC area indexes of Az=0.882+/-0.02 and Az=0.877+/-0.01 respectively. After merging the MPEG-7 homogeneous textural features with the directional neighborhood features the performance of the BPANN increased providing an ROC area index of Az=0.91+/-0.01. MPEG-7 homogeneous textural descriptor significantly improved the morphology-based detection scheme.

  6. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma.

    Science.gov (United States)

    Avet-Loiseau, Hervé; Fonseca, Rafael; Siegel, David; Dimopoulos, Meletios A; Špička, Ivan; Masszi, Tamás; Hájek, Roman; Rosiñol, Laura; Goranova-Marinova, Vesselina; Mihaylov, Georgi; Maisnar, Vladimír; Mateos, Maria-Victoria; Wang, Michael; Niesvizky, Ruben; Oriol, Albert; Jakubowiak, Andrzej; Minarik, Jiri; Palumbo, Antonio; Bensinger, William; Kukreti, Vishal; Ben-Yehuda, Dina; Stewart, A Keith; Obreja, Mihaela; Moreau, Philippe

    2016-09-01

    The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391. © 2016 by The American Society of Hematology.

  7. Bone Mass and Strength are Significantly Improved in Mice Overexpressing Human WNT16 in Osteocytes.

    Science.gov (United States)

    Alam, Imranul; Reilly, Austin M; Alkhouli, Mohammed; Gerard-O'Riley, Rita L; Kasipathi, Charishma; Oakes, Dana K; Wright, Weston B; Acton, Dena; McQueen, Amie K; Patel, Bhavmik; Lim, Kyung-Eun; Robling, Alexander G; Econs, Michael J

    2017-04-01

    Recently, we demonstrated that osteoblast-specific overexpression of human WNT16 increased both cortical and trabecular bone mass and structure in mice. To further identify the cell-specific role of Wnt16 in bone homeostasis, we created transgenic (TG) mice overexpressing human WNT16 in osteocytes using Dmp1 promoter (Dmp1-hWNT16 TG) on C57BL/6 (B6) background. We analyzed bone phenotypes and serum bone biomarkers, performed gene expression analysis and measured dynamic bone histomorphometry in Dmp1-hWNT16 TG and wild-type (WT) mice. Compared to WT mice, Dmp1-hWNT16 TG mice exhibited significantly higher whole-body, spine and femoral aBMD, BMC and trabecular (BV/TV, Tb.N, and Tb.Th) and cortical (bone area and thickness) parameters in both male and female at 12 weeks of age. Femur stiffness and ultimate force were also significantly improved in the Dmp1-hWNT16 TG female mice, compared to sex-matched WT littermates. In addition, female Dmp1-hWNT16 TG mice displayed significantly higher MS/BS, MAR and BFR/BS compared to the WT mice. Gene expression analysis demonstrated significantly higher mRNA level of Alp in both male and female Dmp1-hWNT16 TG mice and significantly higher levels of Osteocalcin, Opg and Rankl in the male Dmp1-hWNT16 TG mice in bone tissue compared to sex-matched WT mice. These results indicate that WNT16 plays a critical role for acquisition of both cortical and trabecular bone mass and strength. Strategies designed to use WNT16 as a target for therapeutic interventions will be valuable to treat osteoporosis and other low bone mass conditions.

  8. Radiotherapy is associated with significant improvement in local and regional control in Merkel cell carcinoma

    International Nuclear Information System (INIS)

    Kang, Susan H; Haydu, Lauren E; Goh, Robin Yeong Hong; Fogarty, Gerald B

    2012-01-01

    Merkel cell carcinoma (MCC) is a rare tumour of skin. This study is a retrospective audit of patients with MCC from St Vincent’s and Mater Hospital, Sydney, Australia. The aim of this study was to investigate the influence of radiotherapy (RT) on the local and regional control of MCC lesions and survival of patients with MCC. The data bases in anatomical pathology, RT and surgery. We searched for patients having a diagnosis of MCC between 1996 and 2007. Patient, tumour and treatment characteristics were collected and analysed. Univariate survival analysis of categorical variables was conducted with the Kaplan-Meier method together with the Log-Rank test for statistical significance. Continuous variables were assessed using the Cox regression method. Multivariate analysis was performed for significant univariate results. Sixty seven patients were found. Sixty two who were stage I-III and were treated with radical intent were analysed. 68% were male. The median age was 74 years. Forty-two cases (68%) were stage I or II, and 20 cases (32%) were stage III. For the subset of 42 stage I and II patients, those that had RT to their primary site had a 2-year local recurrence free survival of 89% compared with 36% for patients not receiving RT (p<0.001). The cumulative 2-year regional recurrence free survival for patients having adjuvant regional RT was 84% compared with 43% for patients not receiving this treatment (p<0.001). Immune status at initial surgery was a significant predictor for OS and MCCSS. In a multivariate analysis combining macroscopic size (mm) and immune status at initial surgery, only immune status remained a significant predictor of overall survival (HR=2.096, 95% CI: 1.002-4.385, p=0.049). RT is associated with significant improvement in local and regional control in Merkel cell carcinoma. Immunosuppression is an important factor in overall survival

  9. Integration of biomimicry and nanotechnology for significantly improved detection of circulating tumor cells (CTCs).

    Science.gov (United States)

    Myung, Ja Hye; Park, Sin-Jung; Wang, Andrew Z; Hong, Seungpyo

    2017-12-13

    Circulating tumor cells (CTCs) have received a great deal of scientific and clinical attention as a biomarker for diagnosis and prognosis of many types of cancer. Given their potential significance in clinics, a variety of detection methods, utilizing the recent advances in nanotechnology and microfluidics, have been introduced in an effort of achieving clinically significant detection of CTCs. However, effective detection and isolation of CTCs still remain a tremendous challenge due to their extreme rarity and phenotypic heterogeneity. Among many approaches that are currently under development, this review paper focuses on a unique, promising approach that takes advantages of naturally occurring processes achievable through application of nanotechnology to realize significant improvement in sensitivity and specificity of CTC capture. We provide an overview of successful outcome of this biomimetic CTC capture system in detection of tumor cells from in vitro, in vivo, and clinical pilot studies. We also emphasize the clinical impact of CTCs as biomarkers in cancer diagnosis and predictive prognosis, which provides a cost-effective, minimally invasive method that potentially replaces or supplements existing methods such as imaging technologies and solid tissue biopsy. In addition, their potential prognostic values as treatment guidelines and that ultimately help to realize personalized therapy are discussed. Copyright © 2017. Published by Elsevier B.V.

  10. 78 FR 8446 - Center for Drug Evaluation and Research; Prescription Drug Labeling Improvement and Enhancement...

    Science.gov (United States)

    2013-02-06

    ... utility of the prescription drug labeling as a communication tool and to discuss strategies for making it... the Web site after this document publishes in the Federal Register.) All holders of marketing... before June 30, 2001, and for generic drugs. The initiative is anticipated to take place over several...

  11. Functionally engineered nanosized particles in pharmaceutics: improved oral delivery of poorly water-soluble drugs.

    Science.gov (United States)

    Ozeki, Tetsuya; Tagami, Tatsuaki

    2013-01-01

    The development of drug nanoparticles has attracted substantial attention because of their potential to improve the dissolution rate and oral availability of poorly water-soluble drugs. This review summarizes the recent articles that discussed nanoparticle-based oral drug delivery systems. The preparation methods were categorized as top-down and bottom-up methods, which are common methods for preparing drug nanoparticles. In addition, methods of handling drug nanoparticles (e.g., one-step preparation of nanocomposites which are microparticles containing drug nanoparticles) were introduced for the effective preservation of drug nanoparticles. The carrier-based preparation of drug nanoparticles was also introduced as a potentially promising oral drug delivery system.

  12. Significant Improvement of Organic Thin-Film Transistor Mobility Utilizing an Organic Heterojunction Buffer Layer

    International Nuclear Information System (INIS)

    Pan Feng; Qian Xian-Rui; Huang Li-Zhen; Wang Hai-Bo; Yan Dong-Hang

    2011-01-01

    High-mobility vanadyl phthalocyanine (VOPc)/5,5‴-bis(4-fluorophenyl)-2,2':5',2″:5″,2‴-quaterthiophene (F2-P4T) thin-film transistors are demonstrated by employing a copper hexadecafluorophthalocyanine (F 16 CuPc)/copper phthalocyanine (CuPc) heterojunction unit, which are fabricated at different substrate temperatures, as a buffer layer. The highest mobility of 4.08cm 2 /Vs is achieved using a F 16 CuPc/CuPc organic heterojunction buffer layer fabricated at high substrate temperature. Compared with the random small grain-like morphology of the room-temperature buffer layer, the high-temperature organic heterojunction presents a large-sized fiber-like film morphology, resulting in an enhanced conductivity. Thus the contact resistance of the transistor is significantly reduced and an obvious improvement in device mobility is obtained. (cross-disciplinary physics and related areas of science and technology)

  13. Significant improvement of optical traps by tuning standard water immersion objectives

    International Nuclear Information System (INIS)

    Reihani, S Nader S; Mir, Shahid A; Richardson, Andrew C; Oddershede, Lene B

    2011-01-01

    Focused infrared lasers are widely used for micromanipulation and visualization of biological specimens. An inherent practical problem is that off-the-shelf commercial microscope objectives are designed for use with visible and not infrared wavelengths. Less aberration is introduced by water immersion objectives than by oil immersion ones, however, even water immersion objectives induce significant aberration. We present a simple method to reduce the spherical aberration induced by water immersion objectives, namely by tuning the correction collar of the objective to a value that is ∼ 10% lower than the physical thickness of the coverslip. This results in marked improvements in optical trapping strengths of up to 100% laterally and 600% axially from a standard microscope objective designed for use in the visible range. The results are generally valid for any water immersion objective with any numerical aperture

  14. Significant improvement in the electrical characteristics of Schottky barrier diodes on molecularly modified Gallium Nitride surfaces

    Science.gov (United States)

    Garg, Manjari; Naik, Tejas R.; Pathak, C. S.; Nagarajan, S.; Rao, V. Ramgopal; Singh, R.

    2018-04-01

    III-Nitride semiconductors face the issue of localized surface states, which causes fermi level pinning and large leakage current at the metal semiconductor interface, thereby degrading the device performance. In this work, we have demonstrated the use of a Self-Assembled Monolayer (SAM) of organic molecules to improve the electrical characteristics of Schottky barrier diodes (SBDs) on n-type Gallium Nitride (n-GaN) epitaxial films. The electrical characteristics of diodes were improved by adsorption of SAM of hydroxyl-phenyl metallated porphyrin organic molecules (Zn-TPPOH) onto the surface of n-GaN. SAM-semiconductor bonding via native oxide on the n-GaN surface was confirmed using X-ray photoelectron spectroscopy measurements. Surface morphology and surface electronic properties were characterized using atomic force microscopy and Kelvin probe force microscopy. Current-voltage characteristics of different metal (Cu, Ni) SBDs on bare n-GaN were compared with those of Cu/Zn-TPPOH/n-GaN and Ni/Zn-TPPOH/n-GaN SBDs. It was found that due to the molecular monolayer, the surface potential of n-GaN was decreased by ˜350 mV. This caused an increase in the Schottky barrier height of Cu and Ni SBDs from 1.13 eV to 1.38 eV and 1.07 eV to 1.22 eV, respectively. In addition to this, the reverse bias leakage current was reduced by 3-4 orders of magnitude for both Cu and Ni SBDs. Such a significant improvement in the electrical performance of the diodes can be very useful for better device functioning.

  15. pEPito: a significantly improved non-viral episomal expression vector for mammalian cells

    Directory of Open Access Journals (Sweden)

    Ogris Manfred

    2010-03-01

    Full Text Available Abstract Background The episomal replication of the prototype vector pEPI-1 depends on a transcription unit starting from the constitutively expressed Cytomegalovirus immediate early promoter (CMV-IEP and directed into a 2000 bp long matrix attachment region sequence (MARS derived from the human β-interferon gene. The original pEPI-1 vector contains two mammalian transcription units and a total of 305 CpG islands, which are located predominantly within the vector elements necessary for bacterial propagation and known to be counterproductive for persistent long-term transgene expression. Results Here, we report the development of a novel vector pEPito, which is derived from the pEPI-1 plasmid replicon but has considerably improved efficacy both in vitro and in vivo. The pEPito vector is significantly reduced in size, contains only one transcription unit and 60% less CpG motives in comparison to pEPI-1. It exhibits major advantages compared to the original pEPI-1 plasmid, including higher transgene expression levels and increased colony-forming efficiencies in vitro, as well as more persistent transgene expression profiles in vivo. The performance of pEPito-based vectors was further improved by replacing the CMV-IEP with the human CMV enhancer/human elongation factor 1 alpha promoter (hCMV/EF1P element that is known to be less affected by epigenetic silencing events. Conclusions The novel vector pEPito can be considered suitable as an improved vector for biotechnological applications in vitro and for non-viral gene delivery in vivo.

  16. Electronic monitoring in combination with direct observation as a means to significantly improve hand hygiene compliance.

    Science.gov (United States)

    Boyce, John M

    2017-05-01

    Monitoring hand hygiene compliance among health care personnel (HCP) is an essential element of hand hygiene promotion programs. Observation by trained auditors is considered the gold standard method for establishing hand hygiene compliance rates. Advantages of observational surveys include the unique ability to establish compliance with all of the World Health Organization "My 5 Moments for Hand Hygiene" initiative Moments and to provide just-in-time coaching. Disadvantages include the resources required for observational surveys, insufficient sample sizes, and nonstandardized methods of conducting observations. Electronic and camera-based systems can monitor hand hygiene performance on all work shifts without a Hawthorne effect and provide significantly more data regarding hand hygiene performance. Disadvantages include the cost of installation, variable accuracy in estimating compliance rates, issues related to acceptance by HCP, insufficient data regarding their cost-effectiveness and influence on health care-related infection rates, and the ability of most systems to monitor only surrogates for Moments 1, 4, and 5. Increasing evidence suggests that monitoring only Moments 1, 4, and 5 provides reasonable estimates of compliance with all 5 Moments. With continued improvement of electronic monitoring systems, combining electronic monitoring with observational methods may provide the best information as part of a multimodal strategy to improve and sustain hand hygiene compliance rates among HCP. Copyright © 2017 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.

  17. An On-Chip RBC Deformability Checker Significantly Improves Velocity-Deformation Correlation

    Directory of Open Access Journals (Sweden)

    Chia-Hung Dylan Tsai

    2016-10-01

    Full Text Available An on-chip deformability checker is proposed to improve the velocity–deformation correlation for red blood cell (RBC evaluation. RBC deformability has been found related to human diseases, and can be evaluated based on RBC velocity through a microfluidic constriction as in conventional approaches. The correlation between transit velocity and amount of deformation provides statistical information of RBC deformability. However, such correlations are usually only moderate, or even weak, in practical evaluations due to limited range of RBC deformation. To solve this issue, we implemented three constrictions of different width in the proposed checker, so that three different deformation regions can be applied to RBCs. By considering cell responses from the three regions as a whole, we practically extend the range of cell deformation in the evaluation, and could resolve the issue about the limited range of RBC deformation. RBCs from five volunteer subjects were tested using the proposed checker. The results show that the correlation between cell deformation and transit velocity is significantly improved by the proposed deformability checker. The absolute values of the correlation coefficients are increased from an average of 0.54 to 0.92. The effects of cell size, shape and orientation to the evaluation are discussed according to the experimental results. The proposed checker is expected to be useful for RBC evaluation in medical practices.

  18. Fabrication of CoZn alloy nanowire arrays: Significant improvement in magnetic properties by annealing process

    International Nuclear Information System (INIS)

    Koohbor, M.; Soltanian, S.; Najafi, M.; Servati, P.

    2012-01-01

    Highlights: ► Increasing the Zn concentration changes the structure of NWs from hcp to amorphous. ► Increasing the Zn concentration significantly reduces the Hc value of NWs. ► Magnetic properties of CoZn NWs can be significantly enhanced by appropriate annealing. ► The pH of electrolyte has no significant effect on the properties of the NW arrays. ► Deposition frequency has considerable effects on the magnetic properties of NWs. - Abstract: Highly ordered arrays of Co 1−x Zn x (0 ≤ x ≤ 0.74) nanowires (NWs) with diameters of ∼35 nm and high length-to-diameter ratios (up to 150) were fabricated by co-electrodeposition of Co and Zn into pores of anodized aluminum oxide (AAO) templates. The Co and Zn contents of the NWs were adjusted by varying the ratio of Zn and Co ion concentrations in the electrolyte. The effect of the Zn content, electrodeposition conditions (frequency and pH) and annealing on the structural and magnetic properties (e.g., coercivity (Hc) and squareness (Sq)) of NW arrays were investigated using X-ray diffraction (XRD), scanning electron microscopy, electron diffraction, and alternating gradient force magnetometer (AGFM). XRD patterns reveal that an increase in the concentration of Zn ions of the electrolyte forces the hcp crystal structure of Co NWs to change into an amorphous phase, resulting in a significant reduction in Hc. It was found that the magnetic properties of NWs can be significantly improved by appropriate annealing process. The highest values for Hc (2050 Oe) and Sq (0.98) were obtained for NWs electrodeposited using 0.95/0.05 Co:Zn concentrations at 200 Hz and annealed at 575 °C. While the pH of electrolyte is found to have no significant effect on the structural and magnetic properties of the NW arrays, the electrodeposition frequency has considerable effects on the magnetic properties of the NW arrays. The changes in magnetic property of NWs are rooted in a competition between shape anisotropy and

  19. Fabrication of CoZn alloy nanowire arrays: Significant improvement in magnetic properties by annealing process

    Energy Technology Data Exchange (ETDEWEB)

    Koohbor, M. [Department of Physics, University of Kurdistan, Sanandaj (Iran, Islamic Republic of); Soltanian, S., E-mail: s.soltanian@gmail.com [Department of Physics, University of Kurdistan, Sanandaj (Iran, Islamic Republic of); Department of Electrical and Computer Engineering, University of British Columbia, Vancouver (Canada); Najafi, M. [Department of Physics, University of Kurdistan, Sanandaj (Iran, Islamic Republic of); Department of Physics, Hamadan University of Technology, Hamadan (Iran, Islamic Republic of); Servati, P. [Department of Electrical and Computer Engineering, University of British Columbia, Vancouver (Canada)

    2012-01-05

    Highlights: Black-Right-Pointing-Pointer Increasing the Zn concentration changes the structure of NWs from hcp to amorphous. Black-Right-Pointing-Pointer Increasing the Zn concentration significantly reduces the Hc value of NWs. Black-Right-Pointing-Pointer Magnetic properties of CoZn NWs can be significantly enhanced by appropriate annealing. Black-Right-Pointing-Pointer The pH of electrolyte has no significant effect on the properties of the NW arrays. Black-Right-Pointing-Pointer Deposition frequency has considerable effects on the magnetic properties of NWs. - Abstract: Highly ordered arrays of Co{sub 1-x}Zn{sub x} (0 {<=} x {<=} 0.74) nanowires (NWs) with diameters of {approx}35 nm and high length-to-diameter ratios (up to 150) were fabricated by co-electrodeposition of Co and Zn into pores of anodized aluminum oxide (AAO) templates. The Co and Zn contents of the NWs were adjusted by varying the ratio of Zn and Co ion concentrations in the electrolyte. The effect of the Zn content, electrodeposition conditions (frequency and pH) and annealing on the structural and magnetic properties (e.g., coercivity (Hc) and squareness (Sq)) of NW arrays were investigated using X-ray diffraction (XRD), scanning electron microscopy, electron diffraction, and alternating gradient force magnetometer (AGFM). XRD patterns reveal that an increase in the concentration of Zn ions of the electrolyte forces the hcp crystal structure of Co NWs to change into an amorphous phase, resulting in a significant reduction in Hc. It was found that the magnetic properties of NWs can be significantly improved by appropriate annealing process. The highest values for Hc (2050 Oe) and Sq (0.98) were obtained for NWs electrodeposited using 0.95/0.05 Co:Zn concentrations at 200 Hz and annealed at 575 Degree-Sign C. While the pH of electrolyte is found to have no significant effect on the structural and magnetic properties of the NW arrays, the electrodeposition frequency has considerable effects on

  20. The clinicopathological significance and drug target potential of FHIT in breast cancer, a meta-analysis and literature review.

    Science.gov (United States)

    Su, Yunshu; Wang, Xiaoli; Li, Jun; Xu, Junming; Xu, Lijun

    2015-01-01

    FHIT is a bona fide tumor-suppressor gene and its loss contributes to tumorigenesis of epithelial cancers including breast cancer (BC). However, the association and clinicopathological significance between FHIT promoter hypermethylation and BC remains unclear. The purpose of this study is to conduct a meta-analysis and literature review to investigate the clinicopathological significance of FHIT methylation in BC. A detailed literature search was performed in PubMed, EMBASE, Web of Science, and Google Scholar databases. The data were extracted and assessed by two reviewers independently. Odds ratios with 95% corresponding confidence intervals were calculated. A total of seven relevant articles were available for meta-analysis, which included 985 patients. The frequency of FHIT hypermethylation was significantly increased in invasive ductal carcinoma compared to benign breast disease, the pooled odds ratio was 8.43, Panalysis indicated that the frequency of FHIT hypermethylation was significantly increased in BC compared to benign breast disease. The rate of FHIT hypermethylation in advanced stages of BC was higher than in earlier stages; however, the difference was not statistically significant. Our data suggested that FHIT methylation could be a diagnostic biomarker of BC carcinogenesis. FHIT is a potential drug target for development of demethylation treatment for patients with BC.

  1. Compression stockings significantly improve hemodynamic performance in post-thrombotic syndrome irrespective of class or length.

    Science.gov (United States)

    Lattimer, Christopher R; Azzam, Mustapha; Kalodiki, Evi; Makris, Gregory C; Geroulakos, George

    2013-07-01

    Graduated elastic compression (GEC) stockings have been demonstrated to reduce the morbidity associated with post-thrombotic syndrome. The ideal length or compression strength required to achieve this is speculative and related to physician preference and patient compliance. The aim of this study was to evaluate the hemodynamic performance of four different stockings and determine the patient's preference. Thirty-four consecutive patients (40 legs, 34 male) with post-thrombotic syndrome were tested with four different stockings (Mediven plus open toe, Bayreuth, Germany) of their size in random order: class 1 (18-21 mm Hg) and class II (23-32 mm Hg), below-knee (BK) and above-knee thigh-length (AK). The median age, Venous Clinical Severity Score, Venous Segmental Disease Score, and Villalta scale were 62 years (range, 31-81 years), 8 (range, 1-21), 5 (range, 2-10), and 10 (range, 2-22), respectively. The C of C0-6EsAs,d,pPr,o was C0 = 2, C2 = 1, C3 = 3, C4a = 12, C4b = 7, C5 = 12, C6 = 3. Obstruction and reflux was observed on duplex in 47.5% legs, with deep venous reflux alone in 45%. Air plethysmography was used to measure the venous filling index (VFI), venous volume, and time to fill 90% of the venous volume. Direct pressure measurements were obtained while lying and standing using the PicoPress device (Microlab Elettronica, Nicolò, Italy). The pressure sensor was placed underneath the test stocking 5 cm above and 2 cm posterior to the medial malleolus. At the end of the study session, patients stated their preferred stocking based on comfort. The VFI, venous volume, and time to fill 90% of the venous volume improved significantly with all types of stocking versus no compression. In class I, the VFI (mL/s) improved from a median of 4.9 (range, 1.7-16.3) without compression to 3.7 (range, 0-14) BK (24.5%) and 3.6 (range, 0.6-14.5) AK (26.5%). With class II, the corresponding improvement was to 4.0 (range, 0.3-16.2) BK (18.8%) and 3.7 (range, 0.5-14.2) AK (24

  2. Significant improvement of intestinal microbiota of gibel carp (Carassius auratus gibelio) after traditional Chinese medicine feeding.

    Science.gov (United States)

    Wu, Z B; Gatesoupe, F-J; Li, T T; Wang, X H; Zhang, Q Q; Feng, D Y; Feng, Y Q; Chen, H; Li, A H

    2018-03-01

    Increasing attention has been attracted to intestinal microbiota, due to interactions with nutrition, metabolism and immune defence of the host. Traditional Chinese medicine (TCM) feed additives have been applied in aquaculture to improve fish health, but the interaction with fish gut microbiota is still poorly understood. This study aimed to explore the effect of adding TCM in feed on the intestinal microbiota of gibel carp (Carassius auratus gibelio). Bacterial communities of 16 fish intestinal contents and one water sample were characterized by high-throughput sequencing and analysis of the V4-V5 region of the 16S rRNA gene. The results showed that the composition and structure of the bacterial community were significantly altered by the TCM feeding. Some phyla increased markedly (Proteobacteria, Actinobacteria, Acidobacteria, etc.), while Fusobacteria were significantly reduced. Concurrently, the richness and diversity of the taxonomic units increased, and the microbiota composition of TCM-treated fish was more homogeneous among individuals. At the genus level, the addition of TCM tended to reduce the incidence of potential pathogens (Aeromonas, Acinetobacter and Shewanella), while stimulating the emergence of some potential probiotics (Lactobacillus, Lactococcus, Bacillus and Pseudomonas). These data suggested that the feed additive could regulate the fish intestinal microbiota by reinforcing the microbial balance. This study may provide useful information for further application of TCM for diseases prevention and stress management in aquaculture. © 2017 The Society for Applied Microbiology.

  3. Significant improvement in one-dimensional cursor control using Laplacian electroencephalography over electroencephalography

    Science.gov (United States)

    Boudria, Yacine; Feltane, Amal; Besio, Walter

    2014-06-01

    Objective. Brain-computer interfaces (BCIs) based on electroencephalography (EEG) have been shown to accurately detect mental activities, but the acquisition of high levels of control require extensive user training. Furthermore, EEG has low signal-to-noise ratio and low spatial resolution. The objective of the present study was to compare the accuracy between two types of BCIs during the first recording session. EEG and tripolar concentric ring electrode (TCRE) EEG (tEEG) brain signals were recorded and used to control one-dimensional cursor movements. Approach. Eight human subjects were asked to imagine either ‘left’ or ‘right’ hand movement during one recording session to control the computer cursor using TCRE and disc electrodes. Main results. The obtained results show a significant improvement in accuracies using TCREs (44%-100%) compared to disc electrodes (30%-86%). Significance. This study developed the first tEEG-based BCI system for real-time one-dimensional cursor movements and showed high accuracies with little training.

  4. Induction-heating MOCVD reactor with significantly improved heating efficiency and reduced harmful magnetic coupling

    KAUST Repository

    Li, Kuang-Hui; Alotaibi, Hamad S.; Sun, Haiding; Lin, Ronghui; Guo, Wenzhe; Torres-Castanedo, Carlos G.; Liu, Kaikai; Galan, Sergio V.; Li, Xiaohang

    2018-01-01

    In a conventional induction-heating III-nitride metalorganic chemical vapor deposition (MOCVD) reactor, the induction coil is outside the chamber. Therefore, the magnetic field does not couple with the susceptor well, leading to compromised heating efficiency and harmful coupling with the gas inlet and thus possible overheating. Hence, the gas inlet has to be at a minimum distance away from the susceptor. Because of the elongated flow path, premature reactions can be more severe, particularly between Al- and B-containing precursors and NH3. Here, we propose a structure that can significantly improve the heating efficiency and allow the gas inlet to be closer to the susceptor. Specifically, the induction coil is designed to surround the vertical cylinder of a T-shaped susceptor comprising the cylinder and a top horizontal plate holding the wafer substrate within the reactor. Therefore, the cylinder coupled most magnetic field to serve as the thermal source for the plate. Furthermore, the plate can block and thus significantly reduce the uncoupled magnetic field above the susceptor, thereby allowing the gas inlet to be closer. The results show approximately 140% and 2.6 times increase in the heating and susceptor coupling efficiencies, respectively, as well as a 90% reduction in the harmful magnetic flux on the gas inlet.

  5. Induction-heating MOCVD reactor with significantly improved heating efficiency and reduced harmful magnetic coupling

    KAUST Repository

    Li, Kuang-Hui

    2018-02-23

    In a conventional induction-heating III-nitride metalorganic chemical vapor deposition (MOCVD) reactor, the induction coil is outside the chamber. Therefore, the magnetic field does not couple with the susceptor well, leading to compromised heating efficiency and harmful coupling with the gas inlet and thus possible overheating. Hence, the gas inlet has to be at a minimum distance away from the susceptor. Because of the elongated flow path, premature reactions can be more severe, particularly between Al- and B-containing precursors and NH3. Here, we propose a structure that can significantly improve the heating efficiency and allow the gas inlet to be closer to the susceptor. Specifically, the induction coil is designed to surround the vertical cylinder of a T-shaped susceptor comprising the cylinder and a top horizontal plate holding the wafer substrate within the reactor. Therefore, the cylinder coupled most magnetic field to serve as the thermal source for the plate. Furthermore, the plate can block and thus significantly reduce the uncoupled magnetic field above the susceptor, thereby allowing the gas inlet to be closer. The results show approximately 140% and 2.6 times increase in the heating and susceptor coupling efficiencies, respectively, as well as a 90% reduction in the harmful magnetic flux on the gas inlet.

  6. An Evidence-Based Assessment of the Clinical Significance of Drug-Drug Interactions Between Disease-Modifying Antirheumatic Drugs and Non-Antirheumatic Drugs According to Rheumatologists and Pharmacists

    NARCIS (Netherlands)

    van Roon, Eric N.; van den Bemt, Patricia M. L. A.; Jansen, Tim L. Th. A.; Houtman, Nella M.; van de Laar, Mart A. F. J.; Brouwers, Jacobus R. B. J.

    Background: Clinically relevant drug-drug interactions (DDIs) must be recognized in a timely manner and managed appropriately to prevent adverse drug reactions or therapeutic failure. Because the evidence for most DDIs is based on case reports or poorly documented clinical information, there is a

  7. Improving drug delivery technology for treating neurodegenerative diseases.

    Science.gov (United States)

    Choonara, Yahya E; Kumar, Pradeep; Modi, Girish; Pillay, Viness

    2016-07-01

    Neurodegenerative diseases (NDs) represent intricate challenges for efficient uptake and transport of drugs to the brain mainly due to the restrictive blood-brain barrier (BBB). NDs are characterized by the loss of neuronal subtypes as sporadic and/or familial and several mechanisms of neurodegeneration have been identified. This review attempts to recap, organize and concisely evaluate the advanced drug delivery systems designed for treating common NDs. It highlights key research gaps and opinionates on new neurotherapies to overcome the BBB as an addition to the current treatments of countering oxidative stress, inflammation and apoptotic mechanisms. Current treatments do not fully address the biological, drug and therapeutic factors faced. This has led to the development of vogue treatments such as nose-to-brain technologies, bio-engineered systems, fusion protein chaperones, stem cells, gene therapy, use of natural compounds, neuroprotectants and even vaccines. However, failure of these treatments is mainly due to the BBB and non-specific delivery in the brain. In order to increase neuroavailability various advanced drug delivery systems provide promising alternatives that are able to augment the treatment of Alzheimer's disease and Parkinson's disease. However, much work is still required in this field beyond the preclinical testing phase.

  8. [Does implementation of benchmarking in quality circles improve the quality of care of patients with asthma and reduce drug interaction?].

    Science.gov (United States)

    Kaufmann-Kolle, Petra; Szecsenyi, Joachim; Broge, Björn; Haefeli, Walter Emil; Schneider, Antonius

    2011-01-01

    The purpose of this cluster-randomised controlled trial was to evaluate the efficacy of quality circles (QCs) working either with general data-based feedback or with an open benchmark within the field of asthma care and drug-drug interactions. Twelve QCs, involving 96 general practitioners from 85 practices, were randomised. Six QCs worked with traditional anonymous feedback and six with an open benchmark. Two QC meetings supported with feedback reports were held covering the topics "drug-drug interactions" and "asthma"; in both cases discussions were guided by a trained moderator. Outcome measures included health-related quality of life and patient satisfaction with treatment, asthma severity and number of potentially inappropriate drug combinations as well as the general practitioners' satisfaction in relation to the performance of the QC. A significant improvement in the treatment of asthma was observed in both trial arms. However, there was only a slight improvement regarding inappropriate drug combinations. There were no relevant differences between the group with open benchmark (B-QC) and traditional quality circles (T-QC). The physicians' satisfaction with the QC performance was significantly higher in the T-QCs. General practitioners seem to take a critical perspective about open benchmarking in quality circles. Caution should be used when implementing benchmarking in a quality circle as it did not improve healthcare when compared to the traditional procedure with anonymised comparisons. Copyright © 2011. Published by Elsevier GmbH.

  9. Nicotine Significantly Improves Chronic Stress-Induced Impairments of Cognition and Synaptic Plasticity in Mice.

    Science.gov (United States)

    Shang, Xueliang; Shang, Yingchun; Fu, Jingxuan; Zhang, Tao

    2017-08-01

    The aim of this study was to examine if nicotine was able to improve cognition deficits in a mouse model of chronic mild stress. Twenty-four male C57BL/6 mice were divided into three groups: control, stress, and stress with nicotine treatment. The animal model was established by combining chronic unpredictable mild stress (CUMS) and isolated feeding. Mice were exposed to CUMS continued for 28 days, while nicotine (0.2 mg/kg) was also administrated for 28 days. Weight and sucrose consumption were measured during model establishing period. The anxiety and behavioral despair were analyzed using the forced swim test (FST) and open-field test (OFT). Spatial cognition was evaluated using Morris water maze (MWM) test. Following behavioral assessment, both long-term potentiation (LTP) and depotentiation (DEP) were recorded in the hippocampal dentate gyrus (DG) region. Both synaptic and Notch1 proteins were measured by Western. Nicotine increased stressed mouse's sucrose consumption. The MWM test showed that spatial learning and reversal learning in stressed animals were remarkably affected relative to controls, whereas nicotine partially rescued cognitive functions. Additionally, nicotine considerably alleviated the level of anxiety and the degree of behavioral despair in stressed mice. It effectively mitigated the depression-induced impairment of hippocampal synaptic plasticity, in which both the LTP and DEP were significantly inhibited in stressed mice. Moreover, nicotine enhanced the expression of synaptic and Notch1 proteins in stressed animals. The results suggest that nicotine ameliorates the depression-like symptoms and improves the hippocampal synaptic plasticity closely associated with activating transmembrane ion channel receptors and Notch signaling components. Graphical Abstract ᅟ.

  10. Significant improvements in stability and reproducibility of atomic-scale atomic force microscopy in liquid

    International Nuclear Information System (INIS)

    Akrami, S M R; Nakayachi, H; Fukuma, T; Watanabe-Nakayama, T; Asakawa, H

    2014-01-01

    Recent advancement of dynamic-mode atomic force microscopy (AFM) for liquid-environment applications enabled atomic-scale studies on various interfacial phenomena. However, instabilities and poor reproducibility of the measurements often prevent systematic studies. To solve this problem, we have investigated the effect of various tip treatment methods for atomic-scale imaging and force measurements in liquid. The tested methods include Si coating, Ar plasma, Ar sputtering and UV/O 3 cleaning. We found that all the methods provide significant improvements in both the imaging and force measurements in spite of the tip transfer through the air. Among the methods, we found that the Si coating provides the best stability and reproducibility in the measurements. To understand the origin of the fouling resistance of the cleaned tip surface and the difference between the cleaning methods, we have investigated the tip surface properties by x-ray photoelectron spectroscopy and contact angle measurements. The results show that the contaminations adsorbed on the tip during the tip transfer through the air should desorb from the surface when it is immersed in aqueous solution due to the enhanced hydrophilicity by the tip treatments. The tip surface prepared by the Si coating is oxidized when it is immersed in aqueous solution. This creates local spots where stable hydration structures are formed. For the other methods, there is no active mechanism to create such local hydration sites. Thus, the hydration structure formed under the tip apex is not necessarily stable. These results reveal the desirable tip properties for atomic-scale AFM measurements in liquid, which should serve as a guideline for further improvements of the tip treatment methods. (paper)

  11. Significant improvement of accuracy and precision in the determination of trace rare earths by fluorescence analysis

    International Nuclear Information System (INIS)

    Ozawa, L.; Hersh, H.N.

    1976-01-01

    Most of the rare earths in yttrium, gadolinium and lanthanum oxides emit characteristic fluorescent line spectra under irradiation with photons, electrons and x rays. The sensitivity and selectivity of the rare earth fluorescences are high enough to determine the trace amounts (0.01 to 100 ppM) of rare earths. The absolute fluorescent intensities of solids, however, are markedly affected by the synthesis procedure, level of contamination and crystal perfection, resulting in poor accuracy and low precision for the method (larger than 50 percent error). Special care in preparation of the samples is required to obtain good accuracy and precision. It is found that the accuracy and precision for the determination of trace (less than 10 ppM) rare earths by fluorescence analysis improved significantly, while still maintaining the sensitivity, when the determination is made by comparing the ratio of the fluorescent intensities of the trace rare earths to that of a deliberately added rare earth as reference. The variation in the absolute fluorescent intensity remains, but is compensated for by measuring the fluorescent line intensity ratio. Consequently, the determination of trace rare earths (with less than 3 percent error) is easily made by a photoluminescence technique in which the rare earths are excited directly by photons. Accuracy is still maintained when the absolute fluorescent intensity is reduced by 50 percent through contamination by Ni, Fe, Mn or Pb (about 100 ppM). Determination accuracy is also improved for fluorescence analysis by electron excitation and x-ray excitation. For some rare earths, however, accuracy by these techniques is reduced because indirect excitation mechanisms are involved. The excitation mechanisms and the interferences between rare earths are also reported

  12. Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognition in urban children.

    Science.gov (United States)

    Calderón-Garcidueñas, Lilian; Mora-Tiscareño, Antonieta; Franco-Lira, Maricela; Cross, Janet V; Engle, Randall; Aragón-Flores, Mariana; Gómez-Garza, Gilberto; Jewells, Valerie; Medina-Cortina, Humberto; Solorio, Edelmira; Chao, Chih-Kai; Zhu, Hongtu; Mukherjee, Partha S; Ferreira-Azevedo, Lara; Torres-Jardón, Ricardo; D'Angiulli, Amedeo

    2013-01-01

    Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA) children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children). We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1) and/or inflammatory mediators in MCMA children. Thirty gram of dark cocoa with 680 mg of total flavonols were given daily for 10.11 ± 3.4 days (range 9-24 days) to 18 children (10.55 years, SD = 1.45; 11F/7M). Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p = 0.0002). Fifteen children (83%) showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter (PM) and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer's and Parkinson's diseases.

  13. Model training across multiple breeding cycles significantly improves genomic prediction accuracy in rye (Secale cereale L.).

    Science.gov (United States)

    Auinger, Hans-Jürgen; Schönleben, Manfred; Lehermeier, Christina; Schmidt, Malthe; Korzun, Viktor; Geiger, Hartwig H; Piepho, Hans-Peter; Gordillo, Andres; Wilde, Peer; Bauer, Eva; Schön, Chris-Carolin

    2016-11-01

    Genomic prediction accuracy can be significantly increased by model calibration across multiple breeding cycles as long as selection cycles are connected by common ancestors. In hybrid rye breeding, application of genome-based prediction is expected to increase selection gain because of long selection cycles in population improvement and development of hybrid components. Essentially two prediction scenarios arise: (1) prediction of the genetic value of lines from the same breeding cycle in which model training is performed and (2) prediction of lines from subsequent cycles. It is the latter from which a reduction in cycle length and consequently the strongest impact on selection gain is expected. We empirically investigated genome-based prediction of grain yield, plant height and thousand kernel weight within and across four selection cycles of a hybrid rye breeding program. Prediction performance was assessed using genomic and pedigree-based best linear unbiased prediction (GBLUP and PBLUP). A total of 1040 S 2 lines were genotyped with 16 k SNPs and each year testcrosses of 260 S 2 lines were phenotyped in seven or eight locations. The performance gap between GBLUP and PBLUP increased significantly for all traits when model calibration was performed on aggregated data from several cycles. Prediction accuracies obtained from cross-validation were in the order of 0.70 for all traits when data from all cycles (N CS  = 832) were used for model training and exceeded within-cycle accuracies in all cases. As long as selection cycles are connected by a sufficient number of common ancestors and prediction accuracy has not reached a plateau when increasing sample size, aggregating data from several preceding cycles is recommended for predicting genetic values in subsequent cycles despite decreasing relatedness over time.

  14. Significantly improving trace thallium removal from surface waters during coagulation enhanced by nanosized manganese dioxide.

    Science.gov (United States)

    Huangfu, Xiaoliu; Ma, Chengxue; Ma, Jun; He, Qiang; Yang, Chun; Jiang, Jin; Wang, Yaan; Wu, Zhengsong

    2017-02-01

    Thallium (Tl) is an element of high toxicity and significant accumulation in human body. There is an urgent need for the development of appropriate strategies for trace Tl removal in drinking water treatment plants. In this study, the efficiency and mechanism of trace Tl (0.5 μg/L) removal by conventional coagulation enhanced by nanosized manganese dioxide (nMnO 2 ) were explored in simulated water and two representative surface waters (a river water and a reservoir water obtained from Northeast China). Experimental results showed that nMnO 2 significantly improve Tl(I) removal from selected waters. The removal efficiency was dramatically higher in the simulated water, demonstrating by less than 0.1 μg/L Tl residual. The enhancement of trace Tl removal in the surface waters decreased to a certain extent. Both adjusting water pH to alkaline condition and preoxidation of Tl(I) to Tl(III) benefit trace Tl removal from surface waters. Data also indicated that competitive cation of Ca 2+ decreased the efficiency of trace Tl removal, resulting from the reduction of Tl adsorption on nMnO 2 . Humic acid could largely low Tl removal efficiency during nMnO 2 enhanced coagulation processes. Trace elemental Tl firstly adsorbed on nMnO 2 and then removed accompanying with nMnO 2 settling. The information obtained in the present study may provide a potential strategy for drinking water treatment plants threatened by trace Tl. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. Transporter-Guided Delivery of Nanoparticles to Improve Drug Permeation across Cellular Barriers and Drug Exposure to Selective Cell Types

    Directory of Open Access Journals (Sweden)

    Longfa Kou

    2018-01-01

    Full Text Available Targeted nano-drug delivery systems conjugated with specific ligands to target selective cell-surface receptors or transporters could enhance the efficacy of drug delivery and therapy. Transporters are expressed differentially on the cell-surface of different cell types, and also specific transporters are expressed at higher than normal levels in selective cell types under pathological conditions. They also play a key role in intestinal absorption, delivery via non-oral routes (e.g., pulmonary route and nasal route, and transfer across biological barriers (e.g., blood–brain barrier and blood–retinal barrier. As such, the cell-surface transporters represent ideal targets for nano-drug delivery systems to facilitate drug delivery to selective cell types under normal or pathological conditions and also to avoid off-target adverse side effects of the drugs. There is increasing evidence in recent years supporting the utility of cell-surface transporters in the field of nano-drug delivery to increase oral bioavailability, to improve transfer across the blood–brain barrier, and to enhance delivery of therapeutics in a cell-type selective manner in disease states. Here we provide a comprehensive review of recent advancements in this interesting and important area. We also highlight certain key aspects that need to be taken into account for optimal development of transporter-assisted nano-drug delivery systems.

  16. Significant effect of Ca2+ on improving the heat resistance of lactic acid bacteria.

    Science.gov (United States)

    Huang, Song; Chen, Xiao Dong

    2013-07-01

    The heat resistance of lactic acid bacteria (LAB) has been extensively investigated due to its highly practical significance. Reconstituted skim milk (RSM) has been found to be one of the most effective protectant wall materials for microencapsulating microorganisms during convective drying, such as spray drying. In addition to proteins and carbohydrate, RSM is rich in calcium. It is not clear which component is critical in the RSM protection mechanism. This study investigated the independent effect of calcium. Ca(2+) was added to lactose solution to examine its influence on the heat resistance of Lactobacillus rhamnosus ZY, Lactobacillus casei Zhang, Lactobacillus plantarum P8 and Streptococcus thermophilus ND03. The results showed that certain Ca(2+) concentrations enhanced the heat resistance of the LAB strains to different extents, that is produced higher survival and shorter regrowth lag times of the bacterial cells. In some cases, the improvements were dramatic. More scientifically insightful and more intensive instrumental study of the Ca(2+) behavior around and in the cells should be carried out in the near future. In the meantime, this work may lead to the development of more cost-effective wall materials with Ca(2+) added as a prime factor. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

  17. Targeting Heparin to Collagen within Extracellular Matrix Significantly Reduces Thrombogenicity and Improves Endothelialization of Decellularized Tissues.

    Science.gov (United States)

    Jiang, Bin; Suen, Rachel; Wertheim, Jason A; Ameer, Guillermo A

    2016-12-12

    Thrombosis within small-diameter vascular grafts limits the development of bioartificial, engineered vascular conduits, especially those derived from extracellular matrix (ECM). Here we describe an easy-to-implement strategy to chemically modify vascular ECM by covalently linking a collagen binding peptide (CBP) to heparin to form a heparin derivative (CBP-heparin) that selectively binds a subset of collagens. Modification of ECM with CBP-heparin leads to increased deposition of functional heparin (by ∼7.2-fold measured by glycosaminoglycan composition) and a corresponding reduction in platelet binding (>70%) and whole blood clotting (>80%) onto the ECM. Furthermore, addition of CBP-heparin to the ECM stabilizes long-term endothelial cell attachment to the lumen of ECM-derived vascular conduits, potentially through recruitment of heparin-binding growth factors that ultimately improve the durability of endothelialization in vitro. Overall, our findings provide a simple yet effective method to increase deposition of functional heparin on the surface of ECM-based vascular grafts and thereby minimize thrombogenicity of decellularized tissue, overcoming a significant challenge in tissue engineering of bioartificial vessels and vascularized organs.

  18. Significant Improvement in Chronic Persistent Headaches Caused by Small Rathke Cleft Cysts After Transsphenoidal Surgery.

    Science.gov (United States)

    Fukui, Issei; Hayashi, Yasuhiko; Kita, Daisuke; Sasagawa, Yasuo; Oishi, Masahiro; Tachibana, Osamu; Nakada, Mitsutoshi

    2017-03-01

    Rathke cleft cysts (RCC) usually are asymptomatic and can be observed via the use of conservative methods. Some patients with RCCs, however, have severe headaches even if they are small enough to be confined to the sella, and these small RCCs seldom have been discussed. This study presents an investigation into clinical characteristics of small RCCs associated with severe headaches, demonstrating efficacy and safety of endoscopic transsphenoidal surgery (ETSS) to relieve headaches. In this study, 13 patients with small RCCs (maximum diameter HIT-6) score was calculated both pre- and postoperatively to evaluate headache severity. All patients complained of severe headaches, which disturbed their daily life. Most headaches were nonpulsating and localized in the frontal area. Characteristically, 6 patients (46%) experienced severe headaches with sudden onset that continued chronically. HIT-6 score was 64 on average, meaning headaches affected daily life severely. After surgical decompression of the cyst, headache in all of the patients improved dramatically and HIT-6 score decreased significantly to 37, suggesting that headaches were diminished. No newly developed deficiencies of the anterior pituitary lobe function were detected. Postoperative occurrence of diabetes insipidus was found in 2 patients, both of which were transient. No recurring cysts were found. Severe headaches can develop from small RCCs. In the present study, ETSS was performed on such patients effectively and safely to relieve their headaches. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Successful percutaneous coronary intervention significantly improves coronary sinus blood flow as assessed by transthoracic echocardiography.

    Science.gov (United States)

    Lyubarova, Radmila; Boden, William E; Fein, Steven A; Schulman-Marcus, Joshua; Torosoff, Mikhail

    2018-06-01

    Transthoracic echocardiography (TTE) has been used to assess coronary sinus blood flow (CSBF), which reflects total coronary arterial blood flow. Successful angioplasty is expected to improve coronary arterial blood flow. Changes in CSBF after percutaneous coronary intervention (PCI), as assessed by TTE, have not been systematically evaluated. TTE can be utilized to reflect increased CSBF after a successful, clinically indicated PCI. The study cohort included 31 patients (18 females, 62 ± 11 years old) referred for diagnostic cardiac catheterization for suspected coronary artery disease and possible PCI, when clinically indicated. All performed PCIs were successful, with good angiographic outcome. CSBF per cardiac cycle (mL/beat) was measured using transthoracic two-dimensional and Doppler flow imaging as the product of coronary sinus (CS) area and CS flow time-velocity integral. CSBF per minute (mL/min) was calculated as the product of heart rate and CSBF per cardiac cycle. In each patient, CSBF was assessed prospectively, before and after cardiac catheterization with and without clinically indicated PCI. Within- and between-group differences in CSBF before and after PCI were assessed using repeated measures analysis of variance. Technically adequate CSBF measurements were obtained in 24 patients (77%). In patients who did not undergo PCI, there was no significant change in CSBF (278.1 ± 344.1 versus 342.7 ± 248.5, p = 0.36). By contrast, among patients who underwent PCI, CSBF increased significantly (254.3 ± 194.7 versus 618.3 ± 358.5 mL/min, p < 0.01, p-interaction = 0.03). Other hemodynamic and echocardiographic parameters did not change significantly before and after cardiac catheterization in either treatment group. Transthoracic echocardiographic assessment can be employed to document CSBF changes after angioplasty. Future studies are needed to explore the clinical utility of this noninvasive metric.

  20. Prediction of Effective Drug Combinations by an Improved Naïve Bayesian Algorithm.

    Science.gov (United States)

    Bai, Li-Yue; Dai, Hao; Xu, Qin; Junaid, Muhammad; Peng, Shao-Liang; Zhu, Xiaolei; Xiong, Yi; Wei, Dong-Qing

    2018-02-05

    Drug combinatorial therapy is a promising strategy for combating complex diseases due to its fewer side effects, lower toxicity and better efficacy. However, it is not feasible to determine all the effective drug combinations in the vast space of possible combinations given the increasing number of approved drugs in the market, since the experimental methods for identification of effective drug combinations are both labor- and time-consuming. In this study, we conducted systematic analysis of various types of features to characterize pairs of drugs. These features included information about the targets of the drugs, the pathway in which the target protein of a drug was involved in, side effects of drugs, metabolic enzymes of the drugs, and drug transporters. The latter two features (metabolic enzymes and drug transporters) were related to the metabolism and transportation properties of drugs, which were not analyzed or used in previous studies. Then, we devised a novel improved naïve Bayesian algorithm to construct classification models to predict effective drug combinations by using the individual types of features mentioned above. Our results indicated that the performance of our proposed method was indeed better than the naïve Bayesian algorithm and other conventional classification algorithms such as support vector machine and K-nearest neighbor.

  1. Prediction of Effective Drug Combinations by an Improved Naïve Bayesian Algorithm

    Directory of Open Access Journals (Sweden)

    Li-Yue Bai

    2018-02-01

    Full Text Available Drug combinatorial therapy is a promising strategy for combating complex diseases due to its fewer side effects, lower toxicity and better efficacy. However, it is not feasible to determine all the effective drug combinations in the vast space of possible combinations given the increasing number of approved drugs in the market, since the experimental methods for identification of effective drug combinations are both labor- and time-consuming. In this study, we conducted systematic analysis of various types of features to characterize pairs of drugs. These features included information about the targets of the drugs, the pathway in which the target protein of a drug was involved in, side effects of drugs, metabolic enzymes of the drugs, and drug transporters. The latter two features (metabolic enzymes and drug transporters were related to the metabolism and transportation properties of drugs, which were not analyzed or used in previous studies. Then, we devised a novel improved naïve Bayesian algorithm to construct classification models to predict effective drug combinations by using the individual types of features mentioned above. Our results indicated that the performance of our proposed method was indeed better than the naïve Bayesian algorithm and other conventional classification algorithms such as support vector machine and K-nearest neighbor.

  2. Could a revision of the current guidelines for cancer drug use improve the quality of cancer treatment?

    Directory of Open Access Journals (Sweden)

    Lippert TH

    2014-01-01

    Full Text Available Theodor H Lippert,1 Hans-Jörg Ruoff,1 Manfred Volm2 1Medical Faculty, University of Tübingen, Tübingen, Germany; 2Medical Faculty, University of Heidelberg, Heidelberg, Germany Abstract: Clinical practice guidelines are indispensable for such a variable disease as malignant solid tumors, with the complex possibilities of drug treatment. The current guidelines may be criticized on several points, however. First, there is a lack of information on the outcome of treatment, such as the expected success and failure rates. Treating not only drug responders but also nonresponders, that is, patients with drug resistance, must result in failures. There is no mention of the possibility of excluding the drug nonresponders, identifiable by special laboratory tests and no consideration is given to the different side effects of the recommended drug regimens. Nor are there any instructions concerning tumor cases for which anticancer drug treatment is futile. In such cases, early palliative care may lead to significant improvements in both life quality and life expectancy. Not least, there is no transparency concerning the preparation of the guidelines: persons cannot be identified who could give a statement of conflicts of interest, and responsibility is assumed only by anonymous medical associations. A revision of the current guidelines could considerably improve cancer treatment. Keywords: anticancer drugs, quality of guidelines, critical remarks

  3. Heat storage in forest biomass significantly improves energy balance closure particularly during stable conditions

    Science.gov (United States)

    Lindroth, A.; Mölder, M.; Lagergren, F.

    2009-08-01

    Temperature measurements in trunks and branches in a mature ca. 100 years-old mixed pine and spruce forest in central Sweden were used to estimate the heat storage in the tree biomass. The estimated heat flux in the sample trees and data on biomass distributions were used to scale up to stand level biomass heat fluxes. The rate of change of sensible and latent heat storage in the air layer below the level of the flux measurements was estimated from air temperature and humidity profile measurements and soil heat flux was estimated from heat flux plates and soil temperature measurements. The fluxes of sensible and latent heat from the forest were measured with an eddy covariance system in a tower. The analysis was made for a two-month period in summer of 1995. The tree biomass heat flux was the largest of the estimated storage components and varied between 40 and -35 W m-2 on summer days with nice weather. Averaged over two months the diurnal maximum of total heat storage was 45 W m-2 and the minimum was -35 W m-2. The soil heat flux and the sensible heat storage in air were out of phase with the biomass flux and they reached maximum values that were about 75% of the maximum of the tree biomass heat storage. The energy balance closure improved significantly when the total heat storage was added to the turbulent fluxes. The slope of a regression line with sum of fluxes and storage as independent and net radiation as dependent variable, increased from 0.86 to 0.95 for half-hourly data and the scatter was also reduced. The most significant finding was, however, that during nights with strongly stable conditions when the sensible heat flux dropped to nearly zero, the total storage matched the net radiation nearly perfectly. Another interesting result was that the mean energy imbalance started to increase when the Richardson number became more negative than ca. -0.1. In fact, the largest energy deficit occurred at maximum instability. Our conclusion is that eddy

  4. Significant improvement of eczema with skin care and food elimination in small children.

    Science.gov (United States)

    Norrman, Gunilla; Tomicić, Sara; Böttcher, Malin Fagerås; Oldaeus, Göran; Strömberg, Leif; Fälth-magnusson, Karin

    2005-10-01

    To evaluate common methods of investigation and treatment in children younger than 2 y of age with eczema, with or without sensitization to food allergens. One hundred and twenty-three children younger than 2 y of age with eczema and suspected food allergy were included in this prospective study. The children underwent skin-prick test with cow's milk, fresh hen's egg white and wheat. Specific IgE to milk and egg white was analysed. The eczema extent and severity was estimated with SCORAD before and after treatment. Children with a positive skin-prick test were instructed to exclude that food item from their diet. All children were treated with emollients and topical steroids when needed. Sixty-two of the children were skin-prick positive to at least one of the allergens; 62% had mild, 30% moderate and 8% severe eczema at their first visit. After treatment, 90% had mild, 10% moderate and 0% severe eczema. Forty-six per cent of the children had circulating IgE antibodies to milk or egg white. Ten per cent had specific IgE but negative skin-prick test to the same allergen. This subgroup improved their eczema significantly without elimination diet. The conventional treatments for children with eczema, i.e. skin care and food elimination, are effective. The beneficial effect of skin care as the first step should not be neglected, and it may not be necessary to eliminate food allergens to relieve skin symptoms in all food-sensitized children with eczema.

  5. Introduction of e-learning in dental radiology reveals significantly improved results in final examination.

    Science.gov (United States)

    Meckfessel, Sandra; Stühmer, Constantin; Bormann, Kai-Hendrik; Kupka, Thomas; Behrends, Marianne; Matthies, Herbert; Vaske, Bernhard; Stiesch, Meike; Gellrich, Nils-Claudius; Rücker, Martin

    2011-01-01

    Because a traditionally instructed dental radiology lecture course is very time-consuming and labour-intensive, online courseware, including an interactive-learning module, was implemented to support the lectures. The purpose of this study was to evaluate the perceptions of students who have worked with web-based courseware as well as the effect on their results in final examinations. Users (n(3+4)=138) had access to the e-program from any networked computer at any time. Two groups (n(3)=71, n(4)=67) had to pass a final exam after using the e-course. Results were compared with two groups (n(1)=42, n(2)=48) who had studied the same content by attending traditional lectures. In addition a survey of the students was statistically evaluated. Most of the respondents reported a positive attitude towards e-learning and would have appreciated more access to computer-assisted instruction. Two years after initiating the e-course the failure rate in the final examination dropped significantly, from 40% to less than 2%. The very positive response to the e-program and improved test scores demonstrated the effectiveness of our e-course as a learning aid. Interactive modules in step with clinical practice provided learning that is not achieved by traditional teaching methods alone. To what extent staff savings are possible is part of a further study. Copyright © 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  6. Mapping Soil Properties of Africa at 250 m Resolution: Random Forests Significantly Improve Current Predictions.

    Directory of Open Access Journals (Sweden)

    Tomislav Hengl

    Full Text Available 80% of arable land in Africa has low soil fertility and suffers from physical soil problems. Additionally, significant amounts of nutrients are lost every year due to unsustainable soil management practices. This is partially the result of insufficient use of soil management knowledge. To help bridge the soil information gap in Africa, the Africa Soil Information Service (AfSIS project was established in 2008. Over the period 2008-2014, the AfSIS project compiled two point data sets: the Africa Soil Profiles (legacy database and the AfSIS Sentinel Site database. These data sets contain over 28 thousand sampling locations and represent the most comprehensive soil sample data sets of the African continent to date. Utilizing these point data sets in combination with a large number of covariates, we have generated a series of spatial predictions of soil properties relevant to the agricultural management--organic carbon, pH, sand, silt and clay fractions, bulk density, cation-exchange capacity, total nitrogen, exchangeable acidity, Al content and exchangeable bases (Ca, K, Mg, Na. We specifically investigate differences between two predictive approaches: random forests and linear regression. Results of 5-fold cross-validation demonstrate that the random forests algorithm consistently outperforms the linear regression algorithm, with average decreases of 15-75% in Root Mean Squared Error (RMSE across soil properties and depths. Fitting and running random forests models takes an order of magnitude more time and the modelling success is sensitive to artifacts in the input data, but as long as quality-controlled point data are provided, an increase in soil mapping accuracy can be expected. Results also indicate that globally predicted soil classes (USDA Soil Taxonomy, especially Alfisols and Mollisols help improve continental scale soil property mapping, and are among the most important predictors. This indicates a promising potential for transferring

  7. Optimized distributed systems achieve significant performance improvement on sorted merging of massive VCF files.

    Science.gov (United States)

    Sun, Xiaobo; Gao, Jingjing; Jin, Peng; Eng, Celeste; Burchard, Esteban G; Beaty, Terri H; Ruczinski, Ingo; Mathias, Rasika A; Barnes, Kathleen; Wang, Fusheng; Qin, Zhaohui S

    2018-06-01

    Sorted merging of genomic data is a common data operation necessary in many sequencing-based studies. It involves sorting and merging genomic data from different subjects by their genomic locations. In particular, merging a large number of variant call format (VCF) files is frequently required in large-scale whole-genome sequencing or whole-exome sequencing projects. Traditional single-machine based methods become increasingly inefficient when processing large numbers of files due to the excessive computation time and Input/Output bottleneck. Distributed systems and more recent cloud-based systems offer an attractive solution. However, carefully designed and optimized workflow patterns and execution plans (schemas) are required to take full advantage of the increased computing power while overcoming bottlenecks to achieve high performance. In this study, we custom-design optimized schemas for three Apache big data platforms, Hadoop (MapReduce), HBase, and Spark, to perform sorted merging of a large number of VCF files. These schemas all adopt the divide-and-conquer strategy to split the merging job into sequential phases/stages consisting of subtasks that are conquered in an ordered, parallel, and bottleneck-free way. In two illustrating examples, we test the performance of our schemas on merging multiple VCF files into either a single TPED or a single VCF file, which are benchmarked with the traditional single/parallel multiway-merge methods, message passing interface (MPI)-based high-performance computing (HPC) implementation, and the popular VCFTools. Our experiments suggest all three schemas either deliver a significant improvement in efficiency or render much better strong and weak scalabilities over traditional methods. Our findings provide generalized scalable schemas for performing sorted merging on genetics and genomics data using these Apache distributed systems.

  8. Cyclosporin A significantly improves preeclampsia signs and suppresses inflammation in a rat model.

    Science.gov (United States)

    Hu, Bihui; Yang, Jinying; Huang, Qian; Bao, Junjie; Brennecke, Shaun Patrick; Liu, Huishu

    2016-05-01

    Preeclampsia is associated with an increased inflammatory response. Immune suppression might be an effective treatment. The aim of this study was to examine whether Cyclosporin A (CsA), an immunosuppressant, improves clinical characteristics of preeclampsia and suppresses inflammation in a lipopolysaccharide (LPS) induced preeclampsia rat model. Pregnant rats were randomly divided into 4 groups: group 1 (PE) rats each received LPS via tail vein on gestational day (GD) 14; group 2 (PE+CsA5) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (5mg/kg, ip) on GDs 16, 17 and 18; group 3 (PE+CsA10) rats were pretreated with LPS (1.0 μg/kg) on GD 14 and were then treated with CsA (10mg/kg, ip) on GDs 16, 17 and 18; group 4 (pregnant control, PC) rats were treated with the vehicle (saline) used for groups 1, 2 and 3. Systolic blood pressure, urinary albumin, biometric parameters and the levels of serum cytokines were measured on day 20. CsA treatment significantly reduced LPS-induced systolic blood pressure and the mean 24-h urinary albumin excretion. Pro-inflammatory cytokines IL-6, IL-17, IFN-γ and TNF-α were increased in the LPS treatment group but were reduced in (LPS+CsA) group (Ppreeclampsia signs and attenuated inflammatory responses in the LPS induced preeclampsia rat model which suggests that immunosuppressant might be an alternative management option for preeclampsia. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Parameter definition using vibration prediction software leads to significant drilling performance improvements

    Energy Technology Data Exchange (ETDEWEB)

    Amorim, Dalmo; Hanley, Chris Hanley; Fonseca, Isaac; Santos, Juliana [National Oilwell Varco, Houston TX (United States); Leite, Daltro J.; Borella, Augusto; Gozzi, Danilo [Petroleo Brasileiro S.A. (PETROBRAS), Rio de Janeiro, RJ (Brazil)

    2012-07-01

    The understanding and mitigation of downhole vibration has been a heavily researched subject in the oil industry as it results in more expensive drilling operations, as vibrations significantly diminish the amount of effective drilling energy available to the bit and generate forces that can push the bit or the Bottom Hole Assembly (BHA) off its concentric axis of rotation, producing high magnitude impacts with the borehole wall. In order to drill ahead, a sufficient amount of energy must be supplied by the rig to overcome the resistance of the drilling system, including the reactive torque of the system, drag forces, fluid pressure losses and energy dissipated by downhole vibrations, then providing the bit with the energy required to fail the rock. If the drill string enters resonant modes of vibration, not only does it decreases the amount of available energy to drill, but increases the potential for catastrophic downhole equipment and drilling bit failures. In this sense, the mitigation of downhole vibrations will result in faster, smoother, and cheaper drilling operations. A software tool using Finite Element Analysis (FEA) has been developed to provide better understanding of downhole vibration phenomena in drilling environments. The software tool calculates the response of the drilling system at various input conditions, based on the design of the wellbore along with the geometry of the Bottom Hole Assembly (BHA) and the drill string. It identifies where undesired levels of resonant vibration will be driven by certain combinations of specific drilling parameters, and also which combinations of drilling parameters will result in lower levels of vibration, so the least shocks, the highest penetration rate and the lowest cost per foot can be achieved. With the growing performance of personal computers, complex software systems modeling the drilling vibrations using FEA has been accessible to a wider audience of field users, further complimenting with real time

  10. Waste Minimization Improvements Achieved Through Six Sigma Analysis Result In Significant Cost Savings

    International Nuclear Information System (INIS)

    Mousseau, Jeffrey D.; Jansen, John R.; Janke, David H.; Plowman, Catherine M.

    2003-01-01

    Improved waste minimization practices at the Department of Energy's (DOE) Idaho National Engineering and Environmental Laboratory (INEEL) are leading to a 15% reduction in the generation of hazardous and radioactive waste. Bechtel, BWXT Idaho, LLC (BBWI), the prime management and operations contractor at the INEEL, applied the Six Sigma improvement process to the INEEL Waste Minimization Program to review existing processes and define opportunities for improvement. Our Six Sigma analysis team: composed of an executive champion, process owner, a black belt and yellow belt, and technical and business team members used this statistical based process approach to analyze work processes and produced ten recommendations for improvement. Recommendations ranged from waste generator financial accountability for newly generated waste to enhanced employee recognition programs for waste minimization efforts. These improvements have now been implemented to reduce waste generation rates and are producing positive results

  11. Prescription for antibiotics at drug shops and strategies to improve quality of care and patient safety

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Buregyeya, Esther; Rutebemberwa, Elizeus

    2016-01-01

    OBJECTIVES: The main objective of this study was to assess practices of antibiotic prescription at registered drug shops with a focus on upper respiratory tract infections among children in order to provide data for policy discussions aimed at improving quality of care and patient safety......-line drug for treatment of pneumonia in children according to the guidelines. CONCLUSIONS: There is urgent need to regulate drug shop practices of prescribing and selling antibiotics, for the safety of patients seeking care at these outlets....

  12. Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

    Directory of Open Access Journals (Sweden)

    Fang Li

    2017-05-01

    Full Text Available Huperzine A (Hup-A is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve (AUC of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P<0.01. The absorption rate constant (Ka and the apparent permeability coefficient (Papp for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of Ka and Papp of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration (Cmax of the blocking model were significantly lower than those of the control model (P<0.05. The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%, respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

  13. Improving pharmacokinetic-pharmacodynamic modeling to investigate anti-infective chemotherapy with application to the current generation of antimalarial drugs.

    Directory of Open Access Journals (Sweden)

    Katherine Kay

    Full Text Available Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii multiple drugs within a treatment combination; (iii differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very

  14. Contemporary Management of Acute Aortic Occlusion Has Evolved but Outcomes Have Not Significantly Improved.

    Science.gov (United States)

    Robinson, William P; Patel, Rupal K; Columbo, Jesse A; Flahive, Julie; Aiello, Francesco A; Baril, Donald T; Schanzer, Andres; Messina, Louis M

    2016-07-01

    hospitalization. AAO is now more commonly caused by in situ thrombosis rather than embolism. A high index of suspicion for AAO is required for prompt diagnosis and treatment, particularly when patients present with profound lower extremity neurologic deficit. In comparison with previous reports, the contemporary management of AAO includes increased use of axillobifemoral bypass and now involves endovascular revascularization, although a variety of open surgical procedures are utilized. However, the in-hospital mortality and morbidity of AAO has not decreased significantly over the last 2 decades and mid-term survival remains limited. Further study is required to identify strategies that improve outcomes after AAO. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Improvement of drug exposure data in a registration of congenital abnormalities

    DEFF Research Database (Denmark)

    de Jong van den Berg, L; Feenstra, N; Sørensen, Henrik Toft

    1999-01-01

    We examined the possibilities of improving the retrospective collection of data on drug use during pregnancy. The European Registration of Congenital Anomalies (EUROCAT) has registered information on maternal drug exposure in the northern Netherlands through a question on the notification form fo...

  16. Application of gold nanoparticles for improved drug efficiency

    Science.gov (United States)

    Shittu, K. O.; Bankole, M. T.; Abdulkareem, A. S.; Abubakre, O. K.; Ubaka, A. U.

    2017-09-01

    Due to increasing resistance of microorganisms towards current antibiotics, there is a need for new or enhanced antibiotics. Nanotechnology is a technology that enhances the use of gold nanoparticles (AuNP) in area of medical applications, especially as a drug carrier for targeted drug delivery. In this research, AuNPs was synthesized using biological method via bioreduction of Piper guineense aqueous leaf extract on tetra gold chloride, characterized using UV-Vis spectrophometer, DLS, TEM/EDS and FTIR. The synthesized AuNPs was covalently functionalized with polyethylene glycol and encapsulated with Lincomycin and in vitro dissolution methods was used to evaluate the potential performance of the formulated nanodrug. The nanodrug has highest release efficiency at the 9th minutes (23.4 mg ml-1 for 40 °C) and (29.5 mg ml-1 for 60 °C) compared with the non-nanodrug. The antibacterial potential of the nanodrug was seen on the gram-positive bacteria of Staphylococcus aureus and Streptococcus pyogenes with highest inhibitions of 18 mm (at 40 °C) and 16 mm (at 60 °C) for S. aureus, and 16 mm for S. pyogenes (both at 40 °C and 60 °C). The bacteria growth inhibition continued and lasted for 15 min, while that of non-nanodrug lasted for 9 min with lesser growth inhibition compared to the formulated nanodrug. This work shows that the presence of the AuNPs increased the release efficiency of lincomycin even at a lower concentration and also bacteria growth inhibition thereby suggesting the effectiveness of the nanodrug formulation.

  17. Efficiency improvement of nuclear power plant operation: the significant role of advanced nuclear fuel technologies

    International Nuclear Information System (INIS)

    Van Velde, AA. de; Burtak, F.

    2000-01-01

    In this paper authors deals with nuclear fuel cycle and their economic aspects. At Siemens, the developments focusing on the reduction of fuel cycle costs are currently directed on .further batch average burnup increase, .improvement of fuel reliability, .enlargement of fuel operation margins, .improvement of methods for fuel design and core analysis. These items will be presented in detail in the full paper and illustrated by the global operating experience of Siemens fuel for both PWRs and BWRs. (authors)

  18. Solubility and stability enhancement of curcumin: Improving drug properties of natural pigment

    Directory of Open Access Journals (Sweden)

    M J Ansari

    2016-01-01

    Full Text Available Aim: Water insolubility, low potency, and instability are inherent problems of several herbal medicines. Identity, strength, quality, and purity of herbal products are further compromised during manufacturing and storage. The aim of present work was to evaluate solubility and stability of curcumin, a pigment obtained from dried rhizomes of plant Cucrcuma longa. Materials and Methods: The stoichiometric ratios for inclusion complexation of curcumin with various cyclodextrins (CDs were determined by phase solubility analysis. Grinding, kneading, and freeze-drying were employed to determine optimum complexation. Complexes were evaluated for drug inclusion, solubility, and stability. Results: Stability constants were 11200 M−1 , 1557 M−1 , 2858 M−1 , and 2206 M−1 for α-, β-, γ-CD, and dimethyl β-CD (DIMEB, respectively, thus indicating good complex formation. Theoretical amounts of curcumin in binary products were between 80% and 97% with a maximum of 96.8% in curcumin-β-CD freeze-dried product. The complexation resulted in a marked improvement in the solubility of curcumin up to 60, 55, 56, and 1500 folds by α-, β-, γ-CD, and DIMEB, respectively. Inclusion complexation protected the drug from hydrolytic degradations as only 20-40% degradation was observed at the end of 8 h as opposed to >70% for pure curcumin. Conclusion: A significant improvement in the solubility and stability was observed with curcumin-CD complex as compared to pure curcumin.

  19. Deformable Hollow Periodic Mesoporous Organosilica Nanocapsules for Significantly Improved Cellular Uptake.

    Science.gov (United States)

    Teng, Zhaogang; Wang, Chunyan; Tang, Yuxia; Li, Wei; Bao, Lei; Zhang, Xuehua; Su, Xiaodan; Zhang, Fan; Zhang, Junjie; Wang, Shouju; Zhao, Dongyuan; Lu, Guangming

    2018-01-31

    Mesoporous solids have been widely used in various biomedical areas such as drug delivery and tumor therapy. Although deformability has been recognized as a prime important characteristic influencing cellular uptake, the synthesis of deformable mesoporous solids is still a great challenge. Herein, deformable thioether-, benzene-, and ethane-bridged hollow periodic mesoporous organosilica (HPMO) nanocapsules have successfully been synthesized for the first time by a preferential etching approach. The prepared HPMO nanocapsules possess uniform diameters (240-310 nm), high surface areas (up to 878 m 2 ·g -1 ), well-defined mesopores (2.6-3.2 nm), and large pore volumes (0.33-0.75 m 3 ·g -1 ). Most importantly, the HPMO nanocapsules simultaneously have large hollow cavities (164-270 nm), thin shell thicknesses (20-38 nm), and abundant organic moiety in the shells, which endow a lower Young's modulus (E Y ) of 3.95 MPa than that of solid PMO nanoparticles (251 MPa). The HPMOs with low E Y are intrinsically flexible and deformable in the solution, which has been well-characterized by liquid cell electron microscopy. More interestingly, it is found that the deformable HPMOs can easily enter into human breast cancer MCF-7 cells via a spherical-to-oval morphology change, resulting in a 26-fold enhancement in cellular uptake (43.1% cells internalized with nanocapsules versus 1.65% cells with solid counterparts). The deformable HPMO nanocapsules were further loaded with anticancer drug doxorubicin (DOX), which shows high killing effects for MCF-7 cells, demonstrating the promise for biomedical applications.

  20. Millisecond photo-thermal process on significant improvement of supercapacitor’s performance

    International Nuclear Information System (INIS)

    Wang, Kui; Wang, Jixiao; Wu, Ying; Zhao, Song; Wang, Zhi; Wang, Shichang

    2016-01-01

    Graphical abstract: A high way for charge transfer is created by a millisecond photo-thermal process which could decrease contact resistance among nanomaterials and improve the electrochemical performances. - Highlights: • Improve conductivity among nanomaterials with a millisecond photo-thermal process. • The specific capacitance can increase about 25% with an photo-thermal process. • The circle stability and rate capability can be improved above 10% with photo-thermal process. • Provide a new way that create electron path to improve electrochemical performance. - Abstract: Supercapacitors fabricated with nanomaterials usually have high specific capacitance and excellent performance. However, the small size of nanomaterials renders a considerable limitation of the contact area among nanomaterials, which is harmful to charge carrier transfer. This fact may hinder the development and application of nanomaterials in electrochemical storage systems. Here, a millisecond photo-thermal process was introduced to create a charge carries transfer path to decrease the contact resistance among nanomaterials, and enhance the electrochemical performance of supercapacitors. Polyaniline (PANI) nanowire, as a model nanomaterial, was used to modify electrodes under different photo-thermal process conditions. The modified electrodes were characterized by scanning electronic microscopy (SEM), cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and the results were analysed by equivalent circuit simulation. These results demonstrate that the photo-thermal process can alter the morphology of PANI nanowires, lower the charge transfer resistances and thus improve the performance of electrodes. The specific capacitance increase of the modified electrodes is about 25%. The improvement of the circle stability and rate capability are above 10%. To the best of our knowledge, this is the first attempt on research the effect of photo-thermal process on the conductivity

  1. Merits of using color and shape differentiation to improve the speed and accuracy of drug strength identification on over-the-counter medicines by laypeople.

    Science.gov (United States)

    Hellier, Elizabeth; Tucker, Mike; Kenny, Natalie; Rowntree, Anna; Edworthy, Judy

    2010-09-01

    This study aimed to examine the utility of using color and shape to differentiate drug strength information on over-the-counter medicine packages. Medication errors are an important threat to patient safety, and confusions between drug strengths are a significant source of medication error. A visual search paradigm required laypeople to search for medicine packages of a particular strength from among distracter packages of different strengths, and measures of reaction time and error were recorded. Using color to differentiate drug strength information conferred an advantage on search times and accuracy. Shape differentiation did not improve search times and had only a weak effect on search accuracy. Using color to differentiate drug strength information improves drug strength identification performance. Color differentiation of drug strength information may be a useful way of reducing medication errors and improving patient safety.

  2. A Review of New and Developing Technology to Significantly Improve Mars Sample-Return Missions

    Science.gov (United States)

    Carsey, F.; Brophy, J.; Gilmore, M.; Rodgers, D.; Wilcox, B.

    2000-07-01

    A JPL development activity was initiated in FY 1999 for the purpose of examining and evaluating technologies that could materially improve future (i.e., beyond the 2005 launch) Mars sample return missions. The scope of the technology review was comprehensive and end-to-end; the goal was to improve mass, cost, risk, and scientific return. A specific objective was to assess approaches to sample return with only one Earth launch. While the objective of the study was specifically for sample-return, in-situ missions can also benefit from using many of the technologies examined.

  3. Clinicopathological significance and potential drug target of CDH1 in breast cancer: a meta-analysis and literature review

    Directory of Open Access Journals (Sweden)

    Huang R

    2015-09-01

    Full Text Available Ruixue Huang,* Ping Ding,* Fei Yang*Department of Occupational and Environmental Health, School of Public Health, Central South University, Changsha, Hunan, People’s Republic of China*All authors contributed equally to this workAbstract: CDH1, as a tumor suppressor gene, contributes sporadic breast cancer (BC progression. However, the association between CDH1 hypermethylation and BC, and its clinicopathological significance remains unclear. We conducted a meta-analysis to investigate the relationship between the CDH1 methylation profile and the major clinicopathological features. A detailed literature was searched through the electronic databases PubMed, Web of Science™, and EMBASE™ for related research publications. The data were extracted and assessed by two reviewers independently. Odds ratios (ORs with corresponding confidence intervals (CIs were calculated and summarized respectively. The frequency of CDH1 methylation was significantly higher in invasive ductal carcinoma than in normal breast tissues (OR =5.83, 95% CI 3.76–9.03, P<0.00001. CDH1 hypermethylation was significantly higher in estrogen receptor (ER-negative BC than in ER-positive BC (OR =0.62, 95% CI 0.43–0.87, P=0.007. In addition, we found that the CDH1 was significantly methylated in HER2-negative BC than in HER2-positive BC (OR =0.26, 95% CI 0.15–0.44, P<0.00001. However, CDH1 methylation frequency was not associated with progesterone receptor (PR status, or with grades, stages, or lymph node metastasis of BC patients. Our results indicate that CDH1 hypermethylation is a potential novel drug target for developing personalized therapy. CDH1 hypermethylation is strongly associated with ER-negative and HER2-negative BC, respectively, suggesting CDH1 methylation status could contribute to the development of novel therapeutic approaches for the treatment of ER-negative or HER2-negative BC with aggressive tumor biology.Keywords: methylation, estrogen receptor, HER2

  4. Improving aerosol drug delivery during invasive mechanical ventilation with redesigned components.

    Science.gov (United States)

    Longest, P Worth; Azimi, Mandana; Golshahi, Laleh; Hindle, Michael

    2014-05-01

    Patients receiving invasive mechanical ventilation with an endotracheal tube (ETT) can often benefit from pharmaceutical aerosols; however, drug delivery through the ventilator circuit is known to be very inefficient. The objective of this study was to improve the delivery of aerosol through an invasive mechanical ventilation system by redesigning circuit components using a streamlining approach. Redesigned components were the T-connector interface between the nebulizer and ventilator line and the Y-connector leading to the ETT. The streamlining approach seeks to minimize aerosol deposition and loss by eliminating sharp changes in flow direction and tubing diameter that lead to flow disruption. Both in vitro experiments and computational fluid dynamic (CFD) simulations were applied to analyze deposition and emitted dose of drug for multiple droplet size distributions, flows, and ETT sizes used in adults. The experimental results demonstrated that the streamlined components improved delivery through the circuit by factors ranging from 1.3 to 1.5 compared with a commercial system for adult ETT sizes of 8 and 9 mm. The overall delivery efficiency was based on the bimodal aspect of the aerosol distributions and could not be predicted by median diameter alone. CFD results indicated a 20-fold decrease in turbulence in the junction region for the streamlined Y resulting in a maximum 9-fold decrease in droplet deposition. The relative effectiveness of the streamlined designs was found to increase with increasing particle size and increasing flow, with a maximum improvement in emitted dose of 1.9-fold. Streamlined components can significantly improve the delivery of pharmaceutical aerosols during mechanical ventilation based on an analysis of multiple aerosol generation devices, ETT sizes, and flows.

  5. Could a revision of the current guidelines for cancer drug use improve the quality of cancer treatment?

    Science.gov (United States)

    Lippert, Theodor H; Ruoff, Hans-Jörg; Volm, Manfred

    2014-01-01

    Clinical practice guidelines are indispensable for such a variable disease as malignant solid tumors, with the complex possibilities of drug treatment. The current guidelines may be criticized on several points, however. First, there is a lack of information on the outcome of treatment, such as the expected success and failure rates. Treating not only drug responders but also nonresponders, that is, patients with drug resistance, must result in failures. There is no mention of the possibility of excluding the drug nonresponders, identifiable by special laboratory tests and no consideration is given to the different side effects of the recommended drug regimens. Nor are there any instructions concerning tumor cases for which anticancer drug treatment is futile. In such cases, early palliative care may lead to significant improvements in both life quality and life expectancy. Not least, there is no transparency concerning the preparation of the guidelines: persons cannot be identified who could give a statement of conflicts of interest, and responsibility is assumed only by anonymous medical associations. A revision of the current guidelines could considerably improve cancer treatment.

  6. Simple PCR assays improve the sensitivity of HIV-1 subtype B drug resistance testing and allow linking of resistance mutations.

    Directory of Open Access Journals (Sweden)

    Jeffrey A Johnson

    Full Text Available BACKGROUND: The success of antiretroviral therapy is known to be compromised by drug-resistant HIV-1 at frequencies detectable by conventional bulk sequencing. Currently, there is a need to assess the clinical consequences of low-frequency drug resistant variants occurring below the detection limit of conventional genotyping. Sensitive detection of drug-resistant subpopulations, however, requires simple and practical methods for routine testing. METHODOLOGY: We developed highly-sensitive and simple real-time PCR assays for nine key drug resistance mutations and show that these tests overcome substantial sequence heterogeneity in HIV-1 clinical specimens. We specifically used early wildtype virus samples from the pre-antiretroviral drug era to measure background reactivity and were able to define highly-specific screening cut-offs that are up to 67-fold more sensitive than conventional genotyping. We also demonstrate that sequencing the mutation-specific PCR products provided a direct and novel strategy to further detect and link associated resistance mutations, allowing easy identification of multi-drug-resistant variants. Resistance mutation associations revealed in mutation-specific amplicon sequences were verified by clonal sequencing. SIGNIFICANCE: Combined, sensitive real-time PCR testing and mutation-specific amplicon sequencing provides a powerful and simple approach that allows for improved detection and evaluation of HIV-1 drug resistance mutations.

  7. Drug supply indicators: Pitfalls and possibilities for improvements to assist comparative analysis.

    Science.gov (United States)

    Singleton, Nicola; Cunningham, Andrew; Groshkova, Teodora; Royuela, Luis; Sedefov, Roumen

    2018-06-01

    Interventions to tackle the supply of drugs are seen as standard components of illicit drug policies. Therefore drug market-related administrative data, such as seizures, price, purity and drug-related offending, are used in most countries for policy monitoring and assessment of the drug situation. International agencies, such as the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and the UN Office of Drugs and Crime, also monitor and report on the drug situation cross-nationally and therefore seek to collect and make available key data in a uniform manner from the countries they cover. However, these data are not primarily collected for this purpose, which makes interpretation and comparative analysis difficult. Examples of limitations of these data sources include: the extent to which they reflect operational priorities rather than market changes; question marks over the robustness of and consistency in data collection methods, and issues around the timeliness of data availability. Such problems are compounded by cultural, social and contextual differences between countries. Making sense of such data is therefore challenging and extreme care needs to be taken using it. Nevertheless, these data provide an important window on a hidden area, so improving the quality of the data collected and expanding its scope should be a priority for those seeking to understand or monitor drug markets and supply reduction. In addition to highlighting some of the potential pitfalls in using supply indicators for comparative analysis, this paper presents a selection of options for improvements based on the current EMCDDA programme of work to improve their supply-related monitoring and analysis. The conceptual framework developed to steer this work may have wider application. Adopting this approach has the potential to provide a richer picture of drug markets, at both national and international levels, and make it easier to compare data between countries. Copyright

  8. Dry coating of micronized API powders for improved dissolution of directly compacted tablets with high drug loading.

    Science.gov (United States)

    Han, Xi; Ghoroi, Chinmay; Davé, Rajesh

    2013-02-14

    Motivated by our recent study showing improved flow and dissolution rate of the active pharmaceutical ingredient (API) powders (20 μm) produced via simultaneous micronization and surface modification through continuous fluid energy milling (FEM) process, the performance of blends and direct compacted tablets with high drug loading is examined. Performance of 50 μm API powders dry coated without micronization is also considered for comparison. Blends of micronized, non-micronized, dry coated or uncoated API powders at 30, 60 and 70% drug loading, are examined. The results show that the blends containing dry coated API powders, even micronized ones, have excellent flowability and high bulk density compared to the blends containing uncoated API, which are required for direct compaction. As the drug loading increases, the difference between dry coated and uncoated blends is more pronounced, as seen in the proposed bulk density-FFC phase map. Dry coating led to improved tablet compactibility profiles, corresponding with the improvements in blend compressibility. The most significant advantage is in tablet dissolution where for all drug loadings, the t(80) for the tablets with dry coated APIs was well under 5 min, indicating that this approach can produce nearly instant release direct compacted tablets at high drug loadings. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Reducing dysfunctional beliefs about sleep does not significantly improve insomnia in cognitive behavioral therapy.

    Science.gov (United States)

    Okajima, Isa; Nakajima, Shun; Ochi, Moeko; Inoue, Yuichi

    2014-01-01

    The present study examined to examine whether improvement of insomnia is mediated by a reduction in sleep-related dysfunctional beliefs through cognitive behavioral therapy for insomnia. In total, 64 patients with chronic insomnia received cognitive behavioral therapy for insomnia consisting of 6 biweekly individual treatment sessions of 50 minutes in length. Participants were asked to complete the Athens Insomnia Scale and the Dysfunctional Beliefs and Attitudes about Sleep scale both at the baseline and at the end of treatment. The results showed that although cognitive behavioral therapy for insomnia greatly reduced individuals' scores on both scales, the decrease in dysfunctional beliefs and attitudes about sleep with treatment did not seem to mediate improvement in insomnia. The findings suggest that sleep-related dysfunctional beliefs endorsed by patients with chronic insomnia may be attenuated by cognitive behavioral therapy for insomnia, but changes in such beliefs are not likely to play a crucial role in reducing the severity of insomnia.

  10. Reducing Dysfunctional Beliefs about Sleep Does Not Significantly Improve Insomnia in Cognitive Behavioral Therapy

    OpenAIRE

    Okajima, Isa; Nakajima, Shun; Ochi, Moeko; Inoue, Yuichi

    2014-01-01

    The present study examined to examine whether improvement of insomnia is mediated by a reduction in sleep-related dysfunctional beliefs through cognitive behavioral therapy for insomnia. In total, 64 patients with chronic insomnia received cognitive behavioral therapy for insomnia consisting of 6 biweekly individual treatment sessions of 50 minutes in length. Participants were asked to complete the Athens Insomnia Scale and the Dysfunctional Beliefs and Attitudes about Sleep scale both at the...

  11. Significant performance improvement obtained in a wireless mesh network using a beamswitching antenna

    CSIR Research Space (South Africa)

    Lysko, AA

    2012-09-01

    Full Text Available mesh network operated in a fixed 11 Mbps mode. The throughput improvement in multi-hop communication obtained in the presence of an interferer is tenfold, from 0.2 Mbps to 2 Mbps. Index Terms?antenna, smart antenna, wireless mesh network, WMN... efficiency in the communications, and active research and development of new methods and technologies enabling this at the physical layer, including multiple antenna techniques, such as multiple input multiple output (MIMO) and smart antennas...

  12. An injectable hybrid nanoparticle-in-oil-in-water submicron emulsion for improved delivery of poorly soluble drugs

    Science.gov (United States)

    Wang, Shuo; Wang, Hua; Liang, Wenquan; Huang, Yongzhuo

    2012-04-01

    Poor drugability problems are commonly seen in a class of chemical entities with poor solubility in water and oil, and moreover, physicochemical instability of these compounds poses extra challenges in design of dosage forms. Such problems contribute a significant high failure rate in new drug development. A hybrid nanoparicle-in-oil-in-water (N/O/W) submicron emulsion was proposed for improved delivery of poorly soluble and unstable drugs (e.g., dihydroartemisinin (DHA)). DHA is known for its potent antimalarial effect and antitumor activity. However, its insolubility and instability impose big challenges for formulations, and so far, no injectable dosage forms are clinically available yet. Therefore, an injectable DHA N/O/W system was developed. Unlike other widely-explored systems (e.g., liposomes, micelles, and emulsions), in which low drug load and only short-term storage are often found, the hybrid submicron emulsion possesses three-fold higher drug-loading capacity than the conventional O/W emulsion. Of note, it can be manufactured into a freeze-drying form and can render its storage up to 6 months even in room temperature. The in vivo studies demonstrated that the PK profiles were significantly improved, and this injectable system was effective in suppressing tumor growth. The strategy provides a useful solution to effective delivery of such a class of drugs.

  13. Nanocrystal: a novel approach to overcome skin barriers for improved topical drug delivery.

    Science.gov (United States)

    Patel, Viral; Sharma, Om Prakash; Mehta, Tejal

    2018-04-01

    Skin is an important route of drug delivery for the treatment of various dermatological conditions. The advent of nanotechnology is paving the roadmaps for topical drug delivery by providing sustained release as well as maintaining a localized effect, outweighing the toxicity concern. Area covered: This review highlighted the morphology of skin, its barrier nature as well as drug penetration pathways after topical application of formulations. The existing methods to improve topical drug delivery, by infringing or permeating the skin barriers, are discussed. This context concretes the foundation to accentuate the need for the development of nanocrystal-based topical formulation. The mechanism of drug release, immediate as well as sustained release, after topical administration of drug nanocrystals is also elaborated. The special emphasis is given on the breakthrough achieved, in topical drug delivery using drug nanocrystals, so far in the plethora of literature, patents, and products, under clinical trial as well as in the market. Expert opinion: The current research on nanocrystals for topical drug delivery is highlighting the breakthroughs achieved so far. The output of these research envisages that topical nanocrystals based formulations can be a novel strategy for the drugs which are facing solubility, bioavailability and toxicity concerns.

  14. Effectiveness of combinations of Ayurvedic drugs in alleviating drug toxicity and improving quality of life of cancer patients treated with chemotherapy.

    Science.gov (United States)

    Deshmukh, Vineeta; Kulkarni, Arvind; Bhargava, Sudhir; Patil, Tushar; Ramdasi, Vijay; Gangal, Sudha; Godse, Vasanti; Datar, Shrinivas; Gujar, Shweta; Sardeshmukh, Sadanand

    2014-11-01

    This study was conducted to assess the effectiveness of combinations of Ayurvedic drugs in alleviating the toxicity of chemotherapy and improving the quality of life of cancer patients. The following was the research question: Can Ayurvedic drugs be used to alleviate the side effects of chemotherapy and improve the quality of life of cancer patients? Random patients with malignancies of different tissues, grades, and stages were divided into two groups according to their treatment modality. Group 1 consisted of 15 patients treated with six cycles of chemotherapy alone and who did not receive any Ayurvedic drugs (control group). Group 2 consisted of patients (divided into three arms) who received Ayurvedic drugs during chemotherapy and after chemotherapy. Nineteen patients in arm 1 received the Ayurvedic drugs Mauktikyukta Kamdudha (MKD) and Mauktikyukta Praval Panchamruta (MPP) along with a full course of chemotherapy. Fifteen patients in arm 2 received the same Ayurvedic treatment, but the treatment was started after completing the sixth cycle of chemotherapy. Eighteen patients in arm 3 received the Suvarnabhasmadi formulation (SBD) in addition to MKD and MPP after completing the sixth cycle of chemotherapy. Treatment was given for 16 weeks in all three arms. Patients from both groups were observed for a period of 6 months. The assessment criteria depended on Common Toxicity Criteria (CTC designed by NIH and NCI): haemogram; weight; physical examination including Quality of Life Questionnaire (QLQ designed by the European Organization of Research and Treatment of Cancer (EORTC)) for functional, symptom and global scores; and Karnofsky score for assessment of general well-being and activities of daily life. ECOG (Eastern Cooperation Oncology Group) score was also additionally included for assessment of symptoms. From amongst the symptomatic criteria, there was significant improvement in all the three arms compared with the control group in nausea, loss of appetite

  15. Intraoperative Sensorcaine significantly improves postoperative pain management in outpatient reduction mammaplasty.

    Science.gov (United States)

    Culliford, Alfred T; Spector, Jason A; Flores, Roberto L; Louie, Otway; Choi, Mihye; Karp, Nolan S

    2007-09-15

    Breast reduction is one of the most frequently performed plastic surgical procedures in the United States; more than 160,500 patients underwent the procedure in 2005. Many outpatient reduction mammaplasty patients report the greatest postoperative discomfort in the first 48 hours. The authors' investigated the effect of intraoperative topical application of the long-acting local anesthetic agent bupivacaine (Sensorcaine or Marcaine) on postoperative pain, time to postanesthesia care unit discharge, and postoperative use of narcotic medication. In a prospective, randomized, single-blind trial, intraoperative use of Sensorcaine versus placebo (normal saline) was compared. Postoperative pain was quantified using the visual analogue scale, and time to discharge from the postanesthesia care unit was recorded. Patients documented their outpatient pain medication usage. Of the 37 patients enrolled in the study, 20 were treated with intraoperative topical Sensorcaine and 17 received placebo. Patients treated with Sensorcaine were discharged home significantly faster (2.9 hours versus 3.8 hours, p = 0.002). The control arm consistently had higher pain scores in the postanesthesia care unit (although not statistically significant) than the Sensorcaine group using the visual analogue scale system. Furthermore, patients receiving Sensorcaine required significantly less narcotic medication while recovering at home (mean, 3.5 tablets of Vicodin) than the control group (mean, 6.4 tablets; p = 0.001). There were no complications resulting from Sensorcaine usage. This prospective, randomized, single-blind study demonstrates that a single dose of intraoperative Sensorcaine provides a safe, inexpensive, and efficacious way to significantly shorten the length of postanesthesia care unit stay and significantly decrease postoperative opioid analgesic use in patients undergoing ambulatory reduction mammaplasty.

  16. Significant Improvements in Pyranometer Nighttime Offsets Using High-Flow DC Ventilation

    Energy Technology Data Exchange (ETDEWEB)

    Kutchenreiter, Mark; Michalski, J.J.; Long, C.N.; Habte, Aron

    2017-05-22

    Accurate solar radiation measurements using pyranometers are required to understand radiative impacts on the Earth's energy budget, solar energy production, and to validate radiative transfer models. Ventilators of pyranometers, which are used to keep the domes clean and dry, also affect instrument thermal offset accuracy. This poster presents a high-level overview of the ventilators for single-black-detector pyranometers and black-and-white pyranometers. For single-black-detector pyranometers with ventilators, high-flow-rate (50-CFM and higher), 12-V DC fans lower the offsets, lower the scatter, and improve the predictability of nighttime offsets compared to lower-flow-rate (35-CFM), 120-V AC fans operated in the same type of environmental setup. Black-and-white pyranometers, which are used to measure diffuse horizontal irradiance, sometimes show minor improvement with DC fan ventilation, but their offsets are always small, usually no more than 1 W/m2, whether AC- or DC-ventilated.

  17. Nitrite addition to acidified sludge significantly improves digestibility, toxic metal removal, dewaterability and pathogen reduction

    Science.gov (United States)

    Du, Fangzhou; Keller, Jürg; Yuan, Zhiguo; Batstone, Damien J.; Freguia, Stefano; Pikaar, Ilje

    2016-12-01

    Sludge management is a major issue for water utilities globally. Poor digestibility and dewaterability are the main factors determining the cost for sludge management, whereas pathogen and toxic metal concentrations limit beneficial reuse. In this study, the effects of low level nitrite addition to acidified sludge to simultaneously enhance digestibility, toxic metal removal, dewaterability and pathogen reduction were investigated. Waste activated sludge (WAS) from a full-scale waste water treatment plant was treated at pH 2 with 10 mg NO2--N/L for 5 h. Biochemical methane potential tests showed an increase in the methane production of 28%, corresponding to an improvement from 247 ± 8 L CH4/kg VS to 317 ± 1 L CH4/kg VS. The enhanced removal of toxic metals further increased the methane production by another 18% to 360 ± 6 L CH4/kg VS (a total increase of 46%). The solids content of dewatered sludge increased from 14.6 ± 1.4% in the control to 18.2 ± 0.8%. A 4-log reduction for both total coliforms and E. coli was achieved. Overall, this study highlights the potential of acidification with low level nitrite addition as an effective and simple method achieving multiple improvements in terms of sludge management.

  18. Efficiency improvement of nuclear power plant operation: the significant role of advanced nuclear fuel technologies

    International Nuclear Information System (INIS)

    Velde Van de, A.; Burtak, F.

    2001-01-01

    Due to the increased liberalisation of the power markets, nuclear power generation is being exposed to high cost reduction pressure. In this paper we highlight the role of advanced nuclear fuel technologies to reduce the fuel cycle costs and therefore increase the efficiency of nuclear power plant operation. The key factor is a more efficient utilisation of the fuel and present developments at Siemens are consequently directed at (i) further increase of batch average burnup, (ii) improvement of fuel reliability, (iii) enlargement of fuel operation margins and (iv) improvement of methods for fuel design and core analysis. As a result, the nuclear fuel cycle costs for a typical LWR have been reduced during the past decades by about US$ 35 million per year. The estimated impact of further burnup increases on the fuel cycle costs is expected to be an additional saving of US$10 - 15 million per year. Due to the fact that the fuel will operate closer to design limits, a careful approach is required when introducing advanced fuel features in reload quantities. Trust and co-operation between the fuel vendors and the utilities is a prerequisite for the common success. (authors)

  19. Significant improvement of mouse cloning technique by treatment with trichostatin A after somatic nuclear transfer

    International Nuclear Information System (INIS)

    Kishigami, Satoshi; Mizutani, Eiji; Ohta, Hiroshi; Hikichi, Takafusa; Thuan, Nguyen Van; Wakayama, Sayaka; Bui, Hong-Thuy; Wakayama, Teruhiko

    2006-01-01

    The low success rate of animal cloning by somatic cell nuclear transfer (SCNT) is believed to be associated with epigenetic errors including abnormal DNA hypermethylation. Recently, we elucidated by using round spermatids that, after nuclear transfer, treatment of zygotes with trichostatin A (TSA), an inhibitor of histone deacetylase, can remarkably reduce abnormal DNA hypermethylation depending on the origins of transferred nuclei and their genomic regions [S. Kishigami, N. Van Thuan, T. Hikichi, H. Ohta, S. Wakayama. E. Mizutani, T. Wakayama, Epigenetic abnormalities of the mouse paternal zygotic genome associated with microinsemination of round spermatids, Dev. Biol. (2005) in press]. Here, we found that 5-50 nM TSA-treatment for 10 h following oocyte activation resulted in more efficient in vitro development of somatic cloned embryos to the blastocyst stage from 2- to 5-fold depending on the donor cells including tail tip cells, spleen cells, neural stem cells, and cumulus cells. This TSA-treatment also led to more than 5-fold increase in success rate of mouse cloning from cumulus cells without obvious abnormality but failed to improve ES cloning success. Further, we succeeded in establishment of nuclear transfer-embryonic stem (NT-ES) cells from TSA-treated cloned blastocyst at a rate three times higher than those from untreated cloned blastocysts. Thus, our data indicate that TSA-treatment after SCNT in mice can dramatically improve the practical application of current cloning techniques

  20. The Improvement of Screening the Significant Factors of Oil Blends as Bio lubricant Base Stock

    International Nuclear Information System (INIS)

    Noor Hajarul Ashikin Shamsuddin; Rozaini Abdullah; Zainab Hamzah; Siti Jamilah Hanim Mohd Yusof

    2015-01-01

    A new formulation bio lubricant base stock was developed by blending of waste cooking oil (WCO) with Jatropha curcas oil (JCO). The objective of this research is to evaluate significant factors contributing to the production of oil blends for bio lubricant application. The significant factors used in this study were oil ratio (WCO:JCO), agitation times (min) and agitation speed (rpm). The blended oil bio based lubricant was used to determine the saponification, acid, peroxide and iodine values. The experimental design used in this study was the 2 level-factorial design. In this experiment, it was found that the effect of oil ratio and interaction of oil ratio and agitation speed gave the most significant effect in oil blends as bio lubricant base stock. The highest ratio of oil blend 80 %:20 % WCO:JCO, with low agitation speed of 300 rpm and low agitation time of 30 minutes gave the optimum results. The acid, saponification, peroxide and iodine values obtained were 0.517±0.08 mg KOH/ g, 126.23±1.62 mg/ g, 7.5±2.0 m eq/ kg and 50.42±2.85 mg/ g respectively. A higher ratio of waste cooking oil blends was found to be favourable as bio lubricant base stock. (author)

  1. EASE-Grid 2.0: Incremental but Significant Improvements for Earth-Gridded Data Sets

    Directory of Open Access Journals (Sweden)

    Matthew H. Savoie

    2012-03-01

    Full Text Available Defined in the early 1990s for use with gridded satellite passive microwave data, the Equal-Area Scalable Earth Grid (EASE-Grid was quickly adopted and used for distribution of a variety of satellite and in situ data sets. Conceptually easy to understand, EASE-Grid suffers from limitations that make it impossible to format in the widely popular GeoTIFF convention without reprojection. Importing EASE-Grid data into standard mapping software packages is nontrivial and error-prone. This article defines a standard for an improved EASE-Grid 2.0 definition, addressing how the changes rectify issues with the original grid definition. Data distributed using the EASE-Grid 2.0 standard will be easier for users to import into standard software packages and will minimize common reprojection errors that users had encountered with the original EASE-Grid definition.

  2. Self-Micro Emulsifying Drug Delivery Systems: a Strategy to Improve Oral Bioavailability

    Directory of Open Access Journals (Sweden)

    Vijay K. Sharma

    Full Text Available Aim: Oral route has always been the favorite route of drug administration in many diseases and till today it is the first way investigated in the development of new dosage forms. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility, thereby pose problems in their formulation. For the therapeutic delivery of lipophilic active moieties (BCS class II drugs, lipid based formulations are inviting increasing attention. Methods: To that aim, from the web sites of PubMed, HCAplus, Thomson, and Registry were used as the main sources to perform the search for the most significant research articles published on the subject. The information was then carefully analyzed, highlighting the most important results in the formulation and development of self-micro emulsifying drug delivery systems as well as its therapeutic activity. Results: Self-emulsifying drug delivery system (SMEDDS has gained more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of drug(s toward specific absorption window in GIT, and protection of drug(s from the unreceptive environment in gut. Conclusions: This article gives a complete overview of SMEDDS as a promising approach to effectively deal with the problem of poorly soluble molecules.

  3. A patient/family-centered strategic plan can drive significant improvement.

    Science.gov (United States)

    Brilli, Richard J; Crandall, Wallace V; Berry, Janet C; Stoverock, Linda; Rosen, Kerry; Budin, Lee; Kelleher, Kelly J; Gleeson, Sean P; Davis, J Terrance

    2014-08-01

    The use of a PFCSP, as a road map to operationalize the hospital's vision, has been a compelling paradigm to achieve significant QI results. The framework is simple yet directly aligns with the IOM domains of quality. It has inspired and helped actively engage hospital personnel in the work required to achieve the goals and vision of the hospital system. Five years after initiating this type of plan, activity is flourishing in each of the domains and midterm results are substantial. We think that the nature of this strategic plan has been an important aspect of our success to date.

  4. An integrated PRA module for fast determination of risk significance and improvement effectiveness

    International Nuclear Information System (INIS)

    Chao, Chun-Chang; Lin, Jyh-Der

    2004-01-01

    With the widely use of PRA technology in risk-informed applications, to predict the changes of CDF and LERF becomes a standard process for risk-informed applications. This paper describes an integrated PRA module prepared for risk-informed applications. The module contains a super risk engine, a super fault tree engine, an advanced PRA model and a tool for data base maintenance. The individual element of the module also works well for purpose other than risk-informed applications. The module has been verified and validated through a series of scrupulous benchmark tests with similar software. The results of the benchmark tests showed that the module has remarkable accuracy and speed even for an extremely large-size top-logic fault tree as well as for the case in which large amount of MCSs may be generated. The risk monitor for nuclear power plants in Taiwan is the first application to adopt the module. The results predicted by the risk monitor are now accepted by the regulatory agency. A tool to determine the risk significance according to the inspection findings will be the next application to adopt the module in the near future. This tool classified the risk significance into four different color codes according to the level of increase on CDF. Experience of application showed that the flexibility, the accuracy and speed of the module make it useful in any risk-informed applications when risk indexes must be determined by resolving a PRA model. (author)

  5. Progressive degradation of alloy 690 and the development of a significant improvement in alloy 800CR

    International Nuclear Information System (INIS)

    Staehle, Roger W.; Arioka, Koji; Tapping, Robert

    2015-01-01

    The present most widely used alloys for tubing in steam generators and structural materials in water cooled reactors are Alloy 690 and Alloy 800. However, both alloys, while improved over Alloy 600 may not meet the needs of longer range applications in the range of 80-100 years. Alloy 690 sustains damage resulting from the formation of cavities at grain boundaries which eventually cover about 50% of the area of the grain boundaries with the remainder covering being covered with carbides. The cavities seem to nucleate on the carbides leaving the grain boundaries a structure of cavities and carbides. Such a structure will lead the Alloy 690 to fail completely. Normal Alloy 800 does not produce such cavities and probably retains a large amount of its corrosion resistance but does sustain progressive SCC at low rate. A new alloy, 800CR, has been developed in a collaboration among Arioka, Tapping, and Staehle. This alloy is based on a Cr composition of 23.5-27% with the remainder retaining the previous Alloy 800 composition. 800CR sustains a crack velocity about 100 times less than Alloy 690 and a negligible rate of initiation. The 800CR, alloy is now seeking a patent. (authors)

  6. Significant improvements of electrical discharge machining performance by step-by-step updated adaptive control laws

    Science.gov (United States)

    Zhou, Ming; Wu, Jianyang; Xu, Xiaoyi; Mu, Xin; Dou, Yunping

    2018-02-01

    In order to obtain improved electrical discharge machining (EDM) performance, we have dedicated more than a decade to correcting one essential EDM defect, the weak stability of the machining, by developing adaptive control systems. The instabilities of machining are mainly caused by complicated disturbances in discharging. To counteract the effects from the disturbances on machining, we theoretically developed three control laws from minimum variance (MV) control law to minimum variance and pole placements coupled (MVPPC) control law and then to a two-step-ahead prediction (TP) control law. Based on real-time estimation of EDM process model parameters and measured ratio of arcing pulses which is also called gap state, electrode discharging cycle was directly and adaptively tuned so that a stable machining could be achieved. To this end, we not only theoretically provide three proved control laws for a developed EDM adaptive control system, but also practically proved the TP control law to be the best in dealing with machining instability and machining efficiency though the MVPPC control law provided much better EDM performance than the MV control law. It was also shown that the TP control law also provided a burn free machining.

  7. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    Science.gov (United States)

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

  8. Community intervention to improve knowledge and practices on commonly used drugs.

    Science.gov (United States)

    Kafle, K K; Karkee, S B; Shrestha, N; Prasad, R R; Bhuju, G B; Das, P L; Chataut, B D

    2010-01-01

    World Health Organisation (WHO) estimates that about half of all medicines are inappropriately prescribed, dispensed and sold and about half of all patients fail to take their medicines properly. The overall objective of the study was improving use of medicines in the community by creating awareness among different target groups. It was a pre-post comparison of intervention implemented at the community level in purposively selected Bhaktapur District of Kathmandu Valley, Nepal. The study was conducted in the private schools of the study district. Twelve schools were randomly selected. Thereafter, students from 6-9 grades were listed from the selected schools. Then 15% of the total students in each grade were randomly selected to get six students from each grade of the each school, totaling 288 students. The households of the selected students served as the sample households for the study. Thus, there were 288 households sampled for the study. The intervention and the targeted intermediary groups consisted of a. training of schools teachers b. training of journalists c. interactive discussions of trained school teachers with school children using key messages and c. communication of key messages through the local F.M. radio, newspaper/magazine. There was a significant increase in correct knowledge on action of antibiotics and excellent knowledge on the methods of administration of antibiotics of households after the intervention. Similarly, there was a significant increase in knowledge on cough as a disease and a significant decrease in the use of cough medicines after intervention. There was also a significant increase in excellent knowledge on the sources of vitamins and a significant decrease in the use of vitamin/tonics after the intervention. The participation of intermediary groups eg. school teachers, journalists and school children in the implementation of intervention were successful. The groups have fulfilled the commitments in implementing the plan of

  9. Significant improvement of pig cloning efficiency by treatment with LBH589 after somatic cell nuclear transfer.

    Science.gov (United States)

    Jin, Jun-Xue; Li, Suo; Gao, Qing-Shan; Hong, Yu; Jin, Long; Zhu, Hai-Ying; Yan, Chang-Guo; Kang, Jin-Dan; Yin, Xi-Jun

    2013-10-01

    The low success rate of animal cloning by somatic cell nuclear transfer (SCNT) associates with epigenetic aberrancy, including the abnormal acetylation of histones. Altering the epigenetic status by histone deacetylase inhibitors (HDACi) enhances the developmental potential of SCNT embryos. In the current study, we examined the effects of LBH589 (panobinostat), a novel broad-spectrum HDACi, on the nuclear reprogramming and development of pig SCNT embryos in vitro. In experiment 1, we compared the in vitro developmental competence of nuclear transfer embryos treated with different concentrations of LBH589. Embryos treated with 50 nM LBH589 for 24 hours showed a significant increase in the rate of blastocyst formation compared with the control or embryos treated with 5 or 500 nM LBH589 (32.4% vs. 11.8%, 12.1%, and 10.0%, respectively, P < 0.05). In experiment 2, we examined the in vitro developmental competence of nuclear transfer embryos treated with 50 nM LBH589 for various intervals after activation and 6-dimethylaminopurine. Embryos treated for 24 hours had higher rates of blastocyst formation than the other groups. In experiment 3, when the acetylation of H4K12 was examined in SCNT embryos treated for 6 hours with 50 nM LBH589 by immunohistochemistry, the staining intensities of these proteins in LBH589-treated SCNT embryos were significantly higher than in the control. In experiment 4, LBH589-treated nuclear transfer and control embryos were transferred into surrogate mothers, resulting in three (100%) and two (66.7%) pregnancies, respectively. In conclusion, LBH589 enhances the nuclear reprogramming and developmental potential of SCNT embryos by altering the epigenetic status and expression, and increasing blastocyst quality. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  10. Silver chlorobromide nanocubes with significantly improved uniformity: synthesis and assembly into photonic crystals

    Energy Technology Data Exchange (ETDEWEB)

    Li, Zheng; Okasinski, John S.; Gosztola, David J.; Ren, Yang; Sun, Yugang

    2015-01-01

    Silver chlorobromide (AgClxBr1-x, 0 < x < 1) nanocubes with a highly uniform size, morphology, and crystallinity have been successfully synthesized through a co-precipitation of Ag+ ions with both Cl- and Br- ions in ethylene glycol containing polyvinyl pyrrolidone at mild temperatures. Compositions of the synthesized nanocubes can be easily tuned by controlling the molar ratio of Cl- to Br- ions in the reaction solutions. The size of the nanocubes is determined by varying a number of parameters including the molar ratio of Cl- to Br- ions, injection rate of Ag+ ions, and reaction temperature. The real-time formation of colloidal AgClxBr1-x nanocubes has been monitored, for the first time, by in situ highenergy synchrotron X-ray diffraction. The time-resolved results reveal that a fast injection rate of Ag+ ions is critical for the formation of AgClxBr1-x nanocubes with a highly pure face-centered cubic crystalline phase. The improved uniformity of the AgClxBr1-x nanocubes is beneficial for assembling them into order superlattices (e.g., photonic crystals) even by simply applying centrifugation forces. The stop band of the resulting photonic crystals can be easily tuned from the ultraviolet to the infrared region by using AgClxBr1-x nanocubes with different sizes. The variation of the dielectric constant of AgClxBr1-x associated with the change of the relative concentration of halide ions provides an additional knob to tune the optical properties of photonic crystals.

  11. The Strasbourg Large Refractor and Dome: Significant Improvements and Failed Attempts

    Science.gov (United States)

    Heck, Andre

    2009-01-01

    Founded by the German Empire in the late 19th century, Strasbourg Astronomical Observatory featured several novelties from the start. According to Mueller (1978), the separation of observing buildings from the study area and from the astronomers' residence was a revolution in observatory construction. The instruments were, as much as possible, isolated from the vibrations of the buildings themselves. "Gas flames" and water were used to reduce temperature effects. Thus the Large Dome (ca 11m diameter), housing the Large Refractor (ca 49cm, then the largest in Germany) and covered by zinc over wood, could be cooled down by water running from the top. Reports (including by the French who took over the observatory after World War I) are however somehow nonexistent on the effective usage and actual efficiency of such a system (which must have generated locally a significant amount of humidity). The paper will detail these technical attempts as well as the specificities of the instruments installed in that new observatory intended as a showcase of German astronomy.

  12. The Last State to Grant Nurse Practitioners DEA Licensure: An Education Improvement Initiative on the Florida Prescription Drug Monitoring Program.

    Science.gov (United States)

    Kellams, Joni R; Maye, John P

    Nurse practitioners (NPs) now have prescriptive authority for controlled substances in all 50 states in the United States. Florida, the last state to grant NPs DEA licensure, has been wrought with prescription diversion practices for a number of years as pill mills, doctor shopping, and overprescribing proliferated. Prescription Drug Monitoring Programs (PDMPs) help curb drug diversion activity and play a key role in reducing the abuse of controlled substances. The primary objective of this education improvement initiative was to increase knowledge of actively licensed NPs in the state of Florida regarding the state's PDMP. The main themes included the drug abuse problem, description and progression of the PDMP, and how to use the Florida PDMP. Upon approval from the institutional review board, this education improvement initiative gauged NP knowledge of the PDMP and main themes before and after an educational PowerPoint intervention. A pretest/posttest questionnaire was administered for assessment of all knowledge questions. One hundred forty-five NPs with active advanced registered NP licenses in Florida completed both the pretest and posttest questionnaires. Descriptive statistics and paired t tests were used for statistical significance testing. Knowledge of the PDMP and the main themes of the education improvement initiative significantly increased (p < .001) from pretest to posttest results. This education improvement initiative had positive effects for NPs on the knowledge of the Florida PDMP and the main themes. This indicated that Florida NPs are able to acquire greater comprehension of the PDMP by an education intervention.

  13. Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique

    Energy Technology Data Exchange (ETDEWEB)

    Hao, Ming; Wang, Yanli, E-mail: ywang@ncbi.nlm.nih.gov; Bryant, Stephen H., E-mail: bryant@ncbi.nlm.nih.gov

    2016-02-25

    Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision–recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets. - Graphical abstract: Flowchart of the proposed RLS-KF algorithm for drug-target interaction predictions. - Highlights: • A nonlinear kernel fusion algorithm is proposed to perform drug-target interaction predictions. • Performance can further be improved by using the recalculated kernel. • Top predictions can be validated by experimental data.

  14. Improved prediction of drug-target interactions using regularized least squares integrating with kernel fusion technique

    International Nuclear Information System (INIS)

    Hao, Ming; Wang, Yanli; Bryant, Stephen H.

    2016-01-01

    Identification of drug-target interactions (DTI) is a central task in drug discovery processes. In this work, a simple but effective regularized least squares integrating with nonlinear kernel fusion (RLS-KF) algorithm is proposed to perform DTI predictions. Using benchmark DTI datasets, our proposed algorithm achieves the state-of-the-art results with area under precision–recall curve (AUPR) of 0.915, 0.925, 0.853 and 0.909 for enzymes, ion channels (IC), G protein-coupled receptors (GPCR) and nuclear receptors (NR) based on 10 fold cross-validation. The performance can further be improved by using a recalculated kernel matrix, especially for the small set of nuclear receptors with AUPR of 0.945. Importantly, most of the top ranked interaction predictions can be validated by experimental data reported in the literature, bioassay results in the PubChem BioAssay database, as well as other previous studies. Our analysis suggests that the proposed RLS-KF is helpful for studying DTI, drug repositioning as well as polypharmacology, and may help to accelerate drug discovery by identifying novel drug targets. - Graphical abstract: Flowchart of the proposed RLS-KF algorithm for drug-target interaction predictions. - Highlights: • A nonlinear kernel fusion algorithm is proposed to perform drug-target interaction predictions. • Performance can further be improved by using the recalculated kernel. • Top predictions can be validated by experimental data.

  15. Single-atom catalysts for CO2 electroreduction with significant activity and selectivity improvements.

    Science.gov (United States)

    Back, Seoin; Lim, Juhyung; Kim, Na-Young; Kim, Yong-Hyun; Jung, Yousung

    2017-02-01

    A single-atom catalyst (SAC) has an electronic structure that is very different from its bulk counterparts, and has shown an unexpectedly high specific activity with a significant reduction in noble metal usage for CO oxidation, fuel cell and hydrogen evolution applications, although physical origins of such performance enhancements are still poorly understood. Herein, by means of density functional theory (DFT) calculations, we for the first time investigate the great potential of single atom catalysts for CO 2 electroreduction applications. In particular, we study a single transition metal atom anchored on defective graphene with single or double vacancies, denoted M@sv-Gr or M@dv-Gr, where M = Ag, Au, Co, Cu, Fe, Ir, Ni, Os, Pd, Pt, Rh or Ru, as a CO 2 reduction catalyst. Many SACs are indeed shown to be highly selective for the CO 2 reduction reaction over a competitive H 2 evolution reaction due to favorable adsorption of carboxyl (*COOH) or formate (*OCHO) over hydrogen (*H) on the catalysts. On the basis of free energy profiles, we identified several promising candidate materials for different products; Ni@dv-Gr (limiting potential U L = -0.41 V) and Pt@dv-Gr (-0.27 V) for CH 3 OH production, and Os@dv-Gr (-0.52 V) and Ru@dv-Gr (-0.52 V) for CH 4 production. In particular, the Pt@dv-Gr catalyst shows remarkable reduction in the limiting potential for CH 3 OH production compared to any existing catalysts, synthesized or predicted. To understand the origin of the activity enhancement of SACs, we find that the lack of an atomic ensemble for adsorbate binding and the unique electronic structure of the single atom catalysts as well as orbital interaction play an important role, contributing to binding energies of SACs that deviate considerably from the conventional scaling relation of bulk transition metals.

  16. Improved Tumor Penetration and Single-Cell Targeting of Antibody-Drug Conjugates Increases Anticancer Efficacy and Host Survival.

    Science.gov (United States)

    Cilliers, Cornelius; Menezes, Bruna; Nessler, Ian; Linderman, Jennifer; Thurber, Greg M

    2018-02-01

    Current antibody-drug conjugates (ADC) have made advances in engineering the antibody, linker, conjugation site, small-molecule payload, and drug-to-antibody ratio (DAR). However, the relationship between heterogeneous intratumoral distribution and efficacy of ADCs is poorly understood. Here, we compared trastuzumab and ado-trastuzumab emtansine (T-DM1) to study the impact of ADC tumor distribution on efficacy. In a mouse xenograft model insensitive to trastuzumab, coadministration of trastuzumab with a fixed dose of T-DM1 at 3:1 and 8:1 ratios dramatically improved ADC tumor penetration and resulted in twice the improvement in median survival compared with T-DM1 alone. In this setting, the effective DAR was lowered, decreasing the amount of payload delivered to each targeted cell but increasing the number of cells that received payload. This result is counterintuitive because trastuzumab acts as an antagonist in vitro and has no single-agent efficacy in vivo , yet improves the effectiveness of T-DM1 in vivo Novel dual-channel fluorescence ratios quantified single-cell ADC uptake and metabolism and confirmed that the in vivo cellular dose of T-DM1 alone exceeded the minimum required for efficacy in this model. In addition, this technique characterized cellular pharmacokinetics with heterogeneous delivery after 1 day, degradation and payload release by 2 days, and in vitro cell killing and in vivo tumor shrinkage 2 to 3 days later. This work demonstrates that the intratumoral distribution of ADC, independent of payload dose or plasma clearance, plays a major role in ADC efficacy. Significance: This study shows how lowering the drug-to-antibody ratio during treatment can improve the intratumoral distribution of a antibody-drug conjugate, with implications for improving the efficacy of this class of cancer drugs. Cancer Res; 78(3); 758-68. ©2017 AACR . ©2017 American Association for Cancer Research.

  17. A guided interview process to improve student pharmacists' identification of drug therapy problems.

    Science.gov (United States)

    Rovers, John; Miller, Michael J; Koenigsfeld, Carrie; Haack, Sally; Hegge, Karly; McCleeary, Erin

    2011-02-10

    To measure agreement between advanced pharmacy practice experience students using a guided interview process and experienced clinical pharmacists using standard practices to identify drug therapy problems. Student pharmacists enrolled in an advanced pharmacy practice experience (APPE) and clinical pharmacists conducted medication therapy management interviews to identify drug therapy problems in elderly patients recruited from the community. Student pharmacists used a guided interview tool, while clinical pharmacists' interviews were conducted using their usual and customary practices. Student pharmacists also were surveyed to determine their perceptions of the interview tool. Fair to moderate agreement was observed on student and clinical pharmacists' identification of 4 of 7 drug therapy problems. Of those, agreement was significantly higher than chance for 3 drug therapy problems (adverse drug reaction, dosage too high, and needs additional drug therapy) and not significant for 1 (unnecessary drug therapy). Students strongly agreed that the interview tool was useful but agreed less strongly on recommending its use in practice. The guided interview process served as a useful teaching aid to assist student pharmacists to identify drug therapy problems.

  18. Omega-3 fatty acid therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation, however, did not significantly improve insulin sensitivity in patients with hypertriglyceridemia.

    Science.gov (United States)

    Oh, Pyung Chun; Koh, Kwang Kon; Sakuma, Ichiro; Lim, Soo; Lee, Yonghee; Lee, Seungik; Lee, Kyounghoon; Han, Seung Hwan; Shin, Eak Kyun

    2014-10-20

    Experimental studies demonstrate that higher intake of omega-3 fatty acids (n-3 FA) improves insulin sensitivity, however, we reported that n-3 FA 2g therapy, most commonly used dosage did not significantly improve insulin sensitivity despite reducing triglycerides by 21% in patients. Therefore, we investigated the effects of different dosages of n-3 FA in patients with hypertriglyceridemia. This was a randomized, single-blind, placebo-controlled, parallel study. Age, sex, and body mass index were matched among groups. All patients were recommended to maintain a low fat diet. Forty-four patients (about 18 had metabolic syndrome/type 2 diabetes mellitus) in each group were given placebo, n-3 FA 1 (O1), 2 (O2), or 4 g (O4), respectively daily for 2 months. n-3 FA therapy dose-dependently and significantly decreased triglycerides and triglycerides/HDL cholesterol and improved flow-mediated dilation, compared with placebo (by ANOVA). However, each n-3 FA therapy did not significantly decrease high-sensitivity C-reactive protein and fibrinogen, compared with placebo. O1 significantly increased insulin levels and decreased insulin sensitivity (determined by QUICKI) and O2 significantly decreased plasma adiponectin levels relative to baseline measurements. Of note, when compared with placebo, each n-3 FA therapy did not significantly change insulin, glucose, adiponectin, glycated hemoglobin levels and insulin sensitivity (by ANOVA). We observed similar results in a subgroup of patients with the metabolic syndrome. n-3 FA therapy dose-dependently and significantly decreased triglycerides and improved flow-mediated dilation. Nonetheless, n-3 FA therapy did not significantly improve acute-phase reactants and insulin sensitivity in patients with hypertriglyceridemia, regardless of dosages. Copyright © 2014. Published by Elsevier Ireland Ltd.

  19. ANTITUBERCULOSIS DRUG DOSAGE FORMS: RANGE, KEY BENEFITS AND PROSPECTS OF TECHNOLOGICAL IMPROVEMENT

    Directory of Open Access Journals (Sweden)

    M. E. Kim

    2016-01-01

    Full Text Available Interest to research in the development of new formulations of antituberculosis drugs due to the high incidence of tuberculosis in the Republic of Kazakhstan and the Russian Federation nowadays, including with acquired drug resistance. The reason for the development of acquired drug resistance is to interrupt the treatment of patients is the high toxicity of antituberculosis drugs. The improving the efficiency of antituberculosis therapy remains one of the most pressing.The aim this study was to review the dosage forms of antituberculosis drugs currently used and the ways to improve them.Methods. The study was conducted on the basis of scientific analysis (eLibrary database, PubMed, Cyberleninca, patent (kzpatents, reference (Klifar, Drugs register and technical literature.Results. It was revealed that the antituberculosis drugs are available in the form of tablets, capsules, granules for oral use and injection solutions. The advantages and disadvantages of oral dosage forms of antituberculosis drugs: tablets, capsules, granules, syrups, suspensions are described. The importance of the development and implementation in practice of pediatric formulations of antituberculosis drugs is mentioned. The state of current research inhaled formulations for the treatment of tuberculosis is described. The prospects of directional inhalation exposure by immobilization of antituberculosis drugs in liposomes, niosomes, nanocapsules, micelles, micro- and nanoparticles are mentioned. The prospect of the rectal formulations use is described. The increase in interest in the molecular encapsulation of medicinal substances with cyclodextrins in connection with the possibility of increasing the bioavailability of active ingredients, reduce the harmful effects on the gastrointestinal tract, extension, elimination of interaction of incompatible components in combination preparations, the protection of unstable substances is

  20. The upright posture improves plantar stepping and alters responses to serotonergic drugs in spinal rats.

    Science.gov (United States)

    Sławińska, Urszula; Majczyński, Henryk; Dai, Yue; Jordan, Larry M

    2012-04-01

    Recent studies on the restoration of locomotion after spinal cord injury have employed robotic means of positioning rats above a treadmill such that the animals are held in an upright posture and engage in bipedal locomotor activity. However, the impact of the upright posture alone, which alters hindlimb loading, an important variable in locomotor control, has not been examined. Here we compared the locomotor capabilities of chronic spinal rats when placed in the horizontal and upright postures. Hindlimb locomotor movements induced by exteroceptive stimulation (tail pinching) were monitored with video and EMG recordings. We found that the upright posture alone significantly improved plantar stepping. Locomotor trials using anaesthesia of the paws and air stepping demonstrated that the cutaneous receptors of the paws are responsible for the improved plantar stepping observed when the animals are placed in the upright posture.We also tested the effectiveness of serotonergic drugs that facilitate locomotor activity in spinal rats in both the horizontal and upright postures. Quipazine and (±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) improved locomotion in the horizontal posture but in the upright posture either interfered with or had no effect on plantar walking. Combined treatment with quipazine and 8-OH-DPAT at lower doses dramatically improved locomotor activity in both postures and mitigated the need to activate the locomotor CPG with exteroceptive stimulation. Our results suggest that afferent input from the paw facilitates the spinal CPG for locomotion. These potent effects of afferent input from the paw should be taken into account when interpreting the results obtained with rats in an upright posture and when designing interventions for restoration of locomotion after spinal cord injury.

  1. Optimization of drug loading to improve physical stability of paclitaxel-loaded long-circulating liposomes.

    Science.gov (United States)

    Kannan, Vinayagam; Balabathula, Pavan; Divi, Murali K; Thoma, Laura A; Wood, George C

    2015-01-01

    The effect of formulation and process parameters on drug loading and physical stability of paclitaxel-loaded long-circulating liposomes was evaluated. The liposomes were prepared by hydration-extrusion method. The formulation parameters such as total lipid content, cholesterol content, saturated-unsaturated lipid ratio, drug-lipid ratio and process parameters such as extrusion pressure and number of extrusion cycles were studied and their impact on drug loading and physical stability was evaluated. A proportionate increase in drug loading was observed with increase in the total phospholipid content. Cholesterol content and saturated lipid content in the bilayer showed a negative influence on drug loading. The short-term stability evaluation of liposomes prepared with different drug-lipid ratios demonstrated that 1:60 as the optimum drug-lipid ratio to achieve a loading of 1-1.3 mg/mL without the risk of physical instability. The vesicle size decreased with an increase in the extrusion pressure and number of extrusion cycles, but no significant trends were observed for drug loading with changes in process pressure or number of cycles. The optimization of formulation and process parameters led to a physically stable formulation of paclitaxel-loaded long-circulating liposomes that maintain size, charge and integrity during storage.

  2. Improving the prediction of the brain disposition for orally administered drugs using BDDCS

    DEFF Research Database (Denmark)

    Broccatelli, Fabio; Larregieu, Caroline A.; Cruciani, Gabriele

    2012-01-01

    outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB...... penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2005-07-26

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

  4. Improving measurement of injection drug risk behavior using item response theory.

    Science.gov (United States)

    Janulis, Patrick

    2014-03-01

    Recent research highlights the multiple steps to preparing and injecting drugs and the resultant viral threats faced by drug users. This research suggests that more sensitive measurement of injection drug HIV risk behavior is required. In addition, growing evidence suggests there are gender differences in injection risk behavior. However, the potential for differential item functioning between genders has not been explored. To explore item response theory as an improved measurement modeling technique that provides empirically justified scaling of injection risk behavior and to examine for potential gender-based differential item functioning. Data is used from three studies in the National Institute on Drug Abuse's Criminal Justice Drug Abuse Treatment Studies. A two-parameter item response theory model was used to scale injection risk behavior and logistic regression was used to examine for differential item functioning. Item fit statistics suggest that item response theory can be used to scale injection risk behavior and these models can provide more sensitive estimates of risk behavior. Additionally, gender-based differential item functioning is present in the current data. Improved measurement of injection risk behavior using item response theory should be encouraged as these models provide increased congruence between construct measurement and the complexity of injection-related HIV risk. Suggestions are made to further improve injection risk behavior measurement. Furthermore, results suggest direct comparisons of composite scores between males and females may be misleading and future work should account for differential item functioning before comparing levels of injection risk behavior.

  5. PEGylated lipid nanocapsules with improved drug encapsulation and controlled release properties.

    Science.gov (United States)

    Hervella, Pablo; Alonso-Sande, Maria; Ledo, Francisco; Lucero, Maria L; Alonso, Maria J; Garcia-Fuentes, Marcos

    2014-01-01

    Drugs with poor lipid and water solubility are some of the most challenging to formulate in nanocarriers, typically resulting in low encapsulation efficiencies and uncontrolled release profiles. PEGylated nanocapsules (PEG-NC) are known for their amenability to diverse modifications that allow the formation of domains with different physicochemical properties, an interesting feature to address a drug encapsulation problem. We explored this problem by encapsulating in PEG-NC the promising anticancer drug candidate F10320GD1, used herein as a model for compounds with such characteristics. The nanocarriers were prepared from Miglyol(®), lecithin and PEG-sterate through a solvent displacement technique. The resulting system was a homogeneous suspension of particles with size around 200 nm. F10320GD1 encapsulation was found to be very poor (<15%) if PEG-NC were prepared using water as continuous phase; but we were able to improve this value to 85% by fixing the pH of the continuous phase to 9. Interestingly, this modification also improved the controlled release properties and the chemical stability of the formulation during storage. These differences in pharmaceutical properties together with physicochemical data suggest that the pH of the continuous phase used for PEG-NC preparation can modify drug allocation, from the external shell towards the inner lipid core of the nanocapsules. Finally, we tested the bioactivity of the drug-loaded PEG-NC in several tumor cell lines, and also in endothelial cells. The results indicated that drug encapsulation led to an improvement on drug cytotoxicity in tumor cells, but not in non-tumor endothelial cells. Altogether, the data confirms that PEG-NC show adequate delivery properties for F10320GD1, and underlines its possible utility as an anticancer therapy.

  6. A proposal for a pharmacokinetic interaction significance classification system (PISCS) based on predicted drug exposure changes and its potential application to alert classifications in product labelling.

    Science.gov (United States)

    Hisaka, Akihiro; Kusama, Makiko; Ohno, Yoshiyuki; Sugiyama, Yuichi; Suzuki, Hiroshi

    2009-01-01

    Pharmacokinetic drug-drug interactions (DDIs) are one of the major causes of adverse events in pharmacotherapy, and systematic prediction of the clinical relevance of DDIs is an issue of significant clinical importance. In a previous study, total exposure changes of many substrate drugs of cytochrome P450 (CYP) 3A4 caused by coadministration of inhibitor drugs were successfully predicted by using in vivo information. In order to exploit these predictions in daily pharmacotherapy, the clinical significance of the pharmacokinetic changes needs to be carefully evaluated. The aim of the present study was to construct a pharmacokinetic interaction significance classification system (PISCS) in which the clinical significance of DDIs was considered with pharmacokinetic changes in a systematic manner. Furthermore, the classifications proposed by PISCS were compared in a detailed manner with current alert classifications in the product labelling or the summary of product characteristics used in Japan, the US and the UK. A matrix table was composed by stratifying two basic parameters of the prediction: the contribution ratio of CYP3A4 to the oral clearance of substrates (CR), and the inhibition ratio of inhibitors (IR). The total exposure increase was estimated for each cell in the table by associating CR and IR values, and the cells were categorized into nine zones according to the magnitude of the exposure increase. Then, correspondences between the DDI significance and the zones were determined for each drug group considering the observed exposure changes and the current classification in the product labelling. Substrate drugs of CYP3A4 selected from three therapeutic groups, i.e. HMG-CoA reductase inhibitors (statins), calcium-channel antagonists/blockers (CCBs) and benzodiazepines (BZPs), were analysed as representative examples. The product labelling descriptions of drugs in Japan, US and UK were obtained from the websites of each regulatory body. Among 220

  7. Addition of 2-(ethylamino)acetonitrile group to nitroxoline results in significantly improved anti-tumor activity in vitro and in vivo.

    Science.gov (United States)

    Mitrović, Ana; Sosič, Izidor; Kos, Špela; Tratar, Urša Lampreht; Breznik, Barbara; Kranjc, Simona; Mirković, Bojana; Gobec, Stanislav; Lah, Tamara; Serša, Gregor; Kos, Janko

    2017-08-29

    Lysosomal cysteine peptidase cathepsin B, involved in multiple processes associated with tumor progression, is validated as a target for anti-cancer therapy. Nitroxoline, a known antimicrobial agent, is a potent and selective inhibitor of cathepsin B, hence reducing tumor progression in vitro and in vivo . In order to further improve its anti-cancer properties we developed a number of derivatives using structure-based chemical synthesis. Of these, the 7-aminomethylated derivative (compound 17 ) exhibited significantly improved kinetic properties over nitroxoline, inhibiting cathepsin B endopeptidase activity selectively. In the present study, we have evaluated its anti-cancer properties. It was more effective than nitroxoline in reducing tumor cell invasion and migration, as determined in vitro on two-dimensional cell models and tumor spheroids, under either endpoint or real time conditions. Moreover, it exhibited improved action over nitroxoline in impairing tumor growth in vivo in LPB mouse fibrosarcoma tumors in C57Bl/6 mice. Taken together, the addition of a 2-(ethylamino)acetonitrile group to nitroxoline at position 7 significantly improves its pharmacological characteristics and its potential for use as an anti-cancer drug.

  8. The use of nationwide on-line prescription records improves the drug history in hospitalized patients

    DEFF Research Database (Denmark)

    Glintborg, Bente; Poulsen, Henrik E; Dalhoff, Kim P

    2008-01-01

    What is already known about this subject: Structured medication interviews improve the medication history upon hospitalization. Pharmacy records are valid lists of the prescribed medications available to individual patients. In Denmark, treating doctors now have access to their patients' pharmacy...... records through a real-time online electronic database What this study adds: Omission errors are frequent among hospitalized patients despite structured drug interviews and home visits. Pharmacy records may be used to minimize patients' recall bias and improve the medication lists....

  9. Legacy data sharing to improve drug safety assessment: the eTOX project

    DEFF Research Database (Denmark)

    Sanz, Ferran; Pognan, François; Steger-Hartmann, Thomas

    2017-01-01

    The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through...

  10. pH-sensitive polymeric nanoparticles to improve oral bioavailability of peptide/protein drugs and poorly water-soluble drugs.

    Science.gov (United States)

    Wang, Xue-Qing; Zhang, Qiang

    2012-10-01

    pH-sensitive polymeric nanoparticles are promising for oral drug delivery, especially for peptide/protein drugs and poorly water-soluble medicines. This review describes current status of pH-sensitive polymeric nanoparticles for oral drug delivery and introduces the mechanisms of drug release from them as well as possible reasons for absorption improvement, with emphasis on our contribution to this field. pH-sensitive polymeric nanoparticles are prepared mainly with polyanions, polycations, their mixtures or cross-linked polymers. The mechanisms of drug release are the result of carriers' dissolution, swelling or both of them at specific pH. The possible reasons for improvement of oral bioavailability include the following: improve drug stability, enhance mucoadhesion, prolong resident time in GI tract, ameliorate intestinal permeability and increase saturation solubility and dissolution rate for poorly water-soluble drugs. As for the advantages of pH-sensitive nanoparticles over conventional nanoparticles, we conclude that (1) most carriers used are enteric-coating materials and their safety has been approved. (2) The rapid dissolution or swelling of carriers at specific pH results in quick drug release and high drug concentration gradient, which is helpful for absorption. (3) At the specific pH carriers dissolve or swell, and the bioadhesion of carriers to mucosa becomes high because nanoparticles turn from solid to gel, which can facilitate drug absorption. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. A network-based drug repositioning infrastructure for precision cancer medicine through targeting significantly mutated genes in the human cancer genomes.

    Science.gov (United States)

    Cheng, Feixiong; Zhao, Junfei; Fooksa, Michaela; Zhao, Zhongming

    2016-07-01

    Development of computational approaches and tools to effectively integrate multidomain data is urgently needed for the development of newly targeted cancer therapeutics. We proposed an integrative network-based infrastructure to identify new druggable targets and anticancer indications for existing drugs through targeting significantly mutated genes (SMGs) discovered in the human cancer genomes. The underlying assumption is that a drug would have a high potential for anticancer indication if its up-/down-regulated genes from the Connectivity Map tended to be SMGs or their neighbors in the human protein interaction network. We assembled and curated 693 SMGs in 29 cancer types and found 121 proteins currently targeted by known anticancer or noncancer (repurposed) drugs. We found that the approved or experimental cancer drugs could potentially target these SMGs in 33.3% of the mutated cancer samples, and this number increased to 68.0% by drug repositioning through surveying exome-sequencing data in approximately 5000 normal-tumor pairs from The Cancer Genome Atlas. Furthermore, we identified 284 potential new indications connecting 28 cancer types and 48 existing drugs (adjusted P < .05), with a 66.7% success rate validated by literature data. Several existing drugs (e.g., niclosamide, valproic acid, captopril, and resveratrol) were predicted to have potential indications for multiple cancer types. Finally, we used integrative analysis to showcase a potential mechanism-of-action for resveratrol in breast and lung cancer treatment whereby it targets several SMGs (ARNTL, ASPM, CTTN, EIF4G1, FOXP1, and STIP1). In summary, we demonstrated that our integrative network-based infrastructure is a promising strategy to identify potential druggable targets and uncover new indications for existing drugs to speed up molecularly targeted cancer therapeutics. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All

  12. Natalizumab Significantly Improves Cognitive Impairment over Three Years in MS: Pattern of Disability Progression and Preliminary MRI Findings.

    Directory of Open Access Journals (Sweden)

    Flavia Mattioli

    Full Text Available Previous studies reported that Multiple Sclerosis (MS patients treated with natalizumab for one or two years exhibit a significant reduction in relapse rate and in cognitive impairment, but the long term effects on cognitive performance are unknown. This study aimed to evaluate the effects of natalizumab on cognitive impairment in a cohort of 24 consecutive patients with relapsing remitting MS treated for 3 years. The neuropsychological tests, as well as relapse number and EDSS, were assessed at baseline and yearly for three years. The impact on cortical atrophy was also considered in a subgroup of them, and are thus to be considered as preliminary. Results showed a significant reduction in the number of impaired neuropsychological tests after three years, a significant decrease in annualized relapse rate at each time points compared to baseline and a stable EDSS. In the neuropsychological assessment, a significant improvement in memory, attention and executive function test scores was detected. Preliminary MRI data show that, while GM volume did not change at 3 years, a significantly greater parahippocampal and prefrontal gray matter density was noticed, the former correlating with neuropsychological improvement in a memory test. This study showed that therapy with Natalizumab is helpful in improving cognitive performance, and is likely to have a protective role on grey matter, over a three years follow-up.

  13. Oral formulation strategies to improve solubility of poorly water-soluble drugs.

    Science.gov (United States)

    Singh, Abhishek; Worku, Zelalem Ayenew; Van den Mooter, Guy

    2011-10-01

    In the past two decades, there has been a spiraling increase in the complexity and specificity of drug-receptor targets. It is possible to design drugs for these diverse targets with advances in combinatorial chemistry and high throughput screening. Unfortunately, but not entirely unexpectedly, these advances have been accompanied by an increase in the structural complexity and a decrease in the solubility of the active pharmaceutical ingredient. Therefore, the importance of formulation strategies to improve the solubility of poorly water-soluble drugs is inevitable, thus making it crucial to understand and explore the recent trends. Drug delivery systems (DDS), such as solid dispersions, soluble complexes, self-emulsifying drug delivery systems (SEDDS), nanocrystals and mesoporous inorganic carriers, are discussed briefly in this review, along with examples of marketed products. This article provides the reader with a concise overview of currently relevant formulation strategies and proposes anticipated future trends. Today, the pharmaceutical industry has at its disposal a series of reliable and scalable formulation strategies for poorly soluble drugs. However, due to a lack of understanding of the basic physical chemistry behind these strategies, formulation development is still driven by trial and error.

  14. Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery.

    Science.gov (United States)

    Lau, Shinying; Fei, Jie; Liu, Haoran; Chen, Weixing; Liu, Ran

    2017-11-10

    Dissolving microneedles have been employed as a safe and convenient transdermal delivery system for drugs and vaccines. To improve effective drug delivery, a multilayered pyramidal dissolving microneedle patch, composed of silk fibroin tips with the ability of robust mechanical strength, rapid dissolution and drug release supported on a flexible polyvinyl alcohol (PVA) pedestal is reported. To show the utility of this approach the ability of the fabricated microneedles to deliver insulin is demonstrated. The dissolving microneedles have sufficient mechanical strength to be inserted into abdomen skin of mice to a depth of approximately 150μm, and release their encapsulated insulin into the skin to cause a hypoglycemic effect. The fabrication of microneedles avoids high temperature which benefits storage stability at room temperature for 20d. This result indicates >99.4% of insulin remained in the microneedles. In comparison to traditional needle-based administration, the proposed multilayered pyramidal dissolving microneedle patches enable self-administration, miniaturization, pain-free administration, drug delivery and drug stability, all being important features in needle free drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. A prototype home robot with an ambient facial interface to improve drug compliance.

    Science.gov (United States)

    Takacs, Barnabas; Hanak, David

    2008-01-01

    We have developed a prototype home robot to improve drug compliance. The robot is a small mobile device, capable of autonomous behaviour, as well as remotely controlled operation via a wireless datalink. The robot is capable of face detection and also has a display screen to provide facial feedback to help motivate patients and thus increase their level of compliance. An RFID reader can identify tags attached to different objects, such as bottles, for fluid intake monitoring. A tablet dispenser allows drug compliance monitoring. Despite some limitations, experience with the prototype suggests that simple and low-cost robots may soon become feasible for care of people living alone or in isolation.

  16. Significant clinical improvement in radiation-induced lumbosacral poly-radiculopathy by a treatment combining pentoxifylline, tocopherol, and clodronate (Pentoclo)

    Energy Technology Data Exchange (ETDEWEB)

    Delanian, S. [Hop St Louis, Serv Oncol Radiotherapie, APHP, F-75010 Paris, (France); Lefaix, J.L. [CEA-LARIA, CIRIL-GANIL, Caen, (France); Maisonobe, T. [Hop La Pitie Salpetriere, Federat Neurophysiol Clin, APHP, Paris, (France)

    2008-07-01

    Radiation-induced (RI) peripheral neuropathy is a rare and severe delayed complication of radiotherapy that is spontaneously irreversible, with no standard of treatment. We previously developed a successful antioxidant treatment in RI fibrosis and necrosis. Two patients with progressive worsening RI lumbosacral poly-radiculopathy experienced over several years a significant clinical improvement in their neurological sensorimotor symptoms with long-term pentoxifylline-tocopherol-clodronate treatment, and good safety. (authors)

  17. The cumulative effect of small dietary changes may significantly improve nutritional intakes in free-living children and adults

    OpenAIRE

    Bornet , Francis; Paineau , Damien; Beaufils , François; Boulier , Alain; Cassuto , Dominique-Adèle; Chwalow , Judith; Combris , Pierre; Couet , Charles; Jouret , Béatrice; Lafay , Lionel; Laville , Martine; Mahé , Sylvain; Ricour , Claude; Romon , Monique; Simon , Chantal

    2010-01-01

    Abstract Background/Objectives: The ELPAS study was an 8-month randomized controlled dietary modification trial designed to test the hypothesis that family dietary coaching would improve nutritional intakes and weight control in 2026 free-living children and parents (Paineau et al., 2008). It resulted in significant nutritional changes, with beneficial effects on body mass index in adults. In these ancillary analyses, we investigated dietary changes throughout the intervention. ...

  18. Pharmacological and physical vessel modulation strategies to improve EPR-mediated drug targeting to tumors.

    Science.gov (United States)

    Ojha, Tarun; Pathak, Vertika; Shi, Yang; Hennink, Wim E; Moonen, Chrit T W; Storm, Gert; Kiessling, Fabian; Lammers, Twan

    2017-09-15

    The performance of nanomedicine formulations depends on the Enhanced Permeability and Retention (EPR) effect. Prototypic nanomedicine-based drug delivery systems, such as liposomes, polymers and micelles, aim to exploit the EPR effect to accumulate at pathological sites, to thereby improve the balance between drug efficacy and toxicity. Thus far, however, tumor-targeted nanomedicines have not yet managed to achieve convincing therapeutic results, at least not in large cohorts of patients. This is likely mostly due to high inter- and intra-patient heterogeneity in EPR. Besides developing (imaging) biomarkers to monitor and predict EPR, another strategy to address this heterogeneity is the establishment of vessel modulation strategies to homogenize and improve EPR. Over the years, several pharmacological and physical co-treatments have been evaluated to improve EPR-mediated tumor targeting. These include pharmacological strategies, such as vessel permeabilization, normalization, disruption and promotion, as well as physical EPR enhancement via hyperthermia, radiotherapy, sonoporation and phototherapy. In the present manuscript, we summarize exemplary studies showing that pharmacological and physical vessel modulation strategies can be used to improve tumor-targeted drug delivery, and we discuss how these advanced combination regimens can be optimally employed to enhance the (pre-) clinical performance of tumor-targeted nanomedicines. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Acid or erythromycin stress significantly improves transformation efficiency through regulating expression of DNA binding proteins in Lactococcus lactis F44.

    Science.gov (United States)

    Wang, Binbin; Zhang, Huawei; Liang, Dongmei; Hao, Panlong; Li, Yanni; Qiao, Jianjun

    2017-12-01

    Lactococcus lactis is a gram-positive bacterium used extensively in the dairy industry and food fermentation, and its biological characteristics are usually improved through genetic manipulation. However, poor transformation efficiency was the main restriction factor for the construction of engineered strains. In this study, the transformation efficiency of L. lactis F44 showed a 56.1-fold increase in acid condition (pH 5.0); meanwhile, erythromycin stress (0.04 μg/mL) promoted the transformation efficiency more significantly (76.9-fold). Notably, the transformation efficiency of F44e (L. lactis F44 harboring empty pLEB124) increased up to 149.1-fold under the synergistic stresses of acid and erythromycin. In addition, the gene expression of some DNA binding proteins (DprA, RadA, RadC, RecA, RecQ, and SsbA) changed correspondingly. Especially for radA, 25.1-fold improvement was detected when F44e was exposed to pH 5.0. Overexpression of some DNA binding proteins could improve the transformation efficiency. The results suggested that acid or erythromycin stress could improve the transformation efficiency of L. lactis through regulating gene expression of DNA binding proteins. We have proposed a simple but promising strategy for improving the transformation efficiency of L. lactis and other hard-transformed microorganisms. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  20. Improved antimicrobial property and controlled drug release kinetics of silver sulfadiazine loaded ordered mesoporous silica

    Directory of Open Access Journals (Sweden)

    Suman Jangra

    2016-09-01

    Full Text Available The present study deals with the loading of silver sulfadiazine into ordered mesoporous silica material by post-impregnation method and its effect on the in vitro release kinetics and antimicrobial property of the drug. The formulated SBA-15 silica material with rope-like morphology and SBA-15-silver sulfadiazine (SBA-AgSD were characterized by UV–visible spectrophotometer, small and wide-angle powder X-ray diffraction (PXRD, field emission scanning electron microscope (FESEM and high resolution transmission electron microscope (HRTEM. Thermo-gravimetric analysis of SBA-AgSD revealed a high loading amount of 52.87%. Nitrogen adsorption–desorption analysis confirmed the drug entrapment into host material by revealing a reduced surface area (214 m2/g and pore diameter (6.7 nm of the SBA-AgSD. The controlled release of silver sulfadiazine drug from the mesoporous silica to simulated gastric, intestinal and body fluids was evaluated. The Korsmeyer–Peppas model fits the drug release data with the non-Fickian diffusion model and zero order kinetics of SBA-AgSD. The antibacterial performance of the SBA-AgSD was evaluated with respect to Staphylococcus aureus, Bacillus subtilis and Pseudomonas aeruginosa. The controlled drug delivery of the SBA-AgSD revealed improved antibacterial activity, thus endorsing its applicability in effective wound dressing.

  1. An Improved Method for Magnetic Nanocarrier Drug Delivery across the Cell Membrane

    Directory of Open Access Journals (Sweden)

    Behzad Mehrafrooz

    2018-01-01

    Full Text Available One of the crucial issues in the pharmacological field is developing new drug delivery systems. The main concern is to develop new methods for improving the drug delivery efficiencies such as low disruptions, precise control of the target of delivery and drug sustainability. Nowadays, there are many various methods for drug delivery systems. Carbon-based nanocarriers are a new efficient tool for translocating drug into the defined area or cells inside the body. These nanocarriers can be functionalized with proteins, peptides and used to transport their freight to cells or defined areas. Since functionalized carbon-based nanocarriers show low toxicity and high biocompatibility, they are used in many nanobiotechnology fields. In this study, different shapes of nanocarrier are investigated, and the suitable magnetic field, which is applied using MRI for the delivery of the nanocarrier, is proposed. In this research, based on the force required to cross the membrane and MD simulations, the optimal magnetic field profile is designed. This optimal magnetic force field is derived from the mathematical model of the system and magnetic particle dynamics inside the nanocarrier. The results of this paper illustrate the effects of the nanocarrier’s shapes on the percentage of success in crossing the membrane and the optimal required magnetic field.

  2. Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

    LENUS (Irish Health Repository)

    Egan, Sean

    2012-08-07

    BACKGROUND: Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. METHODS: A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. RESULTS: The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg\\/kg to 4.78 mg\\/kg\\/day. CONCLUSIONS: Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.

  3. Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: preparation and evaluation.

    Science.gov (United States)

    Guo, Feng; Zhong, Haijun; He, Jing; Xie, Baogang; Liu, Fen; Xu, Helin; Liu, Minmin; Xu, Chunlian

    2011-07-01

    Dipyridamole shows poor and variable bioavailability after oral administration due to pHdependent solubility, low biomembrane permeability as well as being a substrate of P-glycoprotein. In order to improve the oral absorption of dipyridamole, a self-microemulsifying drug delivery system (SMEDDS) for dipyridamole was prepared and evaluated in vitro and in vivo. The optimum formulation was 18% oleic acid, 12% Labrafac lipophile WL 1349, 42% Solutol HS 15 and 28% isopropyl alcohol. It was found that the performance of self-microemulsification with the combination of oleic acid and Labrafac lipophile WL 1349 increased compared with just one oil. The results obtained from an in vitro dissolution assay indicated that dipyridamole in SMEDDS dissolved rapidly and completely in pH 6.8 aqueous media, while the commercial drug tablet was less soluble. An oral bioavailability study in rats showed that dipyridamole in the SMEDDS formulation had a 2.06-fold increased absorption compared with the simple drug suspension. It was evident that SMEDDS may be an effective approach to improve the oral absorption for drugs having pH-dependent solubility.

  4. An initiative to improve the management of clinically significant test results in a large health care network.

    Science.gov (United States)

    Roy, Christopher L; Rothschild, Jeffrey M; Dighe, Anand S; Schiff, Gordon D; Graydon-Baker, Erin; Lenoci-Edwards, Jennifer; Dwyer, Cheryl; Khorasani, Ramin; Gandhi, Tejal K

    2013-11-01

    The failure of providers to communicate and follow up clinically significant test results (CSTR) is an important threat to patient safety. The Massachusetts Coalition for the Prevention of Medical Errors has endorsed the creation of systems to ensure that results can be received and acknowledged. In 2008 a task force was convened that represented clinicians, laboratories, radiology, patient safety, risk management, and information systems in a large health care network with the goals of providing recommendations and a road map for improvement in the management of CSTR and of implementing this improvement plan during the sub-force sequent five years. In drafting its charter, the task broadened the scope from "critical" results to "clinically significant" ones; clinically significant was defined as any result that requires further clinical action to avoid morbidity or mortality, regardless of the urgency of that action. The task force recommended four key areas for improvement--(1) standardization of policies and definitions, (2) robust identification of the patient's care team, (3) enhanced results management/tracking systems, and (4) centralized quality reporting and metrics. The task force faced many challenges in implementing these recommendations, including disagreements on definitions of CSTR and on who should have responsibility for CSTR, changes to established work flows, limitations of resources and of existing information systems, and definition of metrics. This large-scale effort to improve the communication and follow-up of CSTR in a health care network continues with ongoing work to address implementation challenges, refine policies, prepare for a new clinical information system platform, and identify new ways to measure the extent of this important safety problem.

  5. The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Sugiyama, Seigo; Jinnouchi, Hideaki; Kurinami, Noboru; Hieshima, Kunio; Yoshida, Akira; Jinnouchi, Katsunori; Nishimura, Hiroyuki; Suzuki, Tomoko; Miyamoto, Fumio; Kajiwara, Keizo; Jinnouchi, Tomio

    2018-03-30

    Objective Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce cardiovascular events and decrease the body fat mass in patients with type 2 diabetes mellitus (T2DM). We examined whether or not the SGLT2-inhibitor dapagliflozin can improve the endothelial function associated with a reduction in abdominal fat mass. Methods We prospectively recruited patients with uncontrolled (hemoglobin A1c [HbA1c] >7.0%) T2DM who were not being treated by SGLT2 inhibitors. Patients were treated with add-on dapagliflozin (5 mg/day) or non-SGLT2 inhibitor medicines for 6 months to improve their HbA1c. We measured the peripheral microvascular endothelial function as assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and calculated the natural logarithmic transformed value of the RH-PAT index (LnRHI). We then investigated changes in the LnRHI and abdominal fat area using computed tomography (CT). Results The subjects were 54 patients with uncontrolled T2DM (72.2% men) with a mean HbA1c of 8.1%. The HbA1c was significantly decreased in both groups, with no significant difference between the groups. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly increased the LnRHI. The changes in the LnRHI were significantly greater in the dapagliflozin group than in the non-SGLT2 inhibitor group. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly decreased the abdominal visceral fat area, subcutaneous fat area (SFA), and total fat area (TFA) as assessed by CT and significantly increased the plasma adiponectin levels. The percentage changes in the LnRHI were significantly correlated with changes in the SFA, TFA, systolic blood pressure, and adiponectin. Conclusion Add-on treatment with dapagliflozin significantly improves the glycemic control and endothelial function associated with a reduction in the abdominal fat mass in patients with uncontrolled T2DM.

  6. Natural polymers: Best carriers for improving bioavailability of poorly water soluble drugs in solid dispersions

    OpenAIRE

    Sandip Sapkal; Mahesh Narkhede; Mukesh Babhulkar; Gautam Mehetre; Ashish Rathi

    2013-01-01

    ABSTRACTNatural polymers and its modified forms can be used as best alternative for improving bioavailabilityof poorly water soluble drugs in solid dispersion. Most of the natural polymersare hydrophilic and having high swelling capacity. Recent trend towards the use of naturalpolymer demands the replacement of synthetic additives with natural ones. Many plant derivednatural polymers are studied for use in solid dispersion systems, out of which naturalgums, cyclodextrin and carbohydrate are m...

  7. Spontaneous Resolution of Long-Standing Macular Detachment due to Optic Disc Pit with Significant Visual Improvement.

    Science.gov (United States)

    Parikakis, Efstratios A; Chatziralli, Irini P; Peponis, Vasileios G; Karagiannis, Dimitrios; Stratos, Aimilianos; Tsiotra, Vasileia A; Mitropoulos, Panagiotis G

    2014-01-01

    To report a case of spontaneous resolution of a long-standing serous macular detachment associated with an optic disc pit, leading to significant visual improvement. A 63-year-old female presented with a 6-month history of blurred vision and micropsia in her left eye. Her best-corrected visual acuity was 6/24 in the left eye, and fundoscopy revealed serous macular detachment associated with optic disc pit, which was confirmed by optical coherence tomography (OCT). The patient was offered vitrectomy as a treatment alternative, but she preferred to be reviewed conservatively. Three years after initial presentation, neither macular detachment nor subretinal fluid was evident in OCT, while the inner segment/outer segment (IS/OS) junction line was intact. Her visual acuity was improved from 6/24 to 6/12 in her left eye, remaining stable at the 6-month follow-up after resolution. We present a case of spontaneous resolution of a long-standing macular detachment associated with an optic disc pit with significant visual improvement, postulating that the integrity of the IS/OS junction line may be a prognostic factor for final visual acuity and suggesting OCT as an indicator of visual prognosis and the probable necessity of a surgical management.

  8. Spontaneous Resolution ofLong-Standing Macular Detachment due to Optic Disc Pit with Significant Visual Improvement

    Directory of Open Access Journals (Sweden)

    Efstratios A. Parikakis

    2014-03-01

    Full Text Available Purpose: To report a case of spontaneous resolution of a long-standing serous macular detachment associated with an optic disc pit, leading to significant visual improvement. Case Presentation: A 63-year-old female presented with a 6-month history of blurred vision and micropsia in her left eye. Her best-corrected visual acuity was 6/24 in the left eye, and fundoscopy revealed serous macular detachment associated with optic disc pit, which was confirmed by optical coherence tomography (OCT. The patient was offered vitrectomy as a treatment alternative, but she preferred to be reviewed conservatively. Three years after initial presentation, neither macular detachment nor subretinal fluid was evident in OCT, while the inner segment/outer segment (IS/OS junction line was intact. Her visual acuity was improved from 6/24 to 6/12 in her left eye, remaining stable at the 6-month follow-up after resolution. Conclusion: We present a case of spontaneous resolution of a long-standing macular detachment associated with an optic disc pit with significant visual improvement, postulating that the integrity of the IS/OS junction line may be a prognostic factor for final visual acuity and suggesting OCT as an indicator of visual prognosis and the probable necessity of a surgical management.

  9. Drug Abuse Prevention Among Students In Improving The Lives Meaning Through Counseling Logo

    Directory of Open Access Journals (Sweden)

    Kadek Suranata

    2013-03-01

    Full Text Available Abuse of drugs, psychotropic substances, illegal drugs and other addictive substances (drugs among teenagers especially students to be a problem from time to time keeps going on and it seems difficult to be finalized. So also in Indonesia drug abuse prevention efforts at the level of the student and the student assessment has been a great school for education practitioners and also involving relevant agencies such as BNN, BKKBN, the health department and the police. On the other hand, the number of victims of drug abuse among adolescents from year-to-year increase. spiritual intelligence (SQ is low is one of the students to be drug users. Various approaches, models and techniques of counseling has been developed and implemented in schools in order to develop students' potential. Counseling logo is one of the counseling intervention model that was first introduced by Viktor Frankl who seek to build the spiritual dimension of human besides raceway and psychological dimensions, and assume that the meaning of life and a desire for meaningful is the primary motivation of men to achieve meaningful livelihoods (the meaningful life is wanted. This research aimed to develop the logo counseling to improving the lives meaning drug abuse prevention and to know the effectiveness of that model. This research uses  research and development approach or R&D with seven essential steps, namely (1 research and information collecting, (2 planning, (3 developing preliminary from of product, (4 preliminary field testing and product revision, (5 main field test and product revision, (6 operational field test and product revision, and (7 dissemination implementation and institutionalization. The population of this research includes practitioners or school counselors, experts and both state, Junior High School, Senior High Scholl and vocational students in Bali Province. The results of research on the effect of counseling logo on the trend of drug abuse in students in

  10. Mobile phone text messaging improves antihypertensive drug adherence in the community.

    Science.gov (United States)

    Varleta, Paola; Acevedo, Mónica; Akel, Carlos; Salinas, Claudia; Navarrete, Carlos; García, Ana; Echegoyen, Carolina; Rodriguez, Daniel; Gramusset, Lissette; Leon, Sandra; Cofré, Pedro; Retamal, Raquel; Romero, Katerine

    2017-12-01

    Antihypertensive drug adherence (ADA) is a mainstay in blood pressure control. Education through mobile phone short message system (SMS) text messaging could improve ADA. The authors conducted a randomized study involving 314 patients with hypertension with Text messaging intervention improved ADA (risk ratio, 1.3; 95% confidence interval, 1.0-1.6 [Ptext messaging resulted in an increase in reporting ADA in this hypertensive Latino population. This approach could become an effective tool to overcome poor medication adherence in the community. ©2017 Wiley Periodicals, Inc.

  11. Significantly increased detection rate of drugs of abuse in urine following the introduction of new German driving licence re-granting guidelines.

    Science.gov (United States)

    Agius, Ronald; Nadulski, Thomas; Kahl, Hans-Gerhard; Dufaux, Bertin

    2012-02-10

    In this paper we present the first assessment of the new German driving licence re-granting medical and psychological assessment (MPA) guidelines by comparing over 3500 urine samples tested under the old MPA cut-offs to over 5000 samples tested under the new MPA cut-offs. Since the enzyme multiplied immunoassay technique (EMIT) technology used previously was not sensitive enough to screen for drugs at such low concentrations, as suggested by the new MPA guidelines, enzyme-linked immunosorbent assay (ELISA) screening kits were used to screen for the drugs of abuse at the new MPA cut-offs. The above comparison revealed significantly increased detection rates of drug use or exposure during the rehabilitation period as follows: 1.61, 2.33, 3.33, and 7 times higher for 11-nor-delta-9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), morphine, benzoylecgonine and amphetamine respectively. The present MPA guidelines seem to be more effective to detect non-abstinence from drugs of abuse and hence to detecting drivers who do not yet fulfil the MPA requirements to regain their revoked driving licence. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. Improving drug delivery strategies for lymphatic filariasis elimination in urban areas in Ghana.

    Directory of Open Access Journals (Sweden)

    Nana-Kwadwo Biritwum

    2017-05-01

    Full Text Available The Global Program to Eliminate Lymphatic Filariasis (GPELF advocates for the treatment of entire endemic communities, in order to achieve its elimination targets. LF is predominantly a rural disease, and achieving the required treatment coverage in these areas is much easier compared to urban areas that are more complex. In Ghana, parts of the Greater Accra Region with Accra as the capital city are also endemic for LF. Mass Drug Administration (MDA in Accra started in 2006. However, after four years of treatment, the coverage has always been far below the 65% epidemiologic coverage for interrupting transmission. As such, there was a need to identify the reasons for poor treatment coverage and design specific strategies to improve the delivery of MDA. This study therefore set out to identify the opportunities and barriers for implementing MDA in urban settings, and to develop appropriate strategies for MDA in these settings. An experimental, exploratory study was undertaken in three districts in the Greater Accra region. The study identified various types of non-rural settings, the social structures, stakeholders and resources that could be employed for MDA. Qualitative assessment such as in-depth interviews (IDIs and focus group discussions (FGDs with community leaders, community members, health providers, NGOs and other stakeholders in the community was undertaken. The study was carried out in three phases: pre-intervention, intervention and post-intervention phases, to assess the profile of the urban areas and identify reasons for poor treatment coverage using both qualitative and quantitative research methods. The outcomes from the study revealed that, knowledge, attitudes and practices of community members to MDA improved slightly from the pre-intervention phase to the post-intervention phase, in the districts where the interventions were readily implemented by health workers. Many factors such as adequate leadership, funding, planning and

  13. Supply and demand: application of Lean Six Sigma methods to improve drug round efficiency and release nursing time.

    Science.gov (United States)

    Kieran, Maríosa; Cleary, Mary; De Brún, Aoife; Igoe, Aileen

    2017-10-01

    To improve efficiency, reduce interruptions and reduce the time taken to complete oral drug rounds. Lean Six Sigma methods were applied to improve drug round efficiency using a pre- and post-intervention design. A 20-bed orthopaedic ward in a large teaching hospital in Ireland. Pharmacy, nursing and quality improvement staff. A multifaceted intervention was designed which included changes in processes related to drug trolley organization and drug supply planning. A communications campaign aimed at reducing interruptions during nurse-led during rounds was also developed and implemented. Average number of interruptions, average drug round time and variation in time taken to complete drug round. At baseline, the oral drug round took an average of 125 min. Following application of Lean Six Sigma methods, the average drug round time decreased by 51 min. The average number of interruptions per drug round reduced from an average of 12 at baseline to 11 following intervention, with a 75% reduction in drug supply interruptions. Lean Six Sigma methodology was successfully employed to reduce interruptions and to reduce time taken to complete the oral drug round. © The Author 2017. Published by Oxford University Press in association with the International Society for Quality in Health Care. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  14. Multiseed liposomal drug delivery system using micelle gradient as driving force to improve amphiphilic drug retention and its anti-tumor efficacy.

    Science.gov (United States)

    Zhang, Wenli; Li, Caibin; Jin, Ya; Liu, Xinyue; Wang, Zhiyu; Shaw, John P; Baguley, Bruce C; Wu, Zimei; Liu, Jianping

    2018-11-01

    To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL-loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as 'micelle pool' drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation, encapsulation efficiency (EE) comparison, and release studies demonstrated the formation of ML-shell structure for ASL-ML without inter-carrier fusion. The location of drug mainly in inner micelles as well as the superiority of post-loading to the pre-loading method , in which drug in micelles shifted onto the bilayer membrane was an additional positive of this delivery system. It was observed that the drug amphiphilicity and interaction of micelles with drug were the two prerequisites for this active loading method. The extended retention capacity of ML has been verified through the prolonged half-life, reduced paw-lick responses in rats, and enhanced tumor inhibition in model mice. In conclusion, ASL-ML prepared by active loading method can effectively load drug into micelles with expected structure and improve drug retention.

  15. Serotonin-1A receptor gene polymorphism and the ability of antipsychotic drugs to improve attention in schizophrenia.

    Science.gov (United States)

    Sumiyoshi, Tomiki; Tsunoda, Masahiko; Higuchi, Yuko; Itoh, Toru; Seo, Tomonori; Itoh, Hiroko; Suzuki, Michio; Kurachi, Masayoshi

    2010-05-01

    The purpose of this study was to determine if the functional single nucleotide polymorphisms of rs6259 C(-1019)G in the promoter region, which regulates serotonin 5-HT(1A) receptor transcription, affects the ability of antipsychotic drugs to improve attention in patients with schizophrenia. Subjects were neuroleptic-free and meeting DSM-IV-TR criteria for schizophrenia. Psychopathology and attention were evaluated with the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS) at baseline and 3 months after treatment with atypical antipsychotic drugs (AAPDs). DNA was extracted from peripheral blood following standard procedures. Genotyping was performed with HS-Taq assay (LaboPass). Data were available from 30 subjects (male/female=19/11), in which 17 had the CC genotype, three had the GG genotype, and 10 were heterozygous. The 3-month treatment with AAPDs was associated with significant improvements in positive and negative symptoms, but not attention as measured by SANS-Attention subscale in the entire subject group. There were no significant differences in the degree of improvements of SAPS and SANS scores between the CC genotype group and the (C/G plus G/G) combined group. On the other hand, improvement of attention was significantly greater for the former group compared to the latter group (P<0.016), suggesting a detrimental influence of the G-allele. These results provide additional support to the role of 5-HT(1A) receptors in some of the cognitive disturbances of schizophrenia. Further studies with a larger number of subjects are warranted.

  16. Multi-targeted therapy for leprosy: insilico strategy to overcome multi drug resistance and to improve therapeutic efficacy.

    Science.gov (United States)

    Anusuya, Shanmugam; Natarajan, Jeyakumar

    2012-12-01

    Leprosy remains a major public health problem, since single and multi-drug resistance has been reported worldwide over the last two decades. In the present study, we report the novel multi-targeted therapy for leprosy to overcome multi drug resistance and to improve therapeutic efficacy. If multiple enzymes of an essential metabolic pathway of a bacterium were targeted, then the therapy would become more effective and can prevent the occurrence of drug resistance. The MurC, MurD, MurE and MurF enzymes of peptidoglycan biosynthetic pathway were selected for multi targeted therapy. The conserved or class specific active site residues important for function or stability were predicted using evolutionary trace analysis and site directed mutagenesis studies. Ten such residues which were present in at least any three of the four Mur enzymes (MurC, MurD, MurE and MurF) were identified. Among the ten residues G125, K126, T127 and G293 (numbered based on their position in MurC) were found to be conserved in all the four Mur enzymes of the entire bacterial kingdom. In addition K143, T144, T166, G168, H234 and Y329 (numbered based on their position in MurE) were significant in binding substrates and/co-factors needed for the functional events in any three of the Mur enzymes. These are the probable residues for designing newer anti-leprosy drugs in an attempt to reduce drug resistance. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Performance of the Sellick maneuver significantly improves when residents and trained nurses use a visually interactive guidance device in simulation

    International Nuclear Information System (INIS)

    Connor, Christopher W; Saffary, Roya; Feliz, Eddy

    2013-01-01

    We examined the proper performance of the Sellick maneuver, a maneuver used to reduce the risk of aspiration of stomach contents during induction of general anesthesia, using a novel device that measures and visualizes the force applied to the cricoid cartilage using thin-film force sensitive resistors in a form suitable for in vivo use. Performance was tested in three stages with twenty anaesthesiology residents and twenty trained operating room nurses. Firstly, subjects applied force to the cricoid cartilage as was customary to them. Secondly, subjects used the device to guide the application of that force. Thirdly, subjects were again asked to perform the manoeuvre without visual guidance. Each test lasted 1 min and the amount of force applied was measured throughout. Overall, the Sellick maneuver was often not applied properly, with large variance between individual subjects. Performance and inter-subject consistency improved to a very highly significant degree when subjects were able to use the device as a visual guide (p < 0.001). Subsequent significant improvements in performances during the last, unguided test demonstrated that the device initiated learning. (paper)

  18. Performance of the Sellick maneuver significantly improves when residents and trained nurses use a visually interactive guidance device in simulation

    Energy Technology Data Exchange (ETDEWEB)

    Connor, Christopher W; Saffary, Roya; Feliz, Eddy [Department of Anesthesiology Boston Medical Center, Boston, MA (United States)

    2013-12-15

    We examined the proper performance of the Sellick maneuver, a maneuver used to reduce the risk of aspiration of stomach contents during induction of general anesthesia, using a novel device that measures and visualizes the force applied to the cricoid cartilage using thin-film force sensitive resistors in a form suitable for in vivo use. Performance was tested in three stages with twenty anaesthesiology residents and twenty trained operating room nurses. Firstly, subjects applied force to the cricoid cartilage as was customary to them. Secondly, subjects used the device to guide the application of that force. Thirdly, subjects were again asked to perform the manoeuvre without visual guidance. Each test lasted 1 min and the amount of force applied was measured throughout. Overall, the Sellick maneuver was often not applied properly, with large variance between individual subjects. Performance and inter-subject consistency improved to a very highly significant degree when subjects were able to use the device as a visual guide (p < 0.001). Subsequent significant improvements in performances during the last, unguided test demonstrated that the device initiated learning. (paper)

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

    Science.gov (United States)

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

    2017-10-01

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

  20. Cyclodextrins improving the physicochemical and pharmacological properties of antidepressant drugs: a patent review.

    Science.gov (United States)

    Diniz, Tâmara Coimbra; Pinto, Tiago Coimbra Costa; Menezes, Paula Dos Passos; Silva, Juliane Cabral; Teles, Roxana Braga de Andrade; Ximenes, Rosana Christine Cavalcanti; Guimarães, Adriana Gibara; Serafini, Mairim Russo; Araújo, Adriano Antunes de Souza; Quintans Júnior, Lucindo José; Almeida, Jackson Roberto Guedes da Silva

    2018-01-01

    Depression is a serious mood disorder and is one of the most common mental illnesses. Despite the availability of several classes of antidepressants, a substantial percentage of patients are unresponsive to these drugs, which have a slow onset of action in addition to producing undesirable side effects. Some scientific evidence suggests that cyclodextrins (CDs) can improve the physicochemical and pharmacological profile of antidepressant drugs (ADDs). The purpose of this paper is to disclose current data technology prospects involving antidepressant drugs and cyclodextrins. Areas covered: We conducted a patent review to evaluate the antidepressive activity of the compounds complexed in CDs, and we analyzed whether these complexes improved their physicochemical properties and pharmacological action. The present review used 8 specialized patent databases for patent research, using the term 'cyclodextrin' combined with 'antidepressive agents' and its related terms. We found 608 patents. In the end, considering the inclusion criteria, 27 patents reporting the benefits of complexation of ADDs with CDs were included. Expert opinion: The use of CDs can be considered an important tool for the optimization of physicochemical and pharmacological properties of ADDs, such as stability, solubility and bioavailability.

  1. Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma.

    Science.gov (United States)

    Liu, Rong; Colby, Aaron H; Gilmore, Denis; Schulz, Morgan; Zeng, Jialiu; Padera, Robert F; Shirihai, Orian; Grinstaff, Mark W; Colson, Yolonda L

    2016-09-01

    The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) system is described that addresses two unique challenges to improve the outcomes for peritoneal mesothelioma. First, following intraperitoneal administration, eNPs rapidly and specifically localize to tumors. The rate of eNP uptake by tumors is an order of magnitude faster than the rate of uptake in non-malignant cells; and, subsequent accumulation in autophagosomes and disruption of autophagosomal trafficking leads to prolonged intracellular retention of eNPs. The net effect of these combined mechanisms manifests as rapid localization to intraperitoneal tumors within 4 h of injection and persistent intratumoral retention for >14 days. Second, the high tumor-specificity of PTX-eNPs leads to delivery of greater than 100 times higher concentrations of drug in tumors compared to PTX alone and this is maintained for at least seven days following administration. As a result, overall survival of animals with established mesothelioma more than doubled when animals were treated with multiple doses of PTX-eNPs compared to equivalent dosing with PTX or non-responsive PTX-loaded nanoparticles. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Combination of blood tests for significant fibrosis and cirrhosis improves the assessment of liver-prognosis in chronic hepatitis C.

    Science.gov (United States)

    Boursier, J; Brochard, C; Bertrais, S; Michalak, S; Gallois, Y; Fouchard-Hubert, I; Oberti, F; Rousselet, M-C; Calès, P

    2014-07-01

    Recent longitudinal studies have emphasised the prognostic value of noninvasive tests of liver fibrosis and cross-sectional studies have shown their combination significantly improves diagnostic accuracy. To compare the prognostic accuracy of six blood fibrosis tests and liver biopsy, and evaluate if test combination improves the liver-prognosis assessment in chronic hepatitis C (CHC). A total of 373 patients with compensated CHC, liver biopsy (Metavir F) and blood tests targeting fibrosis (APRI, FIB4, Fibrotest, Hepascore, FibroMeter) or cirrhosis (CirrhoMeter) were included. Significant liver-related events (SLRE) and liver-related deaths were recorded during follow-up (started the day of biopsy). During the median follow-up of 9.5 years (3508 person-years), 47 patients had a SLRE and 23 patients died from liver-related causes. For the prediction of first SLRE, most blood tests allowed higher prognostication than Metavir F [Harrell C-index: 0.811 (95% CI: 0.751-0.868)] with a significant increase for FIB4: 0.879 [0.832-0.919] (P = 0.002), FibroMeter: 0.870 [0.812-0.922] (P = 0.005) and APRI: 0.861 [0.813-0.902] (P = 0.039). Multivariate analysis identified FibroMeter, CirrhoMeter and sustained viral response as independent predictors of first SLRE. CirrhoMeter was the only independent predictor of liver-related death. The combination of FibroMeter and CirrhoMeter classifications into a new FM/CM classification improved the liver-prognosis assessment compared to Metavir F staging or single tests by identifying five subgroups of patients with significantly different prognoses. Some blood fibrosis tests are more accurate than liver biopsy for determining liver prognosis in CHC. A new combination of two complementary blood tests, one targeted for fibrosis and the other for cirrhosis, optimises assessment of liver-prognosis. © 2014 John Wiley & Sons Ltd.

  3. Improved Treatment of Pancreatic Cancer With Drug Delivery Nanoparticles Loaded With a Novel AKT/PDK1 Inhibitor.

    Science.gov (United States)

    Kobes, Joseph E; Daryaei, Iman; Howison, Christine M; Bontrager, Jordan G; Sirianni, Rachael W; Meuillet, Emmanuelle J; Pagel, Mark D

    2016-09-01

    This research study sought to improve the treatment of pancreatic cancer by improving the drug delivery of a promising AKT/PDK1 inhibitor, PHT-427, in poly(lactic-co-glycolic) acid (PLGA) nanoparticles. PHT-427 was encapsulated in single-emulsion and double-emulsion PLGA nanoparticles (SE-PLGA-427 and DE-PLGA-427). The drug release rate was evaluated to assess the effect of the second PLGA layer of DE-PLGA-427. Ex vivo cryo-imaging and drug extraction from ex vivo organs was used to assess the whole-body biodistribution in an orthotopic model of MIA PaCa-2 pancreatic cancer. Anatomical magnetic resonance imaging (MRI) was used to noninvasively assess the effects of 4 weeks of nanoparticle drug treatment on tumor size, and diffusion-weighted MRI longitudinally assessed changes in tumor cellularity. DE-PLGA-427 showed delayed drug release and longer drug retention in the pancreas relative to SE-PLGA-427. Diffusion-weighted MRI indicated a consistent decrease in cellularity during drug treatment with both types of drug-loaded nanoparticles. Both SE- and DE-PLGA-427 showed a 6-fold and 4-fold reduction in tumor volume relative to untreated tumors and an elimination of primary pancreatic tumor in 68% of the mice. These results indicated that the PLGA nanoparticles improved drug delivery of PHT-427 to pancreatic tumors, which improved the treatment of MIA PaCa-2 pancreatic cancer.

  4. Induction Based Training leads to Highly Significant Improvements of Objective and Subjective Suturing Ability in Junior Doctors

    Directory of Open Access Journals (Sweden)

    Kevin Garry

    2018-03-01

    Full Text Available Background: Simulation based training has shown to be of benefit in the education of medical students. However, the impact of induction based clinical simulation on surgical ability of qualified doctors remains unclear.The aim of this study was to establish if a 60 minute teaching session integrated into an Emergency Medicine speciality induction program produces statistically significant improvements in objective and subjective suturing abilities of junior doctors commencing an Emergency Medicine rotation.Methods: The objective suturing abilities of 16 Foundation Year Two doctors were analysed using a validated OSATs scale prior to a novel teaching intervention. The doctors then undertook an intensive hour long workshop receiving one to one feedback before undergoing repeat OSATs assessment.Subjective ability was measured using a 5 point likert scale and self-assessed competency reporting interrupted suturing before and after the intervention. Photographs of wound closure before and after the intervention were recorded for further blinded assessment of impact of intervention. A survey regarding continued ability was repeated at four months following the intervention. The study took place on 7/12/16 during the Belfast Health and Social Care Trust Emergency Medicine induction in the Royal Victoria Hospital Belfast. The hospital is a regional level 1 trauma centre that has annual departmental attendances in excess of 200,000.All new junior doctors commencing the Emergency Medicine rotation were invited to partake in the study. All 16 agreed. The group consisted of a mixture of undergraduate and postgraduate medicaldoctors who all had 16 months experience working in a variety of medical or surgical jobs previously.Results: Following the teaching intervention objective and subjective abilities in interrupted suturing showed statistically significant improvement (P>0.005. Self-reporting of competency of independently suturingwounds improved from 50

  5. Outreach nurses in Harm Reduction projects: improving acceptability and availability of medical care to drug users

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    Dvinskykh, Natalya

    2012-07-01

    Full Text Available BACKGROUND: Injection drug users (IDU remain one of the most vulnerable population segments in Ukraine, with HIV prevalence up to 22% among this group. At the same time, drug users lack access to basic health care and reportedly face stigma and discrimination from medical workers. Harm reduction projects in Ukraine partially address this problem by providing regular HIV and STI testing for their clients, and by referring them to medical institutions, where IDU can get free treatment for STI, TB, and ARV therapy for HIV. However, issues of acceptability and availability of medical care for drug users are far from being resolved. METHODS: During 2011, the new approach of ‘outreach nurses’ was piloted by All Ukrainian Harm Reduction Association (UHRA with support from ICF “International HIV/AIDS Alliance in Ukraine”. The aim of the project was to bring medical services closer to IDU by integrating work of medical professionals into a comprehensive package of Harm Reduction project services. The project employed fifteen nurses from five regions of Ukraine. During the project, nurses provided basic medical services, consultations on health improvement issues and referrals. The services were provided at the places convenient for clients: syringe exchange points, community centers, mobile clinics, and at home. RESULTS: The services of the project were well accepted by the clients. From June till December 2011 the project reached 1703 unique clients, with a total of 4525 visits (300 visits per nurse on average. For comparison, in the HR projects that employed surgeons, on average there were 58 visits per doctor (from 30 to 93 during the same period of time. CONCLUSIONS: To improve access to medical care for the drug using population Harm Reduction projects should consider including work of ‘outreach nurses’ to the package of services they provide.

  6. Strategies for improving adherence to antiepileptic drug treatment in people with epilepsy.

    Science.gov (United States)

    Al-Aqeel, Sinaa; Gershuni, Olga; Al-Sabhan, Jawza; Hiligsmann, Mickael

    2017-02-03

    of all ages, one study included participants older than two years, one study targeted caregivers of children with epilepsy, and one study targeted families of children with epilepsy. We identified six ongoing trials. Follow-up time was generally short in most trials, ranging from one to 12 months. The trials examined three main types of interventions: educational interventions, behavioural interventions and mixed interventions. All studies compared treatment versus usual care or 'no intervention', except for two studies. Due to heterogeneity between studies in terms of interventions, methods used to measure adherence and the way the studies were reported, we did not pool the results and these findings were inappropriate to be included in a meta-analysis. Education and counselling of participants with epilepsy resulted in mixed success (moderate-quality evidence). Behavioural interventions such as use of intensive reminders provided more favourable effects on adherence (moderate-quality evidence). The effect on adherence to antiepileptic drugs described by studies of mixed interventions showed improved adherence in the intervention groups compared to the control groups (high-quality evidence). Behavioural interventions such as intensive reminders and the use of mixed interventions demonstrate some positive results; however, we need more reliable evidence on their efficacy, derived from carefully-designed randomised controlled trials before we can draw a firm conclusion. Since the last version of this review, none of the new relevant studies have provided additional information that would lead to significant changes in our conclusions. This current update includes 12 studies, of which six came from the latest searches.

  7. Self-Nanoemulsifying Drug Delivery System of Coenzyme (Q10) with Improved Dissolution, Bioavailability, and Protective Efficiency on Liver Fibrosis.

    Science.gov (United States)

    Khattab, Abeer; Hassanin, Lobna; Zaki, Nashwah

    2017-07-01

    .2), and maximum drug loading efficiency. One hundred percent of CoQ 10 was released from most formulae within 30 min. One hundred percent of CoQ 10 was permeated from all formulae through 10 h. The pharmacokinetic study in rabbits revealed a significant increase in bioavailability of CoQ 10 SNEDDS to 2.1-fold compared with CoQ 10 suspension after oral administration. Comparative effect of the optimized formulae on acute liver injury compared with CoQ 10 powder was also studied; it was found that all the liver biochemical markers as alanine transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), total protein (TP), and albumin were significantly improved at p < 0.05. Also, histochemical and histopthological studies confirm the biochemical results. Our results suggest the potential use of SNEDDS to increase the solubility of liphophilic drug as poorly water-soluble CoQ 10 and improve its oral absorption, so it can be more efficient to improve liver damage compared to CoQ 10 powder. These results demonstrated that CoQ 10 SNEDDS inhibited thioacetamide (TAA)-induced liver fibrosis mainly through suppression of collagen production.

  8. Improving co-amorphous drug formulations by the addition of the highly water soluble amino acid proline

    DEFF Research Database (Denmark)

    Jensen, Katrine Birgitte Tarp; Löbmann, Korbinian; Rades, Thomas

    2014-01-01

    Co-amorphous drug amino acid mixtures were previously shown to be a promising approach to create physically stable amorphous systems with the improved dissolution properties of poorly water-soluble drugs. The aim of this work was to expand the co-amorphous drug amino acid mixture approach...... by combining the model drug, naproxen (NAP), with an amino acid to physically stabilize the co-amorphous system (tryptophan, TRP, or arginine, ARG) and a second highly soluble amino acid (proline, PRO) for an additional improvement of the dissolution rate. Co-amorphous drug-amino acid blends were prepared...... the molecular interactions in the form of hydrogen bonds between all three components in the mixture. A salt formation between the acidic drug, NAP, and the basic amino acid, ARG, was found in co-amorphous NAP–ARG. In comparison to crystalline NAP, binary NAP–TRP and NAP–ARG, it could be shown that the highly...

  9. Vendor-to-vendor education to improve malaria treatment by private drug outlets in Bungoma District, Kenya

    Directory of Open Access Journals (Sweden)

    Makama Sammy

    2003-05-01

    Full Text Available Abstract Background Private outlets are the main suppliers of uncomplicated malaria treatment in Africa. However, they are so numerous that they are difficult for governments to influence and regulate. This study's objective was to evaluate a low-cost outreach education (vendor-to-vendor programme to improve the private sector's compliance with malaria guidelines in Bungoma district, Kenya. The cornerstone of the programme was the district's training of 73 wholesalers who were equipped with customized job aids for distribution to small retailers. Methods Six months after training the wholesalers, the programme was evaluated using mystery shoppers. The shoppers posed as caretakers of sick children needing medication at 252 drug outlets. Afterwards, supervisors assessed the outlets' knowledge, drug stocks, and prices. Results The intervention seems to have had a significant impact on stocking patterns, malaria knowledge and prescribing practices of shops/kiosks, but not consistently on other types of outlets. About 32% of shops receiving job aids prescribed to mystery shoppers the approved first-line drug, sulfadoxine-pyremethamine, as compared to only 3% of the control shops. In the first six months, it is estimated that 500 outlets were reached, at a cost of about $8000. Conclusions Changing private sector knowledge and practices is widely acknowledged to be slow and difficult. The vendor-to-vendor programme seems a feasible district-level strategy for achieving significant improvements in knowledge and practices of shops/kiosks. However, alternate strategies will be needed to influence pharmacies and clinics. Overall, the impact will be only moderate unless national policies and programmes are also introduced.

  10. A Study on Improvement of Solubility of Rofecoxib and its effect on Permeation of Drug from Topical Formulations.

    Science.gov (United States)

    Kulkarni, Madhur; Nagarsenker, Mangal

    2008-01-01

    Rofecoxib, a practically insoluble cox-2 selective nonsteroidal antiinflammatory agent was subjected to improvement in solubility by preparing its binary mixtures with beta cyclodextrin using various methods such as physical mixing, co-grinding, kneading with aqueous methanol and co-evaporation from methanol-water mixture. Characterization of the resulting binary mixtures by differential scanning calorimetry and X-ray diffraction studies indicated partial amorphization of the drug in its binary mixtures. In vitro dissolution studies exhibited remarkable increase in rate and extent of dissolution of the drug from its complexes with beta -cyclodextrin. Pure rofecoxib as well as its co-ground binary mixture were formulated as aqueous gels for topical application. In vitro skin permeation of rofecoxib from formulation containing rofecoxib-cyclodextrin complex was significantly higher (p<0.05) at 1, 2, 12, 18 and 24 hr as compared to formulation containing pure rofecoxib. This could be attributed to better solubility of binary mixture in the aqueous gel vehicle leading to greater concentration gradient between the vehicle and skin and hence higher flux of the drug.

  11. The European Academy laparoscopic “Suturing Training and Testing’’ (SUTT) significantly improves surgeons’ performance

    Science.gov (United States)

    Sleiman, Z.; Tanos, V.; Van Belle, Y.; Carvalho, J.L.; Campo, R.

    2015-01-01

    The efficiency of suturing training and testing (SUTT) model by laparoscopy was evaluated, measuring the suturingskill acquisition of trainee gynecologists at the beginning and at the end of a teaching course. During a workshop organized by the European Academy of Gynecological Surgery (EAGS), 25 participants with three different experience levels in laparoscopy (minor, intermediate and major) performed the 4 exercises of the SUTT model (Ex 1: both hands stitching and continuous suturing, Ex 2: right hand stitching and intracorporeal knotting, Ex 3: left hand stitching and intracorporeal knotting, Ex 4: dominant hand stitching, tissue approximation and intracorporeal knotting). The time needed to perform the exercises is recorded for each trainee and group and statistical analysis used to note the differences. Overall, all trainees achieved significant improvement in suturing time (p psychomotor skills, surgery, teaching, training suturing model. PMID:26977264

  12. High-intensity interval training (swimming) significantly improves the adverse metabolism and comorbidities in diet-induced obese mice.

    Science.gov (United States)

    Motta, Victor F; Aguila, Marcia B; Mandarim-DE-Lacerda, Carlos A

    2016-05-01

    Controlling obesity and other comorbidities in the population is a challenge in modern society. High-intensity interval training (HIIT) combines short periods of high-intensity exercise with long recovery periods or a low-intensity exercise. The aim was to assess the impact of HIIT in the context of diet-induced obesity in the animal model. C57BL/6 mice were fed one of the two diets: standard chow (lean group [LE]) or a high-fat diet (obese group [OB]). After twelve weeks, the animals were divided into non-trained groups (LE-NT and OB-NT) and trained groups (LE-T and OB-T), and began an exercise protocol. For biochemical analysis of inflammatory and lipid profile, we used a colorimetric enzymatic method and an automatic spectrophotometer. One-way ANOVA was used for statistical analysis of the experimental groups with Holm-Sidak post-hoc Test. Two-way ANOVA analyzed the interactions between diet and HIIT protocol. HIIT leads to significant reductions in body mass, blood glucose, glucose tolerance and hepatic lipid profile in T-groups compared to NT-groups. HIIT was able to reduce plasma levels of inflammatory cytokines. Additionally, HIIT improves the insulin immunodensity in the islets, reduces the adiposity and the hepatic steatosis in the T-groups. HIIT improves beta-oxidation and peroxisome proliferator-activated receptor (PPAR)-alpha and reduces lipogenesis and PPAR-gamma levels in the liver. In skeletal muscle, HIIT improves PPAR-alpha and glucose transporter-4 and reduces PPAR-gamma levels. HIIT leads to attenuate the adverse effects caused by a chronic ingestion of a high-fat diet.

  13. Codon Optimization Significantly Improves the Expression Level of α-Amylase Gene from Bacillus licheniformis in Pichia pastoris

    Directory of Open Access Journals (Sweden)

    Jian-Rong Wang

    2015-01-01

    Full Text Available α-Amylase as an important industrial enzyme has been widely used in starch processing, detergent, and paper industries. To improve expression efficiency of recombinant α-amylase from Bacillus licheniformis (B. licheniformis, the α-amylase gene from B. licheniformis was optimized according to the codon usage of Pichia pastoris (P. pastoris and expressed in P. pastoris. Totally, the codons encoding 305 amino acids were optimized in which a total of 328 nucleotides were changed and the G+C content was increased from 47.6 to 49.2%. The recombinants were cultured in 96-deep-well microplates and screened by a new plate assay method. Compared with the wild-type gene, the optimized gene is expressed at a significantly higher level in P. pastoris after methanol induction for 168 h in 5- and 50-L bioreactor with the maximum activity of 8100 and 11000 U/mL, which was 2.31- and 2.62-fold higher than that by wild-type gene. The improved expression level makes the enzyme a good candidate for α-amylase production in industrial use.

  14. Improving Parolees' Participation in Drug Treatment and Other Services through Strengths Case Management.

    Science.gov (United States)

    Prendergast, Michael; Cartier, Jerome J

    2008-01-01

    In an effort to increase participation in community aftercare treatment for substance-abusing parolees, an intervention based on a transitional case management (TCM) model that focuses mainly on offenders' strengths has been developed and is under testing. This model consists of completion, by the inmate, of a self-assessment of strengths that informs the development of the continuing care plan, a case conference call shortly before release, and strengths case management for three months post-release to promote retention in substance abuse treatment and support the participant's access to designated services in the community. The post-release component consists of a minimum of one weekly client/case manager meeting (in person or by telephone) for 12 weeks. The intervention is intended to improve the transition process from prison to community at both the individual and systems level. Specifically, the intervention is designed to improve outcomes in parolee admission to, and retention in, community-based substance-abuse treatment, parolee access to other needed services, and recidivism rates during the first year of parole. On the systems level, the intervention is intended to improve the communication and collaboration between criminal justice agencies, community-based treatment organizations, and other social and governmental service providers. The TCM model is being tested in a multisite study through the Criminal Justice Drug Abuse Treatment Studies (CJ-DATS) research cooperative funded by the National Institute of Drug Abuse.

  15. Comparative Proteomic Characterization of 4 Human Liver-Derived Single Cell Culture Models Reveals Significant Variation in the Capacity for Drug Disposition, Bioactivation, and Detoxication.

    Science.gov (United States)

    Sison-Young, Rowena L C; Mitsa, Dimitra; Jenkins, Rosalind E; Mottram, David; Alexandre, Eliane; Richert, Lysiane; Aerts, Hélène; Weaver, Richard J; Jones, Robert P; Johann, Esther; Hewitt, Philip G; Ingelman-Sundberg, Magnus; Goldring, Christopher E P; Kitteringham, Neil R; Park, B Kevin

    2015-10-01

    In vitro preclinical models for the assessment of drug-induced liver injury (DILI) are usually based on cryopreserved primary human hepatocytes (cPHH) or human hepatic tumor-derived cell lines; however, it is unclear how well such cell models reflect the normal function of liver cells. The physiological, pharmacological, and toxicological phenotyping of available cell-based systems is necessary in order to decide the testing purpose for which they are fit. We have therefore undertaken a global proteomic analysis of 3 human-derived hepatic cell lines (HepG2, Upcyte, and HepaRG) in comparison with cPHH with a focus on drug metabolizing enzymes and transport proteins (DMETs), as well as Nrf2-regulated proteins. In total, 4946 proteins were identified, of which 2722 proteins were common across all cell models, including 128 DMETs. Approximately 90% reduction in expression of cytochromes P450 was observed in HepG2 and Upcyte cells, and approximately 60% in HepaRG cells relative to cPHH. Drug transporter expression was also lower compared with cPHH with the exception of MRP3 and P-gp (MDR1) which appeared to be significantly expressed in HepaRG cells. In contrast, a high proportion of Nrf2-regulated proteins were more highly expressed in the cell lines compared with cPHH. The proteomic database derived here will provide a rational basis for the context-specific selection of the most appropriate 'hepatocyte-like' cell for the evaluation of particular cellular functions associated with DILI and, at the same time, assist in the construction of a testing paradigm which takes into account the in vivo disposition of a new drug. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology.

  16. Complete Au@ZnO core-shell nanoparticles with enhanced plasmonic absorption enabling significantly improved photocatalysis

    Science.gov (United States)

    Sun, Yiqiang; Sun, Yugang; Zhang, Tao; Chen, Guozhu; Zhang, Fengshou; Liu, Dilong; Cai, Weiping; Li, Yue; Yang, Xianfeng; Li, Cuncheng

    2016-05-01

    Nanostructured ZnO exhibits high chemical stability and unique optical properties, representing a promising candidate among photocatalysts in the field of environmental remediation and solar energy conversion. However, ZnO only absorbs the UV light, which accounts for less than 5% of total solar irradiation, significantly limiting its applications. In this article, we report a facile and efficient approach to overcome the poor wettability between ZnO and Au by carefully modulating the surface charge density on Au nanoparticles (NPs), enabling rapid synthesis of Au@ZnO core-shell NPs at room temperature. The resulting Au@ZnO core-shell NPs exhibit a significantly enhanced plasmonic absorption in the visible range due to the Au NP cores. They also show a significantly improved photocatalytic performance in comparison with their single-component counterparts, i.e., the Au NPs and ZnO NPs. Moreover, the high catalytic activity of the as-synthesized Au@ZnO core-shell NPs can be maintained even after many cycles of photocatalytic reaction. Our results shed light on the fact that the Au@ZnO core-shell NPs represent a promising class of candidates for applications in plasmonics, surface-enhanced spectroscopy, light harvest devices, solar energy conversion, and degradation of organic pollutants.Nanostructured ZnO exhibits high chemical stability and unique optical properties, representing a promising candidate among photocatalysts in the field of environmental remediation and solar energy conversion. However, ZnO only absorbs the UV light, which accounts for less than 5% of total solar irradiation, significantly limiting its applications. In this article, we report a facile and efficient approach to overcome the poor wettability between ZnO and Au by carefully modulating the surface charge density on Au nanoparticles (NPs), enabling rapid synthesis of Au@ZnO core-shell NPs at room temperature. The resulting Au@ZnO core-shell NPs exhibit a significantly enhanced plasmonic

  17. Improved consistency in dosing anti-tuberculosis drugs in Taipei, Taiwan.

    Science.gov (United States)

    Chiang, Chen-Yuan; Yu, Ming-Chih; Shih, Hsiu-Chen; Yen, Muh-Yong; Hsu, Yu-Ling; Yang, Shiang-Lin; Lin, Tao-Ping; Bai, Kuan-Jen

    2012-01-01

    It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007-2010 were investigated to assess whether interventions on dosing were effective. Lists of all notified culture positive TB cases in 2007-2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007-2010 (pTaipei City has remarkably improved after health authorities implemented a series of interventions.

  18. Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

    Directory of Open Access Journals (Sweden)

    Alex Avdeef

    2016-06-01

    Full Text Available This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustrating the analysis of both solution and solid state aspects of solubility measurement are presented. Coverage includes drug aggregation in solution (sub-micellar, micellar, complexation, use of mass spectrometry to assess aggregation in saturated solutions, solid state characterization (salts, polymorphs, cocrystals, polymorph creation by potentiometric method, solubility type (water, buffer, intrinsic, temperature, ionic strength, pH measurement, buffer issues, critical knowledge of the pKa, equilibration time (stirring and sedimentation, separating solid from saturated solution, solution handling and adsorption to untreated surfaces, solubility units, and tabulation/graphic presentation of reported data. The goal is to present cohesive recommendations that could lead to better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids.

  19. Single chain Fc-dimer-human growth hormone fusion protein for improved drug delivery.

    Science.gov (United States)

    Zhou, Li; Wang, Hsuan-Yao; Tong, Shanshan; Okamoto, Curtis T; Shen, Wei-Chiang; Zaro, Jennica L

    2017-02-01

    Fc fusion protein technology has been successfully used to generate long-acting forms of several protein therapeutics. In this study, a novel Fc-based drug carrier, single chain Fc-dimer (sc(Fc) 2 ), was designed to contain two Fc domains recombinantly linked via a flexible linker. Since the Fc dimeric structure is maintained through the flexible linker, the hinge region was omitted to further stabilize it against proteolysis and reduce FcγR-related effector functions. The resultant sc(Fc) 2 candidate preserved the neonatal Fc receptor (FcRn) binding. sc(Fc) 2 -mediated delivery was then evaluated using a therapeutic protein with a short plasma half-life, human growth hormone (hGH), as the protein drug cargo. This novel carrier protein showed a prolonged in vivo half-life and increased hGH-mediated bioactivity compared to the traditional Fc-based drug carrier. sc(Fc) 2 technology has the potential to greatly advance and expand the use of Fc-technology for improving the pharmacokinetics and bioactivity of protein therapeutics. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Combat-related intradural gunshot wound to the thoracic spine: significant improvement and neurologic recovery following bullet removal.

    Science.gov (United States)

    Louwes, Thijs M; Ward, William H; Lee, Kendall H; Freedman, Brett A

    2015-02-01

    The vast majority of combat-related penetrating spinal injuries from gunshot wounds result in severe or complete neurological deficit. Treatment is based on neurological status, the presence of cerebrospinal fluid (CSF) fistulas, and local effects of any retained fragment(s). We present a case of a 46-year-old male who sustained a spinal gunshot injury from a 7.62-mm AK-47 round that became lodged within the subarachnoid space at T9-T10. He immediately suffered complete motor and sensory loss. By 24-48 hours post-injury, he had recovered lower extremity motor function fully but continued to have severe sensory loss (posterior cord syndrome). On post-injury day 2, he was evacuated from the combat theater and underwent a T9 laminectomy, extraction of the bullet, and dural laceration repair. At surgery, the traumatic durotomy was widened and the bullet, which was laying on the dorsal surface of the spinal cord, was removed. The dura was closed in a water-tight fashion and fibrin glue was applied. Postoperatively, the patient made a significant but incomplete neurological recovery. His stocking-pattern numbness and sub-umbilical searing dysthesia improved. The spinal canal was clear of the foreign body and he had no persistent CSF leak. Postoperative magnetic resonance imaging of the spine revealed contusion of the spinal cord at the T9 level. Early removal of an intra-canicular bullet in the setting of an incomplete spinal cord injury can lead to significant neurological recovery following even high-velocity and/or high-caliber gunshot wounds. However, this case does not speak to, and prior experience does not demonstrate, significant neurological benefit in the setting of a complete injury.

  1. Prostate health index (phi) and prostate cancer antigen 3 (PCA3) significantly improve diagnostic accuracy in patients undergoing prostate biopsy.

    Science.gov (United States)

    Perdonà, Sisto; Bruzzese, Dario; Ferro, Matteo; Autorino, Riccardo; Marino, Ada; Mazzarella, Claudia; Perruolo, Giuseppe; Longo, Michele; Spinelli, Rosa; Di Lorenzo, Giuseppe; Oliva, Andrea; De Sio, Marco; Damiano, Rocco; Altieri, Vincenzo; Terracciano, Daniela

    2013-02-15

    Prostate health index (phi) and prostate cancer antigen 3 (PCA3) have been recently proposed as novel biomarkers for prostate cancer (PCa). We assessed the diagnostic performance of these biomarkers, alone or in combination, in men undergoing first prostate biopsy for suspicion of PCa. One hundred sixty male subjects were enrolled in this prospective observational study. PSA molecular forms, phi index (Beckman coulter immunoassay), PCA3 score (Progensa PCA3 assay), and other established biomarkers (tPSA, fPSA, and %fPSA) were assessed before patients underwent a 18-core first prostate biopsy. The discriminating ability between PCa-negative and PCa-positive biopsies of Beckman coulter phi and PCA3 score and other used biomarkers were determined. One hundred sixty patients met inclusion criteria. %p2PSA (p2PSA/fPSA × 100), phi and PCA3 were significantly higher in patients with PCa compared to PCa-negative group (median values: 1.92 vs. 1.55, 49.97 vs. 36.84, and 50 vs. 32, respectively, P ≤ 0.001). ROC curve analysis showed that %p2PSA, phi, and PCA3 are good indicator of malignancy (AUCs = 0.68, 0.71, and 0.66, respectively). A multivariable logistic regression model consisting of both the phi index and PCA3 score allowed to reach an overall diagnostic accuracy of 0.77. Decision curve analysis revealed that this "combined" marker achieved the highest net benefit over the examined range of the threshold probability. phi and PCA3 showed no significant difference in the ability to predict PCa diagnosis in men undergoing first prostate biopsy. However, diagnostic performance is significantly improved by combining phi and PCA3. Copyright © 2012 Wiley Periodicals, Inc.

  2. The Significance of Harm Reduction as a Social and Health Care Intervention for Injecting Drug Users: An Exploratory Study of a Needle Exchange Program in Fresno, California.

    Science.gov (United States)

    Clarke, Kris; Harris, Debra; Zweifler, John A; Lasher, Marc; Mortimer, Roger B; Hughes, Susan

    2016-01-01

    Infectious disease remains a significant social and health concern in the United States. Preventing more people from contracting HIV/AIDS or Hepatitis C (HCV), requires a complex understanding of the interconnection between the biomedical and social dimensions of infectious disease. Opiate addiction in the US has skyrocketed in recent years. Preventing more cases of HIV/AIDS and HCV will require dealing with the social determinants of health. Needle exchange programs (NEPs) are based on a harm reduction approach that seeks to minimize the risk of infection and damage to the user and community. This article presents an exploratory small-scale quantitative study of the injection drug using habits of a group of injection drug users (IDUs) at a needle exchange program in Fresno, California. Respondents reported significant decreases in high risk IDU behaviors, including sharing of needles and to a lesser extent re-using of needles. They also reported frequent use of clean paraphernalia. Greater collaboration between social and health outreach professionals at NEPs could provide important frontline assistance to people excluded from mainstream office-based services and enhance efforts to reduce HIV/AIDS or HCV infection.

  3. Lipid Replacement Therapy Drink Containing a Glycophospholipid Formulation Rapidly and Significantly Reduces Fatigue While Improving Energy and Mental Clarity

    Directory of Open Access Journals (Sweden)

    Robert Settineri

    2011-08-01

    Full Text Available Background: Fatigue is the most common complaint of patients seeking general medical care and is often treated with stimulants. It is also important in various physical activities of relatively healthy men and women, such as sports performance. Recent clinical trials using patients with chronic fatigue have shown the benefit of Lipid Replacement Therapy in restoring mitochondrial electron transport function and reducing moderate to severe chronic fatigue. Methods: Lipid Replacement Therapy was administered for the first time as an all-natural functional food drink (60 ml containing polyunsaturated glycophospholipids but devoid of stimulants or herbs to reduce fatigue. This preliminary study used the Piper Fatigue Survey instrument as well as a supplemental questionnaire to assess the effects of the glycophospholipid drink on fatigue and the acceptability of the test drink in adult men and women. A volunteer group of 29 subjects of mean age 56.2±4.5 years with various fatigue levels were randomly recruited in a clinical health fair setting to participate in an afternoon open label trial on the effects of the test drink. Results: Using the Piper Fatigue instrument overall fatigue among participants was reduced within the 3-hour seminar by a mean of 39.6% (p<0.0001. All of the subcategories of fatigue showed significant reductions. Some subjects responded within 15 minutes, and the majority responded within one hour with increased energy and activity and perceived improvements in cognitive function, mental clarity and focus. The test drink was determined to be quite acceptable in terms of taste and appearance. There were no adverse events from the energy drink during the study.Functional Foods in Health and Disease 2011; 8:245-254Conclusions: The Lipid Replacement Therapy functional food drink appeared to be a safe, acceptable and potentially useful new method to reduce fatigue, sustain energy and improve perceptions of mental function.

  4. A matter of timing: identifying significant multi-dose radiotherapy improvements by numerical simulation and genetic algorithm search.

    Directory of Open Access Journals (Sweden)

    Simon D Angus

    -effecitive means of significantly improving clinical efficacy.

  5. A matter of timing: identifying significant multi-dose radiotherapy improvements by numerical simulation and genetic algorithm search.

    Science.gov (United States)

    Angus, Simon D; Piotrowska, Monika Joanna

    2014-01-01

    of significantly improving clinical efficacy.

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

    Science.gov (United States)

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

    2012-01-01

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

  7. Self-nanoemulsifying drug delivery system for enhanced bioavailability and improved hepatoprotective activity of biphenyl dimethyl dicarboxylate.

    Science.gov (United States)

    El-Laithy, Hanan M

    2008-07-01

    Biphenyl Dimethyl Dicarboxylate (BDD) is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-nanoemulsifying drug delivery system (SNEDDS) containing BDD has been successfully prepared using carefully selected ingredients which are less affected by pH and ionic strength changes to improve its bioavailability. SNEDDS is an isotropic mixture of lipid, surfactant, and cosurfactant which are spontaneously emulsified in aqueous medium under gentle digestive motility in the gastrointestinal tract. Pseudo ternary phase diagrams composed of various excipients were plotted to identify self -nano -emulsifying area. Droplet size changes upon dilution with aqueous media and in vitro release of BDD from SNEDDS in 0.1N HCl and phosphate buffer (pH 7.4) were studied and compared with commercial chinese pilules and Pennel capsules. The hepatoprotective activity upon oral administration of SNEDDS against carbon tetrachloride-induced oxidative stress in albino rats was assessed by measuring biochemical parameters like serum glutamic oxalacetate transaminase (SGOT), serum glutamic pyruvate transaminase (SGPT) and lactate dehydrogenase (LDH). Results showed that using a proper ratio of Tween 80 to Transcutol as surfactant and co-surfactant respectively and Miglyol 812 as oil to surfactants mixture resulted in production of infinitely diluted formulations in nano droplet size range. BDD self nano emulsified formula composed of 20% Miglyol 812, 60% Tween 80 and 20% Transcutol released 99% of the drug very rapidly within 10-15 minutes regardless of the pH condition. The oral absorption and bioavailability of BDD self nano emulsified formula in albino rats were significantly enhanced (P<0.01) with an average improvement of 1.7 and 6-folds that of commercial chinese pilules and Pennel capsules respectively. This improvement was also confirmed histopathologically in chemically injured rats and by the significant decrease in elevated liver enzymes

  8. Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery.

    Science.gov (United States)

    Dolor, Aaron; Szoka, Francis C

    2018-06-04

    Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery.

  9. Colloidal silver nanoparticles improve anti-leukemic drug efficacy via amplification of oxidative stress.

    Science.gov (United States)

    Guo, Dawei; Zhang, Junren; Huang, Zhihai; Jiang, Shanxiang; Gu, Ning

    2015-02-01

    Recently, increased reactive oxygen species (ROS) levels and altered redox status in cancer cells have become a novel therapeutic strategy to improve cancer selectivity over normal cells. It has been known that silver nanoparticles (AgNPs) display anti-leukemic activity via ROS overproduction. Hence, we hypothesized that AgNPs could improve therapeutic efficacy of ROS-generating agents against leukemia cells. In the current study, N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid, was used as a drug model of ROS induction to investigate its synergistic effect with AgNPs. The data exhibited that AgNPs with uniform size prepared by an electrochemical method could localize in the lysosomes, mitochondria and cytoplasm of SHI-1 cells. More importantly, AgNPs together with 4-HPR could exhibit more cytotoxicity and apoptosis via overproduction of ROS in comparison with that alone. Taken together, these results reveal that AgNPs combined with ROS-generating drugs could potentially enhance therapeutic efficacy against leukemia cells, thereby providing a novel strategy for AgNPs in leukemia therapy. Copyright © 2015. Published by Elsevier B.V.

  10. Flavonol-rich dark cocoa significantly decreases plasma endothelin-1 and improves cognitive responses in urban children.

    Directory of Open Access Journals (Sweden)

    Lilian eCalderon-Garciduenas

    2013-08-01

    Full Text Available Air pollution exposures are linked to systemic inflammation, cardiovascular and respiratory morbidity and mortality, neuroinflammation and neuropathology in young urbanites. In particular, most Mexico City Metropolitan Area (MCMA children exhibit subtle cognitive deficits, and neuropathology studies show 40% of them exhibiting frontal tau hyperphosphorylation and 51% amyloid-β diffuse plaques (compared to 0% in low pollution control children. We assessed whether a short cocoa intervention can be effective in decreasing plasma endothelin 1 (ET-1 and/or inflammatory mediators in MCMA children. Thirty g of dark cocoa with 680 mg of total flavonols were given daily for 10.11± 3.4 days (range 9 to 24 days to 18 children (10.55yrs, SD =1.45; 11F/7M. Key metabolite ratios in frontal white matter and in hippocampus pre and during cocoa intervention were quantified by magnetic resonance spectroscopy. ET-1 significantly decreased after cocoa treatment (p=0.0002. Fifteen children (83% showed a marginally significant individual improvement in one or both of the applied simple short memory tasks. Endothelial dysfunction is a key feature of exposure to particulate matter and decreased endothelin-1 bioavailability is likely useful for brain function in the context of air pollution. Our findings suggest that cocoa interventions may be critical for early implementation of neuroprotection of highly exposed urban children. Multi-domain nutraceutical interventions could limit the risk for endothelial dysfunction, cerebral hypoperfusion, neuroinflammation, cognitive deficits, structural volumetric detrimental brain effects, and the early development of the neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases.

  11. Preparation and evaluation of azithromycin binary solid dispersions using various polyethylene glycols for the improvement of the drug solubility and dissolution rate

    Directory of Open Access Journals (Sweden)

    Ehsan Adeli

    Full Text Available ABSTRACT Azithromycin is a water-insoluble drug, with a very low bioavailability. In order to increase the solubility and dissolution rate, and consequently increase the bioavailability of poorly-soluble drugs (such as azithromycin, various techniques can be applied. One of such techniques is "solid dispersion". This technique is frequently used to improve the dissolution rate of poorly water-soluble compounds. Owing to its low solubility and dissolution rate, azithromycin does not have a suitable bioavailability. Therefore, the main purpose of this investigation was to increase the solubility and dissolution rate of azithromycin by preparing its solid dispersion, using different Polyethylene glycols (PEG. Preparations of solid dispersions and physical mixtures of azithromycin were made using PEG 4000, 6000, 8000, 12000 and 20000 in various ratios, based on the solvent evaporation method. From the studied drug release profile, it was discovered that the dissolution rate of the physical mixture, as the well as the solid dispersions, were higher than those of the drug alone. There was no chemical incompatibility between the drug and polymer from the observed Infrared (IR spectra. Drug-polymer interactions were also investigated using Differential Scanning Calorimetry (DSC, Powder X-Ray Diffraction (PXRD and Scanning Election Microscopy (SEM. In conclusion, the dissolution rate and solubility of azithromycin were found to improve significantly, using hydrophilic carriers, especially PEG 6000.

  12. Best practices: an electronic drug alert program to improve safety in an accountable care environment.

    Science.gov (United States)

    Griesbach, Sara; Lustig, Adam; Malsin, Luanne; Carley, Blake; Westrich, Kimberly D; Dubois, Robert W

    2015-04-01

    The accountable care organization (ACO), one of the most promising and talked about new models of care, focuses on improving communication and care transitions by tying potential shared savings to specific clinical and financial benchmarks. An important factor in meeting these benchmarks is an ACO's ability to manage medications in an environment where medical and pharmacy care has been integrated. The program described in this article highlights the critical components of Marshfield Clinic's Drug Safety Alert Program (DSAP), which focuses on prioritizing and communicating safety issues related to medications with the goal of reducing potential adverse drug events. Once the medication safety concern is identified, it is reviewed to evaluate whether an alert warrants sending prescribers a communication that identifies individual patients or a general communication to all physicians describing the safety concern. Instead of basing its decisions regarding clinician notification about drug alerts on subjective criteria, the Marshfield Clinic's DSAP uses an internally developed scoring system. The scoring system includes criteria developed from previous drug alerts, such as level of evidence, size of population affected, severity of adverse event identified or targeted, litigation risk, available alternatives, and potential for duration of medication use. Each of the 6 criteria is assigned a weight and is scored based upon the content and severity of the alert received.  In its first 12 months, the program targeted 6 medication safety concerns involving the following medications: topiramate, glyburide, simvastatin, citalopram, pioglitazone, and lovastatin. Baseline and follow-up prescribing data were gathered on the targeted medications. Follow-up review of prescribing data demonstrated that the DSAP provided quality up-to-date safety information that led to changes in drug therapy and to decreases in potential adverse drug events. In aggregate, nearly 10,000 total

  13. Flexible deep-ultraviolet light-emitting diodes for significant improvement of quantum efficiencies by external bending

    KAUST Repository

    Shervin, Shahab; Oh, Seung Kyu; Park, Hyun Jung; Lee, Keon Hwa; Asadirad, Mojtaba; Kim, Seung Hwan; Kim, Jeomoh; Pouladi, Sara; Lee, Sung-Nam; Li, Xiaohang; Kwak, Joon-Seop; Ryou, Jae-Hyun

    2018-01-01

    Deep ultraviolet (DUV) light at the wavelength range of 250‒280 nm (UVC spectrum) is essential for numerous applications such as sterilization, purification, sensing, and communication. III-nitride-based DUV light-emitting diodes (DUV LEDs), like other solid-state lighting sources, offer a great potential to replace the conventional gas-discharged lamps with short lifetimes and toxic-element-bearing nature. However, unlike visible LEDs, the DUV LEDs are still suffering from low quantum efficiencies (QEs) and low optical output powers. In this work, reported is a new route to improve QEs of AlGaN-based DUV LEDs using mechanical flexibility of recently developed bendable thin-film structures. Numerical studies show that electronic band structures of AlGaN heterostructures and resulting optical and electrical characteristics of the devices can be significantly modified by external bending through active control of piezoelectric polarization. Internal quantum efficiency (IQE) is enhanced higher than three times, when the DUV LEDs are moderately bent to induce in-plane compressive strain in the heterostructure. Furthermore, efficiency droop at high injection currents is mitigated and turn-on voltage of diodes decreases with the same bending condition. The concept of bendable DUV LEDs with a controlled external strain can provide a new path for high-output-power and high-efficiency devices.

  14. Flexible deep-ultraviolet light-emitting diodes for significant improvement of quantum efficiencies by external bending

    KAUST Repository

    Shervin, Shahab

    2018-01-26

    Deep ultraviolet (DUV) light at the wavelength range of 250‒280 nm (UVC spectrum) is essential for numerous applications such as sterilization, purification, sensing, and communication. III-nitride-based DUV light-emitting diodes (DUV LEDs), like other solid-state lighting sources, offer a great potential to replace the conventional gas-discharged lamps with short lifetimes and toxic-element-bearing nature. However, unlike visible LEDs, the DUV LEDs are still suffering from low quantum efficiencies (QEs) and low optical output powers. In this work, reported is a new route to improve QEs of AlGaN-based DUV LEDs using mechanical flexibility of recently developed bendable thin-film structures. Numerical studies show that electronic band structures of AlGaN heterostructures and resulting optical and electrical characteristics of the devices can be significantly modified by external bending through active control of piezoelectric polarization. Internal quantum efficiency (IQE) is enhanced higher than three times, when the DUV LEDs are moderately bent to induce in-plane compressive strain in the heterostructure. Furthermore, efficiency droop at high injection currents is mitigated and turn-on voltage of diodes decreases with the same bending condition. The concept of bendable DUV LEDs with a controlled external strain can provide a new path for high-output-power and high-efficiency devices.

  15. Novel ventilation design of combining spacer and mesh structure in sports T-shirt significantly improves thermal comfort.

    Science.gov (United States)

    Sun, Chao; Au, Joe Sau-chuen; Fan, Jintu; Zheng, Rong

    2015-05-01

    This paper reports on novel ventilation design in sports T-shirt, which combines spacer and mesh structure, and experimental evidence on the advantages of design in improving thermal comfort. Evaporative resistance (Re) and thermal insulation (Rc) of T-shirts were measured using a sweating thermal manikin under three different air velocities. Moisture permeability index (i(m)) was calculated to compare the different designed T-shirts. The T-shirts of new and conventional designs were also compared by wearer trials, which were comprised of 30 min treadmill running followed by 10 min rest. Skin temperature, skin relative humidity, heart rate, oxygen inhalation and energy expenditure were monitored, and subjective sensations were asked. Results demonstrated that novel T-shirt has 11.1% significant lower im than control sample under windy condition. The novel T-shirt contributes to reduce the variation of skin temperature and relative humidity up to 37% and 32%, as well as decrease 3.3% energy consumption during exercise. Copyright © 2014 Elsevier Ltd and The Ergonomics Society. All rights reserved.

  16. Significant improvement of thermal stability of glucose 1-dehydrogenase by introducing disulfide bonds at the tetramer interface.

    Science.gov (United States)

    Ding, Haitao; Gao, Fen; Liu, Danfeng; Li, Zeli; Xu, Xiaohong; Wu, Min; Zhao, Yuhua

    2013-12-10

    Rational design was applied to glucose 1-dehydrogenase (LsGDH) from Lysinibacillus sphaericus G10 to improve its thermal stability by introduction of disulfide bridges between subunits. One out of the eleven mutants, designated as DS255, displayed significantly enhanced thermal stability with considerable soluble expression and high specific activity. It was extremely stable at pH ranging from 4.5 to 10.5, as it retained nearly 100% activity after incubating at different buffers for 1h. Mutant DS255 also exhibited high thermostability, having a half-life of 9900min at 50°C, which was 1868-fold as that of its wild type. Moreover, both of the increased free energy of denaturation and decreased entropy of denaturation of DS255 suggested that the enzyme structure was stabilized by the engineered disulfide bonds. On account of its robust stability, mutant DS255 would be a competitive candidate in practical applications of chiral chemicals synthesis, biofuel cells and glucose biosensors. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Imparting improvements in electrochemical sensors: evaluation of different carbon blacks that give rise to significant improvement in the performance of electroanalytical sensing platforms

    International Nuclear Information System (INIS)

    Vicentini, Fernando Campanhã; Ravanini, Amanda E.; Figueiredo-Filho, Luiz C.S.; Iniesta, Jesús; Banks, Craig E.; Fatibello-Filho, Orlando

    2015-01-01

    Three different carbon black materials have been evaluated as a potential modifier, however, only one demonstrated an improvement in the electrochemical properties. The carbon black structures were characterised with SEM, XPS and Raman spectroscopy and found to be very similar to that of amorphous graphitic materials. The modifications utilised were constructed by three different strategies (using ultrapure water, chitosan and dihexadecylphosphate). The fabricated sensors are electrochemically characterised using N,N,N',N'-tetramethyl-para-phenylenediamine and both inner-sphere and outer-sphere redox probes, namely potassium ferrocyanide(II) and hexaammineruthenium(III) chloride, in addition to the biologically relevant and electroactive analytes, dopamine (DA) and acetaminophen (AP). Comparisons are made with an edge-plane pyrolytic graphite and glassy-carbon electrode and the benefits of carbon black implemented as a modifier for sensors within electrochemistry are explored, as well as the characterisation of their electroanalytical performances. We reveal significant improvements in the electrochemical performance (excellent sensitivity, faster heterogeneous electron transfer rate (HET)) over that of a bare glassy-carbon and edge-plane pyrolytic graphite electrode and thus suggest that there are substantial advantages of using carbon black as modifier in the fabrication of electrochemical based sensors. Such work is highly important and informative for those working in the field of electroanalysis where electrochemistry can provide portable, rapid, reliable and accurate sensing protocols (bringing the laboratory into the field), with particular relevance to those searching for new electrode materials

  18. Higher Magnitude Cash Payments Improve Research Follow-up Rates Without Increasing Drug Use or Perceived Coercion

    Science.gov (United States)

    Festinger, David S.; Marlowe, Douglas B.; Dugosh, Karen L.; Croft, Jason R.; Arabia, Patricia L.

    2008-01-01

    In a prior study (Festinger et al., 2005) we found that neither the mode (cash vs. gift card) nor magnitude ($10, $40, or $70) of research follow-up payments increased rates of new drug use or perceptions of coercion. However, higher payments and payments in cash were associated with better follow-up attendance, reduced tracking efforts, and improved participant satisfaction with the study. The present study extended those findings to higher payment magnitudes. Participants from an urban outpatient substance abuse treatment program were randomly assigned to receive $70, $100, $130, or $160 in either cash or a gift card for completing a follow-up assessment at 6 months post-admission (n ≅ 50 per cell). Apart from the payment incentives, all participants received a standardized, minimal platform of follow-up efforts. Findings revealed that neither the magnitude nor mode of payment had a significant effect on new drug use or perceived coercion. Consistent with our previous findings, higher payments and cash payments resulted in significantly higher follow-up rates and fewer tracking calls. In addition participants receiving cash vs. gift cards were more likely to use their payments for essential, non-luxury purchases. Follow-up rates for participants receiving cash payments of $100, $130, and $160 approached or exceeded the FDA required minimum of 70% for studies to be considered in evaluations of new medications. This suggests that the use of higher magnitude payments and cash payments may be effective strategies for obtaining more representative follow-up samples without increasing new drug use or perceptions of coercion. PMID:18395365

  19. Increasing the use of 'smart' pump drug libraries by nurses: a continuous quality improvement project.

    Science.gov (United States)

    Harding, Andrew D

    2012-01-01

    The use of infusion pumps that incorporate "smart" technology (smart pumps) can reduce the risks associated with receiving IV therapies. Smart pump technology incorporates safeguards such as a list of high-alert medications, soft and hard dosage limits, and a drug library that can be tailored to specific patient care areas. Its use can help to improve patient safety and to avoid potentially catastrophic harm associated with medication errors. But when one independent community hospital in Massachusetts switched from older mechanical pumps to smart pumps, it neglected to assign an "owner" to oversee the implementation process. One result was that nurses were using the smart pump library for only 37% of all infusions.To increase pump library usage percentage-thereby reducing the risks associated with infusion and improving patient safety-the hospital undertook a continuous quality improvement project over a four-month period in 2009. With the involvement of direct care nurses, and using quantitative data available from the smart pump software, the nursing quality and pharmacy quality teams identified ways to improve pump and pump library use. A secondary goal was to calculate the hospital's return on investment for the purchase of the smart pumps. Several interventions were developed and, on the first of each month, implemented. By the end of the project, pump library usage had nearly doubled; and the hospital had completely recouped its initial investment.

  20. YH12852, a potent and highly selective 5-HT4 receptor agonist, significantly improves both upper and lower gastrointestinal motility in a guinea pig model of postoperative ileus.

    Science.gov (United States)

    Hussain, Z; Lee, Y J; Yang, H; Jeong, E J; Sim, J Y; Park, H

    2017-10-01

    Postoperative ileus (POI) is a transient gastrointestinal (GI) dysmotility that commonly develops after abdominal surgery. YH12852, a novel, potent and highly selective 5-hydroxytryptamine 4 (5-HT 4 ) receptor agonist, has been shown to improve both upper and lower GI motility in various animal studies and may have applications for the treatment of POI. Here, we investigated the effects and mechanism of action of YH12852 in a guinea pig model of POI to explore its therapeutic potential. The guinea pig model of POI was created by laparotomy, evisceration, and gentle manipulation of the cecum for 60 seconds, followed by closure with sutures under anesthesia. Group 1 received an oral administration of vehicle or YH12852 (1, 3, 10 or 30 mg/kg) only, while POI Group 2 was intraperitoneally pretreated with vehicle or 5-HT 4 receptor antagonist GR113808 (10 mg/kg) prior to oral dosing of vehicle or YH12852 (3 or 10 mg/kg). Upper GI transit was evaluated by assessing the migration of a charcoal mixture in the small intestine, while lower GI transit was assessed via measurement of fecal pellet output (FPO). YH12852 significantly accelerated upper and lower GI transit at the doses of 3, 10, and 30 mg/kg and reached its maximal effect at 10 mg/kg. These effects were significantly blocked by pretreatment of GR113808 10 mg/kg. Oral administration of YH12852 significantly accelerates and restores delayed upper and lower GI transit in a guinea pig model of POI. This drug may serve as a useful candidate for the treatment of postoperative ileus. © 2017 John Wiley & Sons Ltd.

  1. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater

    International Nuclear Information System (INIS)

    Yun, Jumi; Lee, Dae Hoon; Im, Ji Sun; Kim, Hyung-Il

    2012-01-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. - Graphical abstract: The high-performance transdermal drug delivery system could be prepared by combining temperature-responsive hydrogel, thermally conductive graphite oxide with improved interfacial affinity, and efficient micro heater fabricated by a joule heating method. Highlights: ► High performance of transdermal drug delivery system with an easy control of voltage. ► Improved thermal response of hydrogel by graphite oxide incorporation. ► Efficient micro heater fabricated by a joule heating method.

  2. Improvement in transdermal drug delivery performance by graphite oxide/temperature-responsive hydrogel composites with micro heater

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Jumi [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Lee, Dae Hoon [Environment Research Division, Korea Institute of Machinery and Materials, 171 Jang-dong, Yusong-gu, Daejeon 305-343 (Korea, Republic of); Im, Ji Sun [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of); Kim, Hyung-Il, E-mail: hikim@cnu.ac.kr [Department of Fine Chemical Engineering and Applied Chemistry, BK21-E2M, Chungnam National University, Daejeon 305-764 (Korea, Republic of)

    2012-08-01

    Transdermal drug delivery system (TDDS) was prepared with temperature-responsive hydrogel. The graphite was oxidized and incorporated into hydrogel matrix to improve the thermal response of hydrogel. The micro heater was fabricated to control the temperature precisely by adopting a joule heating method. The drug in hydrogel was delivered through a hairless mouse skin by controlling temperature. The efficiency of drug delivery was improved obviously by incorporation of graphite oxide due to the excellent thermal conductivity and the increased interfacial affinity between graphite oxide and hydrogel matrix. The fabricated micro heater was effective in controlling the temperature over lower critical solution temperature of hydrogel precisely with a small voltage less than 1 V. The cell viability test on graphite oxide composite hydrogel showed enough safety for using as a transdermal drug delivery patch. The performance of TDDS could be improved noticeably based on temperature-responsive hydrogel, thermally conductive graphite oxide, and efficient micro heater. - Graphical abstract: The high-performance transdermal drug delivery system could be prepared by combining temperature-responsive hydrogel, thermally conductive graphite oxide with improved interfacial affinity, and efficient micro heater fabricated by a joule heating method. Highlights: Black-Right-Pointing-Pointer High performance of transdermal drug delivery system with an easy control of voltage. Black-Right-Pointing-Pointer Improved thermal response of hydrogel by graphite oxide incorporation. Black-Right-Pointing-Pointer Efficient micro heater fabricated by a joule heating method.

  3. Cryptosporidium and other intestinal parasitic infections among HIV patients in southern Ethiopia: significance of improved HIV-related care.

    Science.gov (United States)

    Shimelis, Techalew; Tassachew, Yayehyirad; Lambiyo, Tariku

    2016-05-10

    Intestinal parasitic infections are known to cause gastroenteritis, leading to higher morbidity and mortality, particularly in people living with HIV/AIDS. This study aimed to determine the prevalence of Cryptosporidium and other intestinal parasitic infections among HIV patients receiving care at a hospital in Ethiopia where previous available baseline data helps assess if improved HIV-related care has reduced infection rates. A cross-sectional study was conducted at Hawassa University Hospital in southern Ethiopia from May, 2013 to March, 2014. A consecutive sample of 491 HIV- infected patients with diarrhea or a CD4 T cell count intestinal parasites. The study was approved by the Institutional Review Board of the College of Medicine and Health Sciences, Hawassa University. Physicians managed participants found to be infected with any pathogenic intestinal parasite. The overall prevalence of intestinal parasitic infections among the study population was 35.8 %. The most prevalent parasites were Cryptosporidium (13.2 %), followed by Entamoeba histolytica/dispar (10.2 %), and Giardia lamblia (7.9 %). The rate of single and multiple infections were 25.5 and 10.3 %, respectively. Patients with a CD4 T cell count intestinal parasitic infection or cryptosporidiosis compared to those with counts ≥ 200 cells/μl, but with some type of diarrhea. The study shows high prevalence of intestinal parasitic infections in the study population. However, the results in the current report are significantly lower compared to previous findings in the same hospital. The observed lower infection rate is encouraging and supports the need to strengthen and sustain the existing intervention measures in order to further reduce intestinal parasitic infections in people living with HIV/AIDS.

  4. Extended-release niacin/laropiprant significantly improves lipid levels in type 2 diabetes mellitus irrespective of baseline glycemic control

    Directory of Open Access Journals (Sweden)

    Bays HE

    2015-02-01

    Full Text Available Harold E Bays,1 Eliot A Brinton,2 Joseph Triscari,3 Erluo Chen,3 Darbie Maccubbin,3 Alexandra A MacLean,3 Kendra L Gibson,3 Rae Ann Ruck,3 Amy O Johnson-Levonas,3 Edward A O’Neill,3 Yale B Mitchel3 1Louisville Metabolic & Atherosclerosis Research Center (L-MARC, Louisville, KY, USA; 2Utah Foundation for Biomedical Research, Salt Lake City, UT, USA; 3Merck & Co, Inc., Whitehouse Station, NJ, USA Background: The degree of glycemic control in patients with type 2 diabetes mellitus (T2DM may alter lipid levels and may alter the efficacy of lipid-modifying agents. Objective: Evaluate the lipid-modifying efficacy of extended-release niacin/laropiprant (ERN/LRPT in subgroups of patients with T2DM with better or poorer glycemic control. Methods: Post hoc analysis of clinical trial data from patients with T2DM who were randomized 4:3 to double-blind ERN/LRPT or placebo (n=796, examining the lipid-modifying effects of ERN/LRPT in patients with glycosylated hemoglobin or fasting plasma glucose levels above and below median baseline levels. Results: At Week 12 of treatment, ERN/LRPT significantly improved low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C, non-high-density lipoprotein cholesterol, triglycerides, and lipoprotein (a, compared with placebo, with equal efficacy in patients above or below median baseline glycemic control. Compared with placebo, over 36 weeks of treatment more patients treated with ERN/LRPT had worsening of their diabetes and required intensification of antihyperglycemic medication, irrespective of baseline glycemic control. Incidences of other adverse experiences were generally low in all treatment groups. Conclusion: The lipid-modifying effects of ERN/LRPT are independent of the degree of baseline glycemic control in patients with T2DM (NCT00485758. Keywords: lipid-modifying agents, hyperglycemia, LDL, HDL, triglycerides

  5. Improved intestinal absorption of a poorly water-soluble oral drug using mannitol microparticles containing a nanosolid drug dispersion.

    Science.gov (United States)

    Nishino, Yukiko; Kubota, Aya; Kanazawa, Takanori; Takashima, Yuuki; Ozeki, Tetsuya; Okada, Hiroaki

    2012-11-01

    A nozzle for a spray dryer that can prepare microparticles of water-soluble carriers containing various nanoparticles in a single step was previously developed in our laboratory. To enhance the solubility and intestinal absorption of poorly water-soluble drugs, we used probucol (PBL) as a poorly water-soluble drug, mannitol (MAN) as a water-soluble carrier for the microparticles, and EUDRAGIT (EUD) as a polymer vehicle for the solid dispersion. PBL-EUD-acetone-methanol and aqueous MAN solutions were simultaneously supplied through different liquid passages of the spray nozzle and dried together. PBL-EUD solid dispersion was nanoprecipitated in the MAN solution using an antisolvent mechanism and rapidly dried by surrounding it with MAN. PBL in the dispersion vehicle was amorphous and had higher physical stability according to powder X-ray diffraction and differential scanning calorimetry analysis. The bioavailability of PBL in PBL-EUD S-100-MAN microparticles after oral administration in rats was markedly higher (14- and 6.2-fold, respectively) than that of the original PBL powder and PBL-MAN microparticles. These results demonstrate that the composite microparticles containing a nanosized solid dispersion of a poorly water-soluble drug prepared using the spray nozzle developed by us should be useful to increase the solubility and bioavailability of drugs after oral administration. Copyright © 2012 Wiley Periodicals, Inc.

  6. Significant inhibitory impact of dibenzyl trisulfide and extracts of Petiveria alliacea on the activities of major drug-metabolizing enzymes in vitro: An assessment of the potential for medicinal plant-drug interactions.

    Science.gov (United States)

    Murray, J; Picking, D; Lamm, A; McKenzie, J; Hartley, S; Watson, C; Williams, L; Lowe, H; Delgoda, R

    2016-06-01

    Dibenzyl trisulfide (DTS) is the major active ingredient expressed in Petiveria alliacea L., a shrub widely used for a range of conditions, such as, arthritis, asthma and cancer. Given its use alone and concomitantly with prescription medicines, we undertook to investigate its impact on the activities of important drug metabolizing enzymes, the cytochromes P450 (CYP), a key family of enzymes involved in many adverse drug reactions. DTS and seven standardized extracts from the plant were assessed for their impact on the activities of CYPs 1A2, 2C19, 2C9, 2D6 and 3A4 on a fluorometric assay. DTS revealed significant impact against the activities of CYPs 1A2, 2C19 and 3A4 with IC50 values of 1.9, 4.0 and 3.2μM, respectively, which are equivalent to known standard inhibitors of these enzymes (furafylline, and tranylcypromine), and the most potent interaction with CYP1A2 displayed irreversible enzyme kinetics. The root extract, drawn with 96% ethanol (containing 2.4% DTS), displayed IC50 values of 5.6, 3.9 and 4.2μg/mL respectively, against the same isoforms, CYPs 1A2, 2C19 and 3A4. These investigations identify DTS as a valuable CYP inhibitor and P. alliacea as a candidate plant worthy of clinical trials to confirm the conclusions that extracts yielding high DTS may lead to clinically relevant drug interactions, whilst extracts yielding low levels of DTS, such as aqueous extracts, are unlikely to cause adverse herb-drug interactions. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients

    NARCIS (Netherlands)

    K. Theys (Kristof); K. Deforche; J. Vercauteren (Jurgen); P. Libin (Pieter); D.A.M.C. van de Vijver (David); J. Albert (Jan); B. Åsjö (Birgitta); M. Bruckova (Marie); R.J. Camacho (Ricardo Jorge); B. Clotet (Bonaventura); Z. Grossman (Zehava); A. Horban (Andrzej); C. Kücherer (Claudia); D. Paraskevis (Dimitrios); E. Puchhammer-Stöckl (Elisabeth); C. Riva (Chiara); L. Ruiz (Lidia); J.-C. Schmit (Jean-Claude); R. Schuurman (Rob); A. Sonnerborg (Anders); D. Stanekova (Danica); D. Struck (Daniel); K. van Laethem (Kristel); A.M.J. Wensing (Annemarie); E. Puchhammer-Stockl E. (Elisabeth); M. Sarcletti (M.); B. Schmied (B.); M. Geit (M.); G. Balluch (G.); A.M. Vandamme (Anne Mieke); I. Derdelinck (Inge); A. Sasse (A.); M. Bogaert (M.); H. Ceunen (H.); A. de Roo (Annie); M. De Wit (Meike); F. Echahidi (F.); K. Fransen (K.); J.-C. Goffard (J.); P. Goubau (Patrick); E. Goudeseune (E.); J.-C. Yombi (J.); P. Lacor (Patrick); C. Liesnard (C.); M. Moutschen (M.); L.A. Pierard; R. Rens (R.); J. Schrooten; D. Vaira (D.); A. van den Heuvel (A.); B. van der Gucht (B.); M. van Ranst (Marc); E. van Wijngaerden (Eric); T. Vandercam; M. Vekemans (M.); C. Verhofstede; N. Clumeck (N.); K. van Laethem (K.); L.G. Kostrikis (Leondios); I. Demetriades (I.); I. Kousiappa (Ioanna); V.L. Demetriou (Victoria); J. Hezka (Johana); M. Linka (Marek); L. Machala (L.); L.B. Jrgensen (L.); J. Gerstoft (J.); L. Mathiesen (L.); C. Pedersen (Court); C. Nielsen (Claus); A. Laursen (A.); B. Kvinesdal (B.); K. Liitsola (Kirsi); M. Ristola (M.); J. Suni (J.); J. Sutinen (J.); K. Korn (Klaus); C. K̈ucherer (C.); P. Braun (P.); G. Poggensee (G.); M. Däumer (M.); D. Eberle (David); O. Hamouda (Osamah); H. Heiken (H.); R. Kaiser (Rolf); H. Knechten (H.); H. M̈uller (H.); S. Neifer (S.); H. Walter (Hauke); B. Gunsenheimer-Bartmeyer (B.); T. Harrer (T.); A. Hatzakis (Angelos); E. Hatzitheodorou (E.); C. Issaris (C.); C. Haida (C.); A. Zavitsanou (A.); G. Magiorkinis (Gkikas); M. Lazanas (M.); L. Chini; N. Magafas (N.); N. Tsogas (N.); V. Paparizos (V.); S. Kourkounti (S.); A. Antoniadou (A.); A. Papadopoulos (A.); P. Panagopoulos (P.); G. Poulakou (G.); V. Sakka (V.); G. Chryssos (G.); S. Drimis (S.); P. Gargalianos (P.); M. Lelekis (M.); G. Xilomenos (G.); M. Psichogiou (M.); G.L. Daikos (George); G. Panos (G.); G. Haratsis (G.); T. Kordossis (T.); A. Kontos (Angelos); G. Koratzanis (G.); M. Theodoridou (M.); G. Mostrou (G.); V. Spoulou (V.); W. Hall (W.); C. de Gascun (Cillian); C. Byrne (C.); M. Duffy (M.); P. Bergin; D. Reidy (D.); G. Farrell; J. Lambert (Julien); E. O'Connor (E.); A. Rochford (A.); J. Low (J.); P. Coakely (P.); S. Coughlan (Suzie); I. Levi (I.); D. Chemtob (D.); C. Balotta (Claudia); C. Mussini (C.); I. Caramma (I.); A. Capetti (A.); M.C. Colombo (M.); C. Rossi (Cesare); F. Prati (Francesco); F. Tramuto (F.); F. Vitale (F.); M. Ciccozzi (M.); G. Angarano (Guiseppe); G. Rezza (G.); R. Hemmer (R.); V. Arendt (V.); T. Staub (T.); F. Schneider (F.); F. Roman (Francois); C.A.B. Boucher (Charles); P.H.M. van Bentum (P. H M); K. Brinkman (Kees); E.L.M. Op de Coul (Eline); M.E. van der Ende (Marchina); I.M. Hoepelman (Ilja Mohandas); M.E.E. van Kasteren (Marjo); J. Juttmann (Job); M. Kuipers (M.); N. Langebeek (Nienke); C. Richter (C.); R.M.W.J. Santegoets (R. M W J); L. Schrijnders-Gudde (L.); R. Schuurman (Rob); B.J.M. van de Ven (B. J M); B. Asjö (Birgitta); V. Ormaasen (Vidar); P. Aavitsland (P.); J. Stanczak (J.); G.P. Stanczak (G.); E. Firlag-Burkacka (E.); A. Wiercinska-Drapalo (A.); E. Jablonowska (E.); E. Malolepsza (E.); M. Leszczyszyn-Pynka (M.); W. Szata (W.); A. de Palma (Andre); F. Borges (F.); T. Paix̃ao (T.); V. Duque (V.); F. Aráujo (F.); M. Stanojevic (Maja); D.J. Jevtovic (D.); D. Salemovic (D.); M. Habekova (M.); M. Mokras (M.); P. Truska (P.); M. Poljak (Mario); D.Z. Babic (Dunja); J. Tomazic (J.); S. Vidmar (Suzanna); P. Karner (P.); C. Gutíerrez (C.); C. deMendoza (C.); I. Erkicia (I.); P. Domingo (P.); X. Camino (X.); M.A. Galindo (Miguel Angel); J.L. Blanco (J.); M. Leal (M.); A. Masabeu (A.); A. Guelar (A.); J.M. Llibre (Josep M.); N. Margall (N.); C. Iribarren (Carlos); S. Gutierrez (S.); J.F. Baldov́i (J.); C.E. Pedreira (Carlos Eduardo); J.M. Gatell (J.); S. Moreno (S.); C. de Mendoza (Carmen); V. Soriano (Virtudes); A. Blaxhult (A.); A. Heidarian (A.); A. Karlsson (A.); K. Aperia-Peipke (K.); I.-M. Bergbrant (I.); M. Gissĺen (M.); M. Svennerholm (M.); P. Bj̈orkman (P.); G. Bratt (G.); M. Carlsson (M.); H. Ekvall (H.); M. Ericsson (M.); M. Ḧofer (M.); B. Johansson (Bert); N. Kuylenstierna (N.); K. Ljungberg (Karl); S. Mäkitalo (S.); A. Strand; K. Öberg (Kjell); T. Berg (Trine)

    2012-01-01

    textabstractBackground: The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory

  8. Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms.

    Directory of Open Access Journals (Sweden)

    Abhijeet Kapoor

    Full Text Available Human dopamine β-hydroxylase (DBH is an important therapeutic target for complex traits. Several single nucleotide polymorphisms (SNPs have also been identified in DBH with potential adverse physiological effect. However, difficulty in obtaining diffractable crystals and lack of a suitable template for modeling the protein has ensured that neither crystallographic three-dimensional structure nor computational model for the enzyme is available to aid rational drug design, prediction of functional significance of SNPs or analytical protein engineering.Adequate biochemical information regarding human DBH, structural coordinates for peptidylglycine alpha-hydroxylating monooxygenase and computational data from a partial model of rat DBH were used along with logical manual intervention in a novel way to build an in silico model of human DBH. The model provides structural insight into the active site, metal coordination, subunit interface, substrate recognition and inhibitor binding. It reveals that DOMON domain potentially promotes tetramerization, while substrate dopamine and a potential therapeutic inhibitor nepicastat are stabilized in the active site through multiple hydrogen bonding. Functional significance of several exonic SNPs could be described from a structural analysis of the model. The model confirms that SNP resulting in Ala318Ser or Leu317Pro mutation may not influence enzyme activity, while Gly482Arg might actually do so being in the proximity of the active site. Arg549Cys may cause abnormal oligomerization through non-native disulfide bond formation. Other SNPs like Glu181, Glu250, Lys239 and Asp290 could potentially inhibit tetramerization thus affecting function.The first three-dimensional model of full-length human DBH protein was obtained in a novel manner with a set of experimental data as guideline for consistency of in silico prediction. Preliminary physicochemical tests validated the model. The model confirms, rationalizes and

  9. Structural insight of dopamine β-hydroxylase, a drug target for complex traits, and functional significance of exonic single nucleotide polymorphisms.

    Science.gov (United States)

    Kapoor, Abhijeet; Shandilya, Manish; Kundu, Suman

    2011-01-01

    Human dopamine β-hydroxylase (DBH) is an important therapeutic target for complex traits. Several single nucleotide polymorphisms (SNPs) have also been identified in DBH with potential adverse physiological effect. However, difficulty in obtaining diffractable crystals and lack of a suitable template for modeling the protein has ensured that neither crystallographic three-dimensional structure nor computational model for the enzyme is available to aid rational drug design, prediction of functional significance of SNPs or analytical protein engineering. Adequate biochemical information regarding human DBH, structural coordinates for peptidylglycine alpha-hydroxylating monooxygenase and computational data from a partial model of rat DBH were used along with logical manual intervention in a novel way to build an in silico model of human DBH. The model provides structural insight into the active site, metal coordination, subunit interface, substrate recognition and inhibitor binding. It reveals that DOMON domain potentially promotes tetramerization, while substrate dopamine and a potential therapeutic inhibitor nepicastat are stabilized in the active site through multiple hydrogen bonding. Functional significance of several exonic SNPs could be described from a structural analysis of the model. The model confirms that SNP resulting in Ala318Ser or Leu317Pro mutation may not influence enzyme activity, while Gly482Arg might actually do so being in the proximity of the active site. Arg549Cys may cause abnormal oligomerization through non-native disulfide bond formation. Other SNPs like Glu181, Glu250, Lys239 and Asp290 could potentially inhibit tetramerization thus affecting function. The first three-dimensional model of full-length human DBH protein was obtained in a novel manner with a set of experimental data as guideline for consistency of in silico prediction. Preliminary physicochemical tests validated the model. The model confirms, rationalizes and provides

  10. Improved oral bioavailability of glyburide by a self-nanoemulsifying drug delivery system.

    Science.gov (United States)

    Liu, Hongzhuo; Shang, Kuimao; Liu, Weina; Leng, Donglei; Li, Ran; Kong, Ying; Zhang, Tianhong

    2014-01-01

    The present study aimed at the development and characterisation of self-nanoemulsifying drug delivery system (SNEDDS) to improve the oral bioavailability of poorly soluble glyburide. The solubility of glyburide was determined in various oils, surfactants and co-surfactants which were grouped into two different combinations to construct ternary phase diagrams. The formulations were evaluated for emulsification time, droplet size, zeta-potential, electrical conductivity and stability of nanoemulsions. The optimised SNEDDS loading with 5 mg/g glyburide comprised 55% Cremophor® RH 40, 15% propanediol and 30% Miglyol® 812, which rapidly formed fine oil-in-water nanoemulsions with 46 ± 4 nm particle size. Compared with the commercial micronised tablets (Glynase®PresTab®), enhanced in vitro release profiles of SNEDDS were observed, resulting in the 1.5-fold increase of AUC following oral administration of SNEDDS in fasting beagle dogs. These results indicated that SNEDDS is a promising drug delivery system for increasing the oral bioavailability of glyburide.

  11. THE USE OF SELECTED ANAESTHETIC DRUGS IN SEARCH OF A METHOD FOR IMPROVING EARTHWORMS’ WELFARE

    Directory of Open Access Journals (Sweden)

    Agnieszka Podolak-Machowska

    2013-07-01

    Full Text Available This paper describes selected effects of body contact of earthworms Dendrobaena veneta Rosa with local anaesthetic (LA drugs used for human anesthesia (lidocaine and prilocaine and anaesthetics for aquatic animals (MS-222. The findings showed safe and effective immobilization of earthworms with prilocaine at a concentration of 0.25-1%. At the applied concentrations lidocaine was safe, but less effective. On the other hand, MS-222, at the applied concentrations had a strongly irritating effect for earthworms and induced convulsive body movements connected with a discharge of coelomic fluid. The results may be relevant both for improving the welfare of earthworms during experiments and for the organization of research involving testing drugs on invertebrates. In this case, by using earthworms as an experimental model and by applying the method for measuring their mobility after contact with anaesthetics, which has been described in this article, it might be possible to replace experiments on guinea pigs, rabbits, rats and mice, which are expensive and require an approval of an ethics committee, with laboratory tests on earthworms.

  12. Evaluating an approach to improving the adoption rate of wireless drug library updates for smart pumps.

    Science.gov (United States)

    Poppe, Lindsey B; Eckel, Stephen F

    2011-01-15

    An academic medical center's approach to improving the adoption rate of wireless drug library updates for smart pumps was evaluated. A multidisciplinary team composed of pharmacy, nursing, medical engineering, materials management, and patient equipment personnel at an academic medical center collaborated to update the drug libraries of more than 1800 smart pumps via a wireless control system. Two pilot tests were completed to identify and resolve issues before the live wireless update was attempted. The second pilot test, a passive approach, produced an adoption rate of 42% of 1804 pumps at the end of one week and a rate of 56% on day 10. The goal of 80% was not achieved until day 22. The change to an active multidisciplinary process three months later produced an adoption rate of 80% for 1869 pumps on day 10, resulting in a 45.4% increase in the adoption rate between the two trials on day 10 (p libraries reduced the amount of time required to reach a goal adoption rate of 80%.

  13. Melt dispersion granules: formulation and evaluation to improve oral delivery of poorly soluble drugs - a case study with valsartan.

    Science.gov (United States)

    Chella, Naveen; Tadikonda, Ramarao

    2015-06-01

    Solid dispersion (SD) technique is a promising strategy to improve the solubility and dissolution of BCS class II drugs. However, only few products are marketed till today based on SD technology due to poor flow properties and stability. The present work was intended to solve these problems by using combination approach, melt dispersion and surface adsorption technologies. The main aim of the present work is to improve the absorption in the stomach (at lower pH) where the absorption window exists for the drug by improving the dissolution, resulting in the enhancement of oral bioavailability of poorly soluble, weakly acidic drug with pH dependant solubility, i.e. valsartan. Melt dispersion granules were prepared in different ratios using different carriers (Gelucire 50/13, PEG 8000 and Pluronic F-68) and lactose as an adsorbent. Similarly, physical mixtures were also prepared at corresponding ratios. The prepared dispersion granules and physical mixtures were characterized by FTIR, DSC and in vitro dissolution studies. DSC studies revealed reduction in the crystallinity with a possibility of presence of amorphous character of drug in the dispersion granules. From dissolution studies, valsartan Gelucire dispersion (GSD4; 1:4 ratio) showed complete drug release in 30 min against the plain drug which showed only 11.31% of drug release in 30 min. Pharmacokinetic studies of optimized formulation in male Wistar rats showed 2.65-fold higher bioavailability and 1.47-fold higher Cmax compared to pure drug. The melt dispersion technology has the potential to improve dissolution and the bioavailability of BCS class II drugs.

  14. Factors affecting the stability of drug-loaded polymeric micelles and strategies for improvement

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Weisai; Li, Caibin; Wang, Zhiyu; Zhang, Wenli, E-mail: zwllz@163.com; Liu, Jianping, E-mail: liujianpingljp@hotmail.com [China Pharmaceutical University, Department of Pharmaceutics (China)

    2016-09-15

    Polymeric micelles (PMs) self-assembled by amphiphilic block copolymers have been used as promising nanocarriers for tumor-targeted delivery due to their favorable properties, such as excellent biocompatibility, prolonged circulation time, favorable particle sizes (10–100 nm) to utilize enhanced permeability and retention effect and the possibility for functionalization. However, PMs can be easily destroyed due to dilution of body fluid and the absorption of proteins in system circulation, which may induce drug leakage from these micelles before reaching the target sites and compromise the therapeutic effect. This paper reviewed the factors that influence stability of micelles in terms of thermodynamics and kinetics consist of the critical micelle concentration of block copolymers, glass transition temperature of hydrophobic segments and polymer–polymer and polymer–cargo interaction. In addition, some effective strategies to improve the stability of micelles were also summarized.Graphical Abstract.

  15. Interventions that effectively target Anopheles funestus mosquitoes could significantly improve control of persistent malaria transmission in south-eastern Tanzania.

    Science.gov (United States)

    Kaindoa, Emmanuel W; Matowo, Nancy S; Ngowo, Halfan S; Mkandawile, Gustav; Mmbando, Arnold; Finda, Marcelina; Okumu, Fredros O

    2017-01-01

    An. arabiensis (44.1%). Though An. arabiensis is still the most abundant vector species here, the remaining malaria transmission is predominantly mediated by An. funestus, possibly due to high insecticide resistance and high survival probabilities. Interventions that effectively target An. funestus mosquitoes could therefore significantly improve control of persistent malaria transmission in south-eastern Tanzania.

  16. Interventions that effectively target Anopheles funestus mosquitoes could significantly improve control of persistent malaria transmission in south–eastern Tanzania

    Science.gov (United States)

    Matowo, Nancy S.; Ngowo, Halfan S.; Mkandawile, Gustav; Mmbando, Arnold; Finda, Marcelina; Okumu, Fredros O.

    2017-01-01

    An. arabiensis (44.1%). Though An. arabiensis is still the most abundant vector species here, the remaining malaria transmission is predominantly mediated by An. funestus, possibly due to high insecticide resistance and high survival probabilities. Interventions that effectively target An. funestus mosquitoes could therefore significantly improve control of persistent malaria transmission in south–eastern Tanzania. PMID:28542335

  17. Global proteomics profiling improves drug sensitivity prediction: results from a multi-omics, pan-cancer modeling approach.

    Science.gov (United States)

    Ali, Mehreen; Khan, Suleiman A; Wennerberg, Krister; Aittokallio, Tero

    2018-04-15

    Proteomics profiling is increasingly being used for molecular stratification of cancer patients and cell-line panels. However, systematic assessment of the predictive power of large-scale proteomic technologies across various drug classes and cancer types is currently lacking. To that end, we carried out the first pan-cancer, multi-omics comparative analysis of the relative performance of two proteomic technologies, targeted reverse phase protein array (RPPA) and global mass spectrometry (MS), in terms of their accuracy for predicting the sensitivity of cancer cells to both cytotoxic chemotherapeutics and molecularly targeted anticancer compounds. Our results in two cell-line panels demonstrate how MS profiling improves drug response predictions beyond that of the RPPA or the other omics profiles when used alone. However, frequent missing MS data values complicate its use in predictive modeling and required additional filtering, such as focusing on completely measured or known oncoproteins, to obtain maximal predictive performance. Rather strikingly, the two proteomics profiles provided complementary predictive signal both for the cytotoxic and targeted compounds. Further, information about the cellular-abundance of primary target proteins was found critical for predicting the response of targeted compounds, although the non-target features also contributed significantly to the predictive power. The clinical relevance of the selected protein markers was confirmed in cancer patient data. These results provide novel insights into the relative performance and optimal use of the widely applied proteomic technologies, MS and RPPA, which should prove useful in translational applications, such as defining the best combination of omics technologies and marker panels for understanding and predicting drug sensitivities in cancer patients. Processed datasets, R as well as Matlab implementations of the methods are available at https://github.com/mehr-een/bemkl-rbps. mehreen

  18. The anti-inflammatory drug carprofen improves long-term outcome and induces gliogenesis after traumatic brain injury.

    Science.gov (United States)

    Thau-Zuchman, Orli; Shohami, Esther; Alexandrovich, Alexander G; Trembovler, Victoria; Leker, Ronen R

    2012-01-20

    Traumatic brain injury (TBI) initiates acute and chronic inflammatory processes involving cyclooxygenase-2 (COX-2), which may have detrimental effects on outcome and especially on brain regeneration. Therefore we aimed to study whether carprofen, a COX-2 inhibitor, would improve outcome and increase neurogenesis after TBI. TBI was induced in Sabra mice that were then treated with vehicle or carprofen for 7 days. Functional outcome was evaluated with the Neurological Severity Score (NSS).Cytokine levels were assessed 4 h post-TBI and water content was measured 24 h post TBI. Mice were given BrdU to label newborn cells for 10 days. The animals were killed 90 days post-TBI and the lesion size as well as newborn cell fate were assessed. Carprofen significantly reduced lesion size (p=0.002), decreased water content in the lesioned cortex (p=0.03), reduced the number of microglia in the lesioned cortex (pCarprofen led to significantly larger improvements in functional outcome (p≤0.008) which were durable over 90 days. Carprofen also induced a threefold increase in the proliferation of new cells in the peri-lesion area (p≤0.002), but newborn cells differentiated mainly into glia in both groups. Carprofen is neuroprotective and induces cell proliferation and gliogenesis after TBI. Treatment with carprofen is consistently associated with better functional outcome. Our results imply that anti-inflammatory drugs may represent novel therapeutic options for TBI.

  19. Genetic Diversity and Selective Pressure in Hepatitis C Virus Genotypes 1-6: Significance for Direct-Acting Antiviral Treatment and Drug Resistance.

    Science.gov (United States)

    Cuypers, Lize; Li, Guangdi; Libin, Pieter; Piampongsant, Supinya; Vandamme, Anne-Mieke; Theys, Kristof

    2015-09-16

    Treatment with pan-genotypic direct-acting antivirals, targeting different viral proteins, is the best option for clearing hepatitis C virus (HCV) infection in chronically infected patients. However, the diversity of the HCV genome is a major obstacle for the development of antiviral drugs, vaccines, and genotyping assays. In this large-scale analysis, genome-wide diversity and selective pressure was mapped, focusing on positions important for treatment, drug resistance, and resistance testing. A dataset of 1415 full-genome sequences, including genotypes 1-6 from the Los Alamos database, was analyzed. In 44% of all full-genome positions, the consensus amino acid was different for at least one genotype. Focusing on positions sharing the same consensus amino acid in all genotypes revealed that only 15% was defined as pan-genotypic highly conserved (≥99% amino acid identity) and an additional 24% as pan-genotypic conserved (≥95%). Despite its large genetic diversity, across all genotypes, codon positions were rarely identified to be positively selected (0.23%-0.46%) and predominantly found to be under negative selective pressure, suggesting mainly neutral evolution. For NS3, NS5A, and NS5B, respectively, 40% (6/15), 33% (3/9), and 14% (2/14) of the resistance-related positions harbored as consensus the amino acid variant related to resistance, potentially impeding treatment. For example, the NS3 variant 80K, conferring resistance to simeprevir used for treatment of HCV1 infected patients, was present in 39.3% of the HCV1a strains and 0.25% of HCV1b strains. Both NS5A variants 28M and 30S, known to be associated with resistance to the pan-genotypic drug daclatasvir, were found in a significant proportion of HCV4 strains (10.7%). NS5B variant 556G, known to confer resistance to non-nucleoside inhibitor dasabuvir, was observed in 8.4% of the HCV1b strains. Given the large HCV genetic diversity, sequencing efforts for resistance testing purposes may need to be

  20. Curcumin-carboxymethyl chitosan (CNC) conjugate and CNC/LHR mixed polymeric micelles as new approaches to improve the oral absorption of P-gp substrate drugs.

    Science.gov (United States)

    Ni, Jiang; Tian, Fengchun; Dahmani, Fatima Zohra; Yang, Hui; Yue, Deren; He, Shuwang; Zhou, Jianping; Yao, Jing

    2016-11-01

    The low oral bioavailability of numerous drugs has been mostly attributed to the significant effect of P-gp-mediated efflux on intestinal drug transport. Herein, we developed mixed polymeric micelles (MPMs) comprised of curcumin-carboxymethyl chitosan (CNC) conjugate, as a potential inhibitor of P-gp-mediated efflux and gastrointestinal absorption enhancer, and low-molecular-weight heparin-all-trans-retinoid acid (LHR) conjugate, as loading material, with the aim to improve the oral absorption of P-gp substrate drugs. CNC conjugate was synthesized by chemical bonding of curcumin (Cur) and carboxymethyl chitosan (CMCS) taking advantage of the inhibition of intestinal P-gp-mediated secretion by Cur and the intestinal absorption enhancement by CMCS. The chemical structure of CNC conjugate was characterized by 1 H NMR with a degree of substitution of Cur of 4.52-10.20%. More importantly, CNC conjugate markedly improved the stability of Cur in physiological pH. Cyclosporine A-loaded CNC/LHR MPMs (CsA-CNC/LHR MPMs) were prepared by dialysis method, with high drug loading 25.45% and nanoscaled particle size (∼200 nm). In situ single-pass perfusion studies in rats showed that both CsA + CNC mixture and CsA-CNC/LHR MPMs achieved significantly higher K a and P eff than CsA suspension in the duodenum and jejunum segments (p CNC mixture and CsA-CNC/LHR MPMs significantly increased the oral bioavailability of CsA as compared to CsA suspension. These results suggest that CNC conjugate might be considered as a promising gastrointestinal absorption enhancer, while CNC/LHR MPMs had the potential to improve the oral absorption of P-gp substrate drugs.

  1. Seized Drugs and Weapons: DEA Needs to Improve Certain Physical Safeguards and Strength Accountability

    National Research Council Canada - National Science Library

    1999-01-01

    This report focuses on DEAs controls over seized drugs and weapons. There is an inherent risk of theft, misuse, and loss of drugs and weapons due to the fact that such evidence typically has a market or "street" value...

  2. [Orphan drugs].

    Science.gov (United States)

    Golocorbin Kon, Svetlana; Vojinović, Aleksandra; Lalić-Popović, Mladena; Pavlović, Nebojsa; Mikov, Momir

    2013-01-01

    Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in "adopting" them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. THE BEGINNING OF ORPHAN DRUGS DEVELOPMENT: This problem was first recognized by Congress of the United States of America in January 1983, and when the "Orphan Drug Act" was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs.

  3. Carrier-Mediated Prodrug Uptake to Improve the Oral Bioavailability of Polar Drugs: An Application to an Oseltamivir Analogue.

    Science.gov (United States)

    Incecayir, Tuba; Sun, Jing; Tsume, Yasuhiro; Xu, Hao; Gose, Tomoka; Nakanishi, Takeo; Tamai, Ikumi; Hilfinger, John; Lipka, Elke; Amidon, Gordon L

    2016-02-01

    The goal of this study was to improve the intestinal mucosal cell membrane permeability of the poorly absorbed guanidino analogue of a neuraminidase inhibitor, oseltamivir carboxylate (GOC) using a carrier-mediated strategy. Valyl amino acid prodrug of GOC with isopropyl-methylene-dioxy linker (GOC-ISP-Val) was evaluated as the potential substrate for intestinal oligopeptide transporter, hPEPT1 in Xenopus laevis oocytes heterologously expressing hPEPT1, and an intestinal mouse perfusion system. The diastereomers of GOC-ISP-Val were assessed for chemical and metabolic stability. Permeability of GOC-ISP-Val was determined in Caco-2 cells and mice. Diastereomer 2 was about 2 times more stable than diastereomer 1 in simulated intestinal fluid and rapidly hydrolyzed to the parent drug in cell homogenates. The prodrug had a 9 times-enhanced apparent permeability (P(app)) in Caco-2 cells compared with the parent drug. Both diastereomer exhibited high effective permeability (P(eff)) in mice, 6.32 ± 3.12 and 5.20 ± 2.81 × 10(-5) cm/s for diastereomer 1 and 2, respectively. GOC-ISP-Val was found to be a substrate of hPEPT1. Overall, this study indicates that the prodrug, GOC-ISP-Val, seems to be a promising oral anti-influenza agent that has sufficient stability at physiologically relevant pHs before absorption, significantly improved permeability via hPEPT1 and potentially rapid activation in the intestinal cells. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  4. Significant survival improvement of patients with recurrent breast cancer in the periods 2001-2008 vs. 1992-2000

    Directory of Open Access Journals (Sweden)

    Nishimura Sumiko

    2011-03-01

    Full Text Available Abstract Background It is unclear whether individualized treatments based on biological factors have improved the prognosis of recurrent breast cancer. The purpose of this study is to evaluate the survival improvement of patients with recurrent breast cancer after the introduction of third generation aromatase inhibitors (AIs and trastuzumab. Methods A total of 407 patients who received first diagnosis of recurrent breast cancer and treatment at National Kyushu Cancer Center between 1992 and 2008 were retrospectively evaluated. As AIs and trastuzumab were approved for clinical use in Japan in 2001, the patients were divided into two time cohorts depending on whether the cancer recurred before or after 2001. Cohort A: 170 patients who were diagnosed between 1992 and 2000. Cohort B: 237 patients who were diagnosed between 2001 and 2008. Tumor characteristics, treatments, and outcome were compared. Results Fourteen percent of cohort A and 76% of cohort B received AIs and/or trastuzumab (P Conclusions The prognosis of patients with recurrent breast cancer was improved over time following the introduction of AIs and trastuzumab and the survival improvement was apparent in HR- and/or HER-2-positive tumors.

  5. Significant Improvement in Sleep in People with Intellectual Disabilities Living in Residential Settings by Non-Pharmaceutical Interventions

    Science.gov (United States)

    Hylkema, T.; Vlaskamp, C.

    2009-01-01

    Background: Although about 15 to 50 percent of people with intellectual disabilities (ID) living in residential settings suffer from sleep problems, scant attention is paid to these problems. Most available studies focus on pharmaceutical solutions. In this study we focus on improving sleep in people with intellectual disabilities living in…

  6. Improving graduation rates for African Americans in drug court: Importance of human relationships and barriers to gaining and sustaining employment.

    Science.gov (United States)

    Gallagher, John Robert; Nordberg, Anne; Dibley, Alyssa R

    2017-11-16

    Drug courts have been an important part of the criminal justice system since 1989. They continue to expand throughout the United States because nearly three decades of research has shown that they are more effective than other interventions, such as traditional probation. There is a pattern, though, in some drug courts where African Americans are less likely to graduate than their Caucasian counterparts. This qualitative study explores this phenomenon by asking African American participants (n = 31) their views on the most helpful aspects of drug court and how drug court could be more helpful in supporting them in graduating the program. Participants felt that the respect and compassion they received from the drug court judge and their case managers, as well as the camaraderie they developed with other participants, was an aspect of drug court that supported them in graduating the program. Next, participants felt that graduation rates would improve if drug court better supported them in gaining employment or sustaining the employment they already had. Implications for drug court practice are discussed.

  7. Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously.

    Science.gov (United States)

    Xing, Qiao; Song, Jia; You, Xiuhua; Xu, Dongling; Wang, Kexin; Song, Jiaqi; Guo, Qin; Li, Pengyu; Wu, Chuanbin; Hu, Haiyan

    2016-09-25

    Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Patient-Centered Tablet Application for Improving Medication Adherence after a Drug-Eluting Stent.

    Science.gov (United States)

    Shah, Vicki; Dileep, Anandu; Dickens, Carolyn; Groo, Vicki; Welland, Betty; Field, Jerry; Baumann, Matthew; Flores, Jose D; Shroff, Adhir; Zhao, Zhongsheng; Yao, Yingwei; Wilkie, Diana J; Boyd, Andrew D

    2016-01-01

    This study's objective was to evaluate a patient-centered educational electronic tablet application, "My Interventional Drug-Eluting Stent Educational App" (MyIDEA) to see if there was an increase in patient knowledge about dual antiplatelet therapy (DAPT) and medication possession ratio (MPR) compared to treatment as usual. In a pilot project, 24 elderly (≥50 years old) research participants were recruited after a drug-eluting stent. Eleven were randomized to the control arm and 13 to the interventional arm. All the participants completed psychological and knowledge questionnaires. Adherence was assessed through MPR, which was calculated at 3 months for all participants who were scheduled for second and third follow-up visits. Relative to control, the interventional group had a 10% average increase in MPR. As compared to the interventional group, more patients in the control group had poor adherence (<80% MPR). The psychological data revealed a single imbalance in anxiety between the control and interventional groups. On average, interventional participants spent 21 min using MyIDEA. Consumer health informatics has enabled us to engage patients with their health data using novel methods. Consumer health technology needs to focus more on patient knowledge and engagement to improve long-term health. MyIDEA takes a unique approach in targeting DAPT from the onset. MyIDEA leverages patient-centered information with clinical care and the electronic health record highlighting the patients' role as a team member in their own health care. The patients think critically about adverse events and how to solve issues before leaving the hospital.

  9. Patient Centered Tablet Application for improving medication adherence after a Drug Eluting Stent

    Directory of Open Access Journals (Sweden)

    Vicki Shah

    2016-12-01

    Full Text Available Background/Aims: This study’s objective was to evaluate a patient-centered educational electronic tablet application, My Interventional Drug-Eluting Stent Educational App (MyIDEA to see if there was an increase in patient knowledge about dual antiplatelet therapy (DAPT and medication possession ratio (MPR compared to treatment as usual. Methods: In a pilot project, 24 elderly (≥50 years-old research participants were recruited after a Drug Eluting Stent. 11 were randomized to the control arm and 13 to the interventional arm. All participants completed psychological and knowledge questionnaires. Adherence was assessed through MPR, which was calculated at three months for all participants who were scheduled for a second and third follow-up visit.Results: Relative to control, the interventional group had a 10% average increase in MPR. As compared to the interventional group, more patients in the control group had poor adherence (<80% MPR. The psychological data revealed a single imbalance in anxiety between the control and interventional groups. On average interventional participants spent 21 minutes using MyIDEA. Discussion: Consumer health informatics has enabled us to engage patients with their health data using novel methods. Consumer health technology needs to focus more on patient knowledge and engagement to improve long term health. MyIDEA takes a unique approach in targeting DAPT from the onset.Conclusion: MyIDEA leverages patient centered information with clinical care and the electronic health record highlighting the patients’ role as a team member in their own healthcare. The patients think critically about adverse events and how to solve issues before leaving the hospital.

  10. Neural basis for the ability of atypical antipsychotic drugs to improve cognition in schizophrenia

    Directory of Open Access Journals (Sweden)

    Tomiki eSumiyoshi

    2013-10-01

    Full Text Available Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT receptors in ameliorating cognitive deficits of schizophrenia.It is noteworthy that atypical antipsychotic drugs, e.g. clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence.The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and GABA neurons. A novel strategy for cognitive enhancement in psychosis may be benefitted by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g. event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some atypical antipsychotic drugs acting directly or indirectly on 5-HT1A receptors.These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia.

  11. Reversible Lansoprazole-Induced Interstitial Lung Disease Showing Improvement after Drug Cessation

    International Nuclear Information System (INIS)

    Hwang, Kyu Won; Woo, Ok Hee; Yong, Hwan Seok; Shin, Bong Kyung; Shim, Jae Jeong; Kang, Eun Young

    2008-01-01

    Lansoprazole is an acid proton-pump inhibitor that is similar to omeprazole. It is used to treat duodenal or gastric ulcers, H. pylori infection, gastroesophageal reflux disease (GERD) or Zollinger-Ellison syndrome. Common adverse effects of lansoprazole are diarrhea, abdominal pain, skin rash and/or itching. Information from U.S. National Library of Medicine warns that this drug can on rare occasion cause cough or cold-like symptoms. The pathophysiological mechanisms of lansoprazole-related pulmonary symptoms are not yet understood. In particular, there are no known reports regarding lansoprazole-induced interstitial lung diseases. We report here a case of interstitial lung disease (ILD) induced by oral administration of lansoprazole, which showed a pattern of nonspecific interstitial pneumonia (NSIP) as detected from a video-assisted thoracoscopic lung biopsy. We believe that this is the first report of a case of pathologically proven lansoprazole-induced ILD for which a surgical lung biopsy was performed. To the best of our knowledge, this is the first description of DI-ILD caused by lansoprazole. The diagnosis was made by considering the radiological, histopathological and clinical findings, including the close temporal relationship between lansoprazole exposure and symptom severity. Other possible causes were excluded due to a lack of a temporal relationship between the symptoms and work history or prednisolone therapy, and no other history of specific allergen exposure. When there is diffuse interstitial lung disease with an unknown etiology, it is important to remember that drugs can be the cause of pulmonary symptoms and it is crucial to take a careful patient history. If there is a recent history of taking lansoprazole in a patient with clinical and radiological findings of diffuse interstitial lung disease, we recommend stopping the medication to see if there is clinical and radiological improvement. That way, one can avoid using invasive procedures to

  12. Drug-coated balloon angioplasty after directional atherectomy improves outcome in restenotic femoropopliteal arteries.

    Science.gov (United States)

    Sixt, Sebastian; Carpio Cancino, Oscar Gerardo; Treszl, András; Beschorner, Ulrich; Macharzina, Roland; Rastan, Aljoscha; Krankenberg, Hans; Neumann, Franz-Josef; Zeller, Thomas

    2013-09-01

    Restenosis remains an unresolved problem despite different treatment modalities and new stent technology in femoropopliteal arteries. No standard therapy has proven to provide acceptable outcome data for this entity. Directional atherectomy alone did not result in satisfactory long-term patency rates. The outcome might be improved in conjunction with drug-coated balloon angioplasty. In this retrospective study, restenotic lesions of the femoropopliteal arteries were treated with directed atherectomy in 89 lesions of consecutive patients (58% male; mean age, 69 ± 11 years). All patients received adjunctive treatment with conventional balloon percutaneous angioplasty (PTA; n = 60) or drug-coated balloon angioplasty (DCB; n = 29). Lesion location was in the stent (DCB [n = 27] vs PTA [n = 36]) and in native restenotic vessels (DCB [n = 2] vs PTA [n = 25]). The 1-year Kaplan-Meier freedom from restenosis estimates (95% confidence intervals) in the DCB and PTA groups were 84.7% (70.9%-98.5%) and 43.8% (30.5%-57.1%), respectively. In a multivariable Cox model for restenosis, DCB treatment had a hazard ratio (95% confidence interval) of 0.28 (0.12-0.66; P = .0036) compared with the PTA group. In the multivariable model for procedural success, the effect of treatment did not differ between PTA and DCB (P = .134). The combination of directed atherectomy with adjunctive DCB is associated with a better event-free survival at 12 months of follow-up compared with PTA after directed atherectomy. Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.

  13. Reversible Lansoprazole-Induced Interstitial Lung Disease Showing Improvement after Drug Cessation

    Energy Technology Data Exchange (ETDEWEB)

    Hwang, Kyu Won; Woo, Ok Hee; Yong, Hwan Seok; Shin, Bong Kyung; Shim, Jae Jeong; Kang, Eun Young [College of Medicine, Korea University, Guro Hospital, Seoul (Korea, Republic of)

    2008-04-15

    Lansoprazole is an acid proton-pump inhibitor that is similar to omeprazole. It is used to treat duodenal or gastric ulcers, H. pylori infection, gastroesophageal reflux disease (GERD) or Zollinger-Ellison syndrome. Common adverse effects of lansoprazole are diarrhea, abdominal pain, skin rash and/or itching. Information from U.S. National Library of Medicine warns that this drug can on rare occasion cause cough or cold-like symptoms. The pathophysiological mechanisms of lansoprazole-related pulmonary symptoms are not yet understood. In particular, there are no known reports regarding lansoprazole-induced interstitial lung diseases. We report here a case of interstitial lung disease (ILD) induced by oral administration of lansoprazole, which showed a pattern of nonspecific interstitial pneumonia (NSIP) as detected from a video-assisted thoracoscopic lung biopsy. We believe that this is the first report of a case of pathologically proven lansoprazole-induced ILD for which a surgical lung biopsy was performed. To the best of our knowledge, this is the first description of DI-ILD caused by lansoprazole. The diagnosis was made by considering the radiological, histopathological and clinical findings, including the close temporal relationship between lansoprazole exposure and symptom severity. Other possible causes were excluded due to a lack of a temporal relationship between the symptoms and work history or prednisolone therapy, and no other history of specific allergen exposure. When there is diffuse interstitial lung disease with an unknown etiology, it is important to remember that drugs can be the cause of pulmonary symptoms and it is crucial to take a careful patient history. If there is a recent history of taking lansoprazole in a patient with clinical and radiological findings of diffuse interstitial lung disease, we recommend stopping the medication to see if there is clinical and radiological improvement. That way, one can avoid using invasive procedures to

  14. Improved Predictions of Drug-Drug Interactions Mediated by Time-Dependent Inhibition of CYP3A.

    Science.gov (United States)

    Yadav, Jaydeep; Korzekwa, Ken; Nagar, Swati

    2018-05-07

    Time-dependent inactivation (TDI) of cytochrome P450s (CYPs) is a leading cause of clinical drug-drug interactions (DDIs). Current methods tend to overpredict DDIs. In this study, a numerical approach was used to model complex CYP3A TDI in human-liver microsomes. The inhibitors evaluated included troleandomycin (TAO), erythromycin (ERY), verapamil (VER), and diltiazem (DTZ) along with the primary metabolites N-demethyl erythromycin (NDE), norverapamil (NV), and N-desmethyl diltiazem (NDD). The complexities incorporated into the models included multiple-binding kinetics, quasi-irreversible inactivation, sequential metabolism, inhibitor depletion, and membrane partitioning. The resulting inactivation parameters were incorporated into static in vitro-in vivo correlation (IVIVC) models to predict clinical DDIs. For 77 clinically observed DDIs, with a hepatic-CYP3A-synthesis-rate constant of 0.000 146 min -1 , the average fold difference between the observed and predicted DDIs was 3.17 for the standard replot method and 1.45 for the numerical method. Similar results were obtained using a synthesis-rate constant of 0.000 32 min -1 . These results suggest that numerical methods can successfully model complex in vitro TDI kinetics and that the resulting DDI predictions are more accurate than those obtained with the standard replot approach.

  15. Brief Communication: Upper Air Relaxation in RACMO2 Significantly Improves Modelled Interannual Surface Mass Balance Variability in Antarctica

    Science.gov (United States)

    van de Berg, W. J.; Medley, B.

    2016-01-01

    The Regional Atmospheric Climate Model (RACMO2) has been a powerful tool for improving surface mass balance (SMB) estimates from GCMs or reanalyses. However, new yearly SMB observations for West Antarctica show that the modelled interannual variability in SMB is poorly simulated by RACMO2, in contrast to ERA-Interim, which resolves this variability well. In an attempt to remedy RACMO2 performance, we included additional upper-air relaxation (UAR) in RACMO2. With UAR, the correlation to observations is similar for RACMO2 and ERA-Interim. The spatial SMB patterns and ice-sheet-integrated SMB modelled using UAR remain very similar to the estimates of RACMO2 without UAR. We only observe an upstream smoothing of precipitation in regions with very steep topography like the Antarctic Peninsula. We conclude that UAR is a useful improvement for regional climate model simulations, although results in regions with steep topography should be treated with care.

  16. Improving winter leaf area index estimation in evergreen coniferous forests and its significance in carbon and water fluxes modeling

    Science.gov (United States)

    Wang, R.; Chen, J. M.; Luo, X.

    2016-12-01

    Modeling of carbon and water fluxes at the continental and global scales requires remotely sensed LAI as inputs. For evergreen coniferous forests (ENF), severely underestimated winter LAI has been one of the issues for mostly available remote sensing products, which could cause negative bias in the modeling of Gross Primary Productivity (GPP) and evapotranspiration (ET). Unlike deciduous trees which shed all the leaves in winter, conifers retains part of their needles and the proportion of the retained needles depends on the needle longevity. In this work, the Boreal Ecosystem Productivity Simulator (BEPS) was used to model GPP and ET at eight FLUXNET Canada ENF sites. Two sets of LAI were used as the model inputs: the 250m 10-day University of Toronto (U of T) LAI product Version 2 and the corrected LAI based on the U of T LAI product and the needle longevity of the corresponding tree species at individual sites. Validating model daily GPP (gC/m2) against site measurements, the mean RMSE over eight sites decreases from 1.85 to 1.15, and the bias changes from -0.99 to -0.19. For daily ET (mm), mean RMSE decreases from 0.63 to 0.33, and the bias changes from -0.31 to -0.16. Most of the improvements occur in the beginning and at the end of the growing season when there is large correction of LAI and meanwhile temperature is still suitable for photosynthesis and transpiration. For the dormant season, the improvement in ET simulation mostly comes from the increased interception of precipitation brought by the elevated LAI during that time. The results indicate that model performance can be improved by the application the corrected LAI. Improving the winter RS LAI can make a large impact on land surface carbon and energy budget.

  17. Polyelectrolyte Complex Based Interfacial Drug Delivery System with Controlled Loading and Improved Release Performance for Bone Therapeutics

    Directory of Open Access Journals (Sweden)

    David Vehlow

    2016-03-01

    Full Text Available An improved interfacial drug delivery system (DDS based on polyelectrolyte complex (PEC coatings with controlled drug loading and improved release performance was elaborated. The cationic homopolypeptide poly(l-lysine (PLL was complexed with a mixture of two cellulose sulfates (CS of low and high degree of substitution, so that the CS and PLL solution have around equal molar charged units. As drugs the antibiotic rifampicin (RIF and the bisphosphonate risedronate (RIS were integrated. As an important advantage over previous PEC systems this one can be centrifuged, the supernatant discarded, the dense pellet phase (coacervate separated, and again redispersed in fresh water phase. This behavior has three benefits: (i Access to the loading capacity of the drug, since the concentration of the free drug can be measured by spectroscopy; (ii lower initial burst and higher residual amount of drug due to removal of unbound drug and (iii complete adhesive stability due to the removal of polyelectrolytes (PEL excess component. It was found that the pH value and ionic strength strongly affected drug content and release of RIS and RIF. At the clinically relevant implant material (Ti40Nb similar PEC adhesive and drug release properties compared to the model substrate were found. Unloaded PEC coatings at Ti40Nb showed a similar number and morphology of above cultivated human mesenchymal stem cells (hMSC compared to uncoated Ti40Nb and resulted in considerable production of bone mineral. RIS loaded PEC coatings showed similar effects after 24 h but resulted in reduced number and unhealthy appearance of hMSC after 48 h due to cell toxicity of RIS.

  18. Combination of Albendazole and 2-Methoxyestradiol significantly improves the survival of HCT-116 tumor-bearing nude mice

    International Nuclear Information System (INIS)

    Ehteda, Anahid; Galettis, Peter; Pillai, Krishna; Morris, David L

    2013-01-01

    Albendazole (ABZ) is a microtubule-targeting anthelmintic with a remarkable activity against a variety of human cancer cells. In this study, we examined if the antitumor activity of ABZ could be enhanced by its combination with other microtubule-binding agents. The interactions between ABZ and microtubule-binding agents, paclitaxel, vinblastine, colchicine, and 2-methoxyestradiol were characterized using median effect analysis method in HCT-116 colorectal cancer cells and DU145 prostate cancer cell line. The mechanism underlying the synergistic interaction related to tubulin polymerization and apoptosis was then investigated. Finally, the effect of the combination therapy on the survival of HCT-116 tumor-bearing nude mice was evaluated. Among the tested drugs, a synergistic anti-proliferative effect was observed with the combination of low concentrations of ABZ plus colchicine and ABZ plus 2-methoxyestradiol (2ME). Exploring the mechanism of the interaction between ABZ and 2ME revealed that the combination therapy synergistically activated the extrinsic pathway of apoptosis. Consistent with in vitro results, the combination of low concentration of ABZ with 2ME prolonged the survival of mice-bearing HCT-116 tumors. High concentration of ABZ in combination with 2ME, however, proved to be less effective than ABZ alone. The combination of low doses of ABZ and 2ME has shown promising results in our pre-clinical model. Additionally, the finding that the combination of two microtubule-binding agents that share the same binding site can act synergistically may lead to the development of new therapeutic strategies in cancer treatment

  19. Development of an improved high resolution mass spectrometry based multi-residue method for veterinary drugs in various food matrices.

    Science.gov (United States)

    Kaufmann, A; Butcher, P; Maden, K; Walker, S; Widmer, M

    2011-08-26

    Multi-residue methods for veterinary drugs or pesticides in food are increasingly often based on ultra performance liquid chromatography (UPLC) coupled to high resolution mass spectrometry (HRMS). Previous available time of flight (TOF) technologies, showing resolutions up to 15,000 full width at half maximum (FWHM), were not sufficiently selective for monitoring low residue concentrations in difficult matrices (e.g. hormones in tissue or antibiotics in honey). The approach proposed in this paper is based on a single stage Orbitrap mass spectrometer operated at 50,000 FWHM. Extracts (liver and kidney) which were produced according to a validated multi-residue method (time of flight detection based) could not be analyzed by Orbitrap because of extensive signal suppression. This required the improvement of established extraction and clean-up procedures. The introduced, more extensive deproteinzation steps and dedicated instrumental settings successfully eliminated these detrimental suppression effects. The reported method, covering more than 100 different veterinary dugs, was validated according to the EU Commission Decision 2002/657/EEC. Validated matrices include muscle, kidney, liver, fish and honey. Significantly better performance parameters (e.g. linearity, reproducibility and detection limits) were obtained when comparing the new method with the older, TOF based method. These improvements are attributed to the higher resolution (50,000 versus 12,000 FWHM) and the superior mass stability of the of the Orbitrap over the previously utilized TOF instrument. Copyright © 2010 Elsevier B.V. All rights reserved.

  20. Not to catch but to deter : simple, less intrusive drug and alcohol tests can improve workplace safety

    Energy Technology Data Exchange (ETDEWEB)

    Stastny, P.

    2009-04-15

    Canadian employees who test positive for drug use have access to a wide range of substance counselling and rehabilitation options. As a result of Canadian human right legislation, drug dependence is considered a disability, and Canadian employers are required to accommodate the employee and retain their position when they are deemed fit for work. While Alberta is considered an employee-friendly province, the oil and gas industry has significant hazards that require a lucid and attentive workforce. As a result, Alberta courts approved pre-employment drug testing in a recent court case. The decision involved an employee who tested positive for traces of marijuana. After being fired, the employee filed a complaint. Although the Queen's Bench decided in favour of the employee, the Alberta Court of Appeal stated that the company's pre-employment drug testing policy did not discriminate against the employee on the basis of a disability. Drug use amongst construction workers and employees in the energy industry has now reached upwards of 24 per cent. While urine testing is a commonly used drug testing method, oral fluid testing is now being more widely adopted in industry. Oral fluids can be used to detect recent drug and alcohol use rather than historical use and can be conducted in the presence of a test administrator. It was concluded that the aim of drug and alcohol testing is to deter substance abuse on the job. 3 figs.

  1. The economics of direct-to-consumer advertising of prescription-only drugs: prescribed to improve consumer welfare?

    Science.gov (United States)

    Morgan, Steven; Mintzes, Barbara; Barer, Morris

    2003-10-01

    According to economic theory, one might expect that the informational content of direct-to-consumer advertising of prescription-only drugs would improve consumers' welfare. However, contrasting the models of consumer and market behaviour underlying this theory with the realities of the prescription-only drug market reveals that this market is distinct in ways that render it unlikely that advertising will serve an unbiased and strictly informative function. A review of qualitative evidence regarding the informational content of drug advertising supports this conclusion. Direct-to-consumer prescription drug advertising concentrates on particular products, and features of those products, to the exclusion of others, and the information provided has frequently been found to be biased or misleading in regulatory and academic evaluations. Governments that have so far resisted direct-to-consumer advertising should invest in independent sources of evidence that could help consumers and professionals to better understand the risks and benefits of treating disease with alternative drug and non-drug therapies, rather than permitting direct-to-consumer prescription drug advertising.

  2. Migration ability and Toll-like receptor expression of human mesenchymal stem cells improves significantly after three-dimensional culture.

    Science.gov (United States)

    Zhou, Panpan; Liu, Zilin; Li, Xue; Zhang, Bing; Wang, Xiaoyuan; Lan, Jing; Shi, Qing; Li, Dong; Ju, Xiuli

    2017-09-16

    While the conventional two-dimensional (2D) culture protocol is well accepted for the culture of mesenchymal stem cells (MSCs), this method fails to recapitulate the in vivo native three-dimensional (3D) cellular microenvironment, and may result in phenotypic changes, and homing and migration capacity impairments. MSC preparation in 3D culture systems has been considered an attractive preparatory and delivery method recently. We seeded human umbilical cord-derived MSCs (hUCMSCs) in a 3D culture system with porcine acellular dermal matrix (PADM), and investigated the phenotypic changes, the expression changes of some important receptors, including Toll-like receptors (TLRs) and C-X-C chemokine receptor type 4 (CXCR4) when hUCMSCs were transferred from 2D to 3D systems, as well as the alterations in in vivo homing and migration potential. It was found that the percentage of CD105-positive cells decreased significantly, whereas that of CD34- and CD271-positive cells increased significantly in 3D culture, compared to that in 2D culture. The mRNA and protein expression levels of TLR2, TLR3, TLR4, TLR6, and CXCR4 in hUCMSCs were increased significantly upon culturing with PADM for 3 days, compared to the levels in 2D culture. The numbers of migratory 3D hUCMSCs in the heart, liver, spleen, and bone marrow were significantly greater than the numbers of 2D hUCMSCs, and the worst migration occurred in 3D + AMD3100 (CXCR4 antagonist) hUCMSCs. These results suggested that 3D culture of hUCMSCs with PADM could alter the phenotypic characteristics of hUCMSCs, increase their TLR and CXCR4 expression levels, and promote their migratory and homing capacity in which CXCR4 plays an important role. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Improvement of drug delivery by hyperthermia treatment using magnetic cubic cobalt ferrite nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Dey, Chaitali, E-mail: chaitalidey29@gmail.com [Centre for Research in Nanoscience & Nanotechnology, Block-JD-2, Sector-III, Salt Lake, Kolkata 700106 (India); Baishya, Kaushik [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India); Ghosh, Arup [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India); Department of Physics, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune 411008 (India); Goswami, Madhuri Mandal, E-mail: madhuri@bose.res.in [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India); Ghosh, Ajay [Dept. of Applied Optics and Photonics, University of Calcutta, Block-JD-2, Sector-III, Salt Lake, Kolkata 700106 (India); Mandal, Kalyan [S.N. Bose National Centre for Basic Sciences, Block-JD, Sector-III, Salt Lake, Kolkata 700106 (India)

    2017-04-01

    In this study, we report a novel synthesis method, characterization and application of a new class of ferromagnetic cubic cobalt ferrite magnetic nanoparticles (MNPs) for hyperthermia therapy and temperature triggered drug release. The MNPs are characterized by XRD, TEM, FESEM, AC magnetic hysteresis and VSM. These MNPs were coated with folic acid and loaded with an anticancer drug. The drug release studies were done at two different temperatures (37 °C and 44 °C) with progress of time. It was found that higher release of drug took place at elevated temperature (44 °C). We have developed a temperature sensitive drug delivery system which releases the heat sensitive drug selectively as the particles are heated up under AC magnetic field and controlled release is possible by changing the external AC magnetic field.

  4. Strategies to improve drug delivery across the blood-brain barrier.

    Science.gov (United States)

    de Boer, Albertus G; Gaillard, Pieter J

    2007-01-01

    The blood-brain barrier (BBB), together with the blood-cerebrospinal-fluid barrier, protects and regulates the homeostasis of the brain. However, these barriers also limit the transport of small-molecule and, particularly, biopharmaceutical drugs such as proteins, genes and interference RNA to the brain, thereby limiting the treatment of many brain diseases. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. In this review, we discuss briefly the biology and physiology of the BBB as the most important barrier for drug transport to the brain and, in more detail, the possibilities for delivering large-molecule drugs, particularly genes, by receptor-mediated nonviral drug delivery to the (human) brain. In addition, the systemic and intracellular pharmacokinetics of nonviral gene delivery, together with targeted brain imaging, are reviewed briefly.

  5. The patient's safety - For a dynamics of improvement. Nr 3. How to analyze your significant radiation protection events?

    International Nuclear Information System (INIS)

    2012-07-01

    The objective of this publication is to present event analysis methods which are the most frequently used by radiotherapy departments. After an indication of key figures concerning radiotherapy patients, sessions and events, the document indicates the objectives and steps of an event analysis. It presents various analysis methods: Ishikawa diagram (or 5M method or causes-effects diagram), the cause tree, the ALARM method (association of litigation and risk management), the ORION method. It proposes a comparison between these five methods, their possibilities, their limits. Good practices are outlined in terms of data acquisition, method choice, event analysis, and improvement actions. The use of the cause tree analysis is commented by members of the Limoges hospital radiotherapy department, and that of the Ishikawa method by a member of the Beauvais hospital

  6. Different surgical strategies for chronic pancreatitis significantly improve long-term outcome: a comparative single center study

    Directory of Open Access Journals (Sweden)

    Hildebrand P

    2010-08-01

    Full Text Available Abstract Objective In general, chronic pancreatitis (CP primarily requires conservative treatment. The chronic pain syndrome and complications make patients seek surgical advice, frequently after years of progression. In the past, surgical procedures involving drainage as well as resection have been employed successfully. The present study compared the different surgical strategies. Patients and Methods From March 2000 until April 2005, a total of 51 patients underwent surgical treatment for CP at the Department of surgery, University of Schleswig-Holstein, Campus Lübeck. Out of those 51 patients, 39 (76.5% were operated according to the Frey procedure, and in 12 cases (23.5% the Whipple procedure was performed. Patient data were documented prospectively throughout the duration of the hospital stay. The evaluation of the postoperative pain score was carried out retrospectively with a validated questionnaire. Results Average operating time was 240 minutes for the Frey group and 411 minutes for the Whipple group. The medium number of blood transfusions was 1 in the Frey group and 4.5 in the Whipple group. Overall morbidity was 21% in the Frey group and 42% in the Whipple group. 30-day mortality was zero for all patients. During the median follow-up period of 50 months, an improvement in pain score was observed in 93% of the patients of the Frey group and 67% of the patients treated according to the Whipple procedure. Conclusion The results show that both the Frey procedure as well as partial pancreaticoduodenectomy are capable of improving chronic pain symptoms in CP. As far as later endocrine and exocrine pancreatic insufficiency is concerned, however, the extended drainage operation according to Frey proves to be advantageous compared to the traditional resection procedure by Whipple. Accordingly, the Frey procedure provides us with an organ-preserving surgical procedure which treats the complications of CP sufficiently, thus being an

  7. Significant improvement of bone mineral density by denosumab treatment in Japanese osteoporotic patients following breast cancer treatment

    Directory of Open Access Journals (Sweden)

    Nakamura Y

    2018-03-01

    Full Text Available Yukio Nakamura,1,2 Mikio Kamimura,3 Akio Morikawa,4 Akira Taguchi,5 Takako Suzuki,1 Hiroyuki Kato1 1Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, 2Department of Orthopedic Surgery, Showa-Inan General Hospital, Komagane, 3Center for Osteoporosis and Spinal Disorders, Kamimura Orthopaedic Clinic, Matsumoto, 4Department of Surgery, Showa-Inan General Hospital, Komagane, 5Department of Oral and Maxillofacial Radiology, School of Dentistry, Matsumoto Dental University, Shiojiri, Japan Background: The aim of this study was to evaluate the effects of denosumab in patients with osteoporosis (OP and non-metastatic breast cancer following treatment of 1 surgery, 2 surgery and aromatase inhibitors, and 3 surgery, aromatase inhibitors, and anti-cancer agents, compared with those in primary OP patients. Patients and methods: In this retrospective 24-month study, patients were divided into the primary OP group (34 cases or OP receiving breast cancer treatment group (breast cancer group; 17 cases. We measured serum calcium, whole parathyroid hormone (PTH, 1,25OH2D3, bone alkaline phosphatase (BAP, tartrate-resistant acid phosphatase-5b (TRACP-5b, and bone mineral density (BMD of the lumbar 1–4 vertebrae (L-BMD and bilateral total hips (H-BMD for 24 months. Results: The percent changes of serum calcium in the breast cancer group were significantly lower than those in the primary OP group at 1 week, 1 and 12 months. The percent changes of whole PTH in the primary OP group were significantly lower than those in the breast cancer group at 2 and 4 months. Significant differences were found between the groups at 18 months (-34.5% in the primary OP group and -52.6% in the breast cancer group, respectively for the percent changes of BAP. Significant differences were found between the groups at 12, 18, and 24 months (-39.7% in the primary OP group and -64.0% in the breast cancer group at 24 months, respectively for the percent

  8. IMPROVEMENT OF SOLUBILITY OF BADLY WATER SOLUBLE DRUG (IBUPROFEN) BY USING SURFACTANTS AND CARRIERS

    OpenAIRE

    Md. Zakaria Faruki*, Rishikesh, Elizabeth Razzaque, Mohiuddin Ahmed Bhuiyan

    2013-01-01

    ABSTRACT: Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of badly water-soluble drugs, their profitable use has been very limited, primarily because of manufacturing difficulties and stability problems. In this study solid solutions of drugs were generally produced by fusion method. The drug along with the excipients (surfactants and carriers) was heated first and then hardened by cooling to room te...

  9. Modulation of electrostatic interactions to improve controlled drug delivery from nanogels

    Energy Technology Data Exchange (ETDEWEB)

    Mauri, Emanuele; Chincarini, Giulia M.F.; Rigamonti, Riccardo; Magagnin, Luca; Sacchetti, Alessandro, E-mail: alessandro.sacchetti@polimi.it; Rossi, Filippo, E-mail: filippo.rossi@polimi.it

    2017-03-01

    The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device. - Highlights: • The design of nanogels as drug delivery systems based on electrostatic interaction among drug and polymers is proposed. • Nanogels can be synthetized tuning their positive charge density, according to the protonation of PEI at different pH. • No biorthogonal chemistry strategies are applied to the polymers or drugs. • Drug release is efficiently modulated by charge density of PEI chains. • The effect of counterion on nanogel synthesis is investigated and allows controlling the drug release.

  10. Biological Evidence for Paradoxical Improvement of Psychiatric Disorder Symptoms by Addictive Drugs.

    Science.gov (United States)

    Müller, Christian P; Kornhuber, Johannes

    2017-06-01

    Addiction biology has focused on the mechanisms of the positive and negative reinforcing actions of addictive drugs but neglected potential benefits. Two new studies provide the first insights into a neurobiology of psychoactive drug instrumentalization. This may help us design better models for addiction neuroscience and opens a new dimension for the development of personalized pharmacotherapy of drug addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Overview of milling techniques for improving the solubility of poorly water-soluble drugs

    Directory of Open Access Journals (Sweden)

    Zhi Hui Loh

    2015-07-01

    Full Text Available Milling involves the application of mechanical energy to physically break down coarse particles to finer ones and is regarded as a “top–down” approach in the production of fine particles. Fine drug particulates are especially desired in formulations designed for parenteral, respiratory and transdermal use. Most drugs after crystallization may have to be comminuted and this physical transformation is required to various extents, often to enhance processability or solubility especially for drugs with limited aqueous solubility. The mechanisms by which milling enhances drug dissolution and solubility include alterations in the size, specific surface area and shape of the drug particles as well as milling-induced amorphization and/or structural disordering of the drug crystal (mechanochemical activation. Technology advancements in milling now enable the production of drug micro- and nano-particles on a commercial scale with relative ease. This review will provide a background on milling followed by the introduction of common milling techniques employed for the micronization and nanonization of drugs. Salient information contained in the cited examples are further extracted and summarized for ease of reference by researchers keen on employing these techniques for drug solubility and bioavailability enhancement.

  12. Significant Improvement Selected Mediators of Inflammation in Phenotypes of Women with PCOS after Reduction and Low GI Diet

    Directory of Open Access Journals (Sweden)

    Małgorzata Szczuko

    2017-01-01

    Full Text Available Many researchers suggest an increased risk of atherosclerosis in women with polycystic ovary syndrome. In the available literature, there are no studies on the mediators of inflammation in women with PCOS, especially after dietary intervention. Eicosanoids (HETE and HODE were compared between the biochemical phenotypes of women with PCOS (normal and high androgens and after the 3-month reduction diet. Eicosanoid profiles (9(S-HODE, 13(S-HODE, 5(S-HETE, 12(S-HETE, 15(S-HETE, 5(S-oxoETE, 16(R-HETE, 16(S-HETE and 5(S, 6(R-lipoxin A4, 5(S, 6(R, 15(R-lipoxin A4 were extracted from 0.5 ml of plasma using solid-phase extraction RP-18 SPE columns. The HPLC separations were performed on a 1260 liquid chromatograph. No significant differences were found in the concentration of analysed eicosanoids in phenotypes of women with PCOS. These women, however, have significantly lower concentration of inflammatory mediators than potentially healthy women from the control group. Dietary intervention leads to a significant (p<0.01 increase in the synthesis of proinflammatory mediators, reaching similar levels as in the control group. The development of inflammatory reaction in both phenotypes of women with PCOS is similar. The pathways for synthesis of proinflammatory mediators in women with PCOS are dormant, but can be stimulated through a reduction diet. Three-month period of lifestyle change may be too short to stimulate the pathways inhibiting inflammatory process.

  13. A study to determine whether targeted education significantly improves the perception of human torture in medical students in India.

    Science.gov (United States)

    Husain, Munawwar; Ghaffar, Usama B; Usmani, Jawed Ahmad; Rivzi, Shameem Jahan

    2010-08-01

    This study was undertaken to find out the knowledge of torture in MBBS students. A fair comparison was done by selecting two groups of medical students; one, to whom torture was not taught ie, pretaught group (PrTG, n = 125), and second, to whom torture was taught in classroom ie, post-taught group (PoTG, n = 110) in more than one sessions. The topic on torture was taught under many headings maximising the effort to cover as much as possible; namely, definition, geographical distribution, types of torture (physical, psychological and sexual), post-torture sequelae, sociopolitical environment prevailing in the country, doctors' involvement in torture, rehabilitation of torture victims and the UNO's role in containment of torture. In all a questionnaire was designed having MCQ types on these aspects. It was found that significant level of difference in perception and knowledge about torture existed amongst the groups, and this was further accentuated in medical and non-medical intratopics. 'P' value of each question was computed separately. It was found that the study was statistically significant and reestablished the need of fortifying the gossameric firmament of education specific to torture.

  14. Drilling for improvement : Statoil and Halliburton report significant cost savings and more accurate well placement at the Leismer demonstration project

    Energy Technology Data Exchange (ETDEWEB)

    Jaremko, D.

    2010-07-15

    This article discussed new improvements in steam assisted gravity drainage (SAGD) made by Statoil and Halliburton at the Leismer demonstration project. The Leismer project is Statoil's inaugural project in oil sands development, and will have a capacity to produce 10,000 barrels per day through 4 separate well pads with 23 well pairs. Challenges to the project included the long lateral sections required for the well pairs to remain parallel to each other while remaining within the target formation. An azimuthal deep resistivity (ADR) tool was used to detect the proximity of the wellbore to shale and water zones. Use of the tool allowed operators to modify the planned well trajectory in order to optimize placements within the reservoir. A rotary steerable system (RSS) was used increase injection times. The project was completed 6 to 8 weeks ahead of schedule. Applications have now been filed for a further 10 phases that will produce 240,000 barrels per day. 1 fig.

  15. Icariin combined with human umbilical cord mesenchymal stem cells significantly improve the impaired kidney function in chronic renal failure.

    Science.gov (United States)

    Li, Wen; Wang, Li; Chu, Xiaoqian; Cui, Huantian; Bian, Yuhong

    2017-04-01

    At present, the main therapy for chronic renal failure (CRF) is dialysis and renal transplantation, but neither obtains satisfactory results. Human umbilical cord mesenchymal stem cells (huMSCs) are isolated from the fetal umbilical cord which has a high self-renewal and multi-directional differentiation potential. Icariin (ICA), a kidney-tonifying Chinese Medicine can enhance the multipotency of huMSCs. Therefore, this work seeks to employ the use of ICA-treated huMSCs for the treatment of chronic renal failure. Blood urea nitrogen and creatinine (Cr) analyses showed amelioration of functional parameters in ICA-treated huMSCs for the treatment of CRF rats at 3, 7, and 14 days after transplantation. ICA-treated huMSCs can obviously increase the number of cells in injured renal tissues at 3, 7, and 14 days after transplantation by optical molecular imaging system. Hematoxylin-eosin staining demonstrated that ICA-treated huMSCs reduced the levels of fibrosis in CRF rats at 14 days after transplantation. Superoxide dismutase and Malondialdehyde analyses showed that ICA-treated huMSCs reduced the oxidative damage in CRF rats. Moreover, transplantation with ICA-treated huMSCs decreased inflammatory responses, promoted the expression of growth factors, and protected injured renal tissues. Taken together, our findings suggest that ICA-treated huMSCs could improve the kidney function in CRF rats.

  16. Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2-ARE signaling activity.

    Science.gov (United States)

    Chen, Li-You; Renn, Ting-Yi; Liao, Wen-Chieh; Mai, Fu-Der; Ho, Ying-Jui; Hsiao, George; Lee, Ai-Wei; Chang, Hung-Ming

    2017-09-01

    Prolonged exposure to gamma-hydroxybutyric acid (GHB) would cause drug intoxication in which impaired cognitive function results from enhanced hippocampal oxidative stress may serve as a major symptom in this deficiency. Considering melatonin possesses significant anti-oxidative efficacy, this study aimed to determine whether melatonin would successfully promote the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling, depress oxidative stress, and rescue hippocampal bioenergetics and cognitive function following drug intoxication injury. Adolescent rats subjected to 10 days of GHB were received melatonin at doses of either 10 or 100 mg/kg. Time-of-flight secondary ion mass spectrometry, biochemical assay, quantitative histochemistry, [ 14 C]-2-deoxyglucose analysis, together with Morris water maze were employed to detect the molecular signaling, oxidative status, bioenergetic level, as well as the cognitive performances, respectively. Results indicated that in GHB-intoxicated rats, enhanced oxidative stress, increased cholesterol level, and decreased anti-oxidative enzymes activities were detected in hippocampal regions. Intense oxidative stress paralleled well with reduced bioenergetics and poor performance in behavioral testing. However, in rats treated with melatonin following GHB intoxication, all above parameters and cognitive function were gradually returned to nearly normal levels. Melatonin also remarkably promoted the translocation of Nrf2 from cytoplasm to nucleus in a dose-dependent manner, thereby increased the Nrf2-ARE signaling-related downstream anti-oxidative enzymes activities. As melatonin effectively rescues hippocampal bioenergetics through depressing the oxidative stress by promoting Nrf2-ARE molecular machinery, this study thus highlights for the first time that clinical use of melatonin may serve as a therapeutic strategy to improve the cognitive function in unsuspecting victims suffered from

  17. Submicron-bubble-enhanced focused ultrasound for blood-brain barrier disruption and improved CNS drug delivery.

    Directory of Open Access Journals (Sweden)

    Ching-Hsiang Fan

    Full Text Available The use of focused ultrasound (FUS with microbubbles has been proven to induce transient blood-brain barrier opening (BBB-opening. However, FUS-induced inertial cavitation of microbubbles can also result in erythrocyte extravasations. Here we investigated whether induction of submicron bubbles to oscillate at their resonant frequency would reduce inertial cavitation during BBB-opening and thereby eliminate erythrocyte extravasations in a rat brain model. FUS was delivered with acoustic pressures of 0.1-4.5 MPa using either in-house manufactured submicron bubbles or standard SonoVue microbubbles. Wideband and subharmonic emissions from bubbles were used to quantify inertial and stable cavitation, respectively. Erythrocyte extravasations were evaluated by in vivo post-treatment magnetic resonance susceptibility-weighted imaging, and finally by histological confirmation. We found that excitation of submicron bubbles with resonant frequency-matched FUS (10 MHz can greatly limit inertial cavitation while enhancing stable cavitation. The BBB-opening was mainly caused by stable cavitation, whereas the erythrocyte extravasation was closely correlated with inertial cavitation. Our technique allows extensive reduction of inertial cavitation to induce safe BBB-opening. Furthermore, the safety issue of BBB-opening was not compromised by prolonging FUS exposure time, and the local drug concentrations in the brain tissues were significantly improved to 60 times (BCNU; 18.6 µg versus 0.3 µg by using chemotherapeutic agent-loaded submicron bubbles with FUS. This study provides important information towards the goal of successfully translating FUS brain drug delivery into clinical use.

  18. Improvement of Fabry Disease-Related Gastrointestinal Symptoms in a Significant Proportion of Female Patients Treated with Agalsidase Beta

    DEFF Research Database (Denmark)

    Wilcox, William R; Feldt-Rasmussen, Ulla; Martins, Ana Maria

    2018-01-01

    of organ involvement. Although variable, gastrointestinal symptoms are among the most common and significant early clinical manifestations; they tend to persist into adulthood if left untreated. To further understand the effects of sustained enzyme replacement therapy (ERT) with agalsidase beta......Fabry disease, an X-linked inherited lysosomal storage disorder, is caused by mutations in the gene encoding α-galactosidase, GLA. In patients with Fabry disease, glycosphingolipids accumulate in various cell types, triggering a range of cellular and tissue responses that result in a wide spectrum...... on gastrointestinal symptoms in heterozygotes, a data analysis of female patients enrolled in the Fabry Registry was conducted. To be included, females of any age must have received agalsidase beta (average dose 1.0 mg/kg every 2 weeks) for at least 2.5 years. Measured outcomes were self-reported gastrointestinal...

  19. Towards an improved prediction of the free radical scavenging potency of flavonoids: the significance of double PCET mechanisms.

    Science.gov (United States)

    Amić, Ana; Marković, Zoran; Dimitrić Marković, Jasmina M; Stepanić, Višnja; Lučić, Bono; Amić, Dragan

    2014-01-01

    The 1H(+)/1e(-) and 2H(+)/2e(-) proton-coupled electron transfer (PCET) processes of free radical scavenging by flavonoids were theoretically studied for aqueous and lipid environments using the PM6 and PM7 methods. The results reported here indicate that the significant contribution of the second PCET mechanism, resulting in the formation of a quinone/quinone methide, effectively discriminates the active from inactive flavonoids. The predictive potency of descriptors related to the energetics of second PCET mechanisms (the second O-H bond dissociation enthalpy (BDE2) related to hydrogen atom transfer (HAT) mechanism, and the second electron transfer enthalpy (ETE2) related to sequential proton loss electron transfer (SPLET) mechanism) are superior to the currently used indices, which are related to the first 1H(+)/1e(-) processes, and could serve as primary descriptors in development of the QSAR (quantitative structure-activity relationships) of flavonoids. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. Pt-decorated GaN nanowires with significant improvement in H2 gas-sensing performance at room temperature.

    Science.gov (United States)

    Abdullah, Q N; Yam, F K; Hassan, Z; Bououdina, M

    2015-12-15

    Superior sensitivity towards H2 gas was successfully achieved with Pt-decorated GaN nanowires (NWs) gas sensor. GaN NWs were fabricated via chemical vapor deposition (CVD) route. Morphology (field emission scanning electron microscopy and transmission electron microscopy) and crystal structure (high resolution X-ray diffraction) characterizations of the as-synthesized nanostructures demonstrated the formation of GaN NWs having a wurtzite structure, zigzaged shape and an average diameter of 30-166nm. The Pt-decorated GaN NWs sensor shows a high response of 250-2650% upon exposure to H2 gas concentration from 7 to 1000ppm respectively at room temperature (RT), and then increases to about 650-4100% when increasing the operating temperature up to 75°C. The gas-sensing measurements indicated that the Pt-decorated GaN NWs based sensor exhibited efficient detection of H2 at low concentration with excellent sensitivity, repeatability, and free hysteresis phenomena over a period of time of 100min. The large surface-to-volume ratio of GaN NWs and the catalytic activity of Pt metal are the most influential factors leading to the enhancement of H2 gas-sensing performances through the improvement of the interaction between the target molecules (H2) and the sensing NWs surface. The attractive low-cost, low power consumption and high-performance of the resultant decorated GaN NWs gas sensor assure their uppermost potential for H2 gas sensor working at low operating temperature. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Disulfide-crosslinked nanomicelles confer cancer-specific drug delivery and improve efficacy of paclitaxel in bladder cancer

    Science.gov (United States)

    Pan, Amy; Zhang, Hongyong; Li, Yuanpei; Lin, Tzu-yin; Wang, Fuli; Lee, Joyce; Cheng, Mingshan; Dall'Era, Marc; Li, Tianhong; deVere White, Ralph; Pan, Chong-Xian; Lam, Kit S.

    2016-10-01

    Chemotherapy commonly used in the treatment of advanced bladder cancer is only moderately effective and associated with significant toxicity. There has been no appreciable improvement in overall survival over the last three decades. The goal of this project is to develop and characterize bladder cancer-specific nanometer-scale micelles loaded with the chemotherapeutic drug paclitaxel (PTX) and determine the anti-tumor activity and toxicity. Micelle-building-material telodendrimers were synthesized through the stepwise conjugation of eight cholic acid units at one terminus of polyethylene glycol (PEG) and a bladder cancer-specific targeting peptide named PLZ4 at the other terminus. To synthesize disulfide-crosslinked PLZ4 nanomicelles (DC-PNM), cysteine was introduced between the cholic acid and PEG. DC-PNM-PTX was synthesized through the evaporation method by loading PTX in the core. The loading capacity of PTX in DC-PNM was 25% (W/W). The loading efficiency was over 99%. DC-PNM-PTX was spherical with the median size of 25 nm. The stability of DC-PNM-PTX was determined in a solution containing sodium docecyl sulfate (SDS). It was stable in a SDS solution, but dissolved within 5 min after the addition of glutathione at the physiological intracellular concentration of 10 mM. In vivo targeting and anti-tumor activity were determined in immunodeficient mice carrying patient-derived bladder cancer xenografts (PDXs). After intravenous administration, DC-PNM specifically targeted the bladder cancer PDXs, but very little to the lung cancer xenografts in the same mice (p < 0.001). DC-PNM loaded with PTX overcame cisplatin resistance, and improved the median survival from 55 d with free PTX to 69.5 d (p = 0.03) of mice carrying PDXs. In conclusion, DC-PNM remained stable in the SDS solution, specifically targeted the bladder cancer xenografts in vivo, and improved the anti-cancer efficacy of PTX.

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

    Directory of Open Access Journals (Sweden)

    Yu D

    2016-01-01

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

  3. Improved forensic hair evidence for drugs of abuse by mass spectrometry

    NARCIS (Netherlands)

    Duvivier, W.F.

    2016-01-01

    Forensic hair analysis can be used as alternative evidence next to body fluids, and to obtain retrospective timeline information of an individual’s drug exposure. Chapter 1 describes the general concepts of drug incorporation into hair, external contamination, and the current

  4. Lidocaine self-sacrificially improves the skin permeation of the acidic and poorly water-soluble drug etodolac via its transformation into an ionic liquid.

    Science.gov (United States)

    Miwa, Yasushi; Hamamoto, Hidetoshi; Ishida, Tatsuhiro

    2016-05-01

    Poor transdermal penetration of active pharmaceutical ingredients (APIs) impairs both bioavailability and therapeutic benefits and is a major challenge in the development of transdermal drug delivery systems. Here, we transformed a poorly water-soluble drug, etodolac, into an ionic liquid in order to improve its hydrophobicity, hydrophilicity and skin permeability. The ionic liquid was prepared by mixing etodolac with lidocaine (1:1, mol/mol). Both the free drug and the transformed ionic liquid were characterized by differential scanning colorimetry (DSC), infrared spectroscopy (IR), and saturation concentration measurements. In addition, in vitro skin-permeation testing was carried out via an ionic liquid-containing patch (Etoreat patch). The lidocaine and etodolac in ionic liquid form led to a relatively lower melting point than either lidocaine or etodolac alone, and this improved the lipophilicity/hydrophilicity of etodolac. In vitro skin-permeation testing demonstrated that the Etoreat patch significantly increased the skin permeation of etodolac (9.3-fold) compared with an etodolac alone patch, although an Etoreat patch did not increase the skin permeation of lidocaine, which was consistent with the results when using a lidocaine alone patch. Lidocaine appeared to self-sacrificially improve the skin permeation of etodolac via its transformation into an ionic liquid. The data suggest that ionic liquids composed of approved drugs may substantially expand the formulation preparation method to meet the challenges of drugs which are characterized by poor rates of transdermal absorption. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  5. Amphoteric Ion-Exchange Membranes with Significantly Improved Vanadium Barrier Properties for All-Vanadium Redox Flow Batteries.

    Science.gov (United States)

    Nibel, Olga; Rojek, Tomasz; Schmidt, Thomas J; Gubler, Lorenz

    2017-07-10

    All-vanadium redox flow batteries (VRBs) have attracted considerable interest as promising energy-storage devices that can allow the efficient utilization of renewable energy sources. The membrane, which separates the porous electrodes in a redox flow cell, is one of the key components in VRBs. High rates of crossover of vanadium ions and water through the membrane impair the efficiency and capacity of a VRB. Thus, membranes with low permeation rate of vanadium species and water are required, also characterized by low resistance and stability in the VRB environment. Here, we present a new design concept for amphoteric ion-exchange membranes, based on radiation-induced grafting of vinylpyridine into an ethylene tetrafluoroethylene base film and a two-step functionalization to introduce cationic and anionic exchange sites, respectively. During long-term cycling, redox flow cells containing these membranes showed higher efficiency, less pronounced electrolyte imbalance, and significantly reduced capacity decay compared to the cells with the benchmark material Nafion 117. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Structure-activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure.

    Science.gov (United States)

    Mook, Robert A; Wang, Jiangbo; Ren, Xiu-Rong; Chen, Minyong; Spasojevic, Ivan; Barak, Larry S; Lyerly, H Kim; Chen, Wei

    2015-09-01

    The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4'-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic

  7. Structure–activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure

    Science.gov (United States)

    Mook, Robert A.; Wang, Jiangbo; Ren, Xiu-Rong; Chen, Minyong; Spasojevic, Ivan; Barak, Larry S.; Lyerly, H. Kim; Chen, Wei

    2015-01-01

    The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4′-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide's low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multifunctional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic

  8. Post-exposure Treatment with Anti-rabies VHH and Vaccine Significantly Improves Protection of Mice from Lethal Rabies Infection

    Science.gov (United States)

    Terryn, Sanne; Francart, Aurélie; Rommelaere, Heidi; Stortelers, Catelijne; Van Gucht, Steven

    2016-01-01

    Post-exposure prophylaxis (PEP) against rabies infection consists of a combination of passive immunisation with plasma-derived human or equine immune globulins and active immunisation with vaccine delivered shortly after exposure. Since anti-rabies immune globulins are expensive and scarce, there is a need for cheaper alternatives that can be produced more consistently. Previously, we generated potent virus-neutralising VHH, also called Nanobodies, against the rabies glycoprotein that are effectively preventing lethal disease in an in vivo mouse model. The VHH domain is the smallest antigen-binding functional fragment of camelid heavy chain-only antibodies that can be manufactured in microbial expression systems. In the current study we evaluated the efficacy of half-life extended anti-rabies VHH in combination with vaccine for PEP in an intranasal rabies infection model in mice. The PEP combination therapy of systemic anti-rabies VHH and intramuscular vaccine significantly delayed the onset of disease compared to treatment with anti-rabies VHH alone, prolonged median survival time (35 versus 14 days) and decreased mortality (60% versus 19% survival rate), when treated 24 hours after rabies virus challenge. Vaccine alone was unable to rescue mice from lethal disease. As reported also for immune globulins, some interference of anti-rabies VHH with the antigenicity of the vaccine was observed, but this did not impede the synergistic effect. Post exposure treatment with vaccine and human anti-rabies immune globulins was unable to protect mice from lethal challenge. Anti-rabies VHH and vaccine act synergistically to protect mice after rabies virus exposure, which further validates the possible use of anti-rabies VHH for rabies PEP. PMID:27483431

  9. Post-exposure Treatment with Anti-rabies VHH and Vaccine Significantly Improves Protection of Mice from Lethal Rabies Infection.

    Directory of Open Access Journals (Sweden)

    Sanne Terryn

    2016-08-01

    Full Text Available Post-exposure prophylaxis (PEP against rabies infection consists of a combination of passive immunisation with plasma-derived human or equine immune globulins and active immunisation with vaccine delivered shortly after exposure. Since anti-rabies immune globulins are expensive and scarce, there is a need for cheaper alternatives that can be produced more consistently. Previously, we generated potent virus-neutralising VHH, also called Nanobodies, against the rabies glycoprotein that are effectively preventing lethal disease in an in vivo mouse model. The VHH domain is the smallest antigen-binding functional fragment of camelid heavy chain-only antibodies that can be manufactured in microbial expression systems. In the current study we evaluated the efficacy of half-life extended anti-rabies VHH in combination with vaccine for PEP in an intranasal rabies infection model in mice. The PEP combination therapy of systemic anti-rabies VHH and intramuscular vaccine significantly delayed the onset of disease compared to treatment with anti-rabies VHH alone, prolonged median survival time (35 versus 14 days and decreased mortality (60% versus 19% survival rate, when treated 24 hours after rabies virus challenge. Vaccine alone was unable to rescue mice from lethal disease. As reported also for immune globulins, some interference of anti-rabies VHH with the antigenicity of the vaccine was observed, but this did not impede the synergistic effect. Post exposure treatment with vaccine and human anti-rabies immune globulins was unable to protect mice from lethal challenge. Anti-rabies VHH and vaccine act synergistically to protect mice after rabies virus exposure, which further validates the possible use of anti-rabies VHH for rabies PEP.

  10. Improvement of dissolution behavior of poorly water soluble drugs by biodegradable polymeric submicron carriers containing sparingly methylated β-cyclodextrin.

    Science.gov (United States)

    Singhavi, Dilesh J; Khan, Shagufta; Yeole, Pramod G

    2013-04-01

    The objective of this study was to develop submicron carriers of two drugs that are practically insoluble in water, i.e. meloxicam and aceclofenac, to improve their dissolution behavior. The phase solubility of the drugs was studied using different concentrations of sparingly methylated β-cyclodextrin, Kleptose(®) Crysmeβ (Crysmeb), in the presence and absence of 0.2 % w/v water-soluble chitosan. Drug-loaded submicron particles (SMPs) were prepared using chitosan chlorhydrate and Crysmeb by the ionotropic gelation method. The SMPs were characterized in terms of powder X-ray diffraction, Fourier transforms infrared spectroscopy, size determination, process yield, drug loading, encapsulation efficiency, surface morphology and in vitro release. The drug loading in the SMPs was enhanced in the presence of Crysmeb. The in vitro drug release was found to be enhanced with SMPs prepared using higher concentrations of Crysmeb. These results indicate that SMPs formed from chitosan chlorhydrate and Crysmeb are promising submicron carriers for enhancing the dissolution of meloxicam and aceclofenac.

  11. Constitutive overexpression of the TaNF-YB4 gene in transgenic wheat significantly improves grain yield.

    Science.gov (United States)

    Yadav, Dinesh; Shavrukov, Yuri; Bazanova, Natalia; Chirkova, Larissa; Borisjuk, Nikolai; Kovalchuk, Nataliya; Ismagul, Ainur; Parent, Boris; Langridge, Peter; Hrmova, Maria; Lopato, Sergiy

    2015-11-01

    Heterotrimeric nuclear factors Y (NF-Ys) are involved in regulation of various vital functions in all eukaryotic organisms. Although a number of NF-Y subunits have been characterized in model plants, only a few have been functionally evaluated in crops. In this work, a number of genes encoding NF-YB and NF-YC subunits were isolated from drought-tolerant wheat (Triticum aestivum L. cv. RAC875), and the impact of the overexpression of TaNF-YB4 in the Australian wheat cultivar Gladius was investigated. TaNF-YB4 was isolated as a result of two consecutive yeast two-hybrid (Y2H) screens, where ZmNF-YB2a was used as a starting bait. A new NF-YC subunit, designated TaNF-YC15, was isolated in the first Y2H screen and used as bait in a second screen, which identified two wheat NF-YB subunits, TaNF-YB2 and TaNF-YB4. Three-dimensional modelling of a TaNF-YB2/TaNF-YC15 dimer revealed structural determinants that may underlie interaction selectivity. The TaNF-YB4 gene was placed under the control of the strong constitutive polyubiquitin promoter from maize and introduced into wheat by biolistic bombardment. The growth and yield components of several independent transgenic lines with up-regulated levels of TaNF-YB4 were evaluated under well-watered conditions (T1-T3 generations) and under mild drought (T2 generation). Analysis of T2 plants was performed in large deep containers in conditions close to field trials. Under optimal watering conditions, transgenic wheat plants produced significantly more spikes but other yield components did not change. This resulted in a 20-30% increased grain yield compared with untransformed control plants. Under water-limited conditions transgenic lines maintained parity in yield performance. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  12. Marrying Step Feed with Secondary Clarifier Improvements to Significantly Increase Peak Wet Weather Treatment Capacity: An Integrated Methodology.

    Science.gov (United States)

    Daigger, Glen T; Siczka, John S; Smith, Thomas F; Frank, David A; McCorquodale, J A

    2017-08-01

      The need to increase the peak wet weather secondary treatment capacity of the City of Akron, Ohio, Water Reclamation Facility (WRF) provided the opportunity to test an integrated methodology for maximizing the peak wet weather secondary treatment capacity of activated sludge systems. An initial investigation, consisting of process modeling of the secondary treatment system and computational fluid dynamics (CFD) analysis of the existing relatively shallow secondary clarifiers (3.3 and 3.7 m sidewater depth in 30.5 m diameter units), indicated that a significant increase in capacity from 416 000 to 684 000 m3/d or more was possible by adding step feed capabilities to the existing bioreactors and upgrading the existing secondary clarifiers. One of the six treatment units at the WRF was modified, and an extensive 2-year testing program was conducted to determine the total peak wet weather secondary treatment capacity achievable. The results demonstrated that a peak wet weather secondary treatment capacity approaching 974 000 m3/d is possible as long as secondary clarifier solids and hydraulic loadings could be separately controlled using the step feed capability provided. Excellent sludge settling characteristics are routinely experienced at the City of Akron WRF, raising concerns that the identified peak wet weather secondary treatment capacity could not be maintained should sludge settling characteristics deteriorate for some reason. Computational fluid dynamics analysis indicated that the impact of the deterioration of sludge settling characteristics could be mitigated and the identified peak wet weather secondary treatment capacity maintained by further use of the step feed capability provided to further reduce secondary clarifier solids loading rates at the identified high surface overflow rates. The results also demonstrated that effluent limits not only for total suspended solids (TSS) and five-day carbonaceous biochemical oxygen demand (cBOD5) could be

  13. PP042. Anti-hypertensive drugs hydralazine, clonidine and labetalol improve trophoblast integration into endothelial cellular networks in vitro.

    Science.gov (United States)

    Xu, B; Charlton, F; Makris, A; Hennessy, A

    2012-07-01

    Preeclampsia is an exaggerated maternal inflammatory state with over-expression of placental soluble fms-like tyrosine kinase 1 (sFlt-1). It is also associated with shallow trophoblast invasion and inadequate transformation of uterine spiral arteries. Antihypertensive drugs administrated in preeclampsia to control blood pressure have been reported to regulate placental and circulating cytokine production from women with preeclampsia. Whether they could modulate the interaction between trophoblast and endothelial cells are not investigated. This study is to examine the effect of pharmacological dose of anti-hypertensive hydralazine, clonidine and labetalol on trophoblast cell integration into inflammatory TNF-a pre-exposed endothelial cellular networks. Human uterine myometrial microvascular endothelial cells (UtMVECs) were pre-incubated with (or without) low dose (0.5ng/ml) inflammatory TNF-a or TNF-a plus sFlt-1 (100ng/ml) for 24hours. These cells were labelled with red fluorescence and seeded on a 24-well culture plate coated with Matrigel. Endothelial tubular structures appeared within 4hours. Green fluorescent-labelled HTR-8/SVneo trophoblast cells were then co-cultured with endothelial cells, with (or without) hydralazine (10μg/ml), clonidine (1.0μg/ml) or labetalol (0.5μg/ml). Red and green fluorescent images were captured after 24hours. Drug effect on HTR-8 cells integration into endothelial cellular networks was quantified by Image Analysis software. The conditioned media were also collected to measure concentrations of free VEGF, PLGF and sFlt-1 by ELISA. When HTR-8/SVneo trophoblast cells were co-cultured with TNF-a pre-incubated endothelial cells, hydralazine and clonidine can significantly increase the trophoblast integration into endothelial cellular networks. This increase was not seen if co-cultured with normal endothelial cells (without TNF-a pre-incubation) or with TNF-a plus sFlt-1 treated endothelial cells. Labetalol could increase the HTR-8

  14. Modulation of electrostatic interactions to improve controlled drug delivery from nanogels.

    Science.gov (United States)

    Mauri, Emanuele; Chincarini, Giulia M F; Rigamonti, Riccardo; Magagnin, Luca; Sacchetti, Alessandro; Rossi, Filippo

    2017-03-01

    The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Ursodeoxycholic Acid Can Improve Liver Transaminase Quantities in Children with Anticonvulsant Drugs Hepatotoxicity: a Pilot Study.

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    Masoumeh Asgarshirazi

    2015-06-01

    Full Text Available The present study has been directed to investigate Ursodeoxycholic Acid (UDCA effect in children, to reduce the high Liver transaminases induced by Anticonvulsant drugs (drug induced hepatitis. This idea has been driven from Cytoprotective and antioxidant properties of UDCA to be used in drug induced inflammation in Liver. Twenty two epileptic patients aged between 4 mo - 3 yr whom were under anticonvulsant therapy with drugs such as valperoic acid, primidone, levetiracetam, Phenobarbital or any combination of them and had shown Liver transaminases rise , after rule out of Viral-Autoimmune, Metabolic and Anatomic causes, have been prescribed UDCA in dose of 10-15 mg/kg/day, at least for 6 months. Any patient who have shown confusing factors such as genetic disorders with liver involvement or spontaneous decline in enzymes or had not treatment compliance has been excluded from the study. Transaminases range changes as well as Probable side effects of the drug have been monitored. The results indicated that UDCA is effective and well tolerable in the children with drug induced hyper transaminasemia. No side effect has been seen and recorded in this study. Based on this study and its results, we recommend UDCA as a safe and effective choice in drug induced hepatotoxicities.

  16. Nanoparticle-based drug delivery to improve the efficacy of antiretroviral therapy in the central nervous system

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    Gomes MJ

    2014-04-01

    Full Text Available Maria João Gomes,1 José das Neves,1,2 Bruno Sarmento1,2 1Instituto de Engenharia Biomédica (INEB, Porto, Portugal; 2Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS, Instituto Superior de Ciências da Saúde-Norte, CESPU, Gandra, Portugal Abstract: Antiretroviral drug therapy plays a cornerstone role in the treatment of human immunodeficiency virus (HIV/acquired immunodeficiency syndrome patients. Despite obvious advances over the past 3 decades, new approaches toward improved management of infected individuals are still required. Drug distribution to the central nervous system (CNS is required in order to limit and control viral infection, but the presence of natural barrier structures, in particular the blood–brain barrier, strongly limits the perfusion of anti-HIV compounds into this anatomical site. Nanotechnology-based approaches may help providing solutions for antiretroviral drug delivery to the CNS by potentially prolonging systemic drug circulation, increasing the crossing and reducing the efflux of active compounds at the blood–brain barrier, and providing cell/tissue-targeting and intracellular drug delivery. After an initial overview on the basic features of HIV infection of the CNS and barriers to active compound delivery to this anatomical site, this review focuses on recent strategies based on antiretroviral drug-loaded solid nanoparticles and drug nanosuspensions for the potential management of HIV infection of the CNS. Keywords: HIV/AIDS, blood–brain barrier, protease inhibitors, efflux transporters, drug targeting

  17. Effectiveness of Cognitive-Behavioral Therapy in the Improvement of Coping Strategies and Addiction Symptoms in Drug-Dependent Patients

    Directory of Open Access Journals (Sweden)

    H BrockieMilan

    2014-12-01

    Full Text Available Objective: This study was carried out to determine the effectiveness of cognitive-behavioral therapy in improving coping strategies and symptoms of drug addiction patients. Method: In a quasi-experimental study, the number of 90drug-dependent patients referring to clinics to stop taking drugs existing in the city of Urmia were divided into two experimental (n=45 groups and control (n=45 using random sampling. The experimental group received 12 sessions of cognitive-behavioral treatment in Carroll style while the control group received only methadone and the physical pills. All the participants completed coping strategies questionnaire at the beginning, during (after three months, and three months after treatment (follow-up. As well, they were assessed for the rate of improvement in symptoms of addiction and process of addiction treatment using by Madzly’s addiction profile questionnaire. Findings: The results proved the effectiveness of cognitive-behavioral therapy and its survival. Conclusion: Cognitive behavioral therapy is very influential in the boost of coping strategies and the improvement of mental and physical health in drug-dependent patients.

  18. Information to Improve Public Perceptions of the Food and Drug Administration (FDA’s Tobacco Regulatory Role

    Directory of Open Access Journals (Sweden)

    Amira Osman

    2018-04-01

    Full Text Available While the Food and Drug Administration (FDA has had regulatory authority over tobacco products since 2009, public awareness of this authority remains limited. This research examines several broad types of information about FDA tobacco regulatory mission that may improve the perceptions of FDA as a tobacco regulator. Using Amazon Mechanical Turk, 1766 adults, smokers and non-smokers, were randomly assigned to view a statement about FDA regulatory authority that varied three information types in a 2 × 2 × 2 between subjects experimental design: (1 FDA’s roles in regulating tobacco (yes/no; (2 The scientific basis of regulations (yes/no; and (3 A potential protective function of regulations (yes/no. Using factorial ANOVA, we estimated the main and interactive effects of all three types of information and of smoking status on the perceptions of FDA. Participants that were exposed to information on FDA roles reported higher FDA credibility and a greater perceived knowledge of FDA than those who did not. Exposure to information about the scientific basis of regulations led to more negative views of the tobacco industry. Participants who learned of the FDA’s commitment to protecting the public reported higher FDA credibility and more positive attitudes toward regulations than those who did not learn of this commitment. We observed no significant interaction effects. The findings suggest that providing information about the regulatory roles and protective characterization of the FDA’s tobacco regulatory mission positively influence public perceptions of FDA and tobacco regulations.

  19. Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer.

    Science.gov (United States)

    Wan, Xiaomeng; Min, Yuanzeng; Bludau, Herdis; Keith, Andrew; Sheiko, Sergei S; Jordan, Rainer; Wang, Andrew Z; Sokolsky-Papkov, Marina; Kabanov, Alexander V

    2018-03-27

    Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline- block-2-butyl-2-oxazoline- block-2-methyl-2-oxazoline) (P(MeOx- b-BuOx- b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

  20. Controlled Substance Reconciliation Accuracy Improvement Using Near Real-Time Drug Transaction Capture from Automated Dispensing Cabinets.

    Science.gov (United States)

    Epstein, Richard H; Dexter, Franklin; Gratch, David M; Perino, Michael; Magrann, Jerry

    2016-06-01

    (Next Day Reports), and May 2014 to September 2015 (Near Real-Time Reports) and reconciled against pharmacy records from the central pharmacy database maintained by the vendor. Control chart (batch means) methods were used between successive epochs to determine if improvement had taken place. During simulation, 100% of 10,000 messages, transmitted at a rate of 1295 per minute, were accurately captured and inserted into the database. Latency (transmission time to local database insertion time) was 46.3 ± 0.44 milliseconds (SEM). During acceptance testing, only 1 of 1384 transactions analyzed had a difference between the near real-time process and what was in the central database; this was for a "John Doe" patient whose name had been changed subsequent to data capture. Once a transaction was entered at the ADC workstation, 84.9% (n = 18 bins; 95% CI, 78.4% to 91.3%) of these transactions were available in the database on the AIMS server within 2 minutes. Within 5 minutes, 98.2% (n = 18 bins; 95% CI, 97.2% to 99.3%) were available. Among 145,642 transactions present in the central pharmacy database, only 24 were missing from the local database table (mean = 0.018%; 95% CI, 0.002% to 0.034%). Implementation of near real-time reporting improved the controlled substance reconciliation error rate compared to the previous Next Day Reports epoch, from 8.8% to 5.2% (difference = -3.6%; 95% CI, -4.3% to -2.8%; P < 10). Errors were distributed among staff, with 50% of discrepancies accounted for by 12.4% of providers and 80% accounted for by 28.5% of providers executing transactions during the Near Real-Time Reports epoch. The near real-time system for the capture of transactional data flowing over the hospital network was highly accurate, reliable, and exhibited acceptable latency. This methodology can be used to implement similar data capture for transactions from their drug ADCs. Reconciliation accuracy improved significantly as a result of implementation. Our approach may be

  1. Integration of Health Services Improves Multiple Healthcare Outcomes Among HIV-infected People Who Inject Drugs in Ukraine

    Science.gov (United States)

    Bachireddy, Chethan; Soule, Michael C.; Izenberg, Jacob M.; Dvoryak, Sergey; Dumchev, Konstantin; Altice, Frederick L.

    2013-01-01

    Background People who inject drugs (PWID) experience poor outcomes and fuel HIV epidemics in middle-income countries in Eastern Europe and Central Asia. We assess integrated/co-located (ICL) healthcare for HIV-infected PWID, which despite international recommendations, is neither widely available nor empirically examined. Methods A 2010 cross-sectional study randomly sampled 296 HIV-infected opioid-dependent PWID from two representative HIV-endemic regions in Ukraine where ICL, non-co-located (NCL) and harm reduction/outreach (HRO) settings are available. ICL settings provide onsite HIV, addiction, and tuberculosis services, NCLs only treat addiction, and HROs provide counseling, needles/syringes, and referrals, but no opioid substitution therapy (OST). The primary outcome was receipt of quality healthcare, measured using a quality healthcare indicator (QHI) composite score representing percentage of eight guidelines-based recommended indicators met for HIV, addiction and tuberculosis treatment. The secondary outcomes were individual QHIs and health-related quality-of-life (HRQoL). Results On average, ICL-participants had significantly higher QHI composite scores compared to NCL- and HRO-participants (71.9% versus 54.8% versus 37.0%, p<0.001) even after controlling for potential confounders. Compared to NCL-participants, ICL-participants were significantly more likely to receive antiretroviral therapy (49.5% versus 19.2%, p<0.001), especially if CD4≤200 (93.8% versus 62.5% p<0.05); guideline-recommended OST dosage (57.3% versus 41.4%, p<0.05); and isoniazid preventive therapy (42.3% versus 11.2%, p<0.001). Subjects receiving OST had significantly higher HRQoL than those not receiving it (p<0.001); however, HRQoL did not differ significantly between ICL- and NCL-participants. Conclusions These findings suggest that OST alone improves quality-of-life, while receiving care in integrated settings collectively and individually improves healthcare quality for PWID

  2. 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

  3. «Love and Other Drugs»: A film with a significant number of resources for training in pharmacology and therapeutics

    Directory of Open Access Journals (Sweden)

    Cándido HERNÁNDEZ-LÓPEZ

    2016-04-01

    Full Text Available The methods and results of a practical exercise based on the movie Love and Other Drugs (2010 by Edward Zwick are presented. The exercise was part of the teaching activities in General Pharmacology, in the third year of the medicine degree. The teaching objectives included to perceive different views on the use of drugs (marketer/prescriber/ patient/society, to obtain critical opinions on promotional activities and to get familiar with the ethical codes controlling advertising activities. Two sessions of 2.5 hours were done, separated by two weeks. During the first one the activity was introduced and organized, and the film was viewed. During the second session the students exposed and discussed work which had been prepared guided by a number of specific questions. The resources present in the film were an excellent vehicle for establishing a strong interaction with students, to guide reflections on the importance of drugs in society, to address the need for ethical codes, the differences between licensed indication and off-label use, and to emphasise the use of the SmPC as key reference information. In conclusion, the exercise served to provide students some tools for ethical consideration on their future responsibilities as decision makers in drug prescribing.

  4. Drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacotherapy

    Directory of Open Access Journals (Sweden)

    Fegert Jörg M

    2009-04-01

    Full Text Available Abstract Most psychotropic drugs used in the treatment of children and adolescents are applied "off label" with a direct risk of under- or overdosing and a delayed risk of long-term side effects. The selection of doses in paediatric psychiatric patients requires a consideration of pharmacokinetic parameters and the development of central nervous system, and warrants specific studies in children and adolescents. Because these are lacking for most of the psychotropic drugs applied in the Child and Adolescent and Psychiatry, therapeutic drug monitoring (TDM is a valid tool to optimise pharmacotherapy and to enable to adjust the dosage of drugs according to the characteristics of the individual patient. Multi-centre TDM studies enable the identification of age- and development-dependent therapeutic ranges of blood concentrations and facilitate a highly qualified standardized documentation in the child and adolescent health care system. In addition, they will provide data for future research on psychopharmacological treatment in children and adolescents, as a baseline for example for clinically relevant interactions with various co-medications. Therefore, a German-Austrian-Swiss "Competence Network on Therapeutic Drug Monitoring in Child and Adolescent Psychiatry" was founded 1 introducing a comprehensive internet data base for the collection of demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents.

  5. Have there been improvements in Alzheimer's disease drug discovery over the past 5 years?

    Science.gov (United States)

    Cacabelos, Ramón

    2018-06-01

    Alzheimer's disease (AD) is the most important neurodegenerative disorder with a global cost worldwide of over $700 billion. Pharmacological treatment accounts for 10-20% of direct costs; no new drugs have been approved during the past 15 years; and the available medications are not cost-effective. Areas covered: A massive scrutiny of AD-related PubMed publications (ps)(2013-2017) identified 42,053ps of which 8,380 (19.60%) were associated with AD treatments. The most prevalent pharmacological categories included neurotransmitter enhancers (11.38%), multi-target drugs (2.45%), anti-Amyloid agents (13.30%), anti-Tau agents (2.03%), natural products and derivatives (25.58%), novel drugs (8.13%), novel targets (5.66%), other (old) drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and others (discovery programs, (vi) the updating of regulatory requirements, (vii) the introduction of pharmacogenomics in drug development and personalized treatments, and (viii) the implementation of preventive programs.

  6. 3-aminopropyl functionalized magnesium phyllosilicate as an organoclay based drug carrier for improving the bioavailability of flurbiprofen

    Directory of Open Access Journals (Sweden)

    Yang L

    2013-10-01

    Full Text Available Liang Yang,1 Soo-Kyung Choi,2 Hyun-Jae Shin,2 Hyo-Kyung Han1 1College of Pharmacy, Dongguk University-Seoul, Siksa-dong, Ilsan-Donggu, Goyang, Gyunggi-do, Korea; 2Department of Chemical and Biochemical Engineering, Chosun University, Gwangju, Korea Abstract: This study aimed to develop an oral delivery system using clay-based organic–inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB was incorporated into AMP clay (FB-AMP at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP(3, dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP(3 after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2, FB-AMP(3 also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP(3 to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic–inorganic hybrid material might be useful to improve the bioavailability of FB. Keywords: poorly water-soluble drugs, aminopropyl functionalized magnesium phyllosilicate, organic clay, oral bioavailability

  7. Drug procurement and management.

    Science.gov (United States)

    Salhotra, V S

    2003-03-01

    A strong drug procurement and management system under the RNTCP is critical to programme success. Significant improvements in manufacturing, inspection, supply, storage and quality control practices and procedures have been achieved due to an intensive RNTCP network. Drugs used in RNTCP are rifampicin, isoniazid, ethambutol, pyrazinamide and streptomycin. Patients of TB are categorised into I, II and III and each category has a different standarised treatment. Procurement, distribution system and quality assurance of drugs are narrated in brief in this article.

  8. A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics

    Energy Technology Data Exchange (ETDEWEB)

    Gagliardi, M., E-mail: mariacristina.gagliardi@iit.it [Center for Micro Bio-Robotics @SSSA, Istituto Italiano di Tecnologia, Viale Rinaldo Piaggio 34, 56025 Pontedera (Italy); Bertero, A. [Department of Biology, Unit of Cellular and Developmental Biology, University of Pisa, S.S.12 Abetone e Brennero 4, 56127 Pisa (Italy); Center for Neuroscience and Cognitive Systems @UNITN, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (Italy); Bardi, G. [Center for Bio-Molecular Nanotechnologies @UniLe, Istituto Italiano di Tecnologia, Via Barsanti, 73010 Arnesano (Italy); Bifone, A. [Center for Neuroscience and Cognitive Systems @UNITN, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (Italy)

    2016-02-01

    This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. - Highlights: • We propose a novel biodegradable nanocarrier for intracellular drug delivery. • Biodegradation rates can be finely tuned by controlling copolymer composition. • Degradation products are less acidic, thus enabling delivery of pH-sensitive cargoes. • We demonstrate intracellular delivery of a non-cell-penetrating model drug. • No significant membrane damage by the polymer nanocarriers is observed.

  9. A poly(ether-ester) copolymer for the preparation of nanocarriers with improved degradation and drug delivery kinetics

    International Nuclear Information System (INIS)

    Gagliardi, M.; Bertero, A.; Bardi, G.; Bifone, A.

    2016-01-01

    This paper reports the synthesis and the physicochemical, functional and biological characterisations of nanocarriers made of a novel di-block biodegradable poly(ether-ester) copolymer. This material presents tunable, fast biodegradation rates, but its products are less acidic than those of other biosorbable polymers like PLGA, thus presenting a better biocompatibility profile and the possibility to carry pH-sensitive payloads. A method for the production of monodisperse and spherical nanoparticles is proposed; drug delivery kinetics and blood protein adsorption were measured to evaluate the functional properties of these nanoparticles as drug carriers. The copolymer was labelled with a fluorescent dye for internalisation tests, and rhodamine B was used as a model cargo to study transport and release inside cultured cells. Biological tests demonstrated good cytocompatibility, significant cell internalisation and the possibility to vehiculate non-cell penetrating moieties into endothelial cells. Taken together, these results support the potential use of this nanoparticulate system for systemic administration of drugs. - Highlights: • We propose a novel biodegradable nanocarrier for intracellular drug delivery. • Biodegradation rates can be finely tuned by controlling copolymer composition. • Degradation products are less acidic, thus enabling delivery of pH-sensitive cargoes. • We demonstrate intracellular delivery of a non-cell-penetrating model drug. • No significant membrane damage by the polymer nanocarriers is observed.

  10. Global Optimization of Ventricular Myocyte Model to Multi-Variable Objective Improves Predictions of Drug-Induced Torsades de Pointes

    Directory of Open Access Journals (Sweden)

    Trine Krogh-Madsen

    2017-12-01

    Full Text Available In silico cardiac myocyte models present powerful tools for drug safety testing and for predicting phenotypical consequences of ion channel mutations, but their accuracy is sometimes limited. For example, several models describing human ventricular electrophysiology perform poorly when simulating effects of long QT mutations. Model optimization represents one way of obtaining models with stronger predictive power. Using a recent human ventricular myocyte model, we demonstrate that model optimization to clinical long QT data, in conjunction with physiologically-based bounds on intracellular calcium and sodium concentrations, better constrains model parameters. To determine if the model optimized to congenital long QT data better predicts risk of drug-induced long QT arrhythmogenesis, in particular Torsades de Pointes risk, we tested the optimized model against a database of known arrhythmogenic and non-arrhythmogenic ion channel blockers. When doing so, the optimized model provided an improved risk assessment. In particular, we demonstrate an elimination of false-positive outcomes generated by the baseline model, in which simulations of non-torsadogenic drugs, in particular verapamil, predict action potential prolongation. Our results underscore the importance of currents beyond those directly impacted by a drug block in determining torsadogenic risk. Our study also highlights the need for rich data in cardiac myocyte model optimization and substantiates such optimization as a method to generate models with higher accuracy of predictions of drug-induced cardiotoxicity.

  11. Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy.

    Science.gov (United States)

    Wang, Chang-Fang; Mäkilä, Ermei M; Kaasalainen, Martti H; Hagström, Marja V; Salonen, Jarno J; Hirvonen, Jouni T; Santos, Hélder A

    2015-04-01

    Dual-drug delivery of antiangiogenic and chemotherapeutic drugs can enhance the therapeutic effect for cancer therapy. Conjugation of methotrexate (MTX) to porous silicon (PSi) nanoparticles (MTX-PSi) with positively charged surface can improve the cellular uptake of MTX and inhibit the proliferation of cancer cells. Herein, MTX-PSi conjugates sustained the release of MTX up to 96 h, and the released fragments including MTX were confirmed by mass spectrometry. The intracellular distribution of the MTX-PSi nanoparticles was confirmed by transmission electron microscopy. Compared to pure MTX, the MTX-PSi achieved similar inhibition of cell proliferation in folate receptor (FR) over-expressing U87 MG cancer cells, and a higher effect in low FR-expressing EA.hy926 cells. Nuclear fragmentation analysis demonstrated programmed cell apoptosis of MTX-PSi in the high/low FR-expressing cancer cells, whereas PSi alone at the same dose had a minor effect on cell apoptosis. Finally, the porous structure of MTX-PSi enabled a successful concomitant loading of another anti-angiogenic hydrophobic drug, sorafenib, and considerably enhanced the dissolution rate of sorafenib. Overall, the MTX-PSi nanoparticles can be used as a platform for combination chemotherapy by simultaneously enhancing the dissolution rate of a hydrophobic drug and sustaining the release of a conjugated chemotherapeutic drug. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  12. Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity

    Science.gov (United States)

    Fan, Rangrang; Li, Xiaoling; Deng, Jiaojiao; Gao, Xiang; Zhou, Liangxue; Zheng, Yu; Tong, Aiping; Zhang, Xiaoning; You, Chao; Guo, Gang

    2016-06-01

    One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer.

  13. A New Concept of a Drug Delivery System with Improved Precision and Patient Safety Features

    Directory of Open Access Journals (Sweden)

    Florian Thoma

    2014-12-01

    Full Text Available This paper presents a novel dosing concept for drug delivery based on a peristaltic piezo-electrically actuated micro membrane pump. The design of the silicon micropump itself is straight-forward, using two piezoelectrically actuated membrane valves as inlet and outlet, and a pump chamber with a piezoelectrically actuated pump membrane in-between. To achieve a precise dosing, this micropump is used to fill a metering unit placed at its outlet. In the final design this metering unit will be made from a piezoelectrically actuated inlet valve, a storage chamber with an elastic cover membrane and a piezoelectrically actuated outlet valve, which are connected in series. During a dosing cycle the metering unit is used to adjust the drug volume to be dispensed before delivery and to control the actually dispensed volume. To simulate the new drug delivery concept, a lumped parameter model has been developed to find the decisive design parameters. With the knowledge taken from the model a drug delivery system is designed that includes a silicon micro pump and, in a first step, a silicon chip with the storage chamber and two commercial microvalves as a metering unit. The lumped parameter model is capable to simulate the maximum flow, the frequency response created by the micropump, and also the delivered volume of the drug delivery system.

  14. Direct binding of radioiodinated monoclonal antibody to tumor cells: significance of antibody purity and affinity for drug targeting or tumor imaging

    International Nuclear Information System (INIS)

    Kennel, S.J.; Foote, L.J.; Lankford, P.K.; Johnson, M.; Mitchell, T.; Braslawsky, G.R.

    1983-01-01

    For MoAb to be used efficiently for drug targeting and tumor imaging, the fraction of antibody binding to tumor cells must be maximized. The authors have studied the binding of 125 I MoAb in three different tumor systems. The fraction of antibody that could be bound to the cell surface was directly proportional to the antibody purity. The affinity constant also limits the fraction of antibody that can bind to cells at a given antigen concentration. Rearrangement of the standard expression for univalent equilibrium binding between two reactants shows that in antigen excess, the maximum fraction of antibody that can bind =Ka[Ag total]/1 + Ka[Ag total]. Binding data using four different MoAb with three cell systems confirm this relationship. Estimates for reasonable concentrations of tumor antigens in vivo indicate that antibodies with binding constants less than 10 8 M -1 are not likely to be useful for drug targeting or tumor imaging

  15. Improving safety-related knowledge, attitude and practices of nurses handling cytotoxic anticancer drug: pharmacists' experience in a general hospital, Malaysia.

    Science.gov (United States)

    Keat, Chan Huan; Sooaid, Nor Suhada; Yun, Cheng Yi; Sriraman, Malathi

    2013-01-01

    An increasing trend of cytotoxic drug use, mainly in cancer treatment, has increased the occupational exposure among the nurses. This study aimed to assess the change of nurses' safety-related knowledge as well as attitude levels and subsequently to assess the change of cytotoxic drug handling practices in wards after a series of pharmacist-based interventions. This prospective interventional study with a before and after design requested a single group of 96 nurses in 15 wards actively providing chemotherapy to answer a self-administered questionnaire. A performance checklist was then used to determine the compliance of all these wards with the recommended safety measures. The first and second assessments took 2 months respectively with a 9-month intervention period. Pharmacist-based interventions included a series of technical, educational and administrative support measures consisting of the initiation of closed-system cytotoxic drug reconstitution (CDR) services, courses, training workshops and guideline updates. The mean age of nurses was 32.2∓6.19 years. Most of them were female (93.8%) and married (72.9%). The mean knowledge score of nurses was significantly increased from 45.5∓10.52 to 73.4∓8.88 out of 100 (p<0.001) at the end of the second assessment. Overall, the mean practice score among the wards was improved from 7.6∓5.51 to 15.3∓2.55 out of 20 (p<0.001). The pharmacist-based interventions improved the knowledge, attitude and safe practices of nurses in cytotoxic drug handling. Further assessment may help to confirm the sustainability of the improved practices.

  16. A community effort to assess and improve drug sensitivity prediction algorithms.

    Science.gov (United States)

    Costello, James C; Heiser, Laura M; Georgii, Elisabeth; Gönen, Mehmet; Menden, Michael P; Wang, Nicholas J; Bansal, Mukesh; Ammad-ud-din, Muhammad; Hintsanen, Petteri; Khan, Suleiman A; Mpindi, John-Patrick; Kallioniemi, Olli; Honkela, Antti; Aittokallio, Tero; Wennerberg, Krister; Collins, James J; Gallahan, Dan; Singer, Dinah; Saez-Rodriguez, Julio; Kaski, Samuel; Gray, Joe W; Stolovitzky, Gustavo

    2014-12-01

    Predicting the best treatment strategy from genomic information is a core goal of precision medicine. Here we focus on predicting drug response based on a cohort of genomic, epigenomic and proteomic profiling data sets measured in human breast cancer cell lines. Through a collaborative effort between the National Cancer Institute (NCI) and the Dialogue on Reverse Engineering Assessment and Methods (DREAM) project, we analyzed a total of 44 drug sensitivity prediction algorithms. The top-performing approaches modeled nonlinear relationships and incorporated biological pathway information. We found that gene expression microarrays consistently provided the best predictive power of the individual profiling data sets; however, performance was increased by including multiple, independent data sets. We discuss the innovations underlying the top-performing methodology, Bayesian multitask MKL, and we provide detailed descriptions of all methods. This study establishes benchmarks for drug sensitivity prediction and identifies approaches that can be leveraged for the development of new methods.

  17. Have VET Reforms Resulted in Improvements in Quality? Illustrations from the Alcohol and Other Drugs Sector

    Science.gov (United States)

    Roche, Ann; Kostadinov, Victoria; White, Michael

    2014-01-01

    Australian vocational education and training (VET) has undergone major reforms since the 1990s, including the introduction of competency based training (CBT) and the "streamlining" of qualifications. This paper examines the impact of these reforms, using the alcohol and other drugs sector as a case illustration. A survey of alcohol and…

  18. CRISPR-Cas9-mediated saturated mutagenesis screen predicts clinical drug resistance with improved accuracy.

    Science.gov (United States)

    Ma, Leyuan; Boucher, Jeffrey I; Paulsen, Janet; Matuszewski, Sebastian; Eide, Christopher A; Ou, Jianhong; Eickelberg, Garrett; Press, Richard D; Zhu, Lihua Julie; Druker, Brian J; Branford, Susan; Wolfe, Scot A; Jensen, Jeffrey D; Schiffer, Celia A; Green, Michael R; Bolon, Daniel N

    2017-10-31

    Developing tools to accurately predict the clinical prevalence of drug-resistant mutations is a key step toward generating more effective therapeutics. Here we describe a high-throughput CRISPR-Cas9-based saturated mutagenesis approach to generate comprehensive libraries of point mutations at a defined genomic location and systematically study their effect on cell growth. As proof of concept, we mutagenized a selected region within the leukemic oncogene BCR-ABL1 Using bulk competitions with a deep-sequencing readout, we analyzed hundreds of mutations under multiple drug conditions and found that the effects of mutations on growth in the presence or absence of drug were critical for predicting clinically relevant resistant mutations, many of which were cancer adaptive in the absence of drug pressure. Using this approach, we identified all clinically isolated BCR-ABL1 mutations and achieved a prediction score that correlated highly with their clinical prevalence. The strategy described here can be broadly applied to a variety of oncogenes to predict patient mutations and evaluate resistance susceptibility in the development of new therapeutics. Published under the PNAS license.

  19. Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery

    NARCIS (Netherlands)

    Boshuisen, Kim; van Schooneveld, Monique M. J.; Uiterwaal, Cuno S. P. M.; Cross, J. Helen; Harrison, Sue; Polster, Tilman; Daehn, Marion; Djimjadi, Sarina; Yalnizoglu, Dilek; Turanli, Guzide; Sassen, Robert; Hoppe, Christian; Kuczaty, Stefan; Barba, Carmen; Kahane, Philippe; Schubert-Bast, Susanne; Reuner, Gitta; Bast, Thomas; Strobl, Karl; Mayer, Hans; de Saint-Martin, Anne; Seegmuller, Caroline; Laurent, Agathe; Arzimanoglou, Alexis; Braun, Kees P. J.

    ObjectiveAntiepileptic drugs (AEDs) have cognitive side effects that, particularly in children, may affect intellectual functioning. With the TimeToStop (TTS) study, we showed that timing of AED withdrawal does not majorly influence long-term seizure outcomes. We now aimed to evaluate the effect of

  20. Improvement of Tenofovir vaginal release from hydrophilic matrices through drug granulation with hydrophobic polymers.

    Science.gov (United States)

    Notario-Pérez, Fernando; Martín-Illana, Araceli; Cazorla-Luna, Raúl; Ruiz-Caro, Roberto; Peña, Juan; Veiga, María-Dolores

    2018-05-30

    Sustained-release vaginal microbicides hold out great hope for the prevention of sexual transmission of HIV from men to women. Tenofovir (TFV) -an antiretroviral drug- sustained-release vaginal compacts combining two release control systems (by drug-loading granules with hydrophobic polymers and incorporating them in a hydrophilic matrix) are proposed in this work as a possible microbicide. The polymers used for the drug granules are Eudragit® RS (ERS), an acrylic derivative, and Zein, a maize protein. The hydrophilic matrix is composed of a mixture of hydroxypropylmethyl cellulose (HPMC) and chitosan (CH). The thermal, microscopic, spectrophotometric and X-ray diffraction analysis showed that the drug was not altered during the granulation process. Studies of TFV release, swelling and ex vivo mucoadhesion were subsequently performed on simulated vaginal fluid. The formulation whereby TFV is granulated using twice its weight in ERS, and then including these granules in a matrix in which the CH predominates over HPMC, allows the sustained release of TFV for 144 h, mucoadhesion to the vaginal mucosa for 150 h and a moderate swelling, making it the most suitable formulation of all those studied. These compacts would therefore offer women protection against the sexual acquisition of HIV. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Improved Conversion Rates in Drug Screening Applications sing Miniaturized Electrochemical Cells with Frit Channels

    NARCIS (Netherlands)

    Odijk, Mathieu; Olthuis, Wouter; van den Berg, Albert; Qiao, L.; Girault, H.

    2012-01-01

    This paper reports a novel design of a miniaturized three-electrode electrochemical cell, the purpose of which is aimed at generating drug metabolites with a high conversion efficiency. The working electrode and the counter electrode are placed in two separate channels to isolate the reaction

  2. Improvement of the Prediction of Drugs Demand Using Spatial Data Mining Tools.

    Science.gov (United States)

    Ramos, M Isabel; Cubillas, Juan José; Feito, Francisco R

    2016-01-01

    The continued availability of products at any store is the major issue in order to provide good customer service. If the store is a drugstore this matter reaches a greater importance, as out of stock of a drug when there is high demand causes problems and tensions in the healthcare system. There are numerous studies of the impact this issue has on patients. The lack of any drug in a pharmacy in certain seasons is very common, especially when some external factors proliferate favoring the occurrence of certain diseases. This study focuses on a particular drug consumed in the city of Jaen, southern Andalucia, Spain. Our goal is to determine in advance the Salbutamol demand. Advanced data mining techniques have been used with spatial variables. These last have a key role to generate an effective model. In this research we have used the attributes that are associated with Salbutamol demand and it has been generated a very accurate prediction model of 5.78% of mean absolute error. This is a very encouraging data considering that the consumption of this drug in Jaen varies 500% from one period to another.

  3. Biomimickry of UPEC Cytoinvasion: A Novel Concept for Improved Drug Delivery in UTI

    Directory of Open Access Journals (Sweden)

    Clara Maria Pichl

    2016-02-01

    Full Text Available Urinary tract infections (UTIs are among the most common bacterial infections. In an increasing number of cases, pathogen (multi-resistance hampers durable treatment success via the standard therapies. On the functional level, the activity of urinary excreted antibiotics is compromized by the efficient tissue colonization mechanism of uropathogenic Escherichia coli (UPEC. Advanced drug delivery systems aim at exploiting a glycan-mediated targeting mechanism, similar to the UPEC invasion pathway, to increase bioavailability. This may be realized by conjugation of intravesically applied drugs or drug carriers to chosen plant lectins. Higher local drug concentrations in or nearby bacterial reservoirs may be gained, with higher chances for complete eradication. In this study, preliminary parameters to clarify the potential of this biorecognitive approach were evaluated. Glycan-triggered interaction cascades and uptake processes of several plant lectins with distinct carbohydrate specificities were characterized, and wheat germ agglutinin (WGA could be identified as the most promising targeter for crossing the urothelial membrane barrier. In partially differentiated primary cells, intracellular accumulation sites were largely identical for GlcNAc- and Mannose-specific lectins. This indicates that WGA-mediated delivery may also enter host cells via the FimH-dependent uptake pathway.

  4. Drug compartmentalization as strategy to improve the physico-chemical properties of diclofenac sodium loaded niosomes for topical applications.

    Science.gov (United States)

    Tavano, Lorena; de Cindio, Bruno; Picci, Nevio; Ioele, Giuseppina; Muzzalupo, Rita

    2014-12-01

    The objective of this research was to study the effect of diclofenac sodium compartmentalization on the physico-chemical properties (such as size, drug entrapment efficiency and percutaneous permeation across rabbit skin) of niosomal vesicles used as carriers. Niosomes were prepared starting from nonionic commercial surfactants belonging to the class of Polysorbates and Pluronics: mixtures of Span 60/F127 and Tween 60/F127 at different ratios were used to obtain vesicles and all formulations were compared in terms of dimensions, morphology, polydispersity index and entrapment efficiency. Moreover, the enhancing effect of niosomes on the ex vivo percutaneous penetration of diclofenac sodium was investigated using Franz-type diffusion chambers and compared to that obtained by using the corresponding drug solution. Results demonstrated that niosomes were spherical and homogeneous in shape. Their size was found to be dependent on the hydrophile-lipophile balance of the surfactant mixture: increasing hydrophobicity resulted in smaller vesicles. Drug incorporation led to a significant variation in vesicle size dependently from the compartment in which the drug was located. The permeation of diclofenac from free solution used as control was found to be lower respect to that obtained for all niosomal formulations, that can be considered as percutaneous permeation enhancers. In particular, the results indicated that the highest cumulative amounts of diclofenac permeated across rabbit skin after 24 h were obtained by formulations in which the drug was located in the aqueous core.

  5. 3-aminopropyl functionalized magnesium phyllosilicate as an organoclay based drug carrier for improving the bioavailability of flurbiprofen.

    Science.gov (United States)

    Yang, Liang; Choi, Soo-Kyung; Shin, Hyun-Jae; Han, Hyo-Kyung

    2013-01-01

    This study aimed to develop an oral delivery system using clay-based organic-inorganic hybrid materials to improve the bioavailability of the drug, flurbiprofen, which is poorly soluble in water. 3-aminopropyl functionalized magnesium phyllosilicate (AMP clay) was synthesized by a one-pot direct sol-gel method, and then flurbiprofen (FB) was incorporated into AMP clay (FB-AMP) at different drug/clay ratios. The structural characteristics of AMP and FB-AMP formulation were confirmed by X-ray diffraction, Fourier transform infrared spectroscopy, and transmission electron microscopy. Among tested formulations, FB-AMP(3), dramatically increased the dissolution of FB and achieved rapid and complete drug release within 2 hours. More than 60% of FB was released from FB-AMP(3) after 30 minutes; the drug was completely dissolved in the water within 2 hours. Under the acidic condition (pH 1.2), FB-AMP(3) also increased the dissolution of FB by up to 47.1% within 1 hour, which was three-fold higher than that of untreated FB. Furthermore, following an oral administration of FB-AMP(3) to Sprague-Dawley rats, the peak plasma concentration and area under the plasma concentration-time curve of FB increased two-fold, and the time to reach the peak plasma concentration was shortened compared with that in the untreated FB. This result suggests that the oral drug delivery system using clay-based organic-inorganic hybrid material might be useful to improve the bioavailability of FB.

  6. Five-year results from a prospective multicentre study of percutaneous pulmonary valve implantation demonstrate sustained removal of significant pulmonary regurgitation, improved right ventricular outflow tract obstruction and improved quality of life

    DEFF Research Database (Denmark)

    Hager, Alfred; Schubert, Stephan; Ewert, Peter

    2017-01-01

    . The EQ-5D quality of life utility index and visual analogue scale scores were both significantly improved six months post PPVI and remained so at five years. CONCLUSIONS: Five-year results following PPVI demonstrate resolved moderate or severe pulmonary regurgitation, improved right ventricular outflow...

  7. Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system

    Directory of Open Access Journals (Sweden)

    Chen ZQ

    2012-02-01

    Full Text Available Zhi-Qiang Chen, Ying Liu, Ji-Hui Zhao, Lan Wang, Nian-Ping FengSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People's Republic of ChinaBackground: Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS was developed to improve the oral bioavailability of indirubin.Methods: A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats.Results: The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor® EL:Transcutol® P (15:40:45, w/w/w. Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS.Conclusion: The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.Keywords: supersaturatable self-microemulsifying drug delivery system, indirubin, bioavailability, oral drug delivery, hydrophilic polymer

  8. E-learning to improve the drug prescribing in the hospitalized elderly patients: the ELICADHE feasibility pilot study.

    Science.gov (United States)

    Franchi, C; Mari, D; Tettamanti, M; Pasina, L; Djade, C D; Mannucci, P M; Onder, G; Bernabei, R; Gussoni, G; Bonassi, S; Nobili, A

    2014-08-01

    E-learning is an efficient and cost-effective educational method. This study aimed at evaluating the feasibility of an educational e-learning intervention, focused on teaching geriatric pharmacology and notions of comprehensive geriatric assessment, to improve drug prescribing to hospitalized elderly patients. Eight geriatric and internal medicine wards were randomized to intervention (e-learning educational program) or control. Clinicians of the two groups had to complete a specific per group e-learning program in 30 days. Then, ten patients (aged ≥75 years) had to be consecutively enrolled collecting clinical data at hospital admission, discharge, and 3 months later. The quality of prescription was evaluated comparing the prevalence of potentially inappropriate medications through Beer's criteria and of potential drug-drug interactions through a specific computerized database. The study feasibility was confirmed by the high percentage (90 %) of clinicians who completed the e-learning program, the recruitment, and follow-up of all planned patients. The intervention was well accepted by all participating clinicians who judged positively (a mean score of >3 points on a scale of 5 points: 0 = useless; 5 = most useful) the specific contents, the methodology applied, the clinical relevance and utility of e-learning contents and tools for the evaluation of the appropriateness of drug prescribing. The pilot study met all the requested goals. The main study is currently ongoing and is planned to finish on July 2015.

  9. Improving titer while maintaining quality of final formulated drug substance via optimization of CHO cell culture conditions in low-iron chemically defined media.

    Science.gov (United States)

    Xu, Jianlin; Rehmann, Matthew S; Xu, Xuankuo; Huang, Chao; Tian, Jun; Qian, Nan-Xin; Li, Zheng Jian

    2018-04-01

    During biopharmaceutical process development, it is important to improve titer to reduce drug manufacturing costs and to deliver comparable quality attributes of therapeutic proteins, which helps to ensure patient safety and efficacy. We previously reported that relative high-iron concentrations in media increased titer, but caused unacceptable coloration of a fusion protein during early-phase process development. Ultimately, the fusion protein with acceptable color was manufactured using low-iron media, but the titer decreased significantly in the low-iron process. Here, long-term passaging in low-iron media is shown to significantly improve titer while maintaining acceptable coloration during late-phase process development. However, the long-term passaging also caused a change in the protein charge variant profile by significantly increasing basic variants. Thus, we systematically studied the effect of media components, seed culture conditions, and downstream processing on productivity and quality attributes. We found that removing β-glycerol phosphate (BGP) from basal media reduced basic variants without affecting titer. Our goals for late-phase process development, improving titer and matching quality attributes to the early-phase process, were thus achieved by prolonging seed culture age and removing BGP. This process was also successfully scaled up in 500-L bioreactors. In addition, we demonstrated that higher concentrations of reactive oxygen species were present in the high-iron Chinese hamster ovary cell cultures compared to that in the low-iron cultures, suggesting a possible mechanism for the drug substance coloration caused by high-iron media. Finally, hypotheses for the mechanisms of titer improvement by both high-iron and long-term culture are discussed.

  10. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs.

    Science.gov (United States)

    Cummings, Steven R; Karpf, David B; Harris, Fran; Genant, Harry K; Ensrud, Kristine; LaCroix, Andrea Z; Black, Dennis M

    2002-03-01

    To estimate how much the improvement in bone mass accounts for the reduction in risk of vertebral fracture that has been observed in randomized trials of antiresorptive treatments for osteoporosis. After a systematic search, we conducted a meta-analysis of 12 trials to describe the relation between improvement in spine bone mineral density and reduction in risk of vertebral fracture in postmenopausal women. We also used logistic models to estimate the proportion of the reduction in risk of vertebral fracture observed with alendronate in the Fracture Intervention Trial that was due to improvement in bone mineral density. Across the 12 trials, a 1% improvement in spine bone mineral density was associated with a 0.03 decrease (95% confidence interval [CI]: 0.02 to 0.05) in the relative risk (RR) of vertebral fracture. The reductions in risk were greater than predicted from improvement in bone mineral density; for example, the model estimated that treatments predicted to reduce fracture risk by 20% (RR = 0.80), based on improvement in bone mineral density, actually reduce the risk of fracture by about 45% (RR = 0.55). In the Fracture Intervention Trial, improvement in spine bone mineral density explained 16% (95% CI: 11% to 27%) of the reduction in the risk of vertebral fracture with alendronate. Improvement in spine bone mineral density during treatment with antiresorptive drugs accounts for a predictable but small part of the observed reduction in the risk of vertebral fracture.

  11. The role of media and communication in improving the use of drugs and other technologies.

    Science.gov (United States)

    Sitthi-amorn, C; Ngamvithayapongse, J

    1998-01-01

    Policy makers, health care providers, and the general public need valid information about the benefits and harmful effects of drugs and technologies to be able to make rational choices in their acquisition, distribution, and use. Effective communication is important for quality choices of drugs and other technologies. In effective communication, the choice of messages and media must correspond to the culture and beliefs of the target groups to make them comprehend and adopt the conclusions. Messages must be presented on a regular basis. Most regulatory agencies do not have enough resources to mount effective communication programs. Private advertising agencies and other stakeholders have definite roles. Valid knowledge must be the basis of dialogues to reduce emotional disputes among various benefit groups in society.

  12. Natural products to improve quality of life targeting for colon drug delivery.

    Science.gov (United States)

    Kim, Hyunjo

    2012-03-01

    The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon such as inflammatory bowel disease, colorectal cancer and ameobiasis, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. Inflammatory Bowel Disease (IBD) such as Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by pro-inflammatory cytokines and chemokine. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease. Many important bioactive compounds have been discovered from natural sources using bioactivity directed fractionation and isolation (BDFl) Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. The present review includes various approaches investigated for colon drug delivery and their site specificity. To achieve successful colonic delivery, a drug needs to be protected from absorption and the environment of the upper gastrointestinal tract and then be abruptly released into the proximal colon, which is considered the optimum site for colon targeted delivery of drugs.

  13. Alendronate-Loaded Modified Drug Delivery Lipid Particles Intended for Improved Oral and Topical Administration

    Directory of Open Access Journals (Sweden)

    Lacramioara Ochiuz

    2016-06-01

    Full Text Available The present paper focuses on solid lipid particles (SLPs, described in the literature as the most effective lipid drug delivery systems that have been introduced in the last decades, as they actually combine the advantages of polymeric particles, hydrophilic/lipophilic emulsions and liposomes. In the current study, we present our most recent advances in the preparation of alendronate (AL-loaded SLPs prepared by hot homogenization and ultrasonication using various ratios of a self-emulsifying lipidic mixture of Compritol 888, Gelucire 44/14, and Cremophor A 25. The prepared AL-loaded SLPs were investigated for their physicochemical, morphological and structural characteristics by dynamic light scattering, differential scanning calorimetry, thermogravimetric and powder X-ray diffraction analysis, infrared spectroscopy, optical and scanning electron microscopy. Entrapment efficacy and actual drug content were assessed by a validated HPLC method. In vitro dissolution tests performed in simulated gastro-intestinal fluids and phosphate buffer solution pH 7.4 revealed a prolonged release of AL of 70 h. Additionally, release kinetics analysis showed that both in simulated gastrointestinal fluids and in phosphate buffer solution, AL is released from SLPs based on equal ratios of lipid excipients following zero-order kinetics, which characterizes prolonged-release drug systems.

  14. Solid formulation of a supersaturable self-microemulsifying drug delivery system for valsartan with improved dissolution and bioavailability.

    Science.gov (United States)

    Yeom, Dong Woo; Chae, Bo Ram; Kim, Jin Han; Chae, Jun Soo; Shin, Dong Jun; Kim, Chang Hyun; Kim, Sung Rae; Choi, Ji Ho; Song, Seh Hyon; Oh, Dongho; Sohn, Se Il; Choi, Young Wook

    2017-11-07

    In order to improve the dissolution and oral bioavailability of valsartan (VST), and reduce the required volume for treatment, we previously formulated a supersaturable self-microemulsifying drug delivery system (SuSMEDDS) composed of VST (80 mg), Capmul ® MCM (13.2 mg), Tween ® 80 (59.2 mg), Transcutol ® P (59.2 mg), and Poloxamer 407 (13.2 mg). In the present study, by using Florite ® PS-10 (119.1 mg) and Vivapur ® 105 (105.6 mg) as solid carriers, VST-loaded solidified SuSMEDDS (S-SuSMEDDS) granules were successfully developed, which possessed good flow properties and rapid drug dissolution. By introducing croscarmellose sodium (31 mg) as a superdisintegrant, S-SuSMEDDS tablets were also successfully formulated, which showed fast disintegration and high dissolution efficiency. Preparation of granules and tablets was successfully optimized using D-optimal mixture design and 3-level factorial design, respectively, resulting in percentage prediction errors of <10%. In pharmacokinetic studies in rats, the relative bioavailability of the optimized granules was 107% and 222% of values obtained for SuSMEDDS and Diovan ® powder, respectively. Therefore, we conclude that novel S-SuSMEDDS formulations offer great potential for developing solid dosage forms of a liquefied formulation such as SuSMEDDS, while improving oral absorption of drugs with poor water solubility.

  15. Designing structural features of novel benznidazole-loaded cationic nanoparticles for inducing slow drug release and improvement of biological efficacy.

    Science.gov (United States)

    Dos Santos-Silva, Alaine M; de Caland, Lilia B; de S L Oliveira, Ana Luíza C; de Araújo-Júnior, Raimundo F; Fernandes-Pedrosa, Matheus F; Cornélio, Alianda Maira; da Silva-Júnior, Arnóbio A

    2017-09-01

    Several polymers have been investigated for producing cationic nanocarriers due to their ability to cross biological barriers. Polycations such as copolymers of polymethylmethacrylate are highlighted due to their biocompatibility and low toxicity. The purpose of this study was to produce small and narrow-sized cationic nanoparticles able to overcome cell membranes and improve the biological activity of benznidazole (BNZ) in normal and cancer cells. The effect of composition and procedure parameters of the used emulsification-solvent evaporation method were controlled for this purpose. The experimental approach included particle size, polydispersity index, zeta potential, atomic force microscopy (AFM), attenuated total reflectance Fourier transforms infrared spectroscopy (ATR- FTIR), drug loading efficiency, and physical stability assays. Spherical and stable (over six weeks) sub 150nm cationic nanoparticles were optimized, with the encapsulation efficiency >80%. The used drug/copolymer ratio modulated the slow drug release, which was adjusted by the parabolic diffusion mathematical model. In addition, the ability of the cationic nanoparticles improve the BNZ uptake in the normal kidney cells (HEK 293) and the human colorectal cancer cells (HT 29) demonstrate that this novel BNZ-loaded cationic has great potential as a chemotherapeutic application of benznidazole. Copyright © 2017. Published by Elsevier B.V.

  16. Students who developed logical reasoning skills reported improved confidence in drug dose calculation: Feedback from remedial maths classes.

    Science.gov (United States)

    Shelton, Chris

    2016-06-01

    The safe administration of drugs is a focus of attention in healthcare. It is regarded as acceptable that a formula card or mnemonic can be used to find the correct dose and fill a prescription even though this removes any requirement for performing the underlying computation. Feedback and discussion in class reveal that confidence in arithmetic skills can be low even when students are able to pass the end of semester drug calculation exam. To see if confidence in the understanding and performance of arithmetic for drug calculations can be increased by emphasising student's innate powers of logical reasoning after reflection. Remedial classes offered for students who have declared a dislike or lack of confidence in arithmetic have been developed from student feedback adopting a reasoning by logical step methodology. Students who gave up two hours of their free learning time were observed to engage seriously with the learning methods, focussing on the innate ability to perform logical reasoning necessary for drug calculation problems. Working in small groups allowed some discussion of the route to the answer and this was followed by class discussion and reflection. The results were recorded as weekly self-assessment scores for confidence in calculation. A self-selecting group who successfully completed the end of semester drug calculation exam reported low to moderate confidence in arithmetic. After four weeks focussing on logical skills a significant increase in self-belief was measured. This continued to rise in students who remained in the classes. Many students hold a negative belief regarding their own mathematical abilities. This restricts the learning of arithmetic skills making alternate routes using mnemonics and memorised steps an attractive alternative. Practising stepwise logical reasoning skills consolidated by personal reflection has been effective in developing student's confidence and awareness of their innate powers of deduction supporting an

  17. Co-delivery of resveratrol and docetaxel via polymeric micelles to improve the treatment of drug-resistant tumors

    DEFF Research Database (Denmark)

    Guo, Xiong; Zhao, Zhiyue; Chen, Dawei

    2018-01-01

    Co-delivery of anti-cancer drugs is promising to improve the efficacy of cancer treatment. This study was aiming to investigate the potential of concurrent delivery of resveratrol (RES) and docetaxel (DTX) via polymeric nanocarriers to treat breast cancer. To this end, methoxyl poly(ethylene glycol...... profiles, and enhanced cytotoxicity in vitro against MCF-7 cells. The AUC(0→t) of DTX and RES in mPEG-PDLA micelles after i.v. administration to rats were 3.0-fold and 1.6-fold higher than that of i.v. injections of the individual drugs. These findings indicated that the co-delivery of RES and DTX using m...

  18. E-learning in order to improve drug prescription for hospitalized older patients: a cluster-randomized controlled study.

    Science.gov (United States)

    Franchi, Carlotta; Tettamanti, Mauro; Djade, Codjo Dgnefa; Pasina, Luca; Mannucci, Pier Mannuccio; Onder, Graziano; Gussoni, Gualberto; Manfellotto, Dario; Bonassi, Stefano; Salerno, Francesco; Nobili, Alessandro

    2016-07-01

    The aim of the study was to evaluate the effect of an e-learning educational program meant to foster the quality of drug prescription in hospitalized elderly patients. Twenty geriatric and internal medicine wards were randomized to intervention (e-learning educational program) or control (basic geriatric pharmacology notions). Logistic regression analysis was used in order to assess the effect of the intervention on the use of potentially inappropriate medication (PIM, primary outcome) at hospital discharge. Secondary outcomes were a reduced prevalence of at least one potential drug-drug interaction (DDI) and potentially severe DDI at discharge. Mortality rate and incidence of re-hospitalizations were other secondary outcomes assessed at the 12-month follow-up. A total of 697 patients (347 in the intervention and 350 in the control arms) were enrolled. No difference in the prevalence of PIM at discharge was found between arms (OR 1.29 95%CI 0.87-1.91). We also found no decrease in the prevalence of DDI (OR 0.67 95%CI 0.34-1.28) and potentially severe DDI (OR 0.86 95%CI 0.63-1.15) at discharge, nor in mortality rates and incidence of re-hospitalization at 12-month follow-up. This e-learning educational program had no clear effect on the quality of drug prescription and clinical outcomes in hospitalized elderly patients. Given the high prevalence of PIMs and potential DDIs recorded in the frame of this study, other approaches should be developed in order to improve the quality of drug prescription in this population. © 2016 The British Pharmacological Society.

  19. Improved Oral Bioavailability Using a Solid Self-Microemulsifying Drug Delivery System Containing a Multicomponent Mixture Extracted from Salvia miltiorrhiza

    Directory of Open Access Journals (Sweden)

    Xiaolin Bi

    2016-04-01

    Full Text Available The active ingredients of salvia (dried root of Salvia miltiorrhiza include both lipophilic (e.g., tanshinone IIA, tanshinone I, cryptotanshinone and dihydrotanshinone I and hydrophilic (e.g., danshensu and salvianolic acid B constituents. The low oral bioavailability of these constituents may limit their efficacy. A solid self-microemulsifying drug delivery system (S-SMEDDS was developed to load the various active constituents of salvia into a single drug delivery system and improve their oral bioavailability. A prototype SMEDDS was designed using solubility studies and phase diagram construction, and characterized by self-emulsification performance, stability, morphology, droplet size, polydispersity index and zeta potential. Furthermore, the S-SMEDDS was prepared by dispersing liquid SMEDDS containing liposoluble extract into a solution containing aqueous extract and hydrophilic polymer, and then freeze-drying. In vitro release of tanshinone IIA, salvianolic acid B, cryptotanshinone and danshensu from the S-SMEDDS was examined, showing approximately 60%–80% of each active component was released from the S-SMEDDS in vitro within 20 min. In vivo bioavailability of these four constituents indicated that the S-SMEDDS showed superior in vivo oral absorption to a drug suspension after oral administration in rats. It can be concluded that the novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of both lipophilic and hydrophilic constituents of salvia. Thus, the S-SMEDDS can be regarded as a promising new method by which to deliver salvia extract, and potentially other multicomponent drugs, by the oral route.

  20. The biological significance of brain barrier mechanisms: help or hindrance in drug delivery to the central nervous system? [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Norman R. Saunders

    2016-03-01

    transporters, that provide an important component of the barrier functions by either preventing entry of or expelling numerous molecules including toxins, drugs, and other xenobiotics. In this review, we summarize these influx and efflux mechanisms in normal developing and adult brain, as well as indicating their likely involvement in a wide range of neuropathologies. There have been extensive attempts to overcome the barrier mechanisms that prevent the entry of many drugs of therapeutic potential into the brain. We outline those that have been tried and discuss why they may so far have been largely unsuccessful. Currently, a promising approach appears to be focal, reversible disruption of the blood-brain barrier using focused ultrasound, but more work is required to evaluate the method before it can be tried in patients. Overall, our view is that much more fundamental knowledge of barrier mechanisms and development of new experimental methods will be required before drug targeting to the brain is likely to be a successful endeavor. In addition, such studies, if applied to brain pathologies such as stroke, trauma, or multiple sclerosis, will aid in defining the contribution of brain barrier pathology to these conditions, either causative or secondary.

  1. Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

    Science.gov (United States)

    Zuberi, Aamir; Lutz, Cathleen

    2016-01-01

    Abstract The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling

  2. Co-overexpressing a Plasma Membrane and a Vacuolar Membrane Sodium/Proton Antiporter Significantly Improves Salt Tolerance in Transgenic Arabidopsis Plants

    Science.gov (United States)

    Pehlivan, Necla; Sun, Li; Jarrett, Philip; Yang, Xiaojie; Mishra, Neelam; Chen, Lin; Kadioglu, Asim; Shen, Guoxin; Zhang, Hong

    2016-01-01

    The Arabidopsis gene AtNHX1 encodes a vacuolar membrane-bound sodium/proton (Na+/H+) antiporter that transports Na+ into the vacuole and exports H+ into the cytoplasm. The Arabidopsis gene SOS1 encodes a plasma membrane-bound Na+/H+ antiporter that exports Na+ to the extracellular space and imports H+ into the plant cell. Plants rely on these enzymes either to keep Na+ out of the cell or to sequester Na+ into vacuoles to avoid the toxic level of Na+ in the cytoplasm. Overexpression of AtNHX1 or SOS1 could improve salt tolerance in transgenic plants, but the improved salt tolerance is limited. NaCl at concentration >200 mM would kill AtNHX1-overexpressing or SOS1-overexpressing plants. Here it is shown that co-overexpressing AtNHX1 and SOS1 could further improve salt tolerance in transgenic Arabidopsis plants, making transgenic Arabidopsis able to tolerate up to 250 mM NaCl treatment. Furthermore, co-overexpression of AtNHX1 and SOS1 could significantly reduce yield loss caused by the combined stresses of heat and salt, confirming the hypothesis that stacked overexpression of two genes could substantially improve tolerance against multiple stresses. This research serves as a proof of concept for improving salt tolerance in other plants including crops. PMID:26985021

  3. Co-overexpressing a Plasma Membrane and a Vacuolar Membrane Sodium/Proton Antiporter Significantly Improves Salt Tolerance in Transgenic Arabidopsis Plants.

    Science.gov (United States)

    Pehlivan, Necla; Sun, Li; Jarrett, Philip; Yang, Xiaojie; Mishra, Neelam; Chen, Lin; Kadioglu, Asim; Shen, Guoxin; Zhang, Hong

    2016-05-01

    The Arabidopsis gene AtNHX1 encodes a vacuolar membrane-bound sodium/proton (Na(+)/H(+)) antiporter that transports Na(+) into the vacuole and exports H(+) into the cytoplasm. The Arabidopsis gene SOS1 encodes a plasma membrane-bound Na(+)/H(+) antiporter that exports Na(+) to the extracellular space and imports H(+) into the plant cell. Plants rely on these enzymes either to keep Na(+) out of the cell or to sequester Na(+) into vacuoles to avoid the toxic level of Na(+) in the cytoplasm. Overexpression of AtNHX1 or SOS1 could improve salt tolerance in transgenic plants, but the improved salt tolerance is limited. NaCl at concentration >200 mM would kill AtNHX1-overexpressing or SOS1-overexpressing plants. Here it is shown that co-overexpressing AtNHX1 and SOS1 could further improve salt tolerance in transgenic Arabidopsis plants, making transgenic Arabidopsis able to tolerate up to 250 mM NaCl treatment. Furthermore, co-overexpression of AtNHX1 and SOS1 could significantly reduce yield loss caused by the combined stresses of heat and salt, confirming the hypothesis that stacked overexpression of two genes could substantially improve tolerance against multiple stresses. This research serves as a proof of concept for improving salt tolerance in other plants including crops. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.

  4. Quality improvement in breast cancer project: compliance with antiresorptive agents and changing patterns of drug use.

    Science.gov (United States)

    Borden, Charles P; Shapiro, Charles L; Ramirez, Maria Teresa; Kotur, Linda; Farrar, William

    2014-02-01

    The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute participated in NCCN's Quality Improvement in Breast Cancer initiative. The Opportunities for Improvement (OFI) team elected to improve concordance with the NCCN Clinical Practice Guidelines in Oncology for Breast Cancer recommendation that all patients diagnosed with skeletal metastases receive bisphosphonates. Assembling a multidisciplinary team of clinicians, researchers, and administrative stakeholders, the OFI team followed Six Sigma's approach to problem-solving known as DMAIC (define, measure, analyze, improve, and control). Baseline concordance was 79%, which was below the recommended target range. Initial analysis quickly revealed that 5 cases were concordant, resulting in a new baseline of 89%. The key root cause identified for the remaining gap was lack of documentation. The solution included education regarding documentation for existing staff, in addition to hard-wiring the material into new physician orientation, discussion of all patients with bone disease at tumor board meetings, and improved consistency with use of the new electronic medical record system. After implementation, the reported concordance was 92%, and the lack of documentation problem decreased from 11% in the baseline study to 6%. The team concluded that use of the NCCN Oncology Outcomes Database as an opportunity for clinical quality improvement initiatives not only is possible but also should be an essential element of any clinical program looking to continuously improve.

  5. Small endogenous molecules as moiety to improve targeting of CNS drugs.

    Science.gov (United States)

    Sutera, Flavia Maria; De Caro, Viviana; Giannola, Libero Italo

    2017-01-01

    A major challenge in the development of novel neuro-therapeutic agents is to effectively overcome the blood-brain barrier (BBB), which acts as a 'working dynamic barrier'. The core problem in the treatment of neurodegenerative diseases is failed delivery of potential medicines due to their inadequate permeation rate. Areas covered: The present review gives a summary of endogenous moieties used in synthesizing prodrugs, derivatives and bioisosteric drugs appositely designed to structurally resemble physiological molecular entities able to be passively absorbed or carried by specific carrier proteins expressed at BBB level. In particular, this overview focuses on aminoacidic, glycosyl, purinergic, ureic and acidic fragments derivatives, most of which can take advantage from BBB carrier-mediated transporters, where passive diffusion is not permitted. Expert opinion: In the authors' perspective, further progress in this field could expedite successful translation of new chemical entities into clinical trials. Careful rationalization of the linkage between endogenous molecular structures and putative transporters binding sites could allow to useful work-flows and libraries for synthesizing new BBB-crossing therapeutic substances and/or multifunctional drugs for treatments of central disorders.

  6. Hydroxypropyl-sulfobutyl-β-cyclodextrin improves the oral bioavailability of edaravone by modulating drug efflux pump of enterocytes.

    Science.gov (United States)

    Rong, Wen-Ting; Lu, Ya-Peng; Tao, Qing; Guo, Miao; Lu, Yu; Ren, Yong; Yu, Shu-Qin

    2014-02-01

    The objective of the study was to evaluate the effect of hydroxypropyl-sulfobutyl-β-cyclodextrin (HP-SBE-βCD) on the bioavailability and intestinal absorption of edaravone, and identify its mechanism of action. We devised HP-SBE-βCD as a carrier and modulator of P-glycoprotein (Pgp) efflux pump, and edaravone as a model drug, and prepared edaravone/HP-SBE-βCD inclusion complex. HP-SBE-βCD improved the water solubility and enhanced the bioavailability of edaravone by 10.3-fold in rats. Then, in situ single-pass intestinal perfusion showed that HP-SBE-βCD had an effect of improving the permeability and inhibiting the efflux of edaravone. Furthermore, the effects of HP-SBE-βCD on Pgp were achieved through interfering with the lipid raft and depleting the cholesterol of enterocytes membrane. From the results, we presented the novel mechanisms. First, edaravone/HP-SBE-βCD had a lower release from the inclusion compound to protect edaravone from the low pH of the stomach. Then, HP-SBE-βCD modulated the membrane microenvironment of intestinal absorption epithelial cells. At last, the result was that HP-SBE-βCD enhanced the absorption of edaravone by interfering with Pgp. In conclusion, HP-SBE-βCD improves the bioavailability of drug not only because of its enhancing water solubility of the drug, but also because it modulates the Pgp-mediated efflux from enterocytes. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

  7. Significant spread of extensively drug-resistant Acinetobacter baumannii genotypes of clonal complex 92 among intensive care unit patients in a university hospital in southern Iran.

    Science.gov (United States)

    Saffari, Fereshteh; Monsen, Tor; Karmostaji, Afsaneh; Azimabad, Fahimeh Bahadori; Widerström, Micael

    2017-11-01

    Infections associated with Acinetobacter baumannii represent an increasing threat in healthcare settings. Therefore, we investigated the epidemiological relationship between clinical isolates of A. baumannii obtained from patients in a university hospital in Bandar Abbas in southern Iran. Sixty-four consecutive non-duplicate clinical isolates collected during 2014-2015 were subjected to susceptibility testing, clonal relationship analysis using PFGE, multilocus variable-number tandem-repeat analysis (MLVA) and multilocus sequence typing (MLST), and examined for the presence of carbapenemases and integrons. Almost all A. baumannii isolates were extensively drug-resistant (XDR; 98 %) and carried an OXA carbapenemase gene (blaOXA-23-like; 98 %) and class 1 integrons (48 %). PFGE and MLST analysis identified three major genotypes, all belonging to clonal complex 92 (CC92): sequence type 848 (ST848) (n=23), ST451 (n=16) and ST195 (n=8). CC92 has previously been documented in the hospital setting in northern Iran, and ST195 has been reported in Arab States of the Persian Gulf. These data suggest national and global transmission of A. baumannii CC92. This report demonstrates the occurrence and potential spread of closely related XDR genotypes of A. baumannii CC92 within a university hospital in southern Iran. These genotypes were found in the majority of the investigated isolates, showed high prevalence of blaOXA-23 and integron class 1, and were associated with stay in the intensive care unit. Very few treatment options remain for healthcare-adapted XDR A. baumannii, and hence effective measures are desperately needed to reduce the spread of these strains and resultant infections in the healthcare setting.

  8. Molecular modeling and simulation studies of recombinant laccase from Yersinia enterocolitica suggests significant role in the biotransformation of non-steroidal anti-inflammatory drugs

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Deepti; Rawat, Surender [Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak 124001, Haryana (India); Waseem, Mohd; Gupta, Sunita; Lynn, Andrew [School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067 (India); Nitin, Mukesh; Ramchiary, Nirala [School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067 (India); Sharma, Krishna Kant, E-mail: kekulsharma@gmail.com [Laboratory of Enzymology and Recombinant DNA Technology, Department of Microbiology, Maharshi Dayanand University, Rohtak 124001, Haryana (India)

    2016-01-08

    The YacK gene from Yersinia enterocolitica strain 7, cloned in pET28a vector and expressed in Escherichia coli BL21 (DE3), showed laccase activity when oxidized with 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and guaiacol. The recombinant laccase protein was purified and characterized biochemically with a molecular mass of ≈58 KDa on SDS-PAGE and showed positive zymogram with ABTS. The protein was highly robust with optimum pH 9.0 and stable at 70 °C upto 12 h with residual activity of 70%. Kinetic constants, K{sub m} values, for ABTS and guaiacol were 675 μM and 2070 μM, respectively, with corresponding Vmax values of 0.125 μmol/ml/min and 6500 μmol/ml/min. It also possess antioxidative property against BSA and Cu{sup 2+}/H{sub 2}O{sub 2} model system. Constant pH MD simulation studies at different protonation states of the system showed ABTS to be most stable at acidic pH, whereas, diclofenac at neutral pH. Interestingly, aspirin drifted out of the binding pocket at acidic and neutral pH, but showed stable binding at alkaline pH. The biotransformation of diclofenac and aspirin by laccase also corroborated the in silico results. This is the first report on biotransformation of non-steroidal anti-inflammatory drugs (NSAIDs) using recombinant laccase from gut bacteria, supported by in silico simulation studies. - Highlights: • Laccase from Yersinia enterocolitica strain 7 was expressed in Escherichia coli BL21 (DE3). • Recombinant laccase was found to be thermostable and alkali tolerant. • The in silico and experimental studied proves the biotransformation of NSAIDs. • Laccase binds to ligands differentially under different protonation state. • Laccase also possesses free radical scavenging property.

  9. Molecular modeling and simulation studies of recombinant laccase from Yersinia enterocolitica suggests significant role in the biotransformation of non-steroidal anti-inflammatory drugs

    International Nuclear Information System (INIS)

    Singh, Deepti; Rawat, Surender; Waseem, Mohd; Gupta, Sunita; Lynn, Andrew; Nitin, Mukesh; Ramchiary, Nirala; Sharma, Krishna Kant

    2016-01-01

    The YacK gene from Yersinia enterocolitica strain 7, cloned in pET28a vector and expressed in Escherichia coli BL21 (DE3), showed laccase activity when oxidized with 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and guaiacol. The recombinant laccase protein was purified and characterized biochemically with a molecular mass of ≈58 KDa on SDS-PAGE and showed positive zymogram with ABTS. The protein was highly robust with optimum pH 9.0 and stable at 70 °C upto 12 h with residual activity of 70%. Kinetic constants, K m values, for ABTS and guaiacol were 675 μM and 2070 μM, respectively, with corresponding Vmax values of 0.125 μmol/ml/min and 6500 μmol/ml/min. It also possess antioxidative property against BSA and Cu 2+ /H 2 O 2 model system. Constant pH MD simulation studies at different protonation states of the system showed ABTS to be most stable at acidic pH, whereas, diclofenac at neutral pH. Interestingly, aspirin drifted out of the binding pocket at acidic and neutral pH, but showed stable binding at alkaline pH. The biotransformation of diclofenac and aspirin by laccase also corroborated the in silico results. This is the first report on biotransformation of non-steroidal anti-inflammatory drugs (NSAIDs) using recombinant laccase from gut bacteria, supported by in silico simulation studies. - Highlights: • Laccase from Yersinia enterocolitica strain 7 was expressed in Escherichia coli BL21 (DE3). • Recombinant laccase was found to be thermostable and alkali tolerant. • The in silico and experimental studied proves the biotransformation of NSAIDs. • Laccase binds to ligands differentially under different protonation state. • Laccase also possesses free radical scavenging property.

  10. Vitamin D and Calcium Addition during Denosumab Therapy over a Period of Four Years Significantly Improves Lumbar Bone Mineral Density in Japanese Osteoporosis Patients

    Directory of Open Access Journals (Sweden)

    Takako Suzuki

    2018-02-01

    Full Text Available This study investigated whether or not vitamin D and calcium supplementation affected bone metabolism and bone mineral density (BMD over a period of four years of denosumab therapy in patients with primary osteoporosis. Patients were divided into a denosumab monotherapy group (22 cases or a denosumab plus vitamin D and calcium supplementation group (combination group, 21 cases. We measured serum bone alkaline phosphatase (BAP, tartrate-resistant acid phosphatase (TRACP-5b, urinary N-terminal telopeptide of type-I collagen (NTX, and BMD of the lumbar 1–4 vertebrae (L-BMD and bilateral hips (H-BMD at baseline and at 12, 24, 36, and 48 months of treatment. There were no significant differences in patient background. Serum BAP, TRACP-5b, and urinary NTX were significantly and comparably inhibited in both groups from 12 to 48 months versus baseline values. L-BMD was significantly increased at every time point in both groups, while H-BMD was significantly increased at every time point in the combination group only. There were significant differences between the groups for L-BMD at 24, 36, and 48 months (P < 0.05 and for H-BMD at 12 months (P < 0.05. Compared with denosumab monotherapy, combination therapy of denosumab plus vitamin D and calcium significantly increased H-BMD at 12 months and L-BMD from 24 to 48 months. These findings indicate that continuous vitamin D and calcium supplementation is important, especially for 12 months to improve H-BMD and from 24 to 48 months to improve L-BMD.

  11. Significant improvement of olfactory performance in sleep apnea patients after three months of nasal CPAP therapy - Observational study and randomized trial.

    Directory of Open Access Journals (Sweden)

    Bettina Boerner

    Full Text Available The olfactory function highly impacts quality of life (QoL. Continuous positive airway pressure is an effective treatment for obstructive sleep apnea (OSA and is often applied by nasal masks (nCPAP. The influence of nCPAP on the olfactory performance of OSA patients is unknown. The aim of this study was to assess the sense of smell before initiation of nCPAP and after three months treatment, in moderate and severe OSA patients.The sense of smell was assessed in 35 patients suffering from daytime sleepiness and moderate to severe OSA (apnea/hypopnea index ≥ 15/h, with the aid of a validated test battery (Sniffin' Sticks before initiation of nCPAP therapy and after three months of treatment. Additionally, adherent subjects were included in a double-blind randomized three weeks CPAP-withdrawal trial (sub-therapeutic CPAP pressure.Twenty five of the 35 patients used the nCPAP therapy for more than four hours per night, and for more than 70% of nights (adherent group. The olfactory performance of these patients improved significantly (p = 0.007 after three months of nCPAP therapy. When considering the entire group of patients, olfaction also improved significantly (p = 0.001. In the randomized phase the sense of smell of six patients deteriorated under sub-therapeutic CPAP pressure (p = 0.046 whereas five patients in the maintenance CPAP group showed no significant difference (p = 0.501.Olfactory performance improved significantly after three months of nCPAP therapy in patients suffering from moderate and severe OSA. It seems that this effect of nCPAP is reversible under sub-therapeutic CPAP pressure.ISRCTN11128866.

  12. Mouse Models for Drug Discovery. Can New Tools and Technology Improve Translational Power?

    Science.gov (United States)

    Zuberi, Aamir; Lutz, Cathleen

    2016-12-01

    The use of mouse models in biomedical research and preclinical drug evaluation is on the rise. The advent of new molecular genome-altering technologies such as CRISPR/Cas9 allows for genetic mutations to be introduced into the germ line of a mouse faster and less expensively than previous methods. In addition, the rapid progress in the development and use of somatic transgenesis using viral vectors, as well as manipulations of gene expression with siRNAs and antisense oligonucleotides, allow for even greater exploration into genomics and systems biology. These technological advances come at a time when cost reductions in genome sequencing have led to the identification of pathogenic mutations in patient populations, providing unprecedented opportunities in the use of mice to model human disease. The ease of genetic engineering in mice also offers a potential paradigm shift in resource sharing and the speed by which models are made available in the public domain. Predictively, the knowledge alone that a model can be quickly remade will provide relief to resources encumbered by licensing and Material Transfer Agreements. For decades, mouse strains have provided an exquisite experimental tool to study the pathophysiology of the disease and assess therapeutic options in a genetically defined system. However, a major limitation of the mouse has been the limited genetic diversity associated with common laboratory mice. This has been overcome with the recent development of the Collaborative Cross and Diversity Outbred mice. These strains provide new tools capable of replicating genetic diversity to that approaching the diversity found in human populations. The Collaborative Cross and Diversity Outbred strains thus provide a means to observe and characterize toxicity or efficacy of new therapeutic drugs for a given population. The combination of traditional and contemporary mouse genome editing tools, along with the addition of genetic diversity in new modeling systems

  13. Effects of a community scorecard on improving the local health system in Eastern Democratic Republic of Congo: qualitative evidence using the most significant change technique.

    Science.gov (United States)

    Ho, Lara S; Labrecque, Guillaume; Batonon, Isatou; Salsi, Viviana; Ratnayake, Ruwan

    2015-01-01

    More than a decade of conflict has weakened the health system in the Democratic Republic of Congo and decreased its ability to respond to the needs of the population. Community scorecards have been conceived as a way to increase accountability and responsiveness of service providers, but there is limited evidence of their effects, particularly in fragile and conflict-affected contexts. This paper describes the implementation of community scorecards within a community-driven reconstruction project in two provinces of eastern Democratic Republic of Congo. Between June 2012 and November 2013, 45 stories of change in the health system were collected from village development committee, health committee, community members (20 men and 18 women) and healthcare providers (n = 7) in 25 sites using the Most Significant Change technique. Stories were analyzed qualitatively for content related to the types and mechanisms of change observed. The most salient changes were related to increased transparency and community participation in health facility management, and improved quality of care. Quality of care included increased access to services, improved patient-provider relationships, improved performance of service providers, and improved maintenance of physical infrastructure. Changes occurred through many different mechanisms including provider actions in response to information, pressure from community representatives, or supervisors; and joint action and improved collaboration by health facility committees and providers. Although it is often assumed that confrontation is a primary mechanism for citizens to change state-provided services, this study demonstrates that healthcare providers may also be motivated to change through other means. Positive experiences of community scorecards can provide a structured space for interface between community members and the health system, allowing users to voice their opinions and preferences and bridge information gaps for both

  14. A significant reduction in the frequency of HIV-1 drug resistance in Québec from 2001 to 2011 is associated with a decrease in the monitored viral load.

    Directory of Open Access Journals (Sweden)

    Hugues Charest

    Full Text Available BACKGROUND: HIV drug resistance represents a major threat for effective treatment. We assessed the trends in the frequency of drug resistance mutations and the monitored viral load (VL in treatment-naïve (TN and treatment-experienced (TE individuals infected with HIV-1 in Québec, Canada, between 2001 and 2011. METHODS AND FINDINGS: Resistance data were obtained from 4,105 and 5,086 genotypic tests performed on TN and TE patients, respectively. Concomitantly, 274,161 VL tests were carried out in the Province. Changes over time in drug resistance frequency and in different categories of VL were assessed using univariate logistic regression. Multiple logistic regression was used to evaluate associations between the rates of certain mutations and antiretroviral prescriptions. From 2001 to 2011, the proportion of undetectable VL test results continually increased, from 42.1% to 75.9%, while a significant decrease in the frequency of resistance mutations associated with protease inhibitors [PI (from 54% to 16%], nucleoside [NRTI (from 78% to 37% and non-nucleoside reverse transcriptase inhibitors [NNRTI (from 44% to 31%] was observed in TE patients. In TN individuals, the overall frequency of transmitted drug resistance was 13.1%. A multiple logistic regression analysis indicated that the introduction of co-formulated emtricitabine/tenofovir or emtricitabine/tenofovir/efavirenz was positively associated with the decrease of the frequency of the M184I/V mutations observed overtime (p = 0.0004. CONCLUSIONS: We observed a significant decrease in the frequency of drug resistance mutations in TE patients, concomitant with a decrease in the proportion of patients with detectable viremia. These findings may be related to both the increased potencies and adherence to therapy associated with newer antiretroviral regimens. Nevertheless, our data demonstrate that broad use of antiretrovirals does not increase the level of circulating drug resistant

  15. Novel designed polyoxyethylene nonionic surfactant with improved safety and efficiency for anticancer drug delivery

    Directory of Open Access Journals (Sweden)

    Li C

    2014-04-01

    Full Text Available Chang Li,1 Chunmeng Sun,1 Shasha Li,1 Peng Han,2 Huimin Sun,3 Ammar Ouahab,1 Yan Shen,1 Yourui Xu,1 Yerong Xiong,1 Jiasheng Tu11State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, 2Chinese Pharmacopoeia Commission, Beijing, 3National Institute for Food and Drug Control, Beijing, People's Republic of ChinaAbstract: In order to limit the adverse reactions caused by polysorbate 80 in Taxotere®, a widely used formulation of docetaxel, a safe and effective nanocarrier for this drug has been developed based on micelles formed by a new class of well-defined polyoxyethylene sorbitol oleate (PSO with sorbitol as the matrix in aqueous solution. The physicochemical properties of the amphiphilic surfactant and the resulting micelles can be easily fine-tuned by the homogeneous sorbitol matrix and pure oleic acid. Composition, critical micelle concentration, and entrapment efficiency were investigated by ultraviolet visible spectroscopy, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, fluorospectrophotometry, and high-performance liquid chromatography. In vitro and in vivo evaluation revealed that PSO had exceptionally low hemolysis and histamine release rates compared with commercial polysorbate 80. Moreover, the tumor targeting delivery of PSO was investigated by in vivo imaging in S180 tumor-bearing mice. The results suggest that this novel delivery system, PSO, provides an acceptable alternative to polysorbate 80 for delivery of docetaxel. Further, due to the hypoallergenic nature of PSO, the mechanism of pseudoallergy caused by the polyoxyethylene nonionic surfactant was investigated. Based on in vitro cell analysis, it was assumed that the initial contact of polyoxyethylene nonionic surfactant with mast cells provoked pseudoallergy via polyamine receptor-mediated endocytosis.Keywords: polyoxyethylene nonionic surfactant, sorbitol, isosorbide, pseudoallergy

  16. Improved design and characterization of PLGA/PLA-coated Chitosan based micro-implants for controlled release of hydrophilic drugs.

    Science.gov (United States)

    Manna, Soumyarwit; Donnell, Anna M; Kaval, Necati; Al-Rjoub, Marwan F; Augsburger, James J; Banerjee, Rupak K

    2018-05-29

    Repetitive intravitreal injections of Methotrexate (MTX), a hydrophilic chemotherapeutic drug, are currently used to treat selected vitreoretinal (VR) diseases, such as intraocular lymphoma. To avoid complications associated with the rapid release of MTX from the injections, a Polylactic acid (PLA) and Chitosan (CS)-based MTX micro-implant prototype was fabricated in an earlier study, which showed a sustained therapeutic release rate of 0.2-2.0 µg/day of MTX for a period ∼1 month in vitro and in vivo. In the current study, different combinations of Poly(lactic-co-glycolic) acid (PLGA)/PLA coatings were used for lipophilic surface modification of the CS-MTX micro-implant, such as PLGA 5050, PLGA 6535 and PLGA 7525 (PLA: PGA - 50:50, 65:35, 75:25, respectively; M.W: 54,400 - 103,000) and different PLA, such as PLA 100 and PLA 250 (MW: 102,000 and 257,000, respectively). This improved the duration of total MTX release from the coated CS-MTX micro-implants to ∼3-5 months. With an increase in PLA content in PLGA and molecular weight of PLA, a) the initial burst of MTX and the mean release rate of MTX can be reduced; and b) the swelling and biodegradation of the micro-implants can be delayed. The controlled drug release mechanism is caused by a combination of diffusion process and hydrolysis of the polymer coating, which can be modulated by a) PLA content in PLGA and b) molecular weight of PLA, as inferred from Korsmeyer Peppas model, Zero order, First order and Higuchi model fits. This improved micro-implant formulation has the potential to serve as a platform for controlled release of hydrophilic drugs to treat selected VR diseases. Copyright © 2018. Published by Elsevier B.V.

  17. Improving the Use of Lipid-lowering Drugs at Brits Hospital | Van ...

    African Journals Online (AJOL)

    Background: When it was found by the Brits Hospital Pharmacy and Therapeutics Committee (PTC) in 2000 that simvastatin was responsible for extremely high costs in a district hospital, it was decided to undertake a quality improvement study to assess and, if appropriate, rectify the situation. Methods: A Quality ...

  18. An integrated approach to improved toxicity prediction for the safety assessment during preclinical drug development using Hep G2 cells

    International Nuclear Information System (INIS)

    Noor, Fozia; Niklas, Jens; Mueller-Vieira, Ursula; Heinzle, Elmar

    2009-01-01

    Efficient and accurate safety assessment of compounds is extremely important in the preclinical development of drugs especially when hepatotoxicty is in question. Multiparameter and time resolved assays are expected to greatly improve the prediction of toxicity by assessing complex mechanisms of toxicity. An integrated approach is presented in which Hep G2 cells and primary rat hepatocytes are compared in frequently used cytotoxicity assays for parent compound toxicity. The interassay variability was determined. The cytotoxicity assays were also compared with a reliable alternative time resolved respirometric assay. The set of training compounds consisted of well known hepatotoxins; amiodarone, carbamazepine, clozapine, diclofenac, tacrine, troglitazone and verapamil. The sensitivity of both cell systems in each tested assay was determined. Results show that careful selection of assay parameters and inclusion of a kinetic time resolved assay improves prediction for non-metabolism mediated toxicity using Hep G2 cells as indicated by a sensitivity ratio of 1. The drugs with EC 50 values 100 μM or lower were considered toxic. The difference in the sensitivity of the two cell systems to carbamazepine which causes toxicity via reactive metabolites emphasizes the importance of human cell based in-vitro assays. Using the described system, primary rat hepatocytes do not offer advantage over the Hep G2 cells in parent compound toxicity evaluation. Moreover, respiration method is non invasive, highly sensitive and allows following the time course of toxicity. Respiration assay could serve as early indicator of changes that subsequently lead to toxicity.

  19. Hot Melt Extruded Amorphous Solid Dispersion of Posaconazole with Improved Bioavailability: Investigating Drug-Polymer Miscibility with Advanced Characterisation

    Directory of Open Access Journals (Sweden)

    Ritesh Fule

    2014-01-01

    Full Text Available Invasive antifungal infections are reasons for morbidity and mortality in immunogenic patients worldwide. Posaconazole is a most promising antifungal agent against all types of invasive infections with high % of cure rate. The marketed suspension formulation has low bioavailability and is needed to be taken with food. In this paper, PCZ hot melt extruded amorphous solid dispersion (SD with immediate release and improved bioavailability was prepared using Soluplus (Sol as primary carrier for solubilization. Surfactants such as PEG 400, Lutrol F27, Lutrol F68, and TPGS are also used in combination with Soluplus to improve the physicochemical performance of the formulation when it comes in contact with GI (gastrointestinal fluid. Drug-polymer miscibility of SD was investigated using advanced techniques. In the in vivo study, the AUC(0–72 and Cmax of PCZ/Soluplus were 11.5 and 11.74 time higher than those of pure PCZ. The formulation of the extrudate SD had an AUC(0–72 and Cmax higher than those with the commercial capsule (Noxafil. Molecular dynamic (MD simulation studies were carried out using in silico molecular modelling to understand the drug-polymer intermolecular behaviour. The results of this research ensure enhanced dissolution and bioavailability of the solid dispersion of PCZ prepared by HME compared with the PCZ suspension.

  20. Nonsteroidal anti-inflammatory drug or glucosamine reduced pain and improved muscle strength with resistance training in a randomized controlled trial of knee osteoarthritis patients

    DEFF Research Database (Denmark)

    Petersen, Susanne G; Beyer, Nina; Hansen, Mette

    2011-01-01

    Petersen SG, Beyer N, Hansen M, Holm L, Aagaard P, Mackey AL, Kjaer M. Nonsteroidal anti-inflammatory drug or glucosamine reduced pain and improved muscle strength with resistance training in a randomized controlled trial of knee osteoarthritis patients.......Petersen SG, Beyer N, Hansen M, Holm L, Aagaard P, Mackey AL, Kjaer M. Nonsteroidal anti-inflammatory drug or glucosamine reduced pain and improved muscle strength with resistance training in a randomized controlled trial of knee osteoarthritis patients....

  1. Gemtuzumab Ozogamicin (GO Inclusion to Induction Chemotherapy Eliminates Leukemic Initiating Cells and Significantly Improves Survival in Mouse Models of Acute Myeloid Leukemia

    Directory of Open Access Journals (Sweden)

    Cathy C Zhang

    2018-01-01

    Full Text Available Gemtuzumab ozogamicin (GO is an anti-CD33 antibody-drug conjugate for the treatment of acute myeloid leukemia (AML. Although GO shows a narrow therapeutic window in early clinical studies, recent reports detailing a modified dosing regimen of GO can be safely combined with induction chemotherapy, and the combination provides significant survival benefits in AML patients. Here we tested whether the survival benefits seen with the combination arise from the enhanced reduction of chemoresidual disease and leukemic initiating cells (LICs. Herein, we use cell line and patient-derived xenograft (PDX AML models to evaluate the combination of GO with daunorubicin and cytarabine (DA induction chemotherapy on AML blast growth and animal survival. DA chemotherapy and GO as separate treatments reduced AML burden but left significant chemoresidual disease in multiple AML models. The combination of GO and DA chemotherapy eliminated nearly all AML burden and extended overall survival. In two small subsets of AML models, chemoresidual disease following DA chemotherapy displayed hallmark markers of leukemic LICs (CLL1 and CD34. In vivo, the two chemoresistant subpopulations (CLL1+/CD117− and CD34+/CD38+ showed higher ability to self-renewal than their counterpart subpopulations, respectively. CD33 was coexpressed in these functional LIC subpopulations. We demonstrate that the GO and DA induction chemotherapy combination more effectively eliminates LICs in AML PDX models than either single agent alone. These data suggest that the survival benefit seen by the combination of GO and induction chemotherapy, nonclinically and clinically, may be attributed to the enhanced reduction of LICs.

  2. National Institute on Drug Abuse International Program: improving opioid use disorder treatment through international research training.

    Science.gov (United States)

    Gust, Steven W; McCormally, Judy

    2018-07-01

    For more than 25 years, the National Institute on Drug Abuse (NIDA) has supported research-training programs, establishing a global research network and expanding the knowledge base on substance use disorders. International research to inform approaches to opioid addiction is particularly important and relevant to the United States, where opioid misuse, addiction, and overdose constitute an emerging public health crisis. This article summarizes the NIDA International Program and illustrates its impact by reviewing recent articles about treatment approaches for opioid use disorders (OUD). Studies in several countries have demonstrated the effectiveness of physician office-based opioid substitution therapies. Other research has demonstrated the effectiveness of different formulations and doses of the opioid antagonist naltrexone, as well as different approaches to providing naloxone to treat opioid overdose. Continuing research into implementation of evidence-based treatment in international settings with limited resources is applicable to US regions that face similar structural, legal, and fiscal constraints. The current review describes international research on OUD treatment and opioid overdose, most coauthored by former NIDA fellows. The findings from outside the United States have important implications for best practices domestically and in other countries that are experiencing increases in OUD prevalence and related overdose deaths.

  3. Improved conversion rates in drug screening applications using miniaturized electrochemical cells with frit channels.

    Science.gov (United States)

    Odijk, Mathieu; Olthuis, Wouter; van den Berg, A; Qiao, Liang; Girault, Hubert

    2012-11-06

    This paper reports a novel design of a miniaturized three-electrode electrochemical cell, the purpose of which is aimed at generating drug metabolites with a high conversion efficiency. The working electrode and the counter electrode are placed in two separate channels to isolate the reaction products generated at both electrodes. The novel design includes connecting channels between these two electrode channels to provide a uniform distribution of the current density over the entire working electrode. In addition, the effect of ohmic drop is decreased. Moreover, two flow resistors are included to ensure an equal flow of analyte through both electrode channels. Total conversion of fast reacting ions is achieved at flow rates up to at least 8 μL/min, while the internal chip volume is only 175 nL. Using this electrochemical chip, the metabolism of mitoxantrone is studied by microchip electrospray ionization-mass spectrometry. At an oxidation potential of 700 mV, all known metabolites from direct oxidation are observed. The electrochemical chip performs equally well, compared to a commercially available cell, but at a 30-fold lower flow of reagents.

  4. Improvement of interaction between PVA and chitosan via magnetite nanoparticles for drug delivery application.

    Science.gov (United States)

    Shagholani, Hamidreza; Ghoreishi, Sayed Mehdi; Mousazadeh, Mohammad

    2015-01-01

    Magnetite nanoparticles were synthesized by coprecipitation under ultrasonication followed by coating with chitosan. Polyvinyl alcohol (PVA) is then combined with the chitosan that coated the magnetite nanoparticles. The combination occurs by hydrogen binding and ionic cross-linking of the amino and hydroxyl groups of chitosan and PVA respectively. The magnetite nanoparticles have an average size of 10.62 nm that was confirmed by TEM. The VSM measurements showed that nanoparticles were superparamagnetic. The coatings on the core nanoparticles were estimated by AAS and the attachments of coating to the nanoparticles were confirmed by FT-IR analysis. Physicochemical properties of nanoparticles were measured by DLS and zeta potential. Naked magnetite, chitosan and PVA coating have zeta potential of +36.4, +48.1 and -12.5 mV respectively. The unspecific adsorption and interaction between nanoparticles and bovine serum albumin (BSA) were investigated systematically by UV-vis spectroscopy method. The nanoparticles that were modified by PVA present low protein adsorption, which makes them a practical choice for preventing opsonization in clinical application and drug delivery. Copyright © 2015. Published by Elsevier B.V.

  5. Improved Lysosomal Trafficking Can Modulate the Potency of Antibody Drug Conjugates.

    Science.gov (United States)

    DeVay, Rachel M; Delaria, Kathy; Zhu, Guoyun; Holz, Charles; Foletti, Davide; Sutton, Janette; Bolton, Gary; Dushin, Russell; Bee, Christine; Pons, Jaume; Rajpal, Arvind; Liang, Hong; Shelton, David; Liu, Shu-Hui; Strop, Pavel

    2017-04-19

    Antibody drug conjugates (ADCs) provide an efficacious and relatively safe means by which chemotherapeutic agents can be specifically targeted to cancer cells. In addition to the selection of antibody targets, ADCs offer a modular design that allows selection of ADC characteristics through the choice of linker chemistries, toxins, and conjugation sites. Many studies have indicated that release of toxins bound to antibodies via noncleavable linker chemistries relies on the internalization and intracellular trafficking of the ADC. While this can make noncleavable ADCs more stable in the serum, it can also result in lower efficacy when their respective targets are not internalized efficiently or are recycled back to the cell surface following internalization. Here, we show that a lysosomally targeted ADC against the protein APLP2 mediates cell killing, both in vitro and in vivo, more effectively than an ADC against Trop2, a protein with less efficient lysosomal targeting. We also engineered a bispecific ADC with one arm targeting HER2 for the purpose of directing the ADC to tumors, and the other arm targeting APLP2, whose purpose is to direct the ADC to lysosomes for toxin release. This proof-of-concept bispecific ADC demonstrates that this technology can be used to shift the intracellular trafficking of a constitutively recycled target by directing one arm of the antibody against a lysosomally delivered protein. Our data also show limitations of this approach and potential future directions for development.

  6. A Newly Improved Modified Method Development and Validation of Bromofenac Sodium Sesquihydrate in Bulk Drug Manufacturing

    OpenAIRE

    Sunil Kumar Yelamanchi V; Useni Reddy Mallu; I. V Kasi Viswanath; D. Balasubramanyam; G. Narshima Murthy

    2016-01-01

    The main objective of this study was to develop a simple, efficient, specific, precise and accurate newly improved modified Reverse Phase High Performance Liquid Chromatographic Purity (or) Related substance method for bromofenac sodium sesquihydrate active pharmaceuticals ingredient dosage form. Validation of analytical method is the confirmation by examination and the provision of objective evidence that the particular requirements for a specific intended use are fulfilled as per ICH, USP...

  7. A facile template method to synthesize significantly improved LiNi0.5Mn1.5O4 using corn stalk as a bio-template

    International Nuclear Information System (INIS)

    Liu, Guiyang; Kong, Xin; Sun, Hongyan; Wang, Baosen; Yi, Zhongzhou; Wang, Quanbiao

    2014-01-01

    In order to simplify the template method for the synthesis of cathode materials for lithium ion batteries, a facile template method using plant stalks as bio-templates has been introduced. Based on this method, LiNi 0.5 Mn 1.5 O 4 spinel with a significantly improved electrochemical performance has been synthesized using corn stalk as a template. X-ray diffraction (XRD), Fourier transform infrared pectroscopy (FTIR) and scanning electron microscope (SEM) have been used to investigate the phase composition and micro-morphologies of the products. Charge-discharge measurements in lithium cells, cyclic voltammetry (CV) and Electrochemical impedance spectroscopy (EIS) have been used to study the electrochemical performance of the products. The results indicate that the templated product exhibits higher crystallinity than that of non-templated product. Both of the templated product and the non-templated product are combination of the ordered space group P4 3 32 and the disordered Fd-3 m. The specific BET surface area of the templated product is about twice larger than that of the non-templated product. Moreover, the electrochemical performances of the templated product including specific capacity, cycling stability and rate capability are significantly improved as compared with the non-templated product, due to its higher crystallinity, larger Li + diffusion coefficient and lower charge transfer resistance

  8. Arthroscopic Debridement for Primary Degenerative Osteoarthritis of the Elbow Leads to Significant Improvement in Range of Motion and Clinical Outcomes: A Systematic Review.

    Science.gov (United States)

    Sochacki, Kyle R; Jack, Robert A; Hirase, Takashi; McCulloch, Patrick C; Lintner, David M; Liberman, Shari R; Harris, Joshua D

    2017-12-01

    The purpose of this investigation was to determine whether arthroscopic debridement of primary elbow osteoarthritis results in statistically significant and clinically relevant improvement in (1) elbow range of motion and (2) clinical outcomes with (3) low complication and reoperation rates. A systematic review was registered with PROSPERO and performed using PRISMA guidelines. Databases were searched for studies that investigated the outcomes of arthroscopic debridement for the treatment of primary osteoarthritis of the elbow in adult human patients. Study methodological quality was analyzed. Studies that included post-traumatic arthritis were excluded. Elbow motion and all elbow-specific patient-reported outcome scores were eligible for analysis. Comparisons between preoperative and postoperative values from each study were made using 2-sample Z-tests (http://in-silico.net/tools/statistics/ztest) using a P value osteoarthritis results in statistically significant and clinically relevant improvement in elbow range of motion and clinical outcomes with low complication and reoperation rates. Systematic review of level IV studies. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

  9. Transplantation of N-Acetyl Aspartyl-Glutamate Synthetase-Activated Neural Stem Cells after Experimental Traumatic Brain Injury Significantly Improves Neurological Recovery

    Directory of Open Access Journals (Sweden)

    Mingfeng Li

    2013-12-01

    Full Text Available Background/Aims: Neural stem cells (NSCs hold considerable potential as a therapeutic tool for repair of the damaged nervous system. In the current study, we examined whether transplanted N-acetyl aspartyl-glutamate synthetase (NAAGS-activated NSCs (NAAGS/NSCs further improve neurological recovery following traumatic brain injury (TBI in Sprague-Dawley rats. Methods: Animals received TBI and stereotactic injection of NSCs, NAAGS/NSCs or phosphate buffered saline without cells (control into the injured cortex. NAAGS protein expression was detected through western blot analysis. Dialysate NAAG levels were analyzed with radioimmunoassay. Cell apoptosis was detected via TUNEL staining. The expression levels of specific pro-inflammatory cytokines were detected with enzyme-linked immunosorbent assay. Results: Groups with transplanted NSCs and NAAGS/NSCs displayed significant recovery of the motor behavior, compared to the control group. At 14 and 21 days post-transplantation, the motor behavior in NAAGS/NSC group was significantly improved than that in NSC group (pConclusion: Our results collectively demonstrate that NAAGS/NSCs provide a more powerful autoplastic therapy for the injured nervous system.

  10. Triazole derivatives with improved in vitro antifungal activity over azole drugs

    Directory of Open Access Journals (Sweden)

    Yu S

    2014-04-01

    Full Text Available Shichong Yu,1,* Xiaoyun Chai,1,* Yanwei Wang,1 Yongbing Cao,2 Jun Zhang,3 Qiuye Wu,1 Dazhi Zhang,1 Yuanying Jiang,2 Tianhua Yan,4 Qingyan Sun11Department of Organic Chemistry, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 2Drug Research Center, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China; 3Overseas Education Faculty of the Second Military Medical University, Shanghai, People's Republic of China; 4Department of Pharmacology, School of Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China*These authors contributed equally to this workAbstract: A series of triazole antifungal agents with piperidine side chains was designed and synthesized. The results of antifungal tests against eight human pathogenic fungi in vitro showed that all the compounds exhibited moderate-to-excellent activities. Molecular docking between 8d and the active site of Candida albicans CYP51 was provided based on the computational docking results. The triazole interacts with the iron of the heme group. The difluorophenyl group is located in the S3 subsite and its fluorine atom (2-F can form H-bonds with Gly307. The side chain is oriented into the S4 subsite and formed hydrophobic and van der Waals interactions with the amino residues. Moreover, the phenyl group in the side chain interacts with the phenol group of Phe380 through the formation of π–π face-to-edge interactions.Keywords: synthesis, CYP51, molecular docking, azole agents

  11. Multi-dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists.

    Science.gov (United States)

    van Rein, Nienke; de Geus, Kristel S; Cannegieter, Suzanne C; Reitsma, Pieter H; van der Meer, Felix J M; Lijfering, Willem M

    2018-01-01

    Multi-dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self-reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non-adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use. We conducted a before-after study in non-adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non-adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison). Eighty-three non-adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD-patients increased 10% (95%CI 2% to 19%) higher as compared with non-MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI -2% to 9%). Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months. Copyright © 2017 John Wiley & Sons, Ltd.

  12. Improved oral bioavailability of poorly water-soluble indirubin by a supersaturatable self-microemulsifying drug delivery system.

    Science.gov (United States)

    Chen, Zhi-Qiang; Liu, Ying; Zhao, Ji-Hui; Wang, Lan; Feng, Nian-Ping

    2012-01-01

    Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin. A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats. The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor(®) EL:Transcutol(®) P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS. The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.

  13. A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol.

    Science.gov (United States)

    Kim, Kyeong Soo; Yang, Eun Su; Kim, Dong Shik; Kim, Dong Wuk; Yoo, Hye Hyun; Yong, Chul Soon; Youn, Yu Seok; Oh, Kyung Taek; Jee, Jun-Pil; Kim, Jong Oh; Jin, Sung Giu; Choi, Han Gon

    2017-11-01

    To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 °C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, C max , and T max values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S-SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG.

  14. How Good Is Good: Improved Tracking and Managing of Safety Goals, Performance Indicators, Production Targets and Significant Events Using Learning Curves

    International Nuclear Information System (INIS)

    Duffey, Rommey B.; Saull, John W.

    2002-01-01

    We show a new way to track and measure safety and performance using learning curves derived on a mathematical basis. When unusual or abnormal events occur in plants and equipment, the regulator and good management practice requires they be reported, investigated, understood and rectified. In addition to reporting so-called 'significant events', both management and the regulator often set targets for individual and collective performance, which are used for both reward and criticism. For almost completely safe systems, like nuclear power plants, commercial aircraft and chemical facilities, many parameters are tracked and measured. Continuous improvement has to be demonstrated, as well as meeting reduced occurrence rates, which are set as management goals or targets. This process usually takes the form of statistics for availability of plant and equipment, forced or unplanned maintenance outage, loss of safety function, safety or procedural violations, etc. These are often rolled up into a set of so-called 'Performance Indicators' as measures of how well safety and operation is being managed at a given facility. The overall operating standards of an industry are also measured. A whole discipline is formed of tracking, measuring, reporting, managing and understanding the plethora of indicators and data. Decreasing occurrence rates and meeting or exceeding goals are seen and rewarded as virtues. Managers and operators need to know how good is their safety management system that has been adopted and used (and paid for), and whether it can itself be improved. We show the importance of accumulated experience in correctly measuring and tracking the decreasing event and error rates speculating a finite minimum rate. We show that the rate of improvement constitutes a measurable 'learning curve', and the attainment of the goals and targets can be affected by the adopted measures. We examine some of the available data on significant events, reportable occurrences, and loss of

  15. Mobile physician reporting of clinically significant events-a novel way to improve handoff communication and supervision of resident on call activities.

    Science.gov (United States)

    Nabors, Christopher; Peterson, Stephen J; Aronow, Wilbert S; Sule, Sachin; Mumtaz, Arif; Shah, Tushar; Eskridge, Etta; Wold, Eric; Stallings, Gary W; Burak, Kathleen Kelly; Goldberg, Randy; Guo, Gary; Sekhri, Arunabh; Mathew, George; Khera, Sahil; Montoya, Jessica; Sharma, Mala; Paudel, Rajiv; Frishman, William H

    2014-12-01

    Reporting of clinically significant events represents an important mechanism by which patient safety problems may be identified and corrected. However, time pressure and cumbersome report entry procedures have discouraged the full participation of physicians. To improve the process, our internal medicine training program developed an easy-to-use mobile platform that combines the reporting process with patient sign-out. Between August 25, 2011, and January 25, 2012, our trainees entered clinically significant events into i-touch/i-phone/i-pad based devices functioning in wireless-synchrony with our desktop application. Events were collected into daily reports that were sent from the handoff system to program leaders and attending physicians to plan for rounds and to correct safety problems. Using the mobile module, residents entered 31 reportable events per month versus the 12 events per month that were reported via desktop during a previous 6-month study period. Advances in information technology now permit clinically significant events that take place during "off hours" to be identified and reported (via handoff) to next providers and to supervisors via collated reports. This information permits hospital leaders to correct safety issues quickly and effectively, while attending physicians are able to use information gleaned from the reports to optimize rounding plans and to provide additional oversight of trainee on call patient management decisions.

  16. Spirulina Supplements Improved the Nutritional Status of Undernourished Children Quickly and Significantly: Experience from Kisantu, the Democratic Republic of the Congo

    Directory of Open Access Journals (Sweden)

    Féfé Khuabi Matondo

    2016-01-01

    Full Text Available Aim. Despite high levels of malnutrition, there is still very little information on the nutritional benefits of Spirulina, a natural alga that provides essential amino acids, rare essential lipids, and numerous minerals and vitamins, to undernourished children in the world. Methods. We carried out a prospective study of 50 children aged between six and 60 months. The intervention group consisted of 16 children who received 10 g of Spirulina daily, as well as the local diet administered by the nutritional centre, and the control group of 34 children who just received the local diet. Both groups of children were assessed on day zero, day 15, and day 30. Results. After treatment, the weight-for-age Z scores and weight-for-height Z scores increased significantly in the intervention group. At day 15, there was a statistically significant difference between the mean corpuscular volume, total proteins, and albumin (p<0.05 in both groups, in favour of the intervention group, and at day 30, this difference extended to all of the studied parameters (p<0.05. Conclusion. This study found that the nutritional status of undernourished children who received Spirulina supplements as well as the local diet administered by the nutritional centre improved quickly and significantly.

  17. Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid.

    Directory of Open Access Journals (Sweden)

    Chandraiah Godugu

    Full Text Available The poor bioavailability of Berberine (BBR and Betulinic acid (BA limits the development of these promising anticancer agents for clinical use. In the current study, BBR and BA in spray dried (SD mucoadhesive microparticle formulations were prepared.A patented dual channel spray gun technology established in our laboratory was used for both formulations. Gastrointestinal (GI permeability studies were carried out using Caco-2 cell monolayer grown in in-vitro system. The oral bioavailability and pharmacokinetic profile of SD formulations were studied in Sprague Dawley rats. A549 orthotopic and H1650 metastatic NSCLC models were utilized for the anticancer evaluations.Pharmacokinetic studies demonstrated that BBR and BA SD formulations resulted in 3.46 and 3.90 fold respectively, significant increase in plasma Cmax concentrations. AUC levels were increased by 6.98 and 7.41 fold in BBR and BA SD formulations, respectively. Compared to untreated controls groups, 49.8 & 53.4% decrease in the tumor volumes was observed in SD formulation groups of BBR and BA, respectively. Molecular studies done on excised tumor (A549 tissue suggested that BBR in SD form resulted in a significant decrease in the survivin, Bcl-2, cyclin D1, MMP-9, HIF-1α, VEGF and CD31 expressions. Cleaved caspase 3, p53 and TUNEL expressions were increased in SD formulations. The RT-PCR analysis on H1650 tumor tissue suggested that p38, Phospho-JNK, Bax, BAD, cleaved caspase 3&8 mRNA expressions were significantly increased in BA SD formulations. Chronic administration of BBR and BA SD formulations did not show any toxicity.Due to significant increase in oral bioavailability and superior anticancer effects, our results suggest that spray drying is a superior alternative formulation approach for oral delivery of BBR and BA.

  18. An improved approach to the analysis of drug-protein binding by distance geometry

    Science.gov (United States)

    Goldblum, A.; Kieber-Emmons, T.; Rein, R.

    1986-01-01

    The calculation of side chain centers of coordinates and the subsequent generation of side chain-side chain and side chain-backbone distance matrices is suggested as an improved method for viewing interactions inside proteins and for the comparison of protein structures. The use of side chain distance matrices is demonstrated with free PTI, and the use of difference distance matrices for side chains is shown for free and trypsin-bound PTI as well as for the X-ray structures of trypsin complexes with PTI and with benzamidine. It is found that conformational variations are reflected in the side chain distance matrices much more than in the standard C-C distance representations.

  19. Scissor-type knife significantly improves self-completion rate of colorectal endoscopic submucosal dissection: Single-center prospective randomized trial.

    Science.gov (United States)

    Yamashina, Takeshi; Takeuchi, Yoji; Nagai, Kengo; Matsuura, Noriko; Ito, Takashi; Fujii, Mototsugu; Hanaoka, Noboru; Higashino, Koji; Uedo, Noriya; Ishihara, Ryu; Iishi, Hiroyasu

    2017-05-01

    Colorectal endoscopic submucosal dissection (C-ESD) is recognized as a difficult procedure. Recently, scissors-type knives were launched to reduce the difficulty of C-ESD. The aim of this study was to evaluate the efficacy and safety of the combined use of a scissors-type knife and a needle-type knife with a water-jet function (WJ needle-knife) for C-ESD compared with using the WJ needle-knife alone. This was a prospective randomized controlled trial in a referral center. Eighty-five patients with superficial colorectal neoplasms were enrolled and randomly assigned to undergo C-ESD using a WJ needle-knife alone (Flush group) or a scissor-type knife-supported WJ needle-knife (SB Jr group). Procedures were conducted by two supervised residents. Primary endpoint was self-completion rate by the residents. Self-completion rate was 67% in the SB Jr group, which was significantly higher than that in the Flush group (39%, P = 0.01). Even after exclusion of four patients in the SB Jr group in whom C-ESD was completed using the WJ needle-knife alone, the self-completion rate was significantly higher (63% vs 39%; P = 0.03). Median procedure time among the self-completion cases did not differ significantly between the two groups (59 vs 51 min; P = 0.14). No fatal adverse events were observed in either group. In this single-center phase II trial, scissor-type knife significantly improved residents' self-completion rate for C-ESD, with no increase in procedure time or adverse events. A multicenter trial would be warranted to confirm the validity of the present study. © 2016 Japan Gastroenterological Endoscopy Society.

  20. Patient Drug Safety Reporting: Diabetes Patients' Perceptions of Drug Safety and How to Improve Reporting of Adverse Events and Product Complaints.

    Science.gov (United States)

    Patel, Puja; Spears, David; Eriksen, Betina Østergaard; Lollike, Karsten; Sacco, Michael

    2018-03-01

    Global health care manufacturer Novo Nordisk commissioned research regarding awareness of drug safety department activities and potential to increase patient feedback. Objectives were to examine patients' knowledge of pharmaceutical manufacturers' responsibilities and efforts regarding drug safety, their perceptions and experiences related to these efforts, and how these factors influence their thoughts and behaviors. Data were collected before and after respondents read a description of a drug safety department and its practices. We conducted quantitative survey research across 608 health care consumers receiving treatment for diabetes in the United States, Germany, United Kingdom, and Italy. This research validated initial, exploratory qualitative research (across 40 comparable consumers from the same countries) which served to guide design of the larger study. Before reading a drug safety department description, 55% of respondents were unaware these departments collect safety information on products and patients. After reading the description, 34% reported the department does more than they expected to ensure drug safety, and 56% reported "more confidence" in the industry as a whole. Further, 66% reported themselves more likely to report an adverse event or product complaint, and 60% reported that they were more likely to contact a drug safety department with questions. The most preferred communication methods were websites/online forums (39%), email (27%), and telephone (25%). Learning about drug safety departments elevates consumers' confidence in manufacturers' safety efforts and establishes potential for patients to engage in increased self-monitoring and reporting. Study results reveal potentially actionable insights for the industry across patient and physician programs and communications.

  1. Call-to-balloon time dashboard in patients with ST-segment elevation myocardial infarction results in significant improvement in the logistic chain.

    Science.gov (United States)

    Hermans, Maaike P J; Velders, Matthijs A; Smeekes, Martin; Drexhage, Olivier S; Hautvast, Raymond W M; Ytsma, Timon; Schalij, Martin J; Umans, Victor A W M

    2017-08-04

    Timely reperfusion with primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI) patients is associated with superior clinical outcomes. Aiming to reduce ischaemic time, an innovative system for home-to-hospital (H2H) time monitoring was implemented, which enabled real-time evaluation of ischaemic time intervals, regular feedback and improvements in the logistic chain. The objective of this study was to assess the results after implementation of the H2H dashboard for monitoring and evaluation of ischaemic time in STEMI patients. Ischaemic time in STEMI patients transported by emergency medical services (EMS) and treated with pPCI in the Noordwest Ziekenhuis, Alkmaar before (2008-2009; n=495) and after the implementation of the H2H dashboard (2011-2014; n=441) was compared. Median time intervals were significantly shorter in the H2H group (door-to-balloon time 32 [IQR 25-43] vs. 40 [IQR 28-55] minutes, p-value dashboard was independently associated with shorter time delays. Real-time monitoring and feedback on time delay with the H2H dashboard improves the logistic chain in STEMI patients, resulting in shorter ischaemic time intervals.

  2. Improving significantly the failure strain and work hardening response of LPSO-strengthened Mg-Y-Zn-Al alloy via hot extrusion speed control

    Science.gov (United States)

    Tan, Xinghe; Chee, Winston; Chan, Jimmy; Kwok, Richard; Gupta, Manoj

    2017-07-01

    The effect of hot extrusion speed on the microstructure and mechanical properties of MgY1.06Zn0.76Al0.42 (at%) alloy strengthened by the novel long-period stacking ordered (LPSO) phase was systematically investigated. Increase in the speed of extrusion accelerated dynamic recrystallization of α-Mg via particle-stimulated nucleation and grain growth in the alloy. The intensive recrystallization and grain growth events weakened the conventional basal texture and Hall-Petch strengthening in the alloy which led to significant improvement in its failure strain from 4.9% to 19.6%. The critical strengthening contribution from LPSO phase known for attributing high strength to the alloy was observed to be greatly undermined by the parallel competition from texture weakening and the adverse Hall-Petch effect when the alloy was extruded at higher speed. Absence of work hardening interestingly observed in the alloy extruded at lower speed was discussed in terms of its ultra-fine grained microstructure which promoted the condition of steady-state defect density in the alloy; where dislocation annihilation balances out the generation of new dislocations during plastic deformation. One approach to improve work hardening response of the alloy to prevent unstable deformation and abrupt failure in service is to increase the grain diameter in the alloy by judiciously increasing the extrusion speed.

  3. Improving DNA double-strand repair inhibitor KU55933 therapeutic index in cancer radiotherapy using nanoparticle drug delivery

    Science.gov (United States)

    Tian, Xi; Lara, Haydee; Wagner, Kyle T.; Saripalli, Srinivas; Hyder, Syed Nabeel; Foote, Michael; Sethi, Manish; Wang, Edina; Caster, Joseph M.; Zhang, Longzhen; Wang, Andrew Z.

    2015-11-01

    Radiotherapy is a key component of cancer treatment. Because of its importance, there has been high interest in developing agents and strategies to further improve the therapeutic index of radiotherapy. DNA double-strand repair inhibitors (DSBRIs) are among the most promising agents to improve radiotherapy. However, their clinical translation has been limited by their potential toxicity to normal tissue. Recent advances in nanomedicine offer an opportunity to overcome this limitation. In this study, we aim to demonstrate the proof of principle by developing and evaluating nanoparticle (NP) formulations of KU55933, a DSBRI. We engineered a NP formulation of KU55933 using nanoprecipitation method with different lipid polymer nanoparticle formulation. NP KU55933 using PLGA formulation has the best loading efficacy as well as prolonged drug release profile. We demonstrated that NP KU55933 is a potent radiosensitizer in vitro using clonogenic assay and is more effective as a radiosensitizer than free KU55933 in vivo using mouse xenograft models of non-small cell lung cancer (NSCLC). Western blots and immunofluorescence showed NP KU55933 exhibited more prolonged inhibition of DNA repair pathway. In addition, NP KU55933 leads to lower skin toxicity than KU55933. Our study supports further investigations using NP to deliver DSBRIs to improve cancer radiotherapy treatment.