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Sample records for rapid drug tolerance

  1. Persistence and drug tolerance in pathogenic yeast

    DEFF Research Database (Denmark)

    Bojsen, Rasmus Kenneth; Regenberg, Birgitte; Folkesson, Sven Anders

    2017-01-01

    In this review, we briefly summarize the current understanding of how fungal pathogens can persist antifungal treatment without heritable resistance mutations by forming tolerant persister cells. Fungal infections tolerant to antifungal treatment have become a major medical problem. One mechanism...... leading to drug recalcitrance is the formation of antifungal persister cells. These cells have wild-type genotype with the ability to survive exposure to antifungal agents due to changed membrane composition, upregulated stress response, and enhanced cell wall integrity. Knowledge of the mechanisms...... are quiescent in G0 of the cell cycle. This knowledge leads us to suggest that the identified shared drug-tolerance mechanisms of persister and quiescent cells may serve as a foundation for developing novel treatment strategies that are independent of growth mode against systemic fungal infections....

  2. Tolerability and safety of antifungal drugs

    Directory of Open Access Journals (Sweden)

    Francesco Scaglione

    2013-08-01

    Full Text Available When treating critically ill patients, as those with fungal infections, attention should be focused on the appropriate use of drugs, especially in terms of dose, safety, and tolerability. The fungal infection itself and the concomitant physiological disorders concur to increase the risk of mortality in these patients, therefore the use of any antifungal agent should be carefully evaluated, considering both the direct action on the target fungus and the adverse effects eventually caused. Among antifungal drugs, echinocandins have the greatest tolerability. In fact, unlike amphotericin B, showing nephrotoxicity, and azoles, which are hepatotoxic, the use of echinocandins doesn’t result in major adverse events.http://dx.doi.org/10.7175/rhc.v4i2s.873

  3. Rapidly separating microneedles for transdermal drug delivery.

    Science.gov (United States)

    Zhu, Dan Dan; Wang, Qi Lei; Liu, Xu Bo; Guo, Xin Dong

    2016-09-01

    The applications of polymer microneedles (MNs) into human skin emerged as an alternative of the conventional hypodermic needles. However, dissolving MNs require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin, which may lead to the low drug delivery efficiency. To address these issues, we introduce rapidly separating MNs that can rapidly deliver drugs into the skin in a minimally invasive way. For the rapidly separating MNs, drug loaded dissolving MNs are mounted on the top of solid MNs, which are made of biodegradable polylactic acid which eliminate the biohazardous waste. These MNs have sufficient mechanical strength to be inserted into the skin with the drug loaded tips fully embedded for subsequent dissolution. Compared with the traditional MNs, rapidly separating MNs achieve over 90% of drug delivery efficiency in 30s while the traditional MNs needs 2min to achieve the same efficiency. With the in vivo test in mice, the micro-holes caused by rapidly separating MNs can heal in 1h, indicating that the rapidly separating MNs are safe for future applications. These results indicate that the design of rapidly separating dissolvable MNs can offer a quick, high efficient, convenient, safe and potentially self-administered method of drug delivery. Polymer microneedles offer an attractive, painless and minimally invasive approach for transdermal drug delivery. However, dissolving microneedles require many minutes to be dissolved in the skin and typically have difficulty being fully inserted into the skin due to the skin deformation, which may lead to the low drug delivery efficiency. In this work we proposed rapidly separating microneedles which can deliver over 90% of drug into the skin in 30s. The in vitro and in vivo results indicate that the new design of these microneedles can offer a quick, high efficient, convenient and safe method for transdermal drug delivery. Copyright © 2016 Acta Materialia Inc

  4. A DNA element regulates drug tolerance and withdrawal in Drosophila.

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    Xiaolei Li

    Full Text Available Drug tolerance and withdrawal are insidious responses to drugs of abuse; the first increases drug consumption while the second punishes abstention. Drosophila generate functional tolerance to benzyl alcohol sedation by increasing neural expression of the slo BK-type Ca(2+ activated K(+ channel gene. After drug clearance this change produces a withdrawal phenotype-increased seizure susceptibility. The drug-induced histone modification profile identified the 6b element (60 nt as a drug responsive element. Genomic deletion of 6b produces the allele, slo (Δ6b, that reacts more strongly to the drug with increased induction, a massive increase in the duration of tolerance, and an increase in the withdrawal phenotype yet does not alter other slo-dependent behaviors. The 6b element is a homeostatic regulator of BK channel gene expression and is the first cis-acting DNA element shown to specifically affect the duration of a drug action.

  5. Comparison of assay formats for drug-tolerant immunogenicity testing.

    Science.gov (United States)

    Butterfield, Anthony M; Chain, Jana S; Ackermann, Bradley L; Konrad, Robert J

    2010-12-01

    Immunogenicity testing is required for safety assessment of biotherapeutic drugs. Because levels observed during biotherapeutic administration can approach the mg/ml range, establishing drug tolerance is significantly important for assay development. Three assay formats for immunogenicity assessment were tested with respect to drug tolerance: Meso Scale Discovery(®) bridging (MSDB), solid-phase extraction with acid dissociation (SPEAD) and affinity capture elution (ACE). Six biotherapeutic drugs were analyzed by the three methods; four monoclonal antibodies, one Fc fusion protein and one Pegylated protein. Overall, ACE performed best for assays involving therapeutic monoclonal antibodies and also functioned well for therapeutic proteins. Despite several advantages, the MSDB assays displayed a potentially significant hook effect. SPEAD was comparable in performance to ACE for the biotherapeutic drugs tested, but suffers the disadvantage of being reagent-intensive. Novel assay formats offer significant advantages for immunogenicity testing, particularly in the design of assays that are tolerant to circulating levels of the biotherapeutic drug.

  6. 77 FR 72254 - New Animal Drugs; Updating Tolerances for Residues of New Animal Drugs in Food

    Science.gov (United States)

    2012-12-05

    ... HUMAN SERVICES Food and Drug Administration 21 CFR Parts 500, 520, 522, 524, 529, 556, and 558 RIN 0910-AG17 New Animal Drugs; Updating Tolerances for Residues of New Animal Drugs in Food AGENCY: Food and Drug Administration, HHS. ACTION: Proposed rule. SUMMARY: The Food and Drug Administration (FDA) is...

  7. Rapid screening for aluminum tolerance in maize (Zea mays L.

    Directory of Open Access Journals (Sweden)

    Carlos Daniel Giaveno

    2000-12-01

    Full Text Available A significant decrease in maize grain yield due to aluminum toxicity is considered to be one of the most important agricultural problems for tropical regions. Genetic improvement is a useful approach to increase maize yield in acid soils, but this requires a rapid and reliable method to discriminate between genotypes. In our work we investigated the feasibility of using hematoxylin staining (HS to detect Al-tolerant plants at the seedling stage. The original population along with two populations obtained after one cycle of divergent selection were evaluated by net root growth (NRG and HS after 7 days in nutrient solution. Results showed a negative correlation between NRG and HS in all populations, in which sensitive plants, characterized by low NRG, exhibited more intense staining than tolerant plants. These results indicate that HS is a useful procedure for selecting Al-tolerant maize seedlings.A importante diminuição nos rendimentos de milho causados pela toxidez produzida pelo alumínio é considerada um dos mais importantes problemas nas regiões tropicais. O melhoramento genético é uma metodologia útil para aumentar os rendimentos do milho em solos ácidos, requerendo um método rápido e seguro que permita diferenciar os diferentes genótipos. O objetivo deste trabalho foi avaliar a possibilidade de utilizar a técnica da coloração com hematoxilina (HS na detecção de plântulas tolerantes ao alumínio. Duas populações obtidas de um ciclo de seleção divergente e a original, foram avaliadas depois de sete dias em solução nutritiva utilizando os parâmetros NRG (crescimento líquido da raiz principal e HS. Os resultados apresentaram uma correlação negativa entre NRG e HS em todas as populações devido ao fato de que as plântulas suscetíveis, caracterizadas por um baixo NRG, apresentaram uma coloração mais intensa do que as tolerantes. Nossos resultados permitem concluir que a técnica de coloração com hematoxilina

  8. 21 CFR 556.1 - General considerations; tolerances for residues of new animal drugs in food.

    Science.gov (United States)

    2010-04-01

    ... new animal drugs in food. 556.1 Section 556.1 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... RESIDUES OF NEW ANIMAL DRUGS IN FOOD General Provisions § 556.1 General considerations; tolerances for residues of new animal drugs in food. (a) Tolerances established in this part are based upon residues of...

  9. Genetic basis for rapidly evolved tolerance in the wild ...

    Science.gov (United States)

    Atlantic killifish (Fundulus heteroclitus) residing in some urban and industrialized estuaries of the US eastern seaboard demonstrate recently evolved and extreme tolerance to toxic aryl hydrocarbon pollutants, characterized as dioxin-like compounds (DLCs). Here we provide an unusually comprehensive accounting (69%) through Quantitative Trait Locus (QTL) analysis of the genetic basis for DLC tolerance in killifish inhabiting an urban estuary contaminated with PCB congeners, the most toxic of which are DLCs. Consistent with mechanistic knowledge of DLC toxicity in fish and other vertebrates, the Aryl Hydrocarbon Receptor (ahr2) region accounts for 17% of trait variation; however, QTLs on independent linkage groups and their interactions have even greater explanatory power (44%). QTLs interpreted within the context of recently available Fundulus genomic resources and shared synteny among fish species suggest adaptation via inter-acting components of a complex stress response network. Some QTLs were also enriched in other killifish populations characterized as DLC tolerant and residing in distant urban estuaries contaminated with unique mixtures of pollutants. Together, our results suggest that DLC tolerance in killifish represents an emerging example of parallel contemporary evolution that has been driven by intense human-mediated selection on natural populations. This manuscript describes experimental studies that contribute to our understanding of the ecological

  10. [Hypersensitivity reactions to non-steroidal anti-inflammatory drugs and tolerance to alternative drugs].

    Science.gov (United States)

    Calvo Campoverde, K; Giner-Muñoz, M T; Martínez Valdez, L; Rojas Volquez, M; Lozano Blasco, J; Machinena, A; Plaza, A M

    2016-03-01

    Hypersensitivity reactions to non-steroidal anti-inflammatory drugs (NSAIDs) are the most common reactions to drugs. The prevalence varies from 0.6 to 5.7% in general population, but there are no data available in children. The aim of this study is to determine the frequency of patients diagnosed with hypersensitivity to NSAIDs, and describe their clinical characteristics, type of hypersensitivity, and tolerance to alternative drugs. Retrospective study was conducted on children with suspected hypersensitivity to NSAIDs from January 2012 to December 2013. The diagnosis was confirmed by oral drug provocation test (DPT) to the drug involved in the group with a history of one episode, while in the group with a history of more than one episode with the same drug the diagnosis was based on clinical data. Subsequently, a DPT with acetylsalicylic acid (ASA) was done in order to classify hypersensitivity into selective or multiple. In those cases with a positive result, a DPT was performed with alternative drugs. Out of a total of 93 children studied, 26 were diagnosed with hypersensitivity to NSAIDs: 7 confirmed by oral DPT, and 19 based on clinical data. Multiple hypersensitivity was diagnosed in 50% of patients. Ibuprofen was involved in all reactions. The most common clinical manifestation was angioedema (44%). Acetaminophen was the best tolerated alternative drug. More than one quarter (28%) of the population studied was diagnosed with hypersensitivity to NSAIDs, and 50% had multiple hypersensitivity. Acetaminophen is a safe alternative in children with hypersensitivity to NSAIDs. Meloxicam may be an alternative in cases that do not tolerate acetaminophen. Copyright © 2015 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.

  11. Rapid tolerance development to the NREM sleep promoting effect of alcohol.

    Science.gov (United States)

    Sharma, Rishi; Sahota, Pradeep; Thakkar, Mahesh M

    2014-04-01

    Alcohol tolerance is a major contributor towards the development of alcohol dependence. Does alcohol intake result in rapid tolerance development to alcohol induced NREM sleep promotion? This has never been examined. Our objective was to examine whether two bouts of alcohol consumption on consecutive days results in rapid tolerance development to alcohol-induced NREM sleep promotion. N/A. N/A. C57BL/6J mice. Mice (N = 5) were implanted with sleep electrodes using standard surgical conditions. Following postoperative recovery and habituation, the experiment was begun. On baseline day, water bottle changes were performed at 10:00 (3 h after dark onset) and 14:00 to mimic conditions during alcohol consumption days. On next 2 days, (Days 1 and 2) mice were allowed to self-administer alcohol (20% v/v) for 4 h beginning at 10:00 and ending at 14:00. Sleep-wakefulness was continuously recorded from 10:00 to 18:00 (8 h; 4 h during alcohol + 4 h post-alcohol) on all 3 days. Although mice consumed comparable amounts of alcohol on Days 1 and 2, NREM sleep and wakefulness were significantly and differentially affected during 4 h post-alcohol period. A robust alcohol-induced NREM sleep promotion was observed on Day 1. However, no such sleep promotion was observed on Day 2, suggesting rapid tolerance development. Our study is the first to demonstrate that alcohol consumption for two consecutive days results in development of rapid tolerance to alcohol-induced sleep promotion.

  12. 77 FR 3653 - Import Tolerances for Residues of Unapproved New Animal Drugs in Food

    Science.gov (United States)

    2012-01-25

    ... of drug residue actually appearing at the time of slaughter of the target animal in the edible... Tolerances for Residues of Unapproved New Animal Drugs in Food AGENCY: Food and Drug Administration, HHS... animal drugs where edible portions of animals imported into the United States may contain residues of...

  13. Genetic studies of acute tolerance, rapid tolerance, and drinking in the dark in the LXS recombinant inbred strains.

    Science.gov (United States)

    Radcliffe, Richard A; Larson, Colin; Bennett, Beth

    2013-12-01

    We hypothesized that rapid tolerance (1-day tolerance) for the duration of the loss of righting reflex ("sleep time" [ST]) was mediated by an increase in acute functional tolerance (AFT). We also hypothesized that increased AFT would correspond to increased drinking. These questions were addressed using the LXS recombinant inbred mouse strain panel. Mice were given a pretreatment dose of either saline or 5 g/kg alcohol on day 1. On day 2, mice were tested for ST (4.1 g/kg) using a method with which it is possible to accurately assess AFT. Genetic correlation analysis was conducted among the ST-related variables and also with "drinking in the dark" (DID) which was previously measured by Saba and colleagues (2011). Saline-pretreated mice showed a continuous distribution of ST ranging from ~40 minutes to over 3 hours. Of the 43 strains tested, 9 showed significantly decreased ST after alcohol pretreatment, while in 3 strains, ST was significantly increased. AFT scores ranged from 0 to over 200 mg% in the saline group, and in the alcohol group, 8 strains showed a significant increase in AFT and 2 strains showed significant decrease in AFT. In the saline group, AFT was significantly correlated with ST (r = -0.47), but not in the alcohol group (r = -0.22). DID was significantly correlated with only AFT in the alcohol pretreated group (r = 0.64). The results suggest that AFT is an important component of the overall ST response, but that the alcohol pretreatment-induced change in AFT does not contribute to rapid ST tolerance. The significant correlation between DID and AFT in the alcohol group suggests that AFT may be a more relevant predictor of drinking behavior than the static measurement of ST. Moreover, preexposure to alcohol seems to change AFT in a way that makes it an even stronger predictor of drinking behavior. Copyright © 2013 by the Research Society on Alcoholism.

  14. Rapid diagnosis of tuberculosis. Detection of drug resistance mechanisms.

    Science.gov (United States)

    Viñuelas-Bayón, Jesús; Vitoria, María Asunción; Samper, Sofía

    2017-10-01

    Tuberculosis is still a serious public health problem, with 10.8 million new cases and 1.8 million deaths worldwide in 2015. The diversity among members of the Mycobacterium tuberculosis complex, the causal agent of tuberculosis, is conducive to the design of different methods for rapid diagnosis. Mutations in the genes involved in resistance mechanisms enable the bacteria to elude the treatment. We have reviewed the methods for the rapid diagnosis of M. tuberculosis complex and the detection of susceptibility to drugs, both of which are necessary to prevent the onset of new resistance and to establish early, appropriate treatment. Copyright © 2017 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  15. Rapid interferometric imaging of printed drug laden multilayer structures

    DEFF Research Database (Denmark)

    Sandler, Niklas; Kassamakov, Ivan; Ehlers, Henrik

    2014-01-01

    /and active pharmaceutical ingredients (API) adhere to each other. This is crucial in order to have predetermined drug release profiles. We also demonstrate non-invasive measurement of a polymer structure in a microfluidic channel. It shown that traceable interferometric 3D microscopy is a viable technique......The developments in printing technologies allow fabrication of micron-size nano-layered delivery systems to personal specifications. In this study we fabricated layered polymer structures for drug-delivery into a microfluidic channel and aimed to interferometrically assure their topography...... and adherence to each other. We present a scanning white light interferometer (SWLI) method for quantitative assurance of the topography of the embedded structure. We determined rapidly in non-destructive manner the thickness and roughness of the structures and whether the printed layers containing polymers or...

  16. Rapidly dissolving polymeric microneedles for minimally invasive intraocular drug delivery.

    Science.gov (United States)

    Thakur, Raghu Raj Singh; Tekko, Ismaiel A; Al-Shammari, Farhan; Ali, Ahlam A; McCarthy, Helen; Donnelly, Ryan F

    2016-12-01

    In this study, dissolving microneedles (MNs) were used to enhance ocular drug delivery of macromolecules. MNs were fabricated using polyvinylpyrrolidone (PVP) polymer of various molecular weights (MWs) containing three model molecules of increasing MW, namely fluorescein sodium and fluorescein isothiocyanate-dextrans (with MW of 70 k and 150 k Da). Arrays (3 × 3) of PVP MNs with conical shape measuring about 800 μm in height with a 300 μm base diameter, containing the model drugs, were fabricated and characterized for their fracture forces, insertion forces (in the sclera and cornea), depth of penetration (using OCT and confocal imaging), dissolution time and in vitro permeation. The average drug content of the MNs (only in MN shafts) ranged from 0.96 to 9.91 μg, and the average moisture content was below 11 %. High MW PVP produced MNs that can withstand higher forces with minimal reduction in needle height. PVP MNs showed rapid dissolution that ranged from 10 to 180 s, which was dependent upon PVP's MW. In vitro studies showed significant enhancement of macromolecule permeation when MNs were used, across both the corneal and scleral tissues, in comparison to topically applied aqueous solutions. Confocal images showed that the macromolecules formed depots within the tissues, which led to sustained permeation. However, use of MNs did not significantly benefit the permeation of small molecules; nevertheless, MN application has the potential for drug retention within the selected ocular tissues unlike topical application for small molecules. The material used in the fabrication of the MNs was found to be biocompatible with retinal cells (i.e. ARPE-19). Overall, this study reported the design and fabrication of minimally invasive rapidly dissolving polymeric MN arrays which were able to deliver high MW molecules to the eye via the intrastromal or intrascleral route. Thus, dissolving MNs have potential applications in enhancing ocular delivery of both small

  17. Rapid evolution of tolerance to toxic Microcystis in two cladoceran grazers.

    Science.gov (United States)

    Jiang, Xiaodong; Gao, Han; Zhang, Lihua; Liang, Huishuang; Zhu, Xiao

    2016-04-28

    Evolutionary adaptation could assist organisms to cope with environmental changes, yet few experimental systems allow us to directly track evolutionary trajectory. Using experimental evolution, evolutionary tolerance to Microcystis aeruginosa was investigated in two cladocerans (Daphnia pulex and Simocephalus vetulus) to test the hypothesis that cladoceran grazers rapidly adapt to toxic cyanobacteria. After exposure for either three or six months, both grazers evolved a higher tolerance. The intrinsic rate of population increases in S. vetulus feeding on cyanobacteria was negatively correlated with that on green algae, which suggests that evolutionary adaptation in tolerance would carry a cost in the absence of cyanobacteria. However, the cyanobacterial selection resulted in a general increase in D. pulex when fed both cyanobacteria and green algae. Following a three-month relaxation of selection, S. vetulus in the selection line exhibited reverse evolution back to their original state when their diets were switched back to pure green algae. The present experimental evolution, both forwards and reverse, not only demonstrates the evolutionary responses of cladoceran grazers to toxic cyanobacterial cells in the laboratory, but also indicates that the grazer-cyanobacteria interaction would be an effective system to empirically study rapid evolution to environmental changes.

  18. Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients

    NARCIS (Netherlands)

    Bloem, Karien; van Leeuwen, Astrid; Verbeek, Gerrit; Nurmohamed, Michael T.; Wolbink, Gerrit Jan; van der Kleij, Desiree; Rispens, Theo

    2015-01-01

    Drug interference complicates assessment of immunogenicity of biologicals and results in an underestimation of anti-drug antibody (ADA) formation. Drug-tolerant assays have the potential to overcome such limitations. However, to which extent drug-tolerant assays provide an unbiased picture of the

  19. Rapid crown root development confers tolerance to zinc deficiency in rice

    Directory of Open Access Journals (Sweden)

    Amrit Kaur eNanda

    2016-03-01

    Full Text Available Zinc (Zn deficiency is one of the leading nutrient disorders in rice (Oryza sativa. Many studies have identified Zn efficient rice genotypes, but causal mechanisms for Zn deficiency tolerance remain poorly understood. Here we report a detailed study of the impact of Zn deficiency on crown root development of rice genotypes, differing in their tolerance to this stress. Zn deficiency delayed crown root development and plant biomass accumulation in both Zn efficient and inefficient genotypes, with the effects being much stronger in the latter. Zn efficient genotypes had developed new crown roots as early as three days after transplanting (DAT to a Zn deficient field and that was followed by a significant increase in total biomass by 7 DAT. Zn-inefficient genotypes developed few new crown roots and did not increase biomass during the first seven days following transplanting. This correlated with Zn efficient genotypes retranslocating a higher proportion of shoot Zn to their roots, compared to Zn inefficient genotypes. These latter genotypes were furthermore not efficient in utilizing the limited Zn for root development. Histological analyses indicated no anomalies in crown tissue of Zn-efficient or inefficient genotypes that would have suggested crown root emergence was impeded. We therefore conclude that the rate of crown root initiation was differentially affected by Zn deficiency between genotypes. Rapid crown root development, following transplanting, was identified as a main causative trait for tolerance to Zn deficiency and better Zn retranslocation from shoot to root was a key attribute of Zn-efficient genotypes.

  20. Drug-coated microneedles for rapid and painless local anesthesia.

    Science.gov (United States)

    Baek, Sung-Hyun; Shin, Ju-Hyung; Kim, Yeu-Chun

    2017-03-01

    This study showed that drug-coated PLLA (Poly (L-lactide)) microneedle arrays can induce rapid and painless local anesthesia. Microneedle arrays were fabricated using a micro-molding technique, and the needle tips were coated with 290.6 ± 45.9 μg of lidocaine, the most widely used local anesthetic worldwide. A dip-coating device was newly designed for the coating step using an optimized coating formulation. Lidocaine coated on the arrays was released rapidly into PBS within 2 min, and its stability in storage lasted 3 weeks at 4, 25, and 37°C. Furthermore, the microneedle arrays showed consistent in vitro skin penetration and delivered 200.8 ± 43.9, 224.2 ± 39.3, and 244.1 ± 19.6 μg of lidocaine into the skin 1, 2, and 5 min after application with a high delivery efficiency of 69, 77, and 84%. Compared to a commercially available topical anesthetic EMLA® cream, a 22.0, 13.6, and 14.0-fold higher amount of lidocaine was delivered into the skin. Note, in vitro skin permeation of Lidocaine was also notably enhanced by a 2-min-application of the lidocaine-coated microneedle arrays. Altogether, these results suggest that the biocompatible lidocaine-coated PLLA microneedle arrays could provide significantly rapid local anesthesia in a painless manner without any of the issues from topical applications or hypodermic injections of local anesthetics.

  1. Erythrocyte adenosine transport. A rapid screening test for cardiovascular drugs.

    Science.gov (United States)

    Yeung, P K; Mosher, S J; Li, R; Farmer, P S; Klassen, G A; Pollak, P T; McMullen, M; Ferrier, G

    1993-11-01

    An erythrocyte (RBC) model based on whole blood was used to investigate the effect of cardiovascular drugs on the uptake of adenosine in vitro. Fresh whole blood obtained from healthy volunteers was allowed to equilibrate with various concentrations (5-1000 microM) of a tested agent. (2-3H)-Adenosine was used as a substrate, and the reaction was terminated after 2 sec of incubation at room temperature by rapid addition of a "Stopping Solution" which was a mixture of erythro-9-(2-hydroxy-3-nonyl)adenine, dipyridamole, and EDTA. The mixture was centrifuged (1760 g, 4 degrees C, 10 min), and the radioactivity of an aliquot of the supernatant was determined by a scintillation counter. The results showed that dipyridamole was the most potent agent tested (IC50 = 0.2 microM). Amongst the calcium antagonists studied, isradipine was most potent, followed by verapamil, clentiazem, diltiazem, and then nifedipine. The racemates of two metabolites of diltiazem, MX and MB, were more potent than the parent drug. The antiarrhythmic agents, amiodarone and sotalol, the two new lipid peroxidation inhibitors, U-74389F and U-78517F, and the anxiolytic agent, alprazolam, were as active as verapamil. The beta-receptor antagonist propranolol and the angiotensin converting enzyme (ACE) inhibitor, enalapril, were practically inactive. In addition, the model was stereoselective such that the S(-)-enantiomer of verapamil was considerably more potent than the R(+)-antipote, whereas d(+)-sotalol was practically inactive compared to racemic sotalol.

  2. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated...... by the desire to experiment and to become otherwise. The objective is to discuss what gets lost, conceptually as well as politically, when we neglect the subsistence of active tolerance within other practices of tolerance, and to develop a theory of active tolerance in which tolerance's mobilizing character...... the current models of restraint and benevolence, other ways of understanding the politics of democratic pluralism might be developed, which will enable us to conceive of tolerance's future in terms different than those currently on offer. Tolerance: A Sensorial Orientation to Politics develops...

  3. Bacterial drug tolerance under clinical conditions is governed by anaerobic adaptation but not anaerobic respiration.

    Science.gov (United States)

    Hemsley, Claudia M; Luo, Jamie X; Andreae, Clio A; Butler, Clive S; Soyer, Orkun S; Titball, Richard W

    2014-10-01

    Noninherited antibiotic resistance is a phenomenon whereby a subpopulation of genetically identical bacteria displays phenotypic tolerance to antibiotics. We show here that compared to Escherichia coli, the clinically relevant genus Burkholderia displays much higher levels of cells that tolerate ceftazidime. By measuring the dynamics of the formation of drug-tolerant cells under conditions that mimic in vivo infections, we show that in Burkholderia bacteria, oxygen levels affect the formation of these cells. The drug-tolerant cells are characterized by an anaerobic metabolic signature and can be eliminated by oxygenating the system or adding nitrate. The transcriptome profile suggests that these cells are not dormant persister cells and are likely to be drug tolerant as a consequence of the upregulation of anaerobic nitrate respiration, efflux pumps, β-lactamases, and stress response proteins. These findings have important implications for the treatment of chronic bacterial infections and the methodologies and conditions that are used to study drug-tolerant and persister cells in vitro. Copyright © 2014 Hemsley et al.

  4. Rapid recovery from transient faults in the fault-tolerant processor with fault-tolerant shared memory

    Science.gov (United States)

    Harper, Richard E.; Butler, Bryan P.

    1990-01-01

    The Draper fault-tolerant processor with fault-tolerant shared memory (FTP/FTSM), which is designed to allow application tasks to continue execution during the memory alignment process, is described. Processor performance is not affected by memory alignment. In addition, the FTP/FTSM incorporates a hardware scrubber device to perform the memory alignment quickly during unused memory access cycles. The FTP/FTSM architecture is described, followed by an estimate of the time required for channel reintegration.

  5. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated by the d...... these alternatives by returning to the notion of tolerance as the endurance of pain, linking this notion to exemplars and theories relevant to the politics of multiculturalism, religious freedom, and free speech....

  6. Tolerance

    DEFF Research Database (Denmark)

    Tønder, Lars

    Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated by the d...... these alternatives by returning to the notion of tolerance as the endurance of pain, linking this notion to exemplars and theories relevant to the politics of multiculturalism, religious freedom, and free speech.......Tolerance: A Sensorial Orientation to Politics is an experiment in re-orientation. The book is based on the wager that tolerance exceeds the more prevalent images of self-restraint and repressive benevolence because neither precludes the possibility of a more “active tolerance” motivated...... by the desire to experiment and to become otherwise. The objective is to discuss what gets lost, conceptually as well as politically, when we neglect the subsistence of active tolerance within other practices of tolerance, and to develop a theory of active tolerance in which tolerance's mobilizing character...

  7. Use of Genomic Estimated Breeding Values Results in Rapid Genetic Gains for Drought Tolerance in Maize

    Directory of Open Access Journals (Sweden)

    B.S. Vivek

    2017-03-01

    Full Text Available More than 80% of the 19 million ha of maize ( L. in tropical Asia is rainfed and prone to drought. The breeding methods for improving drought tolerance (DT, including genomic selection (GS, are geared to increase the frequency of favorable alleles. Two biparental populations (CIMMYT-Asia Population 1 [CAP1] and CAP2 were generated by crossing elite Asian-adapted yellow inbreds (CML470 and VL1012767 with an African white drought-tolerant line, CML444. Marker effects of polymorphic single-nucleotide polymorphisms (SNPs were determined from testcross (TC performance of F families under drought and optimal conditions. Cycle 1 (C1 was formed by recombining the top 10% of the F families based on TC data. Subsequently, (i C2[PerSe_PS] was derived by recombining those C1 plants that exhibited superior per se phenotypes (phenotype-only selection, and (ii C2[TC-GS] was derived by recombining a second set of C1 plants with high genomic estimated breeding values (GEBVs derived from TC phenotypes of F families (marker-only selection. All the generations and their top crosses to testers were evaluated under drought and optimal conditions. Per se grain yields (GYs of C2[PerSe_PS] and that of C2[TC-GS] were 23 to 39 and 31 to 53% better, respectively, than that of the corresponding F population. The C2[TC-GS] populations showed superiority of 10 to 20% over C2[PerSe-PS] of respective populations. Top crosses of C2[TC-GS] showed 4 to 43% superiority of GY over that of C2[PerSe_PS] of respective populations. Thus, GEBV-enabled selection of superior phenotypes (without the target stress resulted in rapid genetic gains for DT.

  8. Rapid Methods for detection of Veterinary Drug residues in Meat

    Directory of Open Access Journals (Sweden)

    Chandan

    2010-10-01

    Full Text Available The use of substances having hormonal or thyreostatic action as well as b-agonists is banned in many countries. However, sometimes forbidden drugs may be added to feeds for illegal administration to farm animals for promoting increased muscle development or increased water retention and thus obtain an economical benefit. The result is a fraudulent overweight of meat but, what is worse, residues of these substances may remain in meat and may pose a real threat to the consumer either through exposure to the residues, transfer of antibiotic resistance or allergy risk. This has exerted a great concern among the meat consumers. The control of the absence of these forbidden substances in animal foods and feeds is regulated in the European Union by Directive 96/23/EC on measures to monitor certain substances and residues in live animals and animal products. Analytical methodology, including criteria for identification and confirmation, for the monitoring of compliance was also given in Decisions 93/256/EEC and 93/257/EEC. More recently, Decision 2002/657/EC provided rules for the analytical methods to be used in testing of official samples. New substances with anabolic properties are being detected year by year increasing the list of forbidden compounds to be tested. Furthermore, the extended practice consisting in the use of “cocktails” (mixtures of low amounts of several substances that exert a synergistic effect to have a similar growth promotion, reduces the margin for an effective analytical detection. Thus, the evolution of the “black market” is making really difficult to have an effective analytical control of the residues of these substances in foods of animal origin. Control laboratories must face an increasing demand of analysis like the growing number of residues to be analysed in different types of samples, the strict guidelines for analytical methodologies according to the latest Directives, the increased costs of such new

  9. Cost-effectiveness of rapid susceptibility testing against second-line drugs for tuberculosis

    NARCIS (Netherlands)

    Dowdy, D. W.; van't Hoog, A.; Shah, M.; Cobelens, F.

    2014-01-01

    Drug susceptibility testing (DST) against second-line tuberculosis drugs (SLDs) is essential for improving outcomes among multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) cases. To evaluate the potential cost-effectiveness of rapid DST for SLDs. We constructed a

  10. Impact of drug tolerability on the selection of antidepressant treatment in patients with major depressive disorder.

    Science.gov (United States)

    Ginsberg, Lawrence D

    2009-12-01

    Despite significant progress in the development of antidepressant therapies, tolerability remains an important factor associated with the selection of appropriate antidepressant treatment. Side effects commonly reported by depressed patients taking antidepressants include weight gain, sexual dysfunction, and gastrointestinal effects.Tolerability issues associated with antidepressants can negatively impact treatment outcomes for patients with major depressive disorder. In addition, a drug's tolerability profile substantially influences a physician's choice of specific antidepressant therapy, Despite the availability of many antidepressants, empirical clinical evidence to guide physicians in making the best choice is limited and not always clear.Thus, it is key for clinicians to understand the short- and long-term outcomes and side effect profiles of the available antidepressants.

  11. Rapid enzymatic test for phenotypic HIV protease drug resistance

    OpenAIRE

    Hoffmann, D.; Assfalg-Machleidt, Irmgard; Nitschko, H; Helm, K. von der; Koszinowski, U.; Machleidt, Werner

    2003-01-01

    A phenotypic resistance test based on recombinant expression of the active HIV protease in E. coli from patient blood samples was developed. The protease is purified in a rapid onestep procedure as active enzyme and tested for inhibition by five selected synthetic inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, and saquinavir) used presently for chemotherapy of HIVinfected patients. The HPLC system used in a previous approach was replaced by a continuous fluorogenic assay suitable f...

  12. Efficacy and tolerability of antihypertensive drugs in diabetic and nondiabetic patients

    Directory of Open Access Journals (Sweden)

    Maria Aslam

    2017-01-01

    Full Text Available Objectives of the Study: The aim of the study was to compare the efficacy and tolerability of different classes of antihypertensive drugs in diabetic and nondiabetic patients (NDPs with essential hypertension. Material and Methods: The study was conducted in Mayo Hospital, Punjab Institute of Cardiology, and National Defence Hospital, Lahore, Pakistan, on 200 hypertensive patients with diabetes and 230 hypertensive patients without (Three hospitals diabetes. Both male and female patients of age between 30 and 80 years with systolic blood pressure (SBP above 130 mmHg and diastolic blood pressure (DBP above 80 mmHg were enrolled in the study. Angiotensin converting enzyme inhibitors (ACEI, beta-blocker (βB, calcium-channel blocker (CCB, diuretics (D, angiotensin receptor blocker (ARB as well as α-blocker classes of antihypertensive drugs were used. These drugs were used as monotherapy as well as combination therapy. The study was conducted for 4 months (July–October. After 4 months, patients were assessed for efficacy by monitoring blood pressure (BP and tolerability by assessing safety profile on renal function, liver function as well as lipid profile. Results: Significant control in mean BP by all drug groups was observed in “both groups that is patients with diabetes and without diabetes.” The efficacy and tolerability data revealed that in diabetic patients with hypertension, the highest decrease in SBP and DBP was observed using monotherapy with ACEI, two-drug combination therapy with ACEI plus diuretic, ARBs plus diuretic, ACEI plus CCBs, three-drug combination therapy with ACEI plus CCBs plus diuretic, and four drug combination therapy with ACEI plus CCBs plus diuretic plus βBs, ARB's plus CCBs plus diuretic plus βBs while in NDPs, monotherapy with diuretic, two-drug combination therapy with ACEI plus CCBs, ACEI plus βBs, three-drug combination therapy with βBs plus ACEI plus D was found more effective in controlling SBP as well

  13. Carbon Nanotube Micro-Needles for Rapid Transdermal Drug Delivery

    Science.gov (United States)

    Lyon, Bradley; Aria, Adrianus Indrat; Gat, Amir; Cosse, Julia; Montemayor, Lauren; Beizaie, Masoud; Gharib, Morteza

    2012-11-01

    By catalyst patterning, bundles of vertically-aligned carbon nanotubes (CNT) can be assembled to create 2D arrays of hollow micro-needles with feature size as small as a few microns. For transdermal drug delivery, the most challenging mechanical requirement is to make the CNT micro-needle small enough so that delivery is painless yet large enough so that the micro-needle can achieve skin penetration. By taking advantage of capillary action and the nanoporosity of CNT bundles, we can wick high strength polymer into the inter-spacing between nanotubes to augment the stiffness of our micro-needles. For low viscous polymers, the large ratio between the micron sized center hole of the micro-needle and the nanopores of the surrounding CNT allow us to wick polymer through the nanotubes while maintaining an open central hole for drug transport. For a transdermal patch prototype with a delivery area less than 1cm x 1cm square, we can fabricate 50 CNT micro-needles that produces a total flow rate up to 100 uL/s with actuation pressure provided by a mere finger tap. From in vitro experiments, we will demonstrate that CNT micro-needles provide a much faster convective delivery of drugs than conventional topical diffusion based patches. We acknowledge Zcube s.r.l for their support of this work.

  14. [Tolerance to coxibs in patients with intolerance to non-steroidal anti-inflammatory drugs (NSAIDs)].

    Science.gov (United States)

    Boehncke, S; Boehncke, W-H

    2005-10-07

    Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause pseudoallergic reactions. Recognition of two different prostaglandin synthase iso-enzymes led to the development of the so-called coxibs preferentially inhibiting cyclooxygenase-2. We studied tolerability of valdecoxib preferentially inhibitng cyclooxygenase-2 in patients with a history of intolerance to NSAIDs. 41 patients (30 female, 11male, age 14-74 years) with a history of intolerance to NSAIDs underwent scratch tests with these drugs and valdecoxib, followed by oral challenge with valdecoxib (maximum single dose: 20 mg; cumulative dose: 35mg) in a double-blind, placebo-controlled manner. The history of intolerance to NSAID comprised urticaria as the leading symptom (n = 26), followed by angioedema (n = 11) and anaphylactoid shock (n = 4). 21 patients reported reactions to only one NSAID, 15 identified 2 different triggering drugs, and 5 patients showed reactions to 3 different NSAIDs. Acetylsalicylic acid (n = 20) and diclofenac (n = 12) were the most frequent causative drugs. Upon oral challenge with valdecoxib, one patient developed generalized urticaria within 30 minutes following the last dose of valdecoxib; symptoms resolved after i. v. injection of 2 mg clemastine and 250 mg prednisolone. All other patients tolerated the oral challenge without adverse effects. Our results are in line with previous studies suggesting that preferential cyclooxygenase-2-inhibitors may safely be used by patients with known intolerance to NSAIDs.

  15. Methods of solving rapid binding target-mediated drug disposition model for two drugs competing for the same receptor.

    Science.gov (United States)

    Yan, Xiaoyu; Chen, Yang; Krzyzanski, Wojciech

    2012-10-01

    The target-mediated drug disposition (TMDD) model has been adopted to describe pharmacokinetics for two drugs competing for the same receptor. A rapid binding assumption introduces total receptor and total drug concentrations while free drug concentrations C (A) and C (B) are calculated from the equilibrium (Gaddum) equations. The Gaddum equations are polynomials in C (A) and C (B) of second degree that have explicit solutions involving complex numbers. The aim of this study was to develop numerical methods to solve the rapid binding TMDD model for two drugs competing for the same receptor that can be implemented in pharmacokinetic software. Algebra, calculus, and computer simulations were used to develop algorithms and investigate properties of solutions to the TMDD model with two drugs competitively binding to the same receptor. A general rapid binding approximation of the TMDD model for two drugs competing for the same receptor has been proposed. The explicit solutions to the equilibrium equations employ complex numbers, which cannot be easily solved by pharmacokinetic software. Numerical bisection algorithm and differential representation were developed to solve the system instead of obtaining an explicit solution. The numerical solutions were validated by MATLAB 7.2 solver for polynomial roots. The applicability of these algorithms was demonstrated by simulating concentration-time profiles resulting from exogenous and endogenous IgG competing for the neonatal Fc receptor (FcRn), and darbepoetin competing with endogenous erythropoietin for the erythropoietin receptor. These models were implemented in ADAPT 5 and Phoenix WinNonlin 6.0, respectively.

  16. A cluster randomised trial introducing rapid diagnostic tests into registered drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Magnussen, Pascal; Lal, Sham

    2015-01-01

    the impact of introducing rapid diagnostic tests for malaria (mRDTs) in registered drug shops in Uganda, with the aim to increase appropriate treatment of malaria with artemisinin-based combination therapy (ACT) in patients seeking treatment for fever in drug shops. METHODS: A cluster-randomized trial...

  17. Rapid culture-based methods for drug-resistance detection in Mycobacterium tuberculosis.

    Science.gov (United States)

    Palomino, Juan Carlos; Martin, Anandi; Von Groll, Andrea; Portaels, Francoise

    2008-10-01

    Tuberculosis still represents a major public health problem, especially in low-resource countries where the burden of the disease is more important. Multidrug-resistant and extensively drug drug-resistant tuberculosis constitute serious problems for the efficient control of the disease stressing the need to investigate resistance to first- and second-line drugs. Conventional methods for detecting drug-resistance in Mycobacterium tuberculosis are slow and cumbersome. The most commonly used proportion method on Löwenstein-Jensen medium or Middlebrook agar requires a minimum of 3-4 weeks to produce results. Several new approaches have been proposed in the last years for the rapid and timely detection of drug-resistance in tuberculosis. This review will address phenotypic culture-based methods for rapid drug susceptibility testing in M. tuberculosis.

  18. Microscopic Observation Drug Susceptibility Assay for Rapid Diagnosis of Lymph Node Tuberculosis and Detection of Drug Resistance.

    Science.gov (United States)

    Kirwan, Daniela E; Ugarte-Gil, Cesar; Gilman, Robert H; Caviedes, Luz; Rizvi, Hasan; Ticona, Eduardo; Chavez, Gonzalo; Cabrera, José Luis; Matos, Eduardo D; Evans, Carlton A; Moore, David A J; Friedland, Jon S

    2016-01-01

    In this study, 132 patients with lymphadenopathy were investigated. Fifty-two (39.4%) were diagnosed with tuberculosis (TB). The microscopic observation drug susceptibility (MODS) assay provided rapid (13 days), accurate diagnosis (sensitivity, 65.4%) and reliable drug susceptibility testing (DST). Despite its lower sensitivity than that of other methods, its faster results and simultaneous DST are advantageous in resource-poor settings, supporting the incorporation of MODS into diagnostic algorithms for extrapulmonary TB. Copyright © 2015 Kirwan et al.

  19. Tolerability and Plasma Drug Level Monitoring of Prolonged Subcutaneous Teicoplanin Treatment for Bone and Joint Infections.

    Science.gov (United States)

    El Samad, Youssef; Lanoix, Jean-Philippe; Bennis, Youssef; Diouf, Momar; Saroufim, Carlo; Brunschweiler, Benoit; Rousseau, Florence; Joseph, Cédric; Hamdad, Farida; Ait Amer Meziane, Mohamed; Routier, Simon; Schmit, Jean-Luc

    2016-10-01

    Teicoplanin is a key drug for the treatment of multiresistant staphylococcal bone and joint infections (BJI), yet can only be administered via a parenteral route. The objective of this study was to evaluate the safety and tolerability of subcutaneous (s.c.) teicoplanin for that indication over 42 days. Thirty patients with Gram-positive cocci BJI were included. Once the target of 25 to 40 mg/liter trough serum concentration was achieved, treatment was switched from an intravenous to an s.c. route. No discontinuation of teicoplanin related to injection site reaction and no severe local adverse event were observed. On multivariate analysis, better tolerability was observed at the beginning of treatment, in patients over 70 years old, and for dosages less than 600 mg. In conclusion, we recommend s.c. administration of teicoplanin when needed. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  20. Tolerability and Plasma Drug Level Monitoring of Prolonged Subcutaneous Teicoplanin Treatment for Bone and Joint Infections

    Science.gov (United States)

    Bennis, Youssef; Diouf, Momar; Saroufim, Carlo; Brunschweiler, Benoit; Rousseau, Florence; Joseph, Cédric; Hamdad, Farida; Ait Amer Meziane, Mohamed; Routier, Simon; Schmit, Jean-Luc

    2016-01-01

    Teicoplanin is a key drug for the treatment of multiresistant staphylococcal bone and joint infections (BJI), yet can only be administered via a parenteral route. The objective of this study was to evaluate the safety and tolerability of subcutaneous (s.c.) teicoplanin for that indication over 42 days. Thirty patients with Gram-positive cocci BJI were included. Once the target of 25 to 40 mg/liter trough serum concentration was achieved, treatment was switched from an intravenous to an s.c. route. No discontinuation of teicoplanin related to injection site reaction and no severe local adverse event were observed. On multivariate analysis, better tolerability was observed at the beginning of treatment, in patients over 70 years old, and for dosages less than 600 mg. In conclusion, we recommend s.c. administration of teicoplanin when needed. PMID:27458228

  1. Rapid chromatin repression by Aire provides precise control of immune tolerance.

    Science.gov (United States)

    Koh, Andrew S; Miller, Erik L; Buenrostro, Jason D; Moskowitz, David M; Wang, Jing; Greenleaf, William J; Chang, Howard Y; Crabtree, Gerald R

    2018-02-01

    Aire mediates the expression of tissue-specific antigens in thymic epithelial cells to promote tolerance against self-reactive T lymphocytes. However, the mechanism that allows expression of tissue-specific genes at levels that prevent harm is unknown. Here we show that Brg1 generates accessibility at tissue-specific loci to impose central tolerance. We found that Aire has an intrinsic repressive function that restricts chromatin accessibility and opposes Brg1 across the genome. Aire exerted this repressive influence within minutes after recruitment to chromatin and restrained the amplitude of active transcription. Disease-causing mutations that impair Aire-induced activation also impair the protein's repressive function, which indicates dual roles for Aire. Together, Brg1 and Aire fine-tune the expression of tissue-specific genes at levels that prevent toxicity yet promote immune tolerance.

  2. Rapid oxygen exchange across the leaves of Littorella uniflora provides tolerance to sediment anoxia

    DEFF Research Database (Denmark)

    Møller, Claus Lindskov; Jensen, Kaj Sand

    2012-01-01

    from water and underlies its greater tolerance to sediment anoxia following organic enrichment. 2. We studied plant response to varying sediment O2 demand and biogeochemistry by measuring photosynthesis, gas exchange across leaves and O2 dynamics in plants during long-term laboratory and field studies...

  3. Rapid identification of mycobacteria and rapid detection of drug resistance in Mycobacterium tuberculosis in cultured isolates and in respiratory specimens.

    Science.gov (United States)

    Yam, Wing-Cheong; Siu, Kit-Hang Gilman

    2013-01-01

    Recent advances in molecular biology and better understanding of the genetic basis of drug resistance have allowed rapid identification of mycobacteria and rapid detection of drug resistance of Mycobacterium tuberculosis present in cultured isolates or in respiratory specimens. In this chapter, several simple nucleic acid amplification-based techniques are introduced as molecular approach for clinical diagnosis of tuberculosis. A one-tube nested IS6110-based polymerase chain reaction (PCR) is used for M. tuberculosis complex identification; the use of a multiplex allele-specific PCR is demonstrated to detect the isoniazid resistance; PCR-sequencing assays are applied for rifampicin and ofloxacin resistance detection and 16S rDNA sequencing is utilized for identification of mycobacterial species from cultures of acid fast bacilli (AFB). Despite the high specificity and sensitivity of the molecular techniques, mycobacterial culture remains the "Gold Standard" for tuberculosis diagnosis. Negative results of molecular tests never preclude the infection or the presence of drug resistance. These technological advancements are, therefore, not intended to replace the conventional tests, but rather have major complementary roles in tuberculosis diagnosis.

  4. Nanocapsules for drug delivery through the skin barrier by tissue-tolerable plasma

    Science.gov (United States)

    Lademann, J.; Patzelt, A.; Richter, H.; Lademann, O.; Baier, G.; Breucker, L.; Landfester, K.

    2013-08-01

    For many years, several attempts have been made to enhance skin penetration by chemical, physical or mechanical manipulation to reduce the barrier function of the skin. The present study demonstrates the possibility of penetration enhancement for 400 nm sized nanocapsules loaded with a model drug consisting of a fluorescent dye by the application of tissue-tolerable plasma (TTP). Therefore, the stability of the nanocapsules and their penetration through the skin barrier prior to and in combination with TTP application was evaluated. The results revealed that the penetration of the nanocapsules could be effectively enhanced when applied in combination with TTP, hence delivering the model drug unaffected by plasma into deeper skin layers. The stability testing showed no significant structural changes of the nanocapsules after contact with TTP. Thus, the present study introduces a new strategy for the penetration enhancement of substances by the combined utilization of nanocapsules and TTP.

  5. Validation of a sample pretreatment protocol to convert a drug-sensitive into a drug-tolerant anti-infliximab antibody immunoassay.

    Science.gov (United States)

    Van Stappen, Thomas; Brouwers, Els; Vermeire, Séverine; Gils, Ann

    2017-02-01

    A meta-analysis revealed that up to 51% of patients treated with infliximab develop anti-drug Abs (ADA) which are associated with loss of response. Detection of ADA is strongly influenced by assay technique since drug-sensitive ADA assays are not able to detect ADA in the presence of drug and therefore underestimate ADA development. In addition, the lack of a calibrator antibody that can be used in a drug-sensitive and drug-tolerant assay hampers an adequate comparison among different assays. Here we present a sample pretreatment protocol to convert the bridging assay, originally developed as a drug-sensitive assay, into a drug-tolerant assay, allowing use of the same assay and calibrator antibody MA-IFX10F9. Using the sample pretreatment protocol, the bridging assay detects antibodies towards infliximab in samples containing up to 5-fold infliximab over anti-infliximab. Analysis of consecutive serum samples from infliximab treated patients revealed that the drug-tolerant assay detects ADA development up to 40 weeks earlier compared to the drug-sensitive assay. In conclusion, the sample pretreatment protocol can be implemented in various assay formats and allows determination of ADA in the presence of drug, providing the possibility for early treatment optimization. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  6. Pirfenidone and nintedanib for pulmonary fibrosis in clinical practice: Tolerability and adverse drug reactions.

    Science.gov (United States)

    Galli, Jonathan A; Pandya, Aloknath; Vega-Olivo, Michelle; Dass, Chandra; Zhao, Huaqing; Criner, Gerard J

    2017-08-01

    The real-world tolerability of pirfenidone and nintedanib in non-clinical trial patients is unknown. Many patients with pulmonary fibrosis have significant medical co-morbidities or baseline characteristics that exclude them from clinical trial participation. We conducted a retrospective chart review study on subjects prescribed nintedanib or pirfenidone for pulmonary fibrosis treatment (any aetiology) from September 2014 to February 2016. A total of 186 subjects were included: 129 received pirfenidone and 57 were prescribed nintedanib and followed up for mean observation periods of 52 ± 17 weeks for pirfenidone and 41 ± 15 weeks for nintedanib. The primary outcome was drug discontinuation as a result of an adverse event. Subjects had significant respiratory impairment at baseline, 63% required home oxygen therapy and mean diffusion capacity of carbon monoxide (DLCO) was 36 ± 14% predicted. Drug discontinuation as a result of an adverse event occurred in 20.9% of subjects on pirfenidone and 26.3% on nintedanib. Drug discontinuation rates for both pirfenidone and nintedanib did not significantly differ from corresponding large clinical trials (ASCEND/CAPACITY and INPULSIS 1 and 2, respectively). Adverse events that occurred with highest frequency on pirfenidone were nausea (26.4%), rash/photosensitivity (14.7%) and dyspepsia/gastroesophageal reflux disease (GERD) (12.4%). Diarrhoea (52.6%) and nausea (29.8%) were reported most often with nintedanib therapy. Patients with pulmonary fibrosis treated with nintedanib or pirfenidone in routine clinical practice had drug tolerability and adverse event profiles comparable with subjects enrolled in clinical trials despite having a greater degree of respiratory impairment and a high prevalence of co-morbid medical conditions. © 2017 Asian Pacific Society of Respirology.

  7. Rapid Method for Isolation of Desiccation-Tolerant Strains and Xeroprotectants▿

    Science.gov (United States)

    Narváez-Reinaldo, J. J.; Barba, I.; González-López, J.; Tunnacliffe, A.; Manzanera, M.

    2010-01-01

    A novel biotechnological process has been developed for the isolation of desiccation-tolerant microorganisms and their xeroprotectants, i.e., compatible solutes involved in long-term stability of biomolecules in the dry state. Following exposure of soil samples to chloroform, we isolated a collection of desiccation-tolerant microorganisms. This collection was screened for the production of xeroprotectants by a variation of the bacterial milking (osmotic downshock) procedure and by a novel air-drying/rehydration (“dry milking”) incubation method. The resultant solutes were shown to protect both proteins and living cells against desiccation damage, thereby validating them as xeroprotectants. Nuclear magnetic resonance (NMR) analytical studies were performed to identify the xeroprotectants; synthetic mixtures of these compounds were shown to perform similarly to natural isolates in drying experiments with proteins and cells. This new approach has biotechnological and environmental implications for the identification of new xeroprotectants of commercial and therapeutic value. PMID:20562279

  8. Local tolerance testing of parenteral drugs: how to put into practice.

    Science.gov (United States)

    Jochims, Karin; Kemkowski, Joerg; Nolte, Thomas; Bartels, Thomas; Heusener, Alexander

    2003-10-01

    Notwithstanding that there are national and international guidelines about local tolerance testing of parenteral drugs in animals, in particular to mention CPMP/SWP/2145/00 (Note for Guidance on Non-Clinical Local Tolerance Testing of Medicinal Products), very heterogeneous study designs have been established in the past. A working group including experts of the leading pharmaceutical industry from German-language countries, named "Arbeitskreis Lokale Verträglichkeit," has been intensively discussing the experimental procedures in detail for a period of six years and has been considering their pros and cons. This team of experts now feels confident to give some recommendations for study conduct besides describing different materials and methods for this type of toxicological study. Special knowledge from toxicologists as well as pathologists from our working group has been taken into account. This paper deals with choice of species, number of animals used, controls, administration sites, volumes, rate and frequency, length of observation period, termination, clinical, macroscopic and histopathological examinations and, finally, overall assessment criteria and conclusion. Our purpose is that this paper may be of value for: *The study director who is inexperienced in the conduction of local tolerance testing and who may need a standard design as his first step into this new field. *The well-versed study director who would like to know how others have done in the past, who may examine self-critically his own practice and who is open to our team's recommendations, tips and tricks from practice. *The specialist at a regulatory authority who, finally, reviews study reports, assesses their format and content and, above all, decides on the approval of a drug product.

  9. Individual variability in clinical effect and tolerability of opioid analgesics - Importance of drug interactions and pharmacogenetics.

    Science.gov (United States)

    Solhaug, Vigdis; Molden, Espen

    2017-10-17

    As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids. To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice. The article was based on unsystematic searches in PubMed to identify literature highlighting the clinical impact of drug interactions and pharmacogenetics as sources of variable response of opioid analgesics. Cytochrome P450 (CYP)-mediated metabolism is an important process for both clinically relevant interactions and pharmacogenetic variability of several opioids. Concomitant use of CYP inhibitors (e.g. paroxetine, fluoxetine and bupropion) or inducers (e.g. carbamazepine, phenobarbital and phenytoin) could counteract the clinical effect or trigger side effects of analgesics in the same manner as genetically determined differences in CYP2D6-mediated metabolism of many opioids. Moreover, combination treatment with drugs that inhibit or induce P-glycoprotein (ABCB1), a blood-brain barrier efflux transporter, may alter the amount ('dose') of opioids distributed to the brain. At the pharmacodynamic level, it is crucial to be aware of the potential risk of interaction causing serotonergic syndrome when combining opioids and serotonergic drugs, in particular antidepressants inhibiting serotonin reuptake (SSRIs and SNRIs). Regarding pharmacogenetics at the receptor level of pain treatment, the knowledge is currently scarce, but an allelic variant of the μ1 opioid receptor (OPRM1) gene has been associated with higher dosage requirement to achieve analgesia. Drug interactions and pharmacogenetic differences may lead to

  10. Real-time PCR using mycobacteriophage DNA for rapid phenotypic drug susceptibility results for Mycobacterium tuberculosis.

    Science.gov (United States)

    Pholwat, Suporn; Ehdaie, Beeta; Foongladda, Suporn; Kelly, Kimberly; Houpt, Eric

    2012-03-01

    Managing drug-resistant Mycobacterium tuberculosis requires drug susceptibility testing, yet conventional drug susceptibility testing is slow, and molecular testing does not yield results for all antituberculous drugs. We addressed these challenges by utilizing real-time PCR of mycobacteriophage D29 DNA to evaluate the drug resistance of clinical M. tuberculosis isolates. Mycobacteriophages infect and replicate in viable bacterial cells faster than bacterial cells replicate and have been used for detection and drug resistance testing for M. tuberculosis either by using reporter cells or phages with engineered reporter constructs. Our primary protocol involved culturing M. tuberculosis isolates for 48 h with and without drugs at critical concentrations, followed by incubation with 10(3) PFU/ml of D29 mycobacteriophage for 24 h and then real-time PCR. Many drugs could be incubated instantly with M. tuberculosis and phage for 24 h alone. The change in phage DNA real-time PCR cycle threshold (C(T)) between control M. tuberculosis and M. tuberculosis treated with drugs was calculated and correlated with conventional agar proportion drug susceptibility results. Specifically, 9 susceptible clinical isolates, 22 multidrug-resistant (MDR), and 1 extensively drug-resistant (XDR) M. tuberculosis strains were used and C(T) control-C(T) drug cutoffs of between +0.3 and -6.0 yielded 422/429 (98%) accurate results for isoniazid, rifampin, streptomycin, ethambutol, amikacin, kanamycin, capreomycin, ofloxacin, moxifloxacin, ethionamide, para-aminosalicylic acid, cycloserine, and linezolid. Moreover, the ΔC(T) values correlated with isolate MIC for most agents. This D29 quantitative PCR assay offers a rapid, accurate, 1- to 3-day phenotypic drug susceptibility test for first- and second-line drugs and may suggest an approximate MIC.

  11. An In Vivo Platform for Rapid High-Throughput Antitubercular Drug Discovery

    Directory of Open Access Journals (Sweden)

    Kevin Takaki

    2012-07-01

    Full Text Available Treatment of tuberculosis, like other infectious diseases, is increasingly hindered by the emergence of drug resistance. Drug discovery efforts would be facilitated by facile screening tools that incorporate the complexities of human disease. Mycobacterium marinum-infected zebrafish larvae recapitulate key aspects of tuberculosis pathogenesis and drug treatment. Here, we develop a model for rapid in vivo drug screening using fluorescence-based methods for serial quantitative assessment of drug efficacy and toxicity. We provide proof-of-concept that both traditional bacterial-targeting antitubercular drugs and newly identified host-targeting drugs would be discovered through the use of this model. We demonstrate the model’s utility for the identification of synergistic combinations of antibacterial drugs and demonstrate synergy between bacterial- and host-targeting compounds. Thus, the platform can be used to identify new antibacterial agents and entirely new classes of drugs that thwart infection by targeting host pathways. The methods developed here should be widely applicable to small-molecule screens for other infectious and noninfectious diseases.

  12. Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens.

    Science.gov (United States)

    Sun, Wei; Park, Yoon-Dong; Sugui, Janyce A; Fothergill, Annette; Southall, Noel; Shinn, Paul; McKew, John C; Kwon-Chung, Kyung J; Zheng, Wei; Williamson, Peter R

    2013-01-01

    A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug), tacrolimus (an immunosuppressive agent) and floxuridine (an antimetabolite) were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

  13. Rapid identification of antifungal compounds against Exserohilum rostratum using high throughput drug repurposing screens.

    Directory of Open Access Journals (Sweden)

    Wei Sun

    Full Text Available A recent large outbreak of fungal infections by Exserohilum rostratum from contaminated compounding solutions has highlighted the need to rapidly screen available pharmaceuticals that could be useful in therapy. The present study utilized two newly-developed high throughput assays to screen approved drugs and pharmaceutically active compounds for identification of potential antifungal agents. Several known drugs were found that have potent effects against E. rostratum including the triazole antifungal posaconazole. Posaconazole is likely to be effective against infections involving septic joints and may provide an alternative for refractory central nervous system infections. The anti-E. rostratum activities of several other drugs including bithionol (an anti-parasitic drug, tacrolimus (an immunosuppressive agent and floxuridine (an antimetabolite were also identified from the drug repurposing screens. In addition, activities of other potential antifungal agents against E. rostratum were excluded, which may avoid unnecessary therapeutic trials and reveals the limited therapeutic alternatives for this outbreak. In summary, this study has demonstrated that drug repurposing screens can be quickly conducted within a useful time-frame. This would allow clinical implementation of identified alternative therapeutics and should be considered as part of the initial public health response to new outbreaks or rapidly-emerging microbial pathogens.

  14. Use of refractometry and colorimetry as field methods to rapidly assess antimalarial drug quality.

    Science.gov (United States)

    Green, Michael D; Nettey, Henry; Villalva Rojas, Ofelia; Pamanivong, Chansapha; Khounsaknalath, Lamphet; Grande Ortiz, Miguel; Newton, Paul N; Fernández, Facundo M; Vongsack, Latsamy; Manolin, Ot

    2007-01-04

    The proliferation of counterfeit and poor-quality drugs is a major public health problem; especially in developing countries lacking adequate resources to effectively monitor their prevalence. Simple and affordable field methods provide a practical means of rapidly monitoring drug quality in circumstances where more advanced techniques are not available. Therefore, we have evaluated refractometry, colorimetry and a technique combining both processes as simple and accurate field assays to rapidly test the quality of the commonly available antimalarial drugs; artesunate, chloroquine, quinine, and sulfadoxine. Method bias, sensitivity, specificity and accuracy relative to high-performance liquid chromatographic (HPLC) analysis of drugs collected in the Lao PDR were assessed for each technique. The HPLC method for each drug was evaluated in terms of assay variability and accuracy. The accuracy of the combined method ranged from 0.96 to 1.00 for artesunate tablets, chloroquine injectables, quinine capsules, and sulfadoxine tablets while the accuracy was 0.78 for enterically coated chloroquine tablets. These techniques provide a generally accurate, yet simple and affordable means to assess drug quality in resource-poor settings.

  15. A practical Bayesian design to identify the maximum tolerated dose contour for drug combination trials.

    Science.gov (United States)

    Zhang, Liangcai; Yuan, Ying

    2016-11-30

    Drug combination therapy has become the mainstream approach to cancer treatment. One fundamental feature that makes combination trials different from single-agent trials is the existence of the maximum tolerated dose (MTD) contour, that is, multiple MTDs. As a result, unlike single-agent phase I trials, which aim to find a single MTD, it is often of interest to find the MTD contour for combination trials. We propose a new dose-finding design, the waterfall design, to find the MTD contour for drug combination trials. Taking the divide-and-conquer strategy, the waterfall design divides the task of finding the MTD contour into a sequence of one-dimensional dose-finding processes, known as subtrials. The subtrials are conducted sequentially in a certain order, such that the results of each subtrial will be used to inform the design of subsequent subtrials. Such information borrowing allows the waterfall design to explore the two-dimensional dose space efficiently using a limited sample size and decreases the chance of overdosing and underdosing patients. To accommodate the consideration that doses on the MTD contour may have very different efficacy or synergistic effects because of drug-drug interaction, we further extend our approach to a phase I/II design with the goal of finding the MTD with the highest efficacy. Simulation studies show that the waterfall design is safer and has higher probability of identifying the true MTD contour than some existing designs. The R package "BOIN" to implement the waterfall design is freely available from CRAN. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  16. A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

    Energy Technology Data Exchange (ETDEWEB)

    Li, Xiaoguang [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Department of Medical Microbiology, Harbin Medical University, Harbin 150086 (China); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Qian, Hua [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Miyamoto, Fusako [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Naito, Takeshi [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Kawaji, Kumi [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Kajiwara, Kazumi [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); JST Innovation Plaza Kyoto, Japan Science and Technology Agency, Nishigyo-ku, Kyoto 615-8245 (Japan); Hattori, Toshio [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Matsuoka, Masao [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); and others

    2012-07-27

    Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.

  17. TranScreen-N: Method for rapid screening of trans-ungual drug delivery enhancers.

    Science.gov (United States)

    Murthy, S Narasimha; Vaka, Siva Ram Kiran; Sammeta, Srinivasa Murthy; Nair, Anroop B

    2009-11-01

    Topical monotherapy of nail diseases such as onychomycosis and nail psoriasis has been less successful due to poor permeability of the human nail plate to topically administered drugs. Chemical enhancers are utilized to improve the drug delivery across the nail plate. Choosing the most effective chemical enhancers for the given drug and formulation is highly critical in determining the efficacy of topical therapy of nail diseases. Screening the large pool of enhancers using currently followed diffusion cell experiments would be tedious and expensive. The main objective of this study is to develop TranScreen-N, a high throughput method of screening trans-ungual drug permeation enhancers. It is a rapid microwell plate based method which involves two different treatment procedures; the simultaneous exposure treatment and the sequential exposure treatment. In the present study, several chemicals were evaluated by TranScreen-N and by diffusion studies in the Franz diffusion cell (FDC). Good agreement of in vitro drug delivery data with TranScreen-N data provided validity to the screening technique. In TranScreen-N technique, the enhancers can be grouped according to whether they need to be applied before or simultaneously with drugs (or by either procedures) to enhance the drug delivery across the nail plate. TranScreen-N technique can significantly reduce the cost and duration required to screen trans-ungual drug delivery enhancers. (c) 2009 Wiley-Liss, Inc. and the American Pharmacists Association

  18. Practical guide to the management of acute and chronic pain in the presence of drug tolerance for the healthcare practitioner.

    Science.gov (United States)

    Vadivelu, Nalini; Singh-Gill, Harman; Kodumudi, Gopal; Kaye, Aaron Joshua; Urman, Richard D; Kaye, Alan David

    2014-01-01

    Drug tolerance has been on the rise in recent years worldwide, and consequently, pain management in our population has become challenging. Discussed in this review are commonly abused drugs and considerations for treating acute and chronic pain states in patients with substance disorders. After marijuana, alcohol, and tobacco, the most widely abused substances are oxycodone (Oxycontin), diazepam (Valium), and methylphenidate (Ritalin). Urine testing can detect metabolites of drugs used by patients and is useful for assessing drug abuse, medication diversion, and drug interactions. The comprehensive treatment of pain in a patient with addictive disorder or tolerance must address 3 issues: the patient's addiction, any associated psychiatric conditions, and the patient's pain. Eliciting a detailed history of drug abuse-illicit drugs as well as prescription drugs-and ascertaining if the patient is currently enrolled in a methadone maintenance program for the treatment of drug addiction is vital. Medical observation, supportive care, multidisciplinary pain management, and timely interventions as necessary are the keys to safe outcomes in these patients.

  19. Introducing rapid diagnostic tests for malaria into registered drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Clarke, Sîan E; Lal, Sham

    2015-01-01

    BACKGROUND: Malaria is a major public health problem in Uganda and the current policy recommends introduction of rapid diagnostic tests for malaria (RDTs) to facilitate effective case management. However, provision of RDTs in drug shops potentially raises a new set of issues, such as adherence...... to RDTs results, management of severe illnesses, referral of patients, and relationship with caretakers. The main objective of the study was to examine the impact of introducing RDTs in registered drug shops in Uganda and document lessons and policy implications for future scale-up of malaria control...... in the private health sector. METHODS: A cluster-randomized trial introducing RDTs into registered drug shops was implemented in central Uganda from October 2010 to July 2012. An evaluation was undertaken to assess the impact and the processes involved with the introduction of RDTs into drug shops, the lessons...

  20. Rapid characterization of the biomechanical properties of drug-treated cells in a microfluidic device

    Science.gov (United States)

    Zhang, Xiaofei; Chu, Henry K.; Zhang, Yang; Bai, Guohua; Wang, Kaiqun; Tan, Qiulin; Sun, Dong

    2015-10-01

    Cell mechanics is closely related to many cell functions. Recent studies have suggested that the deformability of cells can be an effective biomarker to indicate the onset and progression of diseases. In this paper, a microfluidic chip is designed for rapid characterization of the mechanics of drug-treated cells through stretching with dielectrophoresis (DEP) force. This chip was fabricated using PDMS and micro-electrodes were integrated and patterned on the ITO layer of the chip. Leukemia NB4 cells were considered and the effect of all-trans retinoic acid (ATRA) drug on NB4 cells were examined via the microfluidic chip. To induce a DEP force onto the cell, a relatively weak ac voltage was utilized to immobilize a cell at one side of the electrodes. The applied voltage was then increased to 3.5 V pp and the cell started to be stretched along the applied electric field lines. The elongation of the cell was observed using an optical microscope and the results showed that both types of cells were deformed by the induced DEP force. The strain of the NB4 cell without the drug treatment was recorded to be about 0.08 (time t = 180 s) and the drug-treated NB4 cell was about 0.21 (time t = 180 s), indicating a decrease in the stiffness after drug treatment. The elastic modulus of the cell was also evaluated and the modulus changed from 140 Pa to 41 Pa after drug treatment. This microfluidic chip can provide a simple and rapid platform for measuring the change in the biomechanical properties of cells and can potentially be used as the tool to determine the biomechanical effects of different drug treatments for drug discovery and development applications.

  1. A Microfluidic Channel Method for Rapid Drug-Susceptibility Testing of Pseudomonas aeruginosa

    Science.gov (United States)

    Matsumoto, Yoshimi; Grushnikov, Andrey; Kikuchi, Kazuma; Noji, Hiroyuki; Yamaguchi, Akihito; Yagi, Yasushi

    2016-01-01

    The recent global increase in the prevalence of antibiotic-resistant bacteria and lack of development of new therapeutic agents emphasize the importance of selecting appropriate antimicrobials for the treatment of infections. However, to date, the development of completely accelerated drug susceptibility testing methods has not been achieved despite the availability of a rapid identification method. We proposed an innovative rapid method for drug susceptibility testing for Pseudomonas aeruginosa that provides results within 3 h. The drug susceptibility testing microfluidic (DSTM) device was prepared using soft lithography. It consisted of five sets of four microfluidic channels sharing one inlet slot, and the four channels are gathered in a small area, permitting simultaneous microscopic observation. Antimicrobials were pre-introduced into each channel and dried before use. Bacterial suspensions in cation-adjusted Mueller–Hinton broth were introduced from the inlet slot and incubated for 3 h. Susceptibilities were microscopically evaluated on the basis of differences in cell numbers and shapes between drug-treated and control cells, using dedicated software. The results of 101 clinically isolated strains of P. aeruginosa obtained using the DSTM method strongly correlated with results obtained using the ordinary microbroth dilution method. Ciprofloxacin, meropenem, ceftazidime, and piperacillin caused elongation in susceptible cells, while meropenem also induced spheroplast and bulge formation. Morphological observation could alternatively be used to determine the susceptibility of P. aeruginosa to these drugs, although amikacin had little effect on cell shape. The rapid determination of bacterial drug susceptibility using the DSTM method could also be applicable to other pathogenic species, and it could easily be introduced into clinical laboratories without the need for expensive instrumentation. PMID:26872134

  2. A Microfluidic Channel Method for Rapid Drug-Susceptibility Testing of Pseudomonas aeruginosa.

    Directory of Open Access Journals (Sweden)

    Yoshimi Matsumoto

    Full Text Available The recent global increase in the prevalence of antibiotic-resistant bacteria and lack of development of new therapeutic agents emphasize the importance of selecting appropriate antimicrobials for the treatment of infections. However, to date, the development of completely accelerated drug susceptibility testing methods has not been achieved despite the availability of a rapid identification method. We proposed an innovative rapid method for drug susceptibility testing for Pseudomonas aeruginosa that provides results within 3 h. The drug susceptibility testing microfluidic (DSTM device was prepared using soft lithography. It consisted of five sets of four microfluidic channels sharing one inlet slot, and the four channels are gathered in a small area, permitting simultaneous microscopic observation. Antimicrobials were pre-introduced into each channel and dried before use. Bacterial suspensions in cation-adjusted Mueller-Hinton broth were introduced from the inlet slot and incubated for 3 h. Susceptibilities were microscopically evaluated on the basis of differences in cell numbers and shapes between drug-treated and control cells, using dedicated software. The results of 101 clinically isolated strains of P. aeruginosa obtained using the DSTM method strongly correlated with results obtained using the ordinary microbroth dilution method. Ciprofloxacin, meropenem, ceftazidime, and piperacillin caused elongation in susceptible cells, while meropenem also induced spheroplast and bulge formation. Morphological observation could alternatively be used to determine the susceptibility of P. aeruginosa to these drugs, although amikacin had little effect on cell shape. The rapid determination of bacterial drug susceptibility using the DSTM method could also be applicable to other pathogenic species, and it could easily be introduced into clinical laboratories without the need for expensive instrumentation.

  3. Rapid analysis of drug dissolution by paper spray ionization mass spectrometry.

    Science.gov (United States)

    Liu, Yang; Liu, Ning; Zhou, Ya-Nan; Lin, Lan; He, Lan

    2017-03-20

    With a great quantity of solid dosage tested by dissolution technology, developing a rapid and sensitive method to access the content of drug within dissolution media is highly desired by analysts and scientists. Traditionally, dissolution media is not compatible with mass spectrometry since the inorganic salts in the media might damage the mass spectrometer. Here, paper spray ionization mass spectrometry (PSI-MS), one of the ambient mass spectrometry technologies, is developed to characterize the content of drugs in dissolution media. The porous structure of paper can effectively retain salts from entering mass spectrometer. This makes the measurement of drug content within dissolution media by mass spectrometer possible. After the experimental parameters were optimized, calibration curves of model drugs - enalapril, quinapril and benazepril were established by using corresponding deuterated internal standards. PSI-MS was then deployed to characterize the content of enalapril from the dissolution testing of enalapril tablets. The results from PSI-MS are comparable to those from HPLC characterization. More importantly, the analysis time of 6 samples is shortened from 90min to 6min. Detection limit of enalapril maleate tablets by PSI-MS is 1/300 of LC. PSI-MS is rapid, sensitive and accurate in analyzing drug content from dissolution tests. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Formulation of 3D Printed Tablet for Rapid Drug Release by Fused Deposition Modeling (FDM): Screening Polymers for Drug Release, Drug-Polymer Miscibility and Printability.

    Science.gov (United States)

    Solanki, Nayan; Tahsin, Md; Shah, Ankita; Serajuddin, Abu T M

    2017-10-21

    The primary aim of this study was to identify pharmaceutically acceptable amorphous polymers for producing 3D printed tablets of a model drug, haloperidol, for rapid release by fused deposition modeling (FDM). Filaments for 3D printing were prepared by hot melt extrusion at 150°C with 10 and 20% w/w of haloperidol using Kollidon(®) VA64, Kollicoat(®) IR, Affinsiol(™)15 cP and HPMCAS either individually or as binary blends (Kollidon(®) VA64+Affinisol(™)15 cP, 1:1; Kollidon(®) VA64+HPMCAS, 1:1). Dissolution of crushed extrudates was studied at pH 2 and 6.8, and formulations demonstrating rapid dissolution rates were then analyzed for drug-polymer, polymer-polymer and drug-polymer-polymer miscibility by film casting. Polymer-polymer (1:1) and drug-polymer-polymer (1:5:5 and 2:5:5) mixtures were found to be miscible. Tablets with 100 and 60 % infill were printed using MakerBot printer at 210°C, and dissolution tests of tablets were conducted at pH 2 and 6.8. Extruded filaments of Kollidon(®) VA64-Affinisol(™)15 cP mixtures were flexible and had optimum mechanical strength for 3D printing. Tablets containing 10% drug with 60 and 100% infill showed complete drug release at pH 2 in 45 and 120 min, respectively. Relatively high dissolution rates were also observed at pH 6.8. The 1:1-mixture of Kollidon(®) VA64 and Affinisol(™)15 cP was thus identified as a suitable polymer system for 3D printing and rapid drug release. Copyright © 2017. Published by Elsevier Inc.

  5. Introducing rapid diagnostic tests for malaria into drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K; Magnussen, Pascal; Chandler, Clare Ir

    2014-01-01

    BACKGROUND: An intervention was designed to introduce rapid diagnostics tests for malaria (mRDTs) into registered drug shops in Uganda to encourage rational and appropriate treatment of malaria with artemisinin-based combination therapy (ACT). We conducted participatory training of drug shop...... through a cluster randomized trial. In this paper, we present detailed design, implementation and evaluation experiences in order to help inform future studies of a complex nature. METHODS: Three preparatory studies (formative, baseline and willingness-to-pay) were conducted to explore perceptions...

  6. Rapid detoxification of benzodiazepine or Z-drugs dependence using acetylcholinesterase inhibitors.

    Science.gov (United States)

    Lin, Shih-Ku

    2014-07-01

    Dependence on benzodiazepines (BZDs) or Z-drugs (zolpidem, zopicline and zaleplon) is a common clinical phenomenon. Traditional detoxification of BZDs dependence includes tapering used dose gradually and using equivalent doses of long-acting BZDs as substitutes. This kind of regimen tends to take a long time (up to 4weeks) and may require hospitalization. Acetylcholinesterase inhibitors have been shown to reverse BZDs induced sedation. We propose that oral form acetylcholinesterase inhibitors (donepezil, galantamine and rivastigmine) also posses the effect of inhibiting GABA receptors, and act as indirect antagonist, to be applied in the rapid detoxification treatment of BZDs and Z-drug dependence. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. How low can they go when going with the flow? Tolerance of egg and larval fishes to rapid decompression

    Directory of Open Access Journals (Sweden)

    Craig A. Boys

    2016-06-01

    Full Text Available Egg and larval fish that drift downstream are likely to encounter river infrastructure and consequently rapid decompression, which may result in significant injury. Pressure-related injury (or barotrauma has been shown in juvenile fishes when pressure falls sufficiently below that at which the fish has acclimated. There is a presumption that eggs and larvae may be at least as, if not more, susceptible to barotrauma injury because they are far less-developed and more fragile than juveniles, but studies to date report inconsistent results and none have considered the relationship between pressure change and barotrauma over a sufficiently broad range of pressure changes to enable tolerances to be properly determined. To address this, we exposed eggs and larvae of three physoclistic species to rapid decompression in a barometric chamber over a broad range of discrete pressure changes. Eggs, but not larvae, were unaffected by all levels of decompression tested. At exposure pressures below ∼40 kPa, or ∼40% of surface pressure, swim bladder deflation occurred in all species and internal haemorrhage was observed in one species. None of these injuries killed the fish within 24 h, but subsequent mortality cannot be excluded. Consequently, if larval drift is expected where river infrastructure is present, adopting design or operational features which maintain exposure pressures at 40% or more of the pressure to which drifting larvae are acclimated may afford greater protection for resident fishes.

  8. Feasibility Study of Carbon Nanotube Microneedles for Rapid Transdermal Drug Delivery

    OpenAIRE

    Lyon, Bradley J.; Aria, Adrianus I.; Gharib, Morteza

    2013-01-01

    We introduce a new approach for fabricating hollow microneedles using vertically-aligned carbon nanotubes (VA-CNTs) for rapid transdermal drug delivery. Here, we discuss the fabrication of the microneedles emphasizing the overall simplicity and flexibility of the method to allow for potential industrial application. By capitalizing on the nanoporosity of the CNT bundles, uncured polymer can be wicked into the needles ultimately creating a high strength composite of aligned nanotubes and polym...

  9. The mirage of impairing drug concentration thresholds: a rationale for zero tolerance per se driving under the influence of drugs laws.

    Science.gov (United States)

    Reisfield, Gary M; Goldberger, Bruce A; Gold, Mark S; DuPont, Robert L

    2012-06-01

    Motor vehicle crashes are a leading cause of morbidity and mortality in the United States. Drivers with measurable quantities of potentially impairing illicit or prescription drugs in their body fluids are multiple times more likely to be involved in motor vehicle crashes than those without such drugs in their bodies. Drug-related impairment, however, cannot be inferred solely on the basis of the presence of drugs in biological fluids. Thus, for more than a quarter century, there has been a search for drug blood concentrations that are the equivalent of the 0.08 g/dL threshold for alcohol-impaired driving in the United States. We suggest that such equivalents are a mirage, and cannot be determined due to variable drug tolerance, lack of consistent relationships between drug blood concentrations and impairment, innumerable drug combinations and multiple other factors. Thus, while the idea of determining impairing drug concentrations is attractive, it is ultimately unattainable, and withholding drugged driving legislation pending the acquisition of such data is tantamount to a plan for inaction with regard to an important and growing public health and safety problem. We propose specific legislation to address alcohol- and drug-impaired driving in the United States.

  10. Novel drug and soluble target tolerant antidrug antibody assay for therapeutic antibodies bearing the P329G mutation.

    Science.gov (United States)

    Wessels, Uwe; Schick, Eginhard; Ritter, Mirko; Kowalewsky, Frank; Heinrich, Julia; Stubenrauch, Kay

    2017-06-01

    Bridging immunoassays for detection of antidrug antibodies (ADAs) are typically susceptible to high concentrations of residual drug. Sensitive drug-tolerant assays are, therefore, needed. An immune complex assay to detect ADAs against therapeutic antibodies bearing Pro329Gly mutation was established. The assay uses antibodies specific for the Pro329Gly mutation for capture and human soluble Fcγ receptor for detection. When compared with a bridging assay, the new assay showed similar precision, high sensitivity to IgG1 ADA and dramatically improved drug tolerance. However, it was not able to detect early (IgM-based) immune responses. Applied in combination with a bridging assay, the novel assay serves as orthogonal assay for immunogenicity assessment and allows further characterization of ADA responses.

  11. Transient improvement after brief antiepileptic drug withdrawal in the epilepsy monitoring unit--possible relationship to AED tolerance.

    Science.gov (United States)

    Azar, Nabil J; Lagrange, Andre H; Wang, Lily; Song, Yanna; Abou-Khalil, Bassel W

    2010-05-01

    A drug holiday seems to produce seizure interval prolongation (SIP) after reinstitution of antiepileptic drugs (AEDs). This effect was demonstrated mainly with carbamazepine. We evaluated SIP with newer AEDs and tested the relationship of SIP to history of AED tolerance. We prospectively studied patients with refractory epilepsy admitted to the Vanderbilt epilepsy monitoring unit (EMU) over a period of 12 months. We included only patients on levetiracetam, lamotrigine, or oxcarbazepine who had their AEDs withdrawn on admission and reinstituted without change upon discharge. We defined SIP as the interval from EMU discharge to first seizure minus the interval between the last two seizures before EMU admission. A total of 43 patients completed the study; 15 were on monotherapy. SIP was greater than zero in this patient group (p a mean prolongation of 19.4 +/- 28.0 days. The average SIP was higher (p = 0.01) in patients on monotherapy (29.7 +/- 23.8 days) than patients on polytherapy (13.9 +/- 29.0 days). SIP tended to be greater in patients with a prior history of AED tolerance (25.7 +/- 36.8 days) compared to patient with no prior history of AED tolerance (14.0 +/- 16.3 days). SIP does occur after brief AED withdrawal. This effect is greater in patients on monotherapy and tends to be larger in patients with a history of AED tolerance. The SIP effect may be related to the phenomenon of tolerance, clinically seen as resistance to AED therapeutic effect.

  12. Rapid determination of anti-tuberculosis drug resistance from whole-genome sequences

    KAUST Repository

    Coll, Francesc

    2015-05-27

    Mycobacterium tuberculosis drug resistance (DR) challenges effective tuberculosis disease control. Current molecular tests examine limited numbers of mutations, and although whole genome sequencing approaches could fully characterise DR, data complexity has restricted their clinical application. A library (1,325 mutations) predictive of DR for 15 anti-tuberculosis drugs was compiled and validated for 11 of them using genomic-phenotypic data from 792 strains. A rapid online ‘TB-Profiler’ tool was developed to report DR and strain-type profiles directly from raw sequences. Using our DR mutation library, in silico diagnostic accuracy was superior to some commercial diagnostics and alternative databases. The library will facilitate sequence-based drug-susceptibility testing.

  13. mGlu2 Receptor Agonism, but Not Positive Allosteric Modulation, Elicits Rapid Tolerance towards Their Primary Efficacy on Sleep Measures in Rats.

    Directory of Open Access Journals (Sweden)

    Abdallah Ahnaou

    Full Text Available G-protein-coupled receptor (GPCR agonists are known to induce both cellular adaptations resulting in tolerance to therapeutic effects and withdrawal symptoms upon treatment discontinuation. Glutamate neurotransmission is an integral part of sleep-wake mechanisms, which processes have translational relevance for central activity and target engagement. Here, we investigated the efficacy and tolerance potential of the metabotropic glutamate receptors (mGluR2/3 agonist LY354740 versus mGluR2 positive allosteric modulator (PAM JNJ-42153605 on sleep-wake organisation in rats. In vitro, the selectivity and potency of JNJ-42153605 were characterized. In vivo, effects on sleep measures were investigated in rats after once daily oral repeated treatment for 7 days, withdrawal and consecutive re-administration of LY354740 (1-10 mg/kg and JNJ-42153605 (3-30 mg/kg. JNJ-42153605 showed high affinity, potency and selectivity at mGluR2. Binding site analyses and knowledge-based docking confirmed the specificity of JNJ-42153605 at the mGluR2 allosteric binding site. Acute LY354740 and JNJ-42153605 dose-dependently decreased rapid eye movement (REM sleep time and prolonged its onset latency. Sub chronic effects of LY354740 on REM sleep measures disappeared from day 3 onwards, whereas those of JNJ-42153605 were maintained after repeated exposure. LY354740 attenuated REM sleep homeostatic recovery, while this was preserved after JNJ-42153605 administration. JNJ-42153605 enhanced sleep continuity and efficiency, suggesting its potential as an add-on medication for impaired sleep quality during early stages of treatment. Abrupt cessation of JNJ-42153605 did not induce withdrawal phenomena and sleep disturbances, while the initial drug effect was fully reinstated after re-administration. Collectively, long-term treatment with JNJ-42153605 did not induce tolerance phenomena to its primary functional effects on sleep measures, nor adverse effects at withdrawal, while it

  14. Rapid, serial, non-invasive assessment of drug efficacy in mice with autoluminescent Mycobacterium ulcerans infection.

    Directory of Open Access Journals (Sweden)

    Tianyu Zhang

    Full Text Available Buruli ulcer (BU caused by Mycobacterium ulcerans is the world's third most common mycobacterial infection. There is no vaccine against BU and surgery is needed for patients with large ulcers. Although recent experience indicates combination chemotherapy with streptomycin and rifampin improves cure rates, the utility of this regimen is limited by the 2-month duration of therapy, potential toxicity and required parenteral administration of streptomycin, and drug-drug interactions caused by rifampin. Discovery and development of drugs for BU is greatly hampered by the slow growth rate of M. ulcerans, requiring up to 3 months of incubation on solid media to produce colonies. Surrogate markers for evaluating antimicrobial activity in real-time which can be measured serially and non-invasively in infected footpads of live mice would accelerate pre-clinical evaluation of new drugs to treat BU. Previously, we developed bioluminescent M. ulcerans strains, demonstrating proof of concept for measuring luminescence as a surrogate marker for viable M. ulcerans in vitro and in vivo. However, the requirement of exogenous substrate limited the utility of such strains, especially for in vivo experiments.For this study, we engineered M. ulcerans strains that express the entire luxCDABE operon and therefore are autoluminescent due to endogenous substrate production. The selected reporter strain displayed a growth rate and virulence similar to the wild-type parent strain and enabled rapid, real-time monitoring of in vitro and in vivo drug activity, including serial, non-invasive assessments in live mice, producing results which correlated closely with colony-forming unit (CFU counts for a panel of drugs with various mechanisms of action.Our results indicate that autoluminescent reporter strains of M. ulcerans are exceptional tools for pre-clinical evaluation of new drugs to treat BU due to their potential to drastically reduce the time, effort, animals, compound

  15. Rapid Identification of Potential Drugs for Diabetic Nephropathy Using Whole-Genome Expression Profiles of Glomeruli

    Directory of Open Access Journals (Sweden)

    Jingsong Shi

    2016-01-01

    Full Text Available Objective. To investigate potential drugs for diabetic nephropathy (DN using whole-genome expression profiles and the Connectivity Map (CMAP. Methodology. Eighteen Chinese Han DN patients and six normal controls were included in this study. Whole-genome expression profiles of microdissected glomeruli were measured using the Affymetrix human U133 plus 2.0 chip. Differentially expressed genes (DEGs between late stage and early stage DN samples and the CMAP database were used to identify potential drugs for DN using bioinformatics methods. Results. (1 A total of 1065 DEGs (FDR 1.5 were found in late stage DN patients compared with early stage DN patients. (2 Piperlongumine, 15d-PGJ2 (15-delta prostaglandin J2, vorinostat, and trichostatin A were predicted to be the most promising potential drugs for DN, acting as NF-κB inhibitors, histone deacetylase inhibitors (HDACIs, PI3K pathway inhibitors, or PPARγ agonists, respectively. Conclusion. Using whole-genome expression profiles and the CMAP database, we rapidly predicted potential DN drugs, and therapeutic potential was confirmed by previously published studies. Animal experiments and clinical trials are needed to confirm both the safety and efficacy of these drugs in the treatment of DN.

  16. Melanin binding study of clinical drugs with cassette dosing and rapid equilibrium dialysis inserts.

    Science.gov (United States)

    Pelkonen, Laura; Tengvall-Unadike, Unni; Ruponen, Marika; Kidron, Heidi; Del Amo, Eva M; Reinisalo, Mika; Urtti, Arto

    2017-11-15

    Melanin pigment is a negatively charged polymer found in pigmented human tissues. In the eye, iris, ciliary body, choroid and retinal pigment epithelium (RPE) are heavily pigmented. Several drug molecules are known to bind to melanin, but larger sets of drugs have not been compared often in similar test conditions. In this study, we introduce a powerful tool for screening of melanin binding. The binding of a set of 34 compounds to isolated porcine RPE melanin was determined by cassette (n-in-one) dosing in rapid equilibrium dialysis inserts and the binding was quantitated with LC-MS/MS analytics. The compounds represented large variety in melanin binding (from 8.6%, ganciclovir) to over 95% bound (ampicillin and ciprofloxacin). The data provides information on melanin binding of small molecular weight compounds that are used for ocular (e.g. brinzolamide, ganciclovir) and systemic (e.g. tizanidine, indomethacin) therapy. Interestingly, competition among compounds was seen for melanin binding and the binding did not show any correlation with plasma protein binding. These results increase the understanding of melanin binding of ocular drugs and can be further exploited to predict pharmacokinetics in the eye. Pigment binding provides an interesting option for improved drug distribution to retina and choroid that are difficult target tissues in drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Comparison of the pattern, efficacy, and tolerability of self-medicated drugs in primary dysmenorrhea: A questionnaire based survey

    Science.gov (United States)

    Sugumar, Ramya; Krishnaiah, Vasundara; Channaveera, Gokul Shetty; Mruthyunjaya, Shilpa

    2013-01-01

    Objective: To compare the pattern, efficacy, and tolerability of self-medicated drugs and to assess the adequacy of their dose in primary dysmenorrhea (PD). Materials and Methods: A survey using a self-developed, validated, objective, and structured questionnaire as a tool was conducted among subjects with PD. Statistical analysis was carried out using Chi-square test and ANOVA with post-hoc Tuckey's test. Results: Out of 641 respondents, 42% were self-medicated. The pattern of drugs used was: Dicyclomine, an unknown drug, mefenamic acid, mefenamic acid + dicyclomine, and metamizole by 35%, 29%, 26%, 9%, and 1% of respondents, respectively. Mefenamic acid + dicyclomine, the combination was the most efficacious in comparison to other drugs in moderate to severe dysmenorrhea. There was better tolerability with mefenamic acid + dicyclomine group compared to other drugs. Sub-therapeutic doses were used by 86% of self-medicating respondents. Conclusions: The prevailing self-medication practices were inappropriate in a substantial proportion of women with inadequate knowledge regarding appropriate drug choice, therapeutic doses, and their associated side effects. PMID:23716896

  18. Rapid identification of a Mycobacterium tuberculosis full genetic drug resistance profile through whole genome sequencing directly from sputum

    Directory of Open Access Journals (Sweden)

    Camus Nimmo

    2017-09-01

    Discussion: Compared to rapid molecular tests (which can only examine a limited number of mutations and WGS of culture isolates (which requires a culture step, WGS directly from sputum can quickly generate a complete genetic drug resistance profile. In this case, WGS altered the clinical management of drug-resistant tuberculosis and demonstrated potential for guiding individualized drug treatment where second-line drug resistance is common.

  19. A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo.

    Directory of Open Access Journals (Sweden)

    Joyoti Dey

    Full Text Available While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies.

  20. Contribution of the Chromosomal ccdAB Operon to Bacterial Drug Tolerance.

    Science.gov (United States)

    Gupta, Kritika; Tripathi, Arti; Sahu, Alishan; Varadarajan, Raghavan

    2017-10-01

    One of the first identified and best-studied toxin-antitoxin (TA) systems in Escherichia coli is the F-plasmid-based CcdAB system. This system is involved in plasmid maintenance through postsegregational killing. More recently, ccdAB homologs have been found on the chromosome, including in pathogenic strains of E. coli and other bacteria. However, the functional role of chromosomal ccdAB genes, if any, has remained unclear. We show that both the native ccd operon of the E. coli O157 strain (ccdO157) and the ccd operon from the F plasmid (ccdF), when inserted on the E. coli chromosome, lead to protection from cell death under multiple antibiotic stress conditions through formation of persisters, with the O157 operon showing higher protection. While the plasmid-encoded CcdB toxin is a potent gyrase inhibitor and leads to bacterial cell death even under fully repressed conditions, the chromosomally encoded toxin leads to growth inhibition, except at high expression levels, where some cell death is seen. This was further confirmed by transiently activating the chromosomal ccd operon through overexpression of an active-site inactive mutant of F-plasmid-encoded CcdB. Both the ccdF and ccdO157 operons may share common mechanisms for activation under stress conditions, eventually leading to multidrug-tolerant persister cells. This study clearly demonstrates an important role for chromosomal ccd systems in bacterial persistence.IMPORTANCE A large number of free-living and pathogenic bacteria are known to harbor multiple toxin-antitoxin systems, on plasmids as well as on chromosomes. The F-plasmid CcdAB system has been extensively studied and is known to be involved in plasmid maintenance. However, little is known about the function of its chromosomal counterpart, found in several pathogenic E. coli strains. We show that the native chromosomal ccd operon of the E. coli O157 strain is involved in drug tolerance and confers protection from cell death under multiple antibiotic

  1. Ancestral genetic diversity associated with the rapid spread of stress-tolerant coral symbionts in response to Holocene climate change

    KAUST Repository

    Hume, Benjamin C. C.

    2016-04-05

    Coral communities in the Persian/Arabian Gulf (PAG) withstand unusually high salinity levels and regular summer temperature maxima of up to ∼35 °C that kill conspecifics elsewhere. Due to the recent formation of the PAG and its subsequent shift to a hot climate, these corals have had only <6, 000 y to adapt to these extreme conditions and can therefore inform on how coral reefs may respond to global warming. One key to coral survival in the world\\'s warmest reefs are symbioses with a newly discovered alga, Symbiodinium thermophilum. Currently, it is unknown whether this symbiont originated elsewhere or emerged from unexpectedly fast evolution catalyzed by the extreme environment. Analyzing genetic diversity of symbiotic algae across >5, 000 km of the PAG, the Gulf of Oman, and the Red Sea coastline, we show that S. thermophilum is a member of a highly diverse, ancient group of symbionts cryptically distributed outside the PAG. We argue that the adjustment to temperature extremes by PAG corals was facilitated by the positive selection of preadapted symbionts. Our findings suggest that maintaining the largest possible pool of potentially stress-tolerant genotypes by protecting existing biodiversity is crucial to promote rapid adaptation to present-day climate change, not only for coral reefs, but for ecosystems in general.

  2. A history into genetic and epigenetic evolution of food tolerance: how humanity rapidly evolved by drinking milk and eating wheat.

    Science.gov (United States)

    Blanchard, Carine

    2017-12-01

    Human exposure to wheat and milk is almost global worldwide. Yet the introduction of milk and wheat is very recent (5000-10 000 years) when compared to the human evolution. The last 4 decades have seen a rise in food allergy and food intolerance to milk and wheat. Often described as plurifactorial, the cause of allergic diseases is the result from an interplay between genetic predisposition and epigenetic in the context of environmental changes. Genetic and epigenetic understanding and their contribution to allergy or other antigen-driven diseases have considerably advanced in the last few years. Yet, environmental factors are also quite difficult to identify and associate with disease risk. Can we rethink our old findings and learn from human history and recent genetic studies? More than one million years separate Homo habilis to today's mankind, more than 1 million years to develop abilities to obtain food by foraging in diverse environments. One million year to adjust and fine-tune our genetic code and adapt; and only 1% of this time, 10 000 years, to face the three biggest revolutions of the human kind: the agricultural revolution, the industrial revolution and the postindustrial revolution. With big and rapid environmental changes come adaptation but with no time for fine-tuning. Today tolerance and adverse reactions to food may be a testimony of adaptation successes and mistakes.

  3. The ABC of Biofilm Drug Tolerance: the MerR-Like Regulator BrlR Is an Activator of ABC Transport Systems, with PA1874-77 Contributing to the Tolerance of Pseudomonas aeruginosa Biofilms to Tobramycin.

    Science.gov (United States)

    Poudyal, Bandita; Sauer, Karin

    2018-02-01

    A hallmark of biofilms is their tolerance to killing by antimicrobial agents. In Pseudomonas aeruginosa, biofilm drug tolerance requires the c-di-GMP-responsive MerR transcriptional regulator BrlR. However, the mechanism by which BrlR mediates biofilm drug tolerance has not been elucidated. Here, we demonstrate that BrlR activates the expression of at least 7 ABC transport systems, including the PA1874-PA1875-PA1876-PA1877 (PA1874-77) operon, with chromatin immunoprecipitation and DNA binding assays confirming BrlR binding to the promoter region of PA1874-77. Insertional inactivation of the 7 ABC transport systems rendered P. aeruginosa PAO1 biofilms susceptible to tobramycin or norfloxacin. Susceptibility was linked to drug accumulation, with BrlR contributing to norfloxacin accumulation in a manner dependent on multidrug efflux pumps and the PA1874-77 ABC transport system. Inactivation of the respective ABC transport system, furthermore, eliminated the recalcitrance of biofilms to killing by tobramycin but not norfloxacin, indicating that drug accumulation is not linked to biofilm drug tolerance. Our findings indicate for the first time that BrlR, a MerR-type transcriptional activator, activates genes encoding several ABC transport systems, in addition to multiple multidrug efflux pump genes. Moreover, our data confirm a BrlR target contributing to drug tolerance, likely countering the prevailing dogma that biofilm tolerance arises from a multiplicity of factors. Copyright © 2018 American Society for Microbiology.

  4. A novel, high-sensitivity and drug-tolerant sandwich immunoassay for the quantitative measurement of circulating proteins.

    Science.gov (United States)

    Sloan, John H; Ackermann, Bradley L; Carpenter, John W; Nguyen, Huy T; Stopa, Kimberly; Siegel, Robert W; Konrad, Robert J

    2012-02-01

    Accurate measurement of a total protein target (free plus bound) is essential to optimize dose selection for monoclonal antibody drugs. Herein, we describe a novel sandwich immunoassay format in which the biotherapeutic antibody itself serves as the primary detection antibody. A signal is then generated through the addition of a labeled secondary antibody that recognizes the biotherapeutic antibody. The secondary antibody is conjugated with ruthenium to facilitate electrochemiluminescent analysis. Data are presented from the analysis of two protein biomarkers having disparate size and structure; a 4.5 kDa peptide and a 60 kDa protein. In both cases, validated, highly specific assays were developed and shown to be tolerant to elevated levels of the therapeutic monoclonal antibody in question. Our novel format allows drug-tolerant measurement of soluble protein biomarkers targeted by monoclonal antibodies when only two independent epitopes for antibody binding are available and one is recognized by the therapeutic antibody.

  5. Systematic review of the performance of rapid rifampicin resistance testing for drug-resistant tuberculosis.

    Directory of Open Access Journals (Sweden)

    Matthew Arentz

    Full Text Available INTRODUCTION: Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB. However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. METHODS: We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. RESULTS: We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI assay, Nitrate Reductase Assay (NRA and MODS tests: for all tests, negative predictive values were high when rifampicin resistance prevalence was ≤ 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. LIMITATIONS: In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. DISCUSSION: Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

  6. Rapidly Progrediating Aortic Valve Infective Endocarditis in an Intravenous Drug User Treated by Antibiotics and Surgery

    Directory of Open Access Journals (Sweden)

    Malkia S. Swedi

    2012-01-01

    Full Text Available We report the case of a 22-year old male, a self-confessed recreational drug user who developed cardiogenic shock because of severe destruction of the aortic valve by rapidly progressive aortic valve endocarditis. The disease progression was acute; in a matter of days, the clinical manifestations were life-threatening necessitating urgent aortic valve replacement surgery. Cultivation revealed Streptococcus viridans as the microbial agent. Subsequent recovery with antibiotic treatment was without complication. This case report shows that immediately performed transoesophageal echocardiography and early consultation with a cardiac surgeon has fundamental importance in diagnosis and management of acute infective endocarditis in haemodynamically instable patients.

  7. L-form transformation phenomenon in Mycobacterium tuberculosis associated with drug tolerance to ethambutol

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    Georgi Slavchev

    2016-01-01

    Full Text Available Objective/background: Cell wall-deficient bacterial forms (L-forms may occur along with resistance to factors that trigger their appearance. It is of interest to study the relationship between the L-form transformation of Mycobacterium tuberculosis and the exhibition of drug tolerance to ethambutol (EMB, an inhibitor of cell wall synthesis. Methods: L-form variant was produced from a sensitive EMB strain of M. Tuberculosis through a cryogenic stress treatment protocol and was subsequently cultivated in Middlebrook 7H9 semisolid medium, containing EMB in a minimal inhibitory concentration of 2 mg/L. Susceptibility to EMB of the parental strain and its L-form variant was evaluated phenotypically and using polymerase chain reaction-restriction fragment length polymorphism assay targeting a mutation in the embB306 gene fragment. Results: In contrast to the sensitivity to EMB of the parental strain, its L-form variant showed phenotypic resistance to high concentrations of EMB (16 mg/L, but the mutation in embB306 was not found. Electron microscopy observation of the L-form variant showed a heterogenic population of bacteria, with different degrees of cell wall deficiency, as well as cells of protoplastic type without cell walls. Of special interest were the observed capsule-like structures around the L-form cells and the biofilm-like matrix produced by the L-form population. Conclusion: We suggest that the expression of phenotypic resistance to EMB in M. Tuberculosis can be associated with alterations or loss of cell walls in L-form bacteria, respectively, which results in a lack of a specific target for EMB action. In addition, production of capsule-like structures and biofilm matrix by L-forms could contribute to their resistance and survival in the presence of antibacterial agents.

  8. Do thermal tolerances and rapid thermal responses contribute to the invasion potential of Bactrocera dorsalis (Diptera: Tephritidae)?

    Science.gov (United States)

    Pieterse, Welma; Terblanche, John S; Addison, Pia

    2017-04-01

    Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) has shown remarkable range expansion over the past 10years and invaded several new continents including Africa. Here we report results of a detailed assessment of acute high and low temperature survival ability and the plasticity thereof, to test the hypothesis that traits of the thermal niche have contributed to the species' invasion ability. We also assess life-stage-related variation of thermal tolerances to determine potential stage-related environmental sensitivity. The temperatures at which c. 20% of the population survived of B. dorsalis were determined to be -6.5°C and 42.7°C, respectively, when using 2h exposures. Further, four life stages of B. dorsalis (egg, 3rd instar larvae, pupae and adults) were exposed to high and low discriminating temperatures to compare their thermal survival rates. The egg stage was found to be the most resistant life stage to both high and low temperatures, since 44±2.3% survived the low and 60±4.2% survived the high discriminating temperature treatments respectively. Finally, the potential for adult hardening responses to mediate tolerance of extremes was also considered using a diverse range of acute conditions (using 2h exposures to 15°C, 10°C and 5°C and 30°C, 35°C, 37°C and 39°C as hardening temperatures, and some treatments with and without recovery periods between hardening and discriminating temperature treatment). These showed that although some significant hardening responses could be detected in certain treatments (e.g. after exposure to 37°C and 39°C), the magnitude of this plasticity was generally low compared to two other wide-spread and more geographically-range-restricted con-familial species, Ceratitis capitata and C. rosa. In other words, Bactrocera dorsalis adults were unable to rapidly heat- or cold-harden to the same extent as the other Ceratitis species examined to date. These results suggest a narrower thermal niche in B. dorsalis compared

  9. Effect of endotoxin tolerance on drug hepatotoxicity: amelioration of taurolithocholate cholestasis in the perfused rat liver.

    Science.gov (United States)

    Utili, R; Adinolfi, L E; Gaeta, G B; Tripodi, M F; Alvaro, D

    1987-01-01

    Induction of endotoxin tolerance may cause resistance not only to endotoxin itself but also to the hepatotoxic effects of other membrane-active agents. To further study this effect, we tested whether endotoxin tolerance could ameliorate the adverse effects of taurolithocholate (TLCA) which causes cholestasis by altering liver plasma membrane organization. Isolated perfused rat livers from endotoxin-tolerant rats had a lower basal bile flow than control livers. However, a bolus addition of TLCA at 3 X 10(-5) or 5 X 10(-5) M in the perfusate caused a marked and prolonged decrease of bile flow in controls, but only a transient and significantly less pronounced diminution of bile flow in endotoxin-tolerant livers. Likewise, TLCA caused a significantly lower alteration of hepatocyte membrane permeability, as measured by sucrose permeability studies, in endotoxin-tolerant livers than in controls. Analysis of bile acid composition of bile from endotoxin-tolerant livers demonstrated that they excreted greater amounts of total bile acids, in particular TLCA and taurocholate, than controls. These results demonstrated a protective effect of endotoxin-tolerance against TLCA toxicity which may result from an altered interaction of TLCA with liver membranes and an increased clearance of TLCA.

  10. Applying green analytical chemistry for rapid analysis of drugs: Adding health to pharmaceutical industry

    Directory of Open Access Journals (Sweden)

    Nazrul Haq

    2017-02-01

    Full Text Available Green RP-HPLC method for a rapid analysis of olmesartan medoxomil (OLM in bulk drugs, self-microemulsifying drug delivery system (SMEDDS and marketed tablets was developed and validated in the present investigation. The chromatographic identification was achieved on Lichrosphere 250 × 4.0 mm RP C8 column having a 5 μm packing as a stationary phase using a combination of green solvents ethyl acetate:ethanol (50:50% v/v as a mobile phase, at a flow rate of 1.0 mL/min with UV detection at 250 nm. The proposed method was validated for linearity, selectivity, accuracy, precision, reproducibility, robustness, sensitivity and specificity. The utility of the proposed method was verified by an assay of OLM in SMEDDS and commercial tablets. The proposed method was found to be selective, precise, reproducible, accurate, robust, sensitive and specific. The amount of OLM in SMEDDS and commercial tablets was found to be 101.25% and 98.67% respectively. The proposed method successfully resolved OLM peak in the presence of its degradation products which indicated stability-indicating property of the proposed method. These results indicated that the proposed method can be successfully employed for a routine analysis of OLM in bulk drugs and commercial formulations.

  11. Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance.

    Science.gov (United States)

    Lanzi, C; Perego, P; Supino, R; Romanelli, S; Pensa, T; Carenini, N; Viano, I; Colangelo, D; Leone, R; Apostoli, P; Cassinelli, G; Gambetta, R A; Zunino, F

    1998-04-15

    In an attempt to examine the cellular changes associated with cisplatin resistance, we selected a cisplatin-resistant (A43 1/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellular defence systems and other cellular factors probably involved in dealing with cisplatin-induced DNA damage. Resistant cells exhibited decreased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. Analysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G2M arrest in sensitive and resistant cells. Interestingly, a slowdown in S-phase transit was found in A431/Pt cells. A comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to tolerate higher levels of cisplatin-induced DNA damage than their parental counterparts. Analysis of the expression of proteins involved in DNA mismatch repair showed a decreased level of MSH2 in resistant cells. Since MSH2 seems to be involved in recognition of drug-induced DNA damage, this change may account for the increased tolerance to DNA damage observed in the resistant subline. In conclusion, the involvement of accumulation defects and the increased tolerance to cisplatin-induced DNA damage in these cisplatin-resistant cells support the notion that multiple changes contribute to confer a low level of cisplatin resistance.

  12. Real time PCR for the rapid identification and drug susceptibility of Mycobacteria present in Bronchial washings

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    Thilini Piushani Keerthirathne

    2016-10-01

    Full Text Available Abstract Background Mycobacteria have a spectrum of virulence and different susceptibilities to antibiotics. Distinguishing mycobacterial species is vital as patients with non-tuberculous mycobacterial (NTM infections present clinical features that are similar to those of patients with tuberculosis. Thus, rapid differentiation of Mycobacterium tuberculosis complex from NTM is critical to administer appropriate treatment. Hence the aim of the study was to rapid identification of mycobacterial species present in bronchial washings using multiplex real time Polymerase Chain Reaction (PCR and to determine the drug susceptibility in identified mycobacterial species. Methods Sputum smear negative bronchoscopy specimens (n = 150 were collected for a period of one year, from patients attending the General Hospital Kandy, Sri Lanka. The specimens were processed with modified Petroff’s method and were cultured on Löwenstein– Jensen medium. DNA, extracted from the mycobacterial isolates were subjected to a SYBR green mediated real time multiplex, PCR assay with primers specific for the M. tuberculosis complex, M. avium complex, M. chelonae-M.abscessus group and M. fortuitum group. DNA sequencing was performed for the species confirmation, by targeting the 16S rRNA gene and the drug susceptibility testing was performed for the molecularly identified isolates of M. tuberculosis and NTM. Results The optimized SYBR Green mediated multiplex real-time PCR assay was able to identify the presence of genus Mycobacterium in 25 out of 26 AFB positive isolates, two M. tuberculosis complex, three M. avium complex and two isolates belonging to M. chelonae-M. abscessus group. DNA sequencing confirmed the presence of M. tuberculosis, M. chelonae-M. abscessus, M. intracellulare, M. avium, Rhodococcus sp. and M. celatum. Remaining isolates were identified as Mycobacterium sp. All the NTM isolates were sensitive to amikacin and seven were resistant to ciproflaxacin

  13. Tolerance to alternative cyclooxygenase-2 inhibitors in nonsteroidal anti-inflammatory drug hypersensitive patients

    NARCIS (Netherlands)

    W.S.J. Malskat (Wendy S.); A.C. Knulst (André); C.A.F.M. Bruijnzeel-Koomen; Röckmann, H. (Heike)

    2013-01-01

    textabstractBackground: Non-steroidal anti-inflammatory drugs (NSAIDs) frequently cause adverse drug reactions. Many studies have shown that drugs which selectively inhibit the cyclooxygenase-2 enzyme (COX-2) are safe alternatives in the majority of patients. However, hypersensitivity reactions to

  14. Drug-Related Hyponatremic Encephalopathy: Rapid Clinical Response Averts Life-Threatening Acute Cerebral Edema.

    Science.gov (United States)

    Siegel, Arthur J; Forte, Sophie S; Bhatti, Nasir A; Gelda, Steven E

    2016-03-09

    Drug-induced hyponatremia characteristically presents with subtle psychomotor symptoms due to its slow onset, which permits compensatory volume adjustment to hypo-osmolality in the central nervous system. Due mainly to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), this condition readily resolves following discontinuation of the responsible pharmacological agent. Here, we present an unusual case of life-threatening encephalopathy due to adverse drug-related effects, in which a rapid clinical response facilitated emergent treatment to avert life-threatening acute cerebral edema. A 63-year-old woman with refractory depression was admitted for inpatient psychiatric care with a normal physical examination and laboratory values, including a serum sodium [Na+] of 144 mEq/L. She had a grand mal seizure and became unresponsive on the fourth day of treatment with the dual serotonin and norepinephrine reuptake inhibitor [SNRI] duloxetine while being continued on a thiazide-containing diuretic for a hypertensive disorder. Emergent infusion of intravenous hypertonic (3%) saline was initiated after determination of a serum sodium [Na+] of 103 mEq/L with a urine osmolality of 314 mOsm/kg H20 and urine [Na+] of 12 mEq/L. Correction of hyposmolality in accordance with current guidelines resulted in progressive improvement over several days, and she returned to her baseline mental status. Seizures with life-threatening hyponatremic encephalopathy in this case likely resulted from co-occurring SIADH and sodium depletion due to duloxetine and hydrochlorothiazide, respectively. A rapid clinical response expedited diagnosis and emergent treatment to reverse life-threatening acute cerebral edema and facilitate a full recovery without neurological complications.

  15. Treatment of fevers prior to introducing rapid diagnostic tests for malaria in registered drug shops in Uganda

    DEFF Research Database (Denmark)

    Mbonye, Anthony K.; Lal, Sham; Cundill, Bonnie

    2013-01-01

    shops on presenting symptoms, the consultation process, treatment received, and malaria diagnoses. Malaria diagnosis made by drug shop vendors were confirmed by the study team through microscopy examination of a blood slide to ascertain whether appropriate treatment was received. RESULTS: Among febrile......BACKGROUND: Since drug shops play an important role in treatment of fever, introducing rapid diagnostic tests (RDTs) for malaria at drug shops may have the potential of targeting anti-malarial drugs to those with malaria parasites and improve rational drug use. As part of a cluster randomized trial...... to examine impact on appropriate treatment of malaria in drug shops in Uganda and adherence to current malaria treatment policy guidelines, a survey was conducted to estimate baseline prevalence of, and factors associated with, appropriate treatment of malaria to enable effective design and implementation...

  16. Evaluation of rapid alternative methods for drug susceptibility testing in clinical isolates of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Luciano Mengatto

    2006-08-01

    Full Text Available A study was carried out to compare the performance of a commercial method (MGIT and four inexpensive drug susceptibility methods: nitrate reductase assay (NRA, microscopic observation drug susceptibility (MODS assay, MTT test, and broth microdilution method (BMM. A total of 64 clinical isolates of Mycobacterium tuberculosis were studied. The Lowenstein-Jensen proportion method (PM was used as gold standard. MGIT, NRA, MODS, and MTT results were available on an average of less than 10 days, whereas BMM results could be reported in about 20 days. Most of the evaluated tests showed excellent performance for isoniazid and rifampicin, with sensitivity and specificity values > 90%. With most of the assays, sensitivity for ethambutol was low (62-87% whereas for streptomycin, sensitivity values ranged from 84 to 100%; NRA-discrepancies were associated with cultures with a low proportion of EMB-resistant organisms while most discrepancies with quantitative tests (MMT and BMM were seen with isolates whose minimal inhibitory concentrations fell close the cutoff. MGIT is reliable but still expensive. NRA is the most inexpensive and easiest method to perform without changing the organization of the routine PM laboratory performance. While MODS, MTT, and BMM, have the disadvantage from the point of view of biosafety, they offer the possibility of detecting partial resistant strains. This study shows a very good level of agreement of the four low-cost methods compared to the PM for rapid detection of isoniazid, rifampicin and streptomycin resistance (Kappa values > 0.8; more standardization is needed for ethambutol.

  17. Veterinary drug residues in meat: Concerns and rapid methods for detection.

    Science.gov (United States)

    Reig, Milagro; Toldrá, Fidel

    2008-01-01

    The use of substances having hormonal or thyreostatic action as well as β-agonists is banned in the European Union. However, sometimes forbidden drugs may be added to feeds for illegal administration to farm animals for promoting increased muscle development or increased water retention and thus obtain an economical benefit. The result is a fraudulent overweight of meat but, what is worse, residues of these substances may remain in meat and may pose a real threat to the consumer either through exposure to the residues, transfer of antibiotic resistance or allergy risk. This has exerted a great concern among European consumers. The control of the absence of these forbidden substances in animal foods and feeds is regulated in the European Union by Directive96/23/EC on measures to monitor certain substances and residues in live animals and animal products. Analytical methodology, including criteria for identification and confirmation, for the monitoring of compliance was also given in Decisions 93/256/EEC and 93/257/EEC. More recently, Decision 2002/657/EC provided rules for the analytical methods to be used in testing of official samples. A crucial step is the screening of veterinary drug residues in live animals, feeds and animal products in view of the remarkable number of samples and large variety of residues to be analysed. In recent years, different rapid methods having easy performance, high sensitivity and high throughput have been proposed and are being extensively used. These methods as well as other new methods are reviewed in this manuscript.

  18. Acceptability of rapid oral fluid HIV testing among male injection drug users in Taiwan, 1997 and 2007.

    Science.gov (United States)

    Lyu, Shu-Yu; Morisky, Donald E; Yeh, Ching-Ying; Twu, Shiing-Jer; Peng, Eugene Yu-Chang; Malow, Robert M

    2011-04-01

    Rapid oral fluid HIV testing (rapid oral testing) is in the process of being adapted in Taiwan and elsewhere given its advantages over prior HIV testing methods. To guide this process, we examined the acceptability of rapid oral testing at two time points (i.e., 1997 and 2007) among one of the highest risk populations, male injection drug users (IDUs). For this purpose, an anonymous self-administered survey was completed by HIV-negative IDUs involved in the criminal justice system in 1997 (N (1)=137 parolees) and 2007 (N (2)=106 prisoners). A social marketing model helped guide the design of our questionnaire to assess the acceptability of rapid oral testing. This included assessing a new product, across four marketing dimensions: product, price, promotion, and place. Results revealed that in both 1997 and 2007, over 90% indicated that rapid oral testing would be highly acceptable, particularly if the cost was under US$6, and that a pharmacy would be the most appropriate and accessible venue for selling the rapid oral testing kits. The vast majority of survey respondents believed that the cost of rapid oral testing should be federally subsidized and that television and newspaper advertisements would be the most effective media to advertise for rapid oral testing. Both the 1997 and 2007 surveys suggested that rapid oral HIV testing would be particularly accepted in Taiwan by IDUs after release from the criminal justice system.

  19. Rapid detection of drug resistance and mutational patterns of extensively drug-resistant strains by a novel GenoType® MTBDRsl assay.

    Science.gov (United States)

    Singh, A K; Maurya, A K; Kant, S; Umrao, J; Kushwaha, R A S; Nag, V L; Dhole, T N

    2013-01-01

    The emergence of extensively drug-resistant tuberculosis (XDR-TB) is a major concern in the India. The burden of XDR-TB is increasing due to inadequate monitoring, lack of proper diagnosis, and treatment. The GenoType ® Mycobacterium tuberculosis drug resistance second line (MTBDRsl) assay is a novel line probe assay used for the rapid detection of mutational patterns conferring resistance to XDR-TB. The aim of this study was to study the rapid detection of drug resistance and mutational patterns of the XDR-TB by a novel GenoType ® MTBDRsl assay. We evaluated 98 multidrug-resistant (MDR) M. tuberculosis isolates for second line drugs susceptibility testing by 1% proportion method (BacT/ALERT 3D system) and GenoType ® MTBDRsl assay for rapid detection of conferring drug resistance to XDR-TB. A total of seven (17.4%) were identified as XDR-TB by using standard phenotypic method. The concordance between phenotypic and GenoType ® MTBDRsl assay was 91.7-100% for different antibiotics. The sensitivity and specificity of the MTBDRsl assay were 100% and 100% for aminoglycosides; 100% and 100% for fluoroquinolones; 91.7% and 100% for ethambutol. The most frequent mutations and patterns were gyrA MUT1 (A90V) in seven (41.2%) and gyrA + WT1-3 + MUT1 in four (23.5%); rrs MUT1 (A1401G) in 11 (64.7%), and rrs WT1-2 + MUT1 in eight (47.1%); and embB MUT1B (M306V) in 11 (64.7%) strains. These data suggest that the GenoType ® MTBDRsl assay is rapid, novel test for detection of resistance to second line anti-tubercular drugs. This assay provides additional information about the frequency and mutational patterns responsible for XDR-TB resistance.

  20. Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) of therapeutic agents as the future direction.

    Science.gov (United States)

    Budker, Vladimir G; Monahan, Sean D; Subbotin, Vladimir M

    2014-12-01

    Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities. One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity. Although loco-regional delivery has been most prominent in cancers of the liver, soft tissues and serosal peritoneal malignancies, survival benefits are very far from desirable. This review discusses the evolution of loco-regional treatments, the present approaches and offers rapidly reversible hydrophobization of drugs as the new future direction. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Rapid assessment of drug use and sexual HIV risk patterns among ...

    African Journals Online (AJOL)

    This exploratory study examines the links between drug use and high-risk sexual practices and HIV in vulnerable drug-using populations in South Africa, including commercial sex workers (CSWs), men who have sex with men (MSM), injecting drug users (IDUs) and non-injecting drug users who are not CSWs or MSM ...

  2. Drugs used in Africa as dyes: I. Skin absorption and tolerability of Bixa orellana L.

    Science.gov (United States)

    Germano, M P; de Pasquale, R; Rapisarda, A; Monteleone, D; Keita, A; Sanogo, R

    1997-06-01

    Bixa orellana L. (Bixaceae) seed extract, used in Africa as a dye, was employed to evaluate the onset of the possible topical localized responses of the rabbit skin in single application, after repeated application and after UV exposure. Histologic studies were also carried out to evaluate the possible damage and penetration of Bixa colouring matter into the rabbit hairless skin and into the hairs. The study showed that Bixa orellana has a good cutaneous tolerability and may encourage the use as a source of colouring matter in cosmetology. Copyright © 1997 Gustav Fischer Verlag. Published by Elsevier GmbH.. All rights reserved.

  3. Validation of a rapid lateral flow test for the simultaneous determination of β-lactam drugs and flunixin in raw milk.

    Science.gov (United States)

    Douglas, David; Banaszewski, Katie; Juskelis, Rima; Al-Taher, Fadwa; Chen, Yang; Cappozzo, Jack; McRobbie, Lindsay; Salter, Robert S

    2012-07-01

    β-Lactam antibiotics are the most commonly used drugs on dairy farms. β-Lactam residues in milk are kept out of the human milk supply with good agricultural practices and mandatory truck screening performed by the dairy industry under Appendix N of the Pasteurized Milk Ordinance. Flunixin, a nonsteroidal and anti-inflammatory drug, appears in dairy cattle tissue residues with a frequency similar to the occurrence of penicillin G. This creates concern that flunixin residues could be in milk and would go undetected under current milk screening programs. A single test that combines mandatory β-lactam screening with voluntary flunixin screening is an economical approach for monitoring and controlling for potential flunixin or 5-hydroxyflunixin, the primary flunixin metabolite marker in milk. The objective of this study was to validate a β-lactam and flunixin rapid lateral flow test (LFT) and compare the results obtained with a liquid chromatography-triple quadrupole tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of flunixin and 5-hydroxyflunixin in raw milk with a limit of detection of , 1 ppb, equivalent to 1 ng/ml. Using the LFT, three combined manufactured lots of test strips detected penicillin G at 2.0 ppb, ampicillin at 6.8 ppb, amoxicillin at 5.9 ppb, cephapirin at 13.4 ppb, ceftiofur (total metabolites) at 63 ppb, and 5-hydroxyflunixin at 1.9 ppb at least 90% of the time with 95% confidence. The LFT also detected incurred flunixin milk samples that were analyzed with the LC-MS/MS and diluted to tolerance in raw milk. The detection levels for the LFT are lower than the U.S. safe levels or tolerances and qualify the test to be used in compliance with U.S. milk screening programs.

  4. 76 FR 57907 - Tolerances for Residues of New Animal Drugs in Food; Progesterone

    Science.gov (United States)

    2011-09-19

    ...: Kevin Gaido, Center for Veterinary Medicine (HFV-153), Food and Drug Administration, 7500 Standish Pl... and redelegated to the Center for Veterinary Medicine, 21 CFR part 556 is amended as follows: PART 556... animals: (1) Cattle and sheep--(i) Muscle: 5 parts per billion (ppb). (ii) Liver: 15 ppb. (iii) Kidney: 30...

  5. Cannabis and tolerance: acute drug impairment as a function of cannabis use history

    NARCIS (Netherlands)

    Ramaekers, J.G.; Wel, J.H. van; Spronk, D.B.; Toennes, S.W.; Kuypers, K.P.; Theunissen, E.L.; Verkes, R.J.

    2016-01-01

    Cannabis use history as predictor of neurocognitive response to cannabis intoxication remains subject to scientific and policy debates. The present study assessed the influence of cannabis on neurocognition in cannabis users whose cannabis use history ranged from infrequent to daily use. Drug users

  6. A Bayesian adaptive design for estimating the maximum tolerated dose curve using drug combinations in cancer phase I clinical trials.

    Science.gov (United States)

    Tighiouart, Mourad; Li, Quanlin; Rogatko, André

    2017-01-30

    We present a cancer phase I clinical trial design of a combination of two drugs with the goal of estimating the maximum tolerated dose curve in the two-dimensional Cartesian plane. A parametric model is used to describe the relationship between the doses of the two agents and the probability of dose limiting toxicity. The model is re-parameterized in terms of the probabilities of toxicities at dose combinations corresponding to the minimum and maximum doses available in the trial and the interaction parameter. Trial design proceeds using cohorts of two patients receiving doses according to univariate escalation with overdose control (EWOC), where at each stage of the trial, we seek a dose of one agent using the current posterior distribution of the MTD of this agent given the current dose of the other agent. The maximum tolerated dose curve is estimated as a function of Bayes estimates of the model parameters. Performance of the trial is studied by evaluating its design operating characteristics in terms of safety of the trial and percent of dose recommendation at dose combination neighborhoods around the true MTD curve and under model misspecifications for the true dose-toxicity relationship. The method is further extended to accommodate discrete dose combinations and compared with previous approaches under several scenarios. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  7. The effect of rapid detoxification method with Naltrexone on drug abuse quitting in drug abusers referred to Khorramabad Psychiatric hospital during the first half of the year 2005

    Directory of Open Access Journals (Sweden)

    hedayat Nazari

    2009-03-01

    Full Text Available Background: About 8 percent of Iranian adult population are illicit drug abusers. Affected persons grow more each day. Ominous consequences such as divorce, prostitution, murder and other crimes and infectious diseases such as AIDS and hepatitis take place following drug abuse, as well as a loss equall to 29% of national income for our country. Traditional treatment methods wasted too much time and cost. professional inpatient clinics are not adequate for admission of all care seekers. Rapid detoxification methods are supposed to be better alternatives. Materials and Methods: 140 male drug abusers in two matched groups were assessed from March to September, 2005. They used heroin or opium. Both groups were scheduled for detoxification and were closely observed for 3 months thereafter. First group received Clonidine, Benzodiazepine and Naltrexone besides symptom relieving modalities in first 4 days of treatment. Naltrexone was continued in maintenance dose for one month. Second group received Methadone for one month. Results: Clients age was between 18 to 73 years, with mean age 34 years old. Their intelligence quotients were above the lower limit of normal range. There was no significant difference according to these parameters between two groups. Success rate in rapid detoxification group was 55 % and in Methadone group was 50 %. Relapse in rapid detoxification method occurred less frequent and slower (45 % vs. 50%. In Naltrexone group, better success rate was due to less duration of drug abuse and heroin dependency. In Methadone group, therapy had better results in patients with longer drug abuse history and opium addiction. There was no significant difference between success rate and either drug kind or job, marital status or education level. The most serious adverse effect in both groups was hypotension (10% in Naltrexone and 5 % in Methadone groups.

  8. Reversible antibiotic tolerance induced in Staphylococcus aureus by concurrent drug exposure

    DEFF Research Database (Denmark)

    Haaber, Jakob Krause; Friberg, Cathrine; McCreary, Mark

    2015-01-01

    antibiotic that targets the coinfecting pathogen. While investigating factors that affect bacterial antibiotic sensitivity, we discovered that susceptibility of S. aureus to vancomycin is reduced by concurrent exposure to colistin, a cationic peptide antimicrobial employed to treat infections by Gram......UNLABELLED: Resistance of Staphylococcus aureus to beta-lactam antibiotics has led to increasing use of the glycopeptide antibiotic vancomycin as a life-saving treatment for major S. aureus infections. Coinfection by an unrelated bacterial species may necessitate concurrent treatment with a second......] strains). As colistin-induced vancomycin tolerance is reversible, it may not be detected by routine sensitivity testing and may be responsible for treatment failure at vancomycin doses expected to be clinically effective based on such routine testing. IMPORTANCE: Commonly, antibiotic resistance...

  9. Comparative Genomic Analysis of Rapid Evolution of an Extreme-Drug-Resistant Acinetobacter baumannii Clone

    Science.gov (United States)

    Tan, Sean Yang-Yi; Chua, Song Lin; Liu, Yang; Høiby, Niels; Andersen, Leif Percival; Givskov, Michael; Song, Zhijun; Yang, Liang

    2013-01-01

    The emergence of extreme-drug-resistant (EDR) bacterial strains in hospital and nonhospital clinical settings is a big and growing public health threat. Understanding the antibiotic resistance mechanisms at the genomic levels can facilitate the development of next-generation agents. Here, comparative genomics has been employed to analyze the rapid evolution of an EDR Acinetobacter baumannii clone from the intensive care unit (ICU) of Rigshospitalet at Copenhagen. Two resistant A. baumannii strains, 48055 and 53264, were sequentially isolated from two individuals who had been admitted to ICU within a 1-month interval. Multilocus sequence typing indicates that these two isolates belonged to ST208. The A. baumannii 53264 strain gained colistin resistance compared with the 48055 strain and became an EDR strain. Genome sequencing indicates that A. baumannii 53264 and 48055 have almost identical genomes—61 single-nucleotide polymorphisms (SNPs) were found between them. The A. baumannii 53264 strain was assembled into 130 contigs, with a total length of 3,976,592 bp with 38.93% GC content. The A. baumannii 48055 strain was assembled into 135 contigs, with a total length of 4,049,562 bp with 39.00% GC content. Genome comparisons showed that this A. baumannii clone is classified as an International clone II strain and has 94% synteny with the A. baumannii ACICU strain. The ResFinder server identified a total of 14 antibiotic resistance genes in the A. baumannii clone. Proteomic analyses revealed that a putative porin protein was down-regulated when A. baumannii 53264 was exposed to antimicrobials, which may reduce the entry of antibiotics into the bacterial cell. PMID:23538992

  10. Rapid expansion of intravitreal drug injection procedures, 2000 to 2008: a population-based analysis.

    Science.gov (United States)

    Campbell, Robert J; Bronskill, Susan E; Bell, Chaim M; Paterson, J Michael; Whitehead, Marlo; Gill, Sudeep S

    2010-03-01

    To evaluate patterns of care for age-related macular degeneration following the introduction of vascular endothelial growth factor inhibitors. Using a population-based retrospective design, we studied monthly fee claims for intravitreal injections submitted to the Ontario Health Insurance Plan between January 1, 2000, and March 30, 2008, and linked procedures to the physicians who performed them. This database records physician services provided as part of universal health care insurance coverage in Ontario, Canada. This program covers all residents of Ontario, which had an average population of 12.1 million during the study period. Following regulatory approval of bevacizumab for colorectal cancer in 2005, off-label use of this drug for the treatment of retinal disease, particularly age-related macular degeneration, became increasingly common. The rate of intravitreal injections in Ontario rapidly grew 8-fold, and this growth preceded the availability of ranibizumab by more than a year. Moreover, in 2007, more than 50% of intravitreal injections in Ontario were performed by 3% of ophthalmologists. The development of vascular endothelial growth factor inhibitors has revolutionized the treatment of age-related macular degeneration. To our knowledge, this study is the first to quantify the dramatic uptake of these treatments at a population level. Our findings also suggest that off-label injection of bevacizumab was highly prevalent in Ontario. Serial intravitreal injections requiring direct physician administration and the concentration of injection procedures in the hands of a small number of ophthalmologists have the potential to affect services for other vision-threatening conditions.

  11. Protein tethering enables rapid and label-free SERS platform for screening drugs of abuse (Conference Presentation)

    Science.gov (United States)

    Siddhanta, Soumik; Wróbel, Maciej S.; Barman, Ishan

    2017-02-01

    A quick, cost-effective method for detection of drugs of abuse in biological fluids would be of great value in healthcare, law enforcement, and home testing applications. The alarming rise in narcotics abuse has led to considerable focus on developing potent and versatile analytical tools that can address this societal problem. While laboratory testing plays a key role in the current detection of drug misuse and the evaluation of patients with drug induced intoxication, these typically require expensive reagents and trained personnel, and may take hours to complete. Thus, a significant unmet need is to engineer a facile method that can rapidly detect drugs with little sample preparation, especially the bound fraction that is typically dominant in the blood stream. Here we report an approach that combines the exquisite sensitivity of surface enhanced Raman spectroscopy (SERS) and a facile protein tethering mechanism to reliably detect four different classes of drugs, barbiturate, benzodiazepine, amphetamine and benzoylecgonine. The proposed approach harnesses the reliable and specific attachment of proteins to both drugs and nanoparticle to facilitate the enhancement of spectral markers that are sensitive to the presence of the drugs. In conjunction with chemometric tools, we have shown the ability to quantify these drugs lower than levels achievable by existing clinical immunoassays. Through molecular docking simulations, we also probe the mechanistic underpinnings of the protein tethering approach, opening the door to detection of a broad class of narcotics in biological fluids within a few minutes as well as for groundwater analysis and toxin detection.

  12. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria

    Science.gov (United States)

    Sun, Wei; Weingarten, Rebecca A; Xu, Miao; Southall, Noel; Dai, Sheng; Shinn, Paul; Sanderson, Philip E; Williamson, Peter R; Frank, Karen M; Zheng, Wei

    2016-01-01

    Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pneumoniae. To further improve the efficacy and reduce the effective drug concentrations, we applied a targeted drug combination approach that integrates drugs' clinical antimicrobial susceptibility breakpoints, achievable plasma concentrations, clinical toxicities and mechanisms of action to identify optimal drug combinations. Three sets of three-drug combinations were identified with broad-spectrum activities against 10 MDR clinical isolates including K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Citrobacter freundii, Enterobacter cloacae and Escherichia coli. Colistin–auranofin–ceftazidime and colistin–auranofin–rifabutin suppressed >80% growth of all 10 MDR strains; while rifabutin–colistin–imipenem inhibited >75% of these strains except two Acinetobacter baumannii isolates. The results demonstrate this new assay has potential as a real-time method to identify new drugs and effective drug combinations to combat severe clinical infections with MDR organisms. PMID:27826141

  13. An ETP model (exclusion-tolerance-progression for multi drug resistance

    Directory of Open Access Journals (Sweden)

    Kannan Subburaj

    2005-04-01

    Full Text Available Abstract Background It is known that sensitivity or resistance of tumor cells to a given chemotherapeutic agent is an acquired characteristic(s, depending on the heterogeneity of the tumor mass subjected to the treatment. The clinical success of a chemotherapeutic regimen depends on the ratio of sensitive to resistant cell populations. Results Based on findings from clinical and experimental studies, a unifying model is proposed to delineate the potential mechanism by which tumor cells progress towards multi drug resistance, resulting in failure of chemotherapy. Conclusion It is suggested that the evolution of multi drug resistance is a developmentally orchestrated event. Identifying stage-specific time windows during this process would help to identify valid therapeutic targets for the effective elimination of malignancy.

  14. [Pulmonary tuberculosis: effectiveness and tolerance of a 6-month treatment schedule using 4 drugs].

    Science.gov (United States)

    Romanillos, T; Casagran, A; Barbeta, E; Diestre, J; Grau, J; Marquillas, E; Priu, R; Torner, J

    1990-02-01

    255 patients diagnosed of pulmonary and/or pleural tuberculosis are prospectively studied. All patients received four drugs: isoniazine (INH), rifampin, pirazinamide and ethambutol during the first two months of treatment. Afterwards they continued for four months with two drugs in order to complete the six month treatment period. This schedule has been effective (0.7% of failures) in 99.3% of the patients. Two relapses were detected in the 229 patients who completed the two years follow up. 72 patients (28.2%) presented clinical secondary effects due to the treatment (40 cases of cutaneous affectation, 23 of gastrointestinal intolerance and 8 arthralgias respectively). Also, hyperuricemia was detected in 83% of the patients and a high transaminases level in 42.3%. In 13 patients treatment was cancelled or modified due to the secondary effects. In summary, this schedule of treatment has proved to be effective without an important frequency of serious secondary effects which can be objectively seen in the classical schedules of 9 months with 3 drugs (INH, RF, ET), nevertheless an increased frequency of minor secondary effects were detected.

  15. Rapid, automated, nonradiometric susceptibility testing of Mycobacterium tuberculosis complex to four first-line antituberculous drugs used in standard short-course chemotherapy

    DEFF Research Database (Denmark)

    Johansen, Isik Somuncu; Thomsen, Vibeke Østergaard; Marjamäki, Merja

    2004-01-01

    The increasing prevalence of drug-resistant tuberculosis necessitates rapid and accurate susceptibility testing. The nonradiometric BACTEC Mycobacteria Growth Indicator Tube 960 (MGIT) system for susceptibility testing was evaluated on 222 clinical Mycobacterium tuberculosis complex isolates...... MGIT system is a rapid and reliable alternative for susceptibility testing of M. tuberculosis complex to first-line drugs....

  16. Carboxylesterase 1A2 encoding gene with increased transcription and potential rapid drug metabolism in Asian populations

    DEFF Research Database (Denmark)

    Rasmussen, Henrik Berg; Madsen, Majbritt Busk; Lyauk, Yassine Kamal

    2017-01-01

    The carboxylesterase 1 gene (CES1) encodes a hydrolase implicated in the metabolism of commonly used drugs. CES1A2, a hybrid of CES1 and a CES1-like pseudogene, has a promoter that is weak in most individuals. However, some individuals harbor a promoter haplotype of this gene with two overlapping...... Sp1 sites that confer significantly increased transcription potentially leading to rapid drug metabolism. This CES1A2 haplotype has previously been reported to be common among Asians. Using polymerase chain reaction followed by sequencing, the present study examined variation in the promoter and 5...

  17. A rapid ex vivo tissue model for optimising drug detection and ionisation in MALDI imaging studies.

    Science.gov (United States)

    Huber, K; Aichler, M; Sun, N; Buck, A; Li, Z; Fernandez, I E; Hauck, S M; Zitzelsberger, H; Eickelberg, O; Janssen, K P; Keller, U; Walch, A

    2014-10-01

    The aim of this study was to establish an ex vivo model for a faster optimisation of sample preparation procedures, for example matrix choice, in matrix-assisted laser desorption/ionisation (MALDI) drug imaging studies. The ionisation properties of four drugs, afatinib, erlotinib, irinotecan and pirfenidone, were determined in an ex vivo tissue experiment by spotting decreasing dilution series onto liver sections. Hereby, the drug signals were distinctly detectable using different matrix compounds, which allowed the selection of the optimal matrix for each drug. The analysis of afatinib and erlotinib yielded high drug signals with α-cyano-4-hydroxycinnamic acid matrix, whereas 2,3-dihydroxybenzoic acid was identified as optimal matrix for irinotecan and pirfenidone detection. Our method was validated by a MALDI drug imaging approach of in vivo treated mouse tissue resulting in corresponding findings, indicating the spotting method as an appropriate approach to determine the matrix of choice. The present study shows the accordance between the detection of ex vivo spotted drugs and in vivo administered drugs by MALDI-TOF and MALDI-FT-ICR imaging, which has not been demonstrated so far. Our data suggest the ex vivo tissue spotting method as an easy and reliable model to optimise MALDI imaging measurements and to predict drug detection in tissue sections derived from treated mice prior to the recruitment of laboratory animals, which helps to save animals, time and costs.

  18. Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria

    OpenAIRE

    Sun, Wei; Weingarten, Rebecca A; Xu, Miao; Southall, Noel; Dai, Sheng; Shinn, Paul; Sanderson, Philip E; Williamson, Peter R; Frank, Karen M; Zheng, Wei

    2016-01-01

    Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pne...

  19. Rapid detection of drug resistance and mutational patterns of extensively drug-resistant strains by a novel GenoType® MTBDRsl assay

    Directory of Open Access Journals (Sweden)

    A K Singh

    2013-01-01

    Full Text Available Background: The emergence of extensively drug-resistant tuberculosis (XDR-TB is a major concern in the India. The burden of XDR-TB is increasing due to inadequate monitoring, lack of proper diagnosis, and treatment. The GenoType ® Mycobacterium tuberculosis drug resistance second line (MTBDRsl assay is a novel line probe assay used for the rapid detection of mutational patterns conferring resistance to XDR-TB. Aim: The aim of this study was to study the rapid detection of drug resistance and mutational patterns of the XDR-TB by a novel GenoType ® MTBDRsl assay. Materials and Methods: We evaluated 98 multidrug-resistant (MDR M. tuberculosis isolates for second line drugs susceptibility testing by 1% proportion method (BacT/ALERT 3D system and GenoType ® MTBDRsl assay for rapid detection of conferring drug resistance to XDR-TB. Results: A total of seven (17.4% were identified as XDR-TB by using standard phenotypic method. The concordance between phenotypic and GenoType ® MTBDRsl assay was 91.7-100% for different antibiotics. The sensitivity and specificity of the MTBDRsl assay were 100% and 100% for aminoglycosides; 100% and 100% for fluoroquinolones; 91.7% and 100% for ethambutol. The most frequent mutations and patterns were gyrA MUT1 (A90V in seven (41.2% and gyrA + WT1-3 + MUT1 in four (23.5%; rrs MUT1 (A1401G in 11 (64.7%, and rrs WT1-2 + MUT1 in eight (47.1%; and embB MUT1B (M306V in 11 (64.7% strains. Conclusions: These data suggest that the GenoType ® MTBDRsl assay is rapid, novel test for detection of resistance to second line anti-tubercular drugs. This assay provides additional information about the frequency and mutational patterns responsible for XDR-TB resistance.

  20. Rapid analysis of the interactions between drugs and human serum albumin (HSA) using high-performance affinity chromatography (HPAC).

    Science.gov (United States)

    Kim, Hee Seung; Wainer, Irving W

    2008-07-01

    This study used a combination of zonal elution and frontal affinity chromatography on immobilized human serum albumin (HSA) high-performance affinity chromatography (HPAC) column to examine the association constants of various compounds that have been studied by equilibrium dialysis or ultra filtration. A standard plot was generated from retention factors of reference compounds using zonal elution chromatography against association constants of reference compounds using frontal affinity chromatography. The linear relationship was established (r2=0.9993) between retention factors and association constants of reference compounds. This standard plot was later used for rapid determination of association constants of various drugs which show low to medium binding affinity to HSA. Association constants of those drugs from this study were compared to that of more generally used methods (i.e., equilibrium dialysis or ultra filtration) from literature and resulted in a relatively high correlation (r2=0.945) value. This combination of zonal elution and frontal affinity chromatography method for determining association constants showed several advantages against traditional methods. Depending on drugs of interest, an association constant of drug to HSA can be measured as fast as 1.5 min. Other notable advantages include an ease of automation and its ability to distinguish association constants of chiral compounds at the same time. The same approach could be used for studying interaction of other drugs and proteins and should further improve overall drug screening process.

  1. Rapid Detection and Identification of Overdose Drugs in Saliva by Surface-Enhanced Raman Scattering Using Fused Gold Colloids

    Directory of Open Access Journals (Sweden)

    Frank Inscore

    2011-07-01

    Full Text Available The number of drug-related emergency room visits in the United States doubled from 2004 to 2009 to 4.6 million. Consequently there is a critical need to rapidly identify the offending drug(s, so that the appropriate medical care can be administered. In an effort to meet this need we have been investigating the ability of surface-enhanced Raman spectroscopy (SERS to detect and identify numerous drugs in saliva at ng/mL concentrations within 10 minutes. Identification is provided by matching measured spectra to a SERS library comprised of over 150 different drugs, each of which possess a unique spectrum. Trace detection is provided by fused gold colloids trapped within a porous glass matrix that generate SERS. Speed is provided by a syringe-driven sample system that uses a solid-phase extraction capillary combined with a SERS-active capillary in series. Spectral collection is provided by a portable Raman analyzer. Here we describe successful measurement of representative illicit, prescribed, and over-the-counter drugs by SERS, and 50 ng/mL cocaine in saliva as part of a focused study.

  2. Adenovirus-vectored drug-vaccine duo as a rapid-response tool for conferring seamless protection against influenza.

    Directory of Open Access Journals (Sweden)

    Jianfeng Zhang

    Full Text Available Few other diseases exert such a huge toll of suffering as influenza. We report here that intranasal (i.n. administration of E1/E3-defective (ΔE1E3 adenovirus serotype 5 (Ad5 particles rapidly induced an anti-influenza state as a means of prophylactic therapy which persisted for several weeks in mice. By encoding an influenza virus (IFV hemagglutinin (HA HA1 domain, an Ad5-HA1 vector conferred rapid protection as a prophylactic drug followed by elicitation of sustained protective immunity as a vaccine for inducing seamless protection against influenza as a drug-vaccine duo (DVD in a single package. Since Ad5 particles induce a complex web of host responses, which could arrest influenza by activating a specific arm of innate immunity to impede IFV growth in the airway, it is conceivable that this multi-pronged influenza DVD may escape the fate of drug resistance that impairs the current influenza drugs.

  3. How low can they go when going with the flow? Tolerance of egg and larval fishes to rapid decompression

    Energy Technology Data Exchange (ETDEWEB)

    Boys, Craig A.; Robinson, Wayne; Miller, Brett; Pflugrath, Brett; Baumgartner, Lee J.; Navarro, Anna; Brown, Richard; Deng, Zhiqun

    2016-05-26

    Egg and larval fish that drift downstream are likely to encounter river infrastructure and consequently rapid decompression, which may result in significant injury. In juvenile fish, pressure-related injury (or barotrauma) occurs when pressures fall sufficiently below the pressure at which the fish has acclimated. Because eggs and larvae are less-developed and more fragile than juveniles, there is a presumption that they may be at least as, if not more, susceptible to barotrauma injury, but studies to date report inconsistent results and none have considered the relationship between pressure change and barotrauma over a sufficiently broad range of pressure changes to enable detrimental levels to be properly determined. To address this, we exposed eggs and larvae of three physoclistic species to rapid decompression in a barometric chamber over a broad range of discrete pressure changes. Eggs, but not larvae, were unaffected by all levels of decompression tested. At exposure pressures below ~40 kPa, or ~40% of atmospheric pressure, swim bladder deflation occurred in all species and internal haemorrhage was observed in one species. None of these injuries killed the fish within 24 hours, but subsequent mortality cannot be excluded. Consequently, if larval drift is expected, it seems prudent to maintain exposure pressures at river infrastructure at 40% or more of the pressure to which a drifting larvae has acclimated.

  4. Embryonic Zebrafish Model - A Well-Established Method for Rapidly Assessing the Toxicity of Homeopathic Drugs - Toxicity Evaluation of Homeopathic Drugs Using Zebrafish Embryo Model -

    Directory of Open Access Journals (Sweden)

    Himanshu R Gupta

    2016-12-01

    exposure times used in this study. The embryonic zebrafish model is recommended as a well-established method for rapidly assessing the toxicity of homeopathic drugs.

  5. Rapid identification of drug-type strains in Cannabis sativa using loop-mediated isothermal amplification assay.

    Science.gov (United States)

    Kitamura, Masashi; Aragane, Masako; Nakamura, Kou; Watanabe, Kazuhito; Sasaki, Yohei

    2017-01-01

    In Cannabis sativa L., tetrahydrocannabinol (THC) is the primary psychoactive compound and exists as the carboxylated form, tetrahydrocannabinolic acid (THCA). C. sativa is divided into two strains based on THCA content-THCA-rich (drug-type) strains and THCA-poor (fiber-type) strains. Both strains are prohibited by law in many countries including Japan, whereas the drug-type strains are regulated in Canada and some European countries. As the two strains cannot be discriminated by morphological analysis, a simple method for identifying the drug-type strains is required for quality control in legal cultivation and forensic investigation. We have developed a novel loop-mediated isothermal amplification (LAMP) assay for identifying the drug-type strains of C. sativa. We designed two selective LAMP primer sets for on-site or laboratory use, which target the drug-type THCA synthase gene. The LAMP assay was accomplished within approximately 40 min. The assay showed high specificity for the drug-type strains and its sensitivity was the same as or higher than that of conventional polymerase chain reaction. We also showed the effectiveness of melting curve analysis that was conducted after the LAMP assay. The melting temperature values of the drug-type strains corresponded to those of the cloned drug-type THCA synthase gene, and were clearly different from those of the cloned fiber-type THCA synthase gene. Moreover, the LAMP assay with simple sample preparation could be accomplished within 1 h from sample treatment to identification without the need for special devices or techniques. Our rapid, sensitive, specific, and simple assay is expected to be applicable to laboratory and on-site detection.

  6. Introducing rapid diagnostic tests for malaria into registered drug shops in Uganda: lessons learned and policy implications.

    Science.gov (United States)

    Mbonye, Anthony K; Clarke, Sîan E; Lal, Sham; Chandler, Clare I; Hutchinson, Eleanor; Hansen, Kristian S; Magnussen, Pascal

    2015-11-14

    Malaria is a major public health problem in Uganda and the current policy recommends introduction of rapid diagnostic tests for malaria (RDTs) to facilitate effective case management. However, provision of RDTs in drug shops potentially raises a new set of issues, such as adherence to RDTs results, management of severe illnesses, referral of patients, and relationship with caretakers. The main objective of the study was to examine the impact of introducing RDTs in registered drug shops in Uganda and document lessons and policy implications for future scale-up of malaria control in the private health sector. A cluster-randomized trial introducing RDTs into registered drug shops was implemented in central Uganda from October 2010 to July 2012. An evaluation was undertaken to assess the impact and the processes involved with the introduction of RDTs into drug shops, the lessons learned and policy implications. Introducing RDTs into drug shops was feasible. To scale-up this intervention however, drug shop practices need to be regulated since the registration process was not clear, supervision was inadequate and record keeping was poor. Although initially it was anticipated that introducing a new practice of record keeping would be cumbersome, but at evaluation this was not found to be a constraint. This presents an important lesson for introducing health management information system into drug shops. Involving stakeholders, especially the district health team, in the design was important for ownership and sustainability. The involvement of village health teams in community sensitization to the new malaria treatment and diagnosis policy was a success and this strategy is recommended for future interventions. Introducing RDTs into drug shops was feasible and it increased appropriate treatment of malaria with artemisinin-based combination therapy. It is anticipated that the lessons presented will help better implementation of similar interventions in the private sector.

  7. Application of lean manufacturing concepts to drug discovery: rapid analogue library synthesis.

    Science.gov (United States)

    Weller, Harold N; Nirschl, David S; Petrillo, Edward W; Poss, Michael A; Andres, Charles J; Cavallaro, Cullen L; Echols, Martin M; Grant-Young, Katherine A; Houston, John G; Miller, Arthur V; Swann, R Thomas

    2006-01-01

    The application of parallel synthesis to lead optimization programs in drug discovery has been an ongoing challenge since the first reports of library synthesis. A number of approaches to the application of parallel array synthesis to lead optimization have been attempted over the years, ranging from widespread deployment by (and support of) individual medicinal chemists to centralization as a service by an expert core team. This manuscript describes our experience with the latter approach, which was undertaken as part of a larger initiative to optimize drug discovery. In particular, we highlight how concepts taken from the manufacturing sector can be applied to drug discovery and parallel synthesis to improve the timeliness and thus the impact of arrays on drug discovery.

  8. Drug-Related Hyponatremic Encephalopathy: Rapid Clinical Response Averts Life-Threatening Acute Cerebral Edema

    OpenAIRE

    Siegel, Arthur J; Forte, Sophie S.; Bhatti, Nasir A.; Gelda, Steven E.

    2016-01-01

    Patient: Female, 63 Final Diagnosis: Drug-induced hyponatremic encephalopathy Symptoms: Seizures ? coma Medication: Hypertonic 3% saline infusion Clinical Procedure: ? Specialty: Internal Medicine Objective: Unusual clinical course Background: Drug-induced hyponatremia characteristically presents with subtle psychomotor symptoms due to its slow onset, which permits compensatory volume adjustment to hypo-osmolality in the central nervous system. Due mainly to the syndrome of inappropriate anti...

  9. Surface-stress sensors for rapid and ultrasensitive detection of active free drugs in human serum

    Science.gov (United States)

    Ndieyira, Joseph W.; Kappeler, Natascha; Logan, Stephen; Cooper, Matthew A.; Abell, Chris; McKendry, Rachel A.; Aeppli, Gabriel

    2014-03-01

    There is a growing appreciation that mechanical signals can be as important as chemical and electrical signals in biology. To include such signals in a systems biology description for understanding pathobiology and developing therapies, quantitative experiments on how solution-phase and surface chemistry together produce biologically relevant mechanical signals are needed. Because of the appearance of drug-resistant hospital `superbugs', there is currently great interest in the destruction of bacteria by bound drug-target complexes that stress bacterial cell membranes. Here, we use nanomechanical cantilevers as surface-stress sensors, together with equilibrium theory, to describe quantitatively the mechanical response of a surface receptor to different antibiotics in the presence of competing ligands in solution. The antibiotics examined are the standard, Food and Drug Administration-approved drug of last resort, vancomycin, and the yet-to-be approved oritavancin, which shows promise for controlling vancomycin-resistant infections. The work reveals variations among strong and weak competing ligands, such as proteins in human serum, that determine dosages in drug therapies. The findings further enhance our understanding of the biophysical mode of action of the antibiotics and will help develop better treatments, including choice of drugs as well as dosages, against pathogens.

  10. A high throughput solubility assay for drug discovery using microscale shake-flask and rapid UHPLC-UV-CLND quantification.

    Science.gov (United States)

    Lin, Baiwei; Pease, Joseph H

    2016-04-15

    The rapid determination of key physical properties of lead compounds is essential to the drug discovery process. Solubility is one of the most important properties since good solubility is needed not only for obtaining reliable in vitro and in vivo assay results in early discovery but also to ensure sufficient concentration of the drug being in circulation to get the desired therapeutic exposure at the target of interest. In order for medicinal chemists to tune solubility of lead compounds, a rapid assay is needed to provide solubility data that is accurate and predictive so that it can be reliably used for designing the next generation of compounds with improved properties. To ensure speed and data quality, we developed a high throughput solubility assay that utilizes a single calibration UHPLC-UV-CLND method and a 24h shake-flask format for rapid quantification. A set of 46 model compounds was used to demonstrate that the method is accurate, reproducible and predictive. Here we present development of the assay, including evaluation of quantification method, filtration membranes, equilibrium times, DMSO concentrations, and buffer conditions. A comparison of thermodynamic solubility results to our high throughput 24h shake-flask solubility assay results is also discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Prospective multicentre evaluation of the direct nitrate reductase assay for the rapid detection of extensively drug-resistant tuberculosis.

    Science.gov (United States)

    Martin, Anandi; Imperiale, Belen; Ravolonandriana, Pascaline; Coban, Ahmet Yilmaz; Akgunes, Alper; Ikram, Aamer; Satti, Luqman; Odoun, Mathieu; Pandey, Pooja; Mishra, Manvi; Affolabi, Dissou; Singh, Urvashi; Rasolofo, Voahangy; Morcillo, Nora; Vandamme, Peter; Palomino, Juan Carlos

    2014-02-01

    To perform a multicentre study evaluating the performance of the direct nitrate reductase assay (NRA) for the detection of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in sputum samples. The study was conducted in six laboratories performing tuberculosis diagnosis that were located in six different countries. The NRA was performed directly on sputum samples in parallel with the reference method used at each site. Detection of resistance was performed for rifampicin, isoniazid, ofloxacin and kanamycin. Excellent agreement was obtained for all drugs tested at the majority of sites. The accuracy was 93.7%-100% for rifampicin, 88.2%-100% for isoniazid, 94.6%-100% for ofloxacin and 100% for kanamycin. The majority of NRA results were available at day 21 for sites 1, 2 and 5. Site 3 had a turnaround time of 13.9 days, at site 4 it was 18.4 days and at site 6 it was 16.2 days. The contamination rate ranged between 2.5% and 12%. Rapid detection of drug resistance by the direct NRA on sputum smear-positive samples was accurate and easy to implement in clinical diagnostic laboratories, making it a good alternative for rapid screening for MDR and XDR tuberculosis.

  12. Comparative Genomic Analysis of Rapid Evolution of an Extreme-Drug-Resistant Acinetobacter baumannii Clone

    DEFF Research Database (Denmark)

    Tan, Sean Yang-Yi; Chua, Song Lin; Liu, Yang

    2013-01-01

    , comparative genomics has been employed to analyze the rapid evolution of an EDR Acinetobacter baumannii clone from the intensive care unit (ICU) of Rigshospitalet at Copenhagen. Two resistant A. baumannii strains, 48055 and 53264, were sequentially isolated from two individuals who had been admitted to ICU...

  13. Rhabdomyolysis in MDMA intoxication : A rapid and underestimated killer. "clean" Ecstasy, a safe party drug?

    NARCIS (Netherlands)

    Eede, Herve Vanden; Montenij, Leon J.; Touw, Daan J.; Norris, Elizabeth M.

    Background: Ecstasy is a popular drug among young adults. It is often thought to be safe. The dose of methylenedioxymethamphetamine (MDMA) in a tablet of Ecstasy varies greatly, and there is also a difference in individual response to a dose of MDMA. Objectives: To increase the awareness of

  14. Direct nitrate reductase assay versus microscopic observation drug susceptibility test for rapid detection of MDR-TB in Uganda.

    Directory of Open Access Journals (Sweden)

    Freddie Bwanga

    Full Text Available The most common method for detection of drug resistant (DR TB in resource-limited settings (RLSs is indirect susceptibility testing on Lowenstein-Jensen medium (LJ which is very time consuming with results available only after 2-3 months. Effective therapy of DR TB is therefore markedly delayed and patients can transmit resistant strains. Rapid and accurate tests suitable for RLSs in the diagnosis of DR TB are thus highly needed. In this study we compared two direct techniques--Nitrate Reductase Assay (NRA and Microscopic Observation Drug Susceptibility (MODS for rapid detection of MDR-TB in a high burden RLS. The sensitivity, specificity, and proportion of interpretable results were studied. Smear positive sputum was collected from 245 consecutive re-treatment TB patients attending a TB clinic in Kampala, Uganda. Samples were processed at the national reference laboratory and tested for susceptibility to rifampicin and isoniazid with direct NRA, direct MODS and the indirect LJ proportion method as reference. A total of 229 specimens were confirmed as M. tuberculosis, of these interpretable results were obtained in 217 (95% with either the NRA or MODS. Sensitivity, specificity and kappa agreement for MDR-TB diagnosis was 97%, 98% and 0.93 with the NRA; and 87%, 95% and 0.78 with the MODS, respectively. The median time to results was 10, 7 and 64 days with NRA, MODS and the reference technique, respectively. The cost of laboratory supplies per sample was low, around 5 USD, for the rapid tests. The direct NRA and MODS offered rapid detection of resistance almost eight weeks earlier than with the reference method. In the study settings, the direct NRA was highly sensitive and specific. We consider it to have a strong potential for timely detection of MDR-TB in RLS.

  15. Asthma and Rhinitis Induced by Selective Immediate Reactions to Paracetamol and Non-steroidal Anti-inflammatory Drugs in Aspirin Tolerant Subjects.

    Science.gov (United States)

    Pérez-Alzate, Diana; Blanca-López, Natalia; Doña, Inmaculada; Agúndez, José A; García-Martín, Elena; Cornejo-García, José A; Perkins, James R; Blanca, Miguel; Canto, Gabriela

    2016-01-01

    In subjects with non-steroidal anti-inflammatory drugs (NSAIDs)- exacerbated respiratory disease (NERD) symptoms are triggered by acetyl salicylic acid (ASA) and other strong COX-1 inhibitors, and in some cases by weak COX-1 or by selective COX-2 inhibitors. The mechanism involved is related to prostaglandin pathway inhibition and leukotriene release. Subjects who react to a single NSAID and tolerate others are considered selective responders, and often present urticaria and/or angioedema and anaphylaxis (SNIUAA). An immunological mechanism is implicated in these reactions. However, anecdotal evidence suggests that selective responders who present respiratory airway symptoms may also exist. Our objective was to determine if subjects might develop selective responses to NSAIDs/paracetamol that manifest as upper/lower airways respiratory symptoms. For this purpose, we studied patients reporting asthma and/or rhinitis induced by paracetamol or a single NSAID that tolerated ASA. An allergological evaluation plus controlled challenge with ASA was carried out. If ASA tolerance was found, we proceeded with an oral challenge with the culprit drug. The appearance of symptoms was monitored by a clinical questionnaire and by measuring FEV1 and/or nasal airways volume changes pre and post challenge. From a total of 21 initial cases, we confirmed the appearance of nasal and/or bronchial manifestations in ten, characterized by a significant decrease in FEV1% and/or a decrease in nasal volume cavity after drug administration. All cases tolerated ASA. This shows that ASA tolerant subjects with asthma and/or rhinitis induced by paracetamol or a single NSAID without skin/systemic manifestations exist. Whether these patients represent a new clinical phenotype to be included within the current classification of hypersensitivity reactions to NSAIDs requires further investigation.

  16. Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome.

    Science.gov (United States)

    Svendsen, Torleiv; Brodtkorb, Eylert; Reimers, Arne; Molden, Espen; Sætre, Erik; Johannessen, Svein I; Johannessen Landmark, Cecilie

    2017-01-01

    Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy. This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible. TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53μmol/L (range 13-132μmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium <137mmol/L) was present in 36% of the patients, and lead to discontinuation in three. Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Evaluation of GenoType® MTBDRplus assay for rapid detection of drug susceptibility testing of multi-drug resistance tuberculosis in Northern India.

    Science.gov (United States)

    Maurya, Anand Kumar; Umrao, Jyoti; Singh, Amresh Kumar; Kant, Surya; Kushwaha, Ram Awadh Singh; Dhole, Tapan N

    2013-01-01

    The problem of multi-drug resistance tuberculosis (MDR-TB) is growing in several hotspots throughout the world. Rapid and accurate diagnosis of MDR-TB is crucial to facilitate early treatment and to reduce its spread in the community. The aim of the present study was to evaluate the new, novel GenoType® MTBDRplus assay for rapid detection of drug susceptibility testing (DST) of MDR-TB cases in Northern India. A total of 550 specimens were collected from highly suspected drug resistant from pulmonary and extra-pulmonary TB cases. All the specimens were processed by Ziehl- Neelsen staining, culture, differentiation by the GenoType® CM assay, first line DST using BacT/ALERT 3D system and GenoType® MTBDRplus assay. The concordance of the GenoType® MTBDRplus assay was calculated in comparison with conventional DST results. Overall the sensitivity for detection of rifampicin, isoniazid and MDR-TB resistance by GenoType® MTBDRplus assay was 98.0%, 98.4% and 98.2% respectively. Out of 55 MDR-TB strains, 45 (81.8%), 52 (94.5%) and 17 (30.9%) strains showed mutation in rpoB, katG and inhA genes respectively (P < 0.05). The most prominent mutations in rpoB, katG and inhA genes were; 37 (67.3%) in S531L, 52 (94.5%) in S315T1 and 11 (20%) in C15T regions respectively (P < 0.05). Our study demonstrated a high concordance between the GenoType® MTBDRplus assay resistance patterns and those were observed by conventional DST with good sensitivity, specificity with short turnaround times and to control new cases of MDR-TB in countries with a high prevalence of MDR-TB.

  18. An Implantable MEMS Drug Delivery Device for Rapid Delivery in Ambulatory Emergency Care

    Science.gov (United States)

    2009-06-01

    vol. 32, pp. 377-379, 2000. I. Singer and H. L. Edmonds, "Head-up tilt testing predicts syncope during ventricular tachycardia in implantable... pulse through it, as has been demonstrated in the past (Maloney, 2005). The limitations of this solution are: the significant increase in current to...H. Brem, M. J. Cima, and R. Langer, "Multi- pulse drug delivery from a resorbable polymeric microchip device," Nature Materials, vol. 2, pp. 767-772

  19. Clinical perspectives on the influence of drug formulation on patient tolerability and use of commonly prescribed antidepressants in major depressive disorder

    Directory of Open Access Journals (Sweden)

    Matthew A Fuller

    2013-01-01

    Full Text Available The purpose of this review is to summarize the formulation options for currently available antidepressants, and discuss examples of the influence that formulation may have on the pharmacologic and clinical profiles of the medications. A review of current literature suggests that differences in drug-delivery technologies can lead to variations in the pharmacokinetic and pharmacodynamic profiles of generic and branded drugs, despite generic drugs being required to meet bioequivalence standards compared with their branded counterparts. These differences may influence the effectiveness and tolerability of treatment. Recent reports have highlighted the need for individualized treatment regimens and careful assessment of tolerability and efficacy when switching patients from brand to generic formulations. There is a growing body of evidence indicating that differences in formulation can substantially impact drug pharmacokinetics and pharmacodynamics, which in turn, can affect drug effects. The clinical impact of these differences remains unclear. Further research is needed to clarify the influence of antidepressant formulations on treatment adherence, patient preference, and quality of life, and how this impacts clinical practice with regard to brand versus generic treatment selection.

  20. Efficacy and tolerability of adjunctive brivaracetam in patients with prior antiepileptic drug exposure: A post-hoc study.

    Science.gov (United States)

    Asadi-Pooya, Ali A; Sperling, Michael R; Chung, Steve; Klein, Pavel; Diaz, Anyzeila; Elmoufti, Sami; Schiemann, Jimmy; Whitesides, John

    2017-03-01

    Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period. Patients taking concomitant LEV at enrollment were excluded from this analysis. Patients were categorized by their status of prior exposure to LEV, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LTG), to investigate any consistent trend towards reduced response in AED-exposed subgroups compared to AED-naïve subgroups, regardless of the mechanism of action. Study completion rates, percent reduction from baseline in focal seizure frequency over placebo, ≥50% responder rates, and tolerability were evaluated for each subgroup. A total of 1160 patients were investigated. Study completion rates were similar in the AED-exposed subgroups and AED-naïve subgroups. In subgroups with (531 patients) or without (629 patients) prior LEV exposure, ≥50% responder rates for each dose of BRV compared with placebo were generally higher among the LEV-naïve subgroups than the previously LEV-exposed subgroups. LEV-exposed subgroups receiving BRV doses ≥50mg/day showed greater ≥50% responder rates than those receiving placebo. Similar results were observed for CBZ, TPM, and LTG. Previous treatment failure with commonly prescribed AEDs (LEV, CBZ, TPM, or LTG) is associated with a reduced response to BRV irrespective of the mechanism of action. Hence, this post-hoc analysis indicates that previous treatment failure with LEV

  1. Has introduction of rapid drug susceptibility testing at diagnosis impacted treatment outcomes among previously treated tuberculosis patients in Gujarat, India?

    Science.gov (United States)

    Dave, Paresh; Vadera, Bhavin; Kumar, Ajay M V; Chinnakali, Palanivel; Modi, Bhavesh; Solanki, Rajesh; Patel, Pranav; Patel, Prakash; Pujara, Kirit; Nimavat, Pankaj; Shah, Amar; Bharaswadkar, Sandeep; Rade, Kiran; Parmar, Malik; Nair, Sreenivas Achuthan

    2015-01-01

    Revised National TB Control Programme (RNTCP) in India recommends that all previously-treated TB (PT) patients are offered drug susceptibility testing (DST) at diagnosis, using rapid diagnostics and screened out for rifampicin resistance before being treated with standardized, eight-month, retreatment regimen. This is intended to improve the early diagnosis of rifampicin resistance and its appropriate management and improve the treatment outcomes among the rest of the patients. In this state-wide study from Gujarat, India, we assess proportion of PT patients underwent rapid DST at diagnosis and the impact of this intervention on their treatment outcomes. This is a retrospective cohort study involving review of electronic patient-records maintained routinely under RNTCP. All PT patients registered for treatment in Gujarat during January-June 2013 were included. Information on DST and treatment outcomes were extracted from 'presumptive DR-TB patient register' and TB treatment register respectively. We performed a multivariate analysis to assess if getting tested is independently associated with unfavourable outcomes (death, loss-to-follow-up, failure, transfer out). Of 5,829 PT patients, 5306(91%) were tested for drug susceptibility with rapid diagnostics. Overall, 71% (4,113) TB patients were successfully treated - 72% among tested versus 60% among non-tested. Patients who did not get tested at diagnosis had a 34% higher risk of unsuccessful outcomes as compared to those who got tested (aRR - 1.34; 95% CI 1.20-1.50) after adjusting for age, sex, HIV status and type of TB. Unfavourable outcomes (particularly failure and switched to category IV) were higher among INH-resistant patients (39%) as compared to INH-sensitive (29%). Offering DST at diagnosis improved the treatment outcomes among PT patients. However, even among tested, treatment outcomes remained suboptimal and were related to INH resistance and high loss-to-follow-up. These need to be addressed urgently

  2. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2015-08-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  3. Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

    Directory of Open Access Journals (Sweden)

    Yuri Pevzner

    2014-05-01

    Full Text Available Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and in vitro experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

  4. Desorption electrospray ionisation mass spectrometry: A rapid screening tool for veterinary drug preparations and forensic samples from hormone crime investigations

    Energy Technology Data Exchange (ETDEWEB)

    Nielen, M.W.F. [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands)], E-mail: michel.nielen@wur.nl; Hooijerink, H. [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Claassen, F.C. [Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands); Engelen, M.C. van [RIKILT Institute of Food Safety, P.O. Box 230, 6700 AE Wageningen (Netherlands); Beek, T.A. van [Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen (Netherlands)

    2009-04-01

    Hormone and veterinary drug screening and forensics can benefit from the recent developments in desorption electrospray ionisation (DESI) mass spectrometry (MS). In this work the feasibility of DESI application has been studied. Using a linear ion trap or quadrupole time-of-flight (TOF) MS instrument both full-scan and data-dependent collision-induced dissociation MS{sup n} spectra were acquired in seconds without sample preparation. Preliminary data are presented for the rapid screening of (pro)hormone supplement samples, an illegal steroid cocktail and forensic samples from veterinary drug investigations. The potential of this DESI approach is clearly demonstrated since compounds observed could be independently confirmed by liquid chromatography/TOFMS with accurate mass measurement, and/or proton nuclear magnetic resonance spectroscopy. Specific concerns related to false-positive and false-negative findings due to limitations in quantification and memory-effects are briefly discussed. It is envisaged that DESI will achieve a prominent role in hormone and veterinary drug analysis in the near future.

  5. Elongation of fibers from highly viscous dextran solutions enables fabrication of rapidly dissolving drug carrying fabrics.

    Science.gov (United States)

    Frampton, John P; Lai, David; Lounds, Maxwell; Chung, Kyeongwoon; Kim, Jinsang; Mansfield, John F; Takayama, Shuichi

    2015-01-28

    A simple method is presented for forming thread-like fibers from highly viscous dextran solutions. Based on the cohesive and adhesive forces between a dextran solution and the substrate to which it is applied, multiple fibers of approximately 10 μm in diameter can be elongated simultaneously. These fibers can be woven into multiple layers to produce fabrics of varying fiber orientations and mechanical properties. Various bioactive agents can be incorporated into the dextran solution prior to fiber formation, including hemostatic and antibiotic agents. Fabrics containing thrombin are capable of coagulating human platelet poor plasma in vitro. Fabrics containing antibiotics are capable of suppressing bacterial growth in a disk diffusion assay. These data suggest that this new material composed entirely of dextran has promise as a drug delivery component in wound dressings. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis.

    Directory of Open Access Journals (Sweden)

    Matthew T G Holden

    2009-07-01

    Full Text Available Streptococcus suis is a zoonotic pathogen that infects pigs and can occasionally cause serious infections in humans. S. suis infections occur sporadically in human Europe and North America, but a recent major outbreak has been described in China with high levels of mortality. The mechanisms of S. suis pathogenesis in humans and pigs are poorly understood.The sequencing of whole genomes of S. suis isolates provides opportunities to investigate the genetic basis of infection. Here we describe whole genome sequences of three S. suis strains from the same lineage: one from European pigs, and two from human cases from China and Vietnam. Comparative genomic analysis was used to investigate the variability of these strains. S. suis is phylogenetically distinct from other Streptococcus species for which genome sequences are currently available. Accordingly, approximately 40% of the approximately 2 Mb genome is unique in comparison to other Streptococcus species. Finer genomic comparisons within the species showed a high level of sequence conservation; virtually all of the genome is common to the S. suis strains. The only exceptions are three approximately 90 kb regions, present in the two isolates from humans, composed of integrative conjugative elements and transposons. Carried in these regions are coding sequences associated with drug resistance. In addition, small-scale sequence variation has generated pseudogenes in putative virulence and colonization factors.The genomic inventories of genetically related S. suis strains, isolated from distinct hosts and diseases, exhibit high levels of conservation. However, the genomes provide evidence that horizontal gene transfer has contributed to the evolution of drug resistance.

  7. Rapid evolution of virulence and drug resistance in the emerging zoonotic pathogen Streptococcus suis.

    Science.gov (United States)

    Holden, Matthew T G; Hauser, Heidi; Sanders, Mandy; Ngo, Thi Hoa; Cherevach, Inna; Cronin, Ann; Goodhead, Ian; Mungall, Karen; Quail, Michael A; Price, Claire; Rabbinowitsch, Ester; Sharp, Sarah; Croucher, Nicholas J; Chieu, Tran Bich; Mai, Nguyen Thi Hoang; Diep, To Song; Chinh, Nguyen Tran; Kehoe, Michael; Leigh, James A; Ward, Philip N; Dowson, Christopher G; Whatmore, Adrian M; Chanter, Neil; Iversen, Pernille; Gottschalk, Marcelo; Slater, Josh D; Smith, Hilde E; Spratt, Brian G; Xu, Jianguo; Ye, Changyun; Bentley, Stephen; Barrell, Barclay G; Schultsz, Constance; Maskell, Duncan J; Parkhill, Julian

    2009-07-15

    Streptococcus suis is a zoonotic pathogen that infects pigs and can occasionally cause serious infections in humans. S. suis infections occur sporadically in human Europe and North America, but a recent major outbreak has been described in China with high levels of mortality. The mechanisms of S. suis pathogenesis in humans and pigs are poorly understood. The sequencing of whole genomes of S. suis isolates provides opportunities to investigate the genetic basis of infection. Here we describe whole genome sequences of three S. suis strains from the same lineage: one from European pigs, and two from human cases from China and Vietnam. Comparative genomic analysis was used to investigate the variability of these strains. S. suis is phylogenetically distinct from other Streptococcus species for which genome sequences are currently available. Accordingly, approximately 40% of the approximately 2 Mb genome is unique in comparison to other Streptococcus species. Finer genomic comparisons within the species showed a high level of sequence conservation; virtually all of the genome is common to the S. suis strains. The only exceptions are three approximately 90 kb regions, present in the two isolates from humans, composed of integrative conjugative elements and transposons. Carried in these regions are coding sequences associated with drug resistance. In addition, small-scale sequence variation has generated pseudogenes in putative virulence and colonization factors. The genomic inventories of genetically related S. suis strains, isolated from distinct hosts and diseases, exhibit high levels of conservation. However, the genomes provide evidence that horizontal gene transfer has contributed to the evolution of drug resistance.

  8. Safety and tolerability of dapsone for the treatment of patients with drug-resistant, partial-onset seizures: an open-label trial.

    Science.gov (United States)

    López-Gómez, Mario; Corona, Teresa; Diaz-Ruiz, Araceli; Ríos, Camilo

    2011-12-01

    Dapsone has shown anti-convulsive properties in animal models of epilepsy. In the present study, we tested the safety and tolerability of dapsone as adjunctive therapy in adult patients with drug-resistant partial-onset seizures. Twenty-two adult patients with drug-resistant partial-onset seizures were included. After a 3-month baseline period, patients received dapsone 100 mg per day, for a 3-month evaluation period. Plasma concentrations of anti-epileptic drugs (AEDs) did not significantly change during the study. No alteration of mean clinical laboratory values was observed. The reported adverse events were: mild methemoglobinemia (50%), headache (31.8%), paleness (27.3%) and somnolence (4.5%).Sixteen of 22 patients reduced their seizure frequency in more than 50% as a result of dapsone treatment. Three subjects remained seizure-free during the entire dapsone treatment period. This open-label study of adjunctive dapsone therapy at 100 mg/day suggests that dapsone is safe, and well-tolerated in adults with drug-resistant partial-onset seizures.

  9. Rapid analysis of interaction between six drugs and β2 -adrenergic receptor by injection amount-dependent method.

    Science.gov (United States)

    Zeng, Kaizhu; Wang, Jing; Sun, Zhenyu; Li, Qian; Liao, Sha; Zhao, Xinfeng; Zheng, Xiaohui

    2017-06-01

    Drug-protein interaction analysis has become a considerable topic in life science which includes clarifying protein functions, explaining drug action mechanisms and uncovering novel drug candidates. This work was to determine the association constants (KA ) of six drugs to β2 -adrenergic receptor by injection amount-dependent method using stationary phase containing the immobilized receptor. The values of KA were calculated to be (25.85 ± 0.035) × 104  m-1 for clorprenaline, (42.51 ± 0.054) × 104  m-1 for clenbuterol, (6.67 ± 0.008) × 104  m-1 for terbutaline, (33.99 ± 0.025) × 104  m-1 for tulobuterol, (7.59 ± 0.011) × 104  m-1 for salbutamol and (78.52 ± 0.087) × 104  m-1 for bambuterol. This rank order agreed well with the data determined by zonal elution, frontal analysis and nonlinear chromatography, even using different batches of β2 -AR column. A good correlation was found between the association constants by the current method and radio-ligand binding assay. Our data indicates that the injection amount-dependent method is a powerful alternative for rapid analysis of ligand-receptor interactions. Copyright © 2016 John Wiley & Sons, Ltd.

  10. Rapid regulation of the plasma membrane H+-ATPase activity is essential to salinity tolerance in two halophyte species, Atriplex lentiformis and Chenopodium quinoa

    Science.gov (United States)

    Bose, Jayakumar; Rodrigo-Moreno, Ana; Lai, Diwen; Xie, Yanjie; Shen, Wenbiao; Shabala, Sergey

    2015-01-01

    Background and Aims The activity of H+-ATPase is essential for energizing the plasma membrane. It provides the driving force for potassium retention and uptake through voltage-gated channels and for Na+ exclusion via Na+/H+ exchangers. Both of these traits are central to plant salinity tolerance; however, whether the increased activity of H+-ATPase is a constitutive trait in halophyte species and whether this activity is upregulated at either the transcriptional or post-translation level remain disputed. Methods The kinetics of salt-induced net H+, Na+ and K+ fluxes, membrane potential and AHA1/2/3 expression changes in the roots of two halophyte species, Atriplex lentiformis (saltbush) and Chenopodium quinoa (quinoa), were compared with data obtained from Arabidopsis thaliana roots. Key Results Intrinsic (steady-state) membrane potential values were more negative in A. lentiformis and C. quinoa compared with arabidopsis (−144 ± 3·3, −138 ± 5·4 and −128 ± 3·3 mV, respectively). Treatment with 100 mm NaCl depolarized the root plasma membrane, an effect that was much stronger in arabidopsis. The extent of plasma membrane depolarization positively correlated with NaCl-induced stimulation of vanadate-sensitive H+ efflux, Na+ efflux and K+ retention in roots (quinoa > saltbush > arabidopsis). NaCl-induced stimulation of H+ efflux was most pronounced in the root elongation zone. In contrast, H+-ATPase AHA transcript levels were much higher in arabidopsis compared with quinoa plants, and 100 mm NaCl treatment led to a further 3-fold increase in AHA1 and AHA2 transcripts in arabidopsis but not in quinoa. Conclusions Enhanced salinity tolerance in the halophyte species studied here is not related to the constitutively higher AHA transcript levels in the root epidermis, but to the plant’s ability to rapidly upregulate plasma membrane H+-ATPase upon salinity treatment. This is necessary for assisting plants to maintain highly negative

  11. Rapid regulation of the plasma membrane H⁺-ATPase activity is essential to salinity tolerance in two halophyte species, Atriplex lentiformis and Chenopodium quinoa.

    Science.gov (United States)

    Bose, Jayakumar; Rodrigo-Moreno, Ana; Lai, Diwen; Xie, Yanjie; Shen, Wenbiao; Shabala, Sergey

    2015-02-01

    The activity of H(+)-ATPase is essential for energizing the plasma membrane. It provides the driving force for potassium retention and uptake through voltage-gated channels and for Na(+) exclusion via Na(+)/H(+) exchangers. Both of these traits are central to plant salinity tolerance; however, whether the increased activity of H(+)-ATPase is a constitutive trait in halophyte species and whether this activity is upregulated at either the transcriptional or post-translation level remain disputed. The kinetics of salt-induced net H(+), Na(+) and K(+) fluxes, membrane potential and AHA1/2/3 expression changes in the roots of two halophyte species, Atriplex lentiformis (saltbush) and Chenopodium quinoa (quinoa), were compared with data obtained from Arabidopsis thaliana roots. Intrinsic (steady-state) membrane potential values were more negative in A. lentiformis and C. quinoa compared with arabidopsis (-144 ± 3·3, -138 ± 5·4 and -128 ± 3·3 mV, respectively). Treatment with 100 mm NaCl depolarized the root plasma membrane, an effect that was much stronger in arabidopsis. The extent of plasma membrane depolarization positively correlated with NaCl-induced stimulation of vanadate-sensitive H(+) efflux, Na(+) efflux and K(+) retention in roots (quinoa > saltbush > arabidopsis). NaCl-induced stimulation of H(+) efflux was most pronounced in the root elongation zone. In contrast, H(+)-ATPase AHA transcript levels were much higher in arabidopsis compared with quinoa plants, and 100 mm NaCl treatment led to a further 3-fold increase in AHA1 and AHA2 transcripts in arabidopsis but not in quinoa. Enhanced salinity tolerance in the halophyte species studied here is not related to the constitutively higher AHA transcript levels in the root epidermis, but to the plant's ability to rapidly upregulate plasma membrane H(+)-ATPase upon salinity treatment. This is necessary for assisting plants to maintain highly negative membrane potential values and to

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

    Science.gov (United States)

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

    2014-07-29

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

  13. Neurophysiological basis of rapid eye movement sleep behavior disorder: informing future drug development

    Directory of Open Access Journals (Sweden)

    Jennum P

    2016-04-01

    Full Text Available Poul Jennum, Julie AE Christensen, Marielle Zoetmulder Department of Clinical Neurophysiology, Faculty of Health Sciences, Danish Center for Sleep Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Abstract: Rapid eye movement (REM sleep behavior disorder (RBD is a parasomnia characterized by a history of recurrent nocturnal dream enactment behavior and loss of skeletal muscle atonia and increased phasic muscle activity during REM sleep: REM sleep without atonia. RBD and associated comorbidities have recently been identified as one of the most specific and potentially sensitive risk factors for later development of any of the alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and other atypical parkinsonian syndromes. Several other sleep-related abnormalities have recently been identified in patients with RBD/Parkinson’s disease who experience abnormalities in sleep electroencephalographic frequencies, sleep–wake transitions, wake and sleep stability, occurrence and morphology of sleep spindles, and electrooculography measures. These findings suggest a gradual involvement of the brainstem and other structures, which is in line with the gradual involvement known in these disorders. We propose that these findings may help identify biomarkers of individuals at high risk of subsequent conversion to parkinsonism. Keywords: motor control, brain stem, hypothalamus, hypocretin

  14. Rapid detection of drugs of abuse in saliva using surface enhanced Raman spectroscopy and microfluidics.

    Science.gov (United States)

    Andreou, Chrysafis; Hoonejani, Mehran R; Barmi, Meysam R; Moskovits, Martin; Meinhart, Carl D

    2013-08-27

    We present a microfluidic device that detects trace concentrations of drugs of abuse in saliva within minutes using surface-enhanced Raman spectroscopy (SERS). Its operation is demonstrated using methamphetamine. The detection scheme exploits concentration gradients of chemicals, fostered by the laminar flow in the device, to control the interactions between the analyte, silver nanoparticles (Ag-NPs), and a salt. Also, since all species interact while advecting downstream, the relevant reaction coordinates occur with respect to the position in the channel. The system was designed to allow the analyte first to diffuse into the side stream containing the Ag-NPs, on which it is allowed to adsorb, before salt ions are introduced, causing the Ag-NPs to aggregate, and so creating species with strong SERS signal. The device allows partial separation via diffusion of the analyte from the complex mixture. Also, the reproducible salt-induced NP aggregation decouples the aggregation reaction (necessary for strong SERS) from the analyte concentration or charge. This method enables the creation of a region where detection of the analyte of interest via SERS is optimal, and dramatically extends the classes of molecules and quality of signals that can be measured using SERS, compared to bulk solution methods. The spatial distribution of the SERS signals was used to map the degree of nanoparticle aggregation and species diffusion in the channel, which, together with numerical simulations, was used to describe the kinetics of the colloid aggregation reaction, and to determine the optimal location in the channel for SERS interrogation.

  15. The use of recently described ionisation techniques for the rapid analysis of some common drugs and samples of biological origin.

    Science.gov (United States)

    Williams, Jonathan P; Patel, Vibhuti J; Holland, Richard; Scrivens, James H

    2006-01-01

    Three ionisation techniques that require no sample preparation or extraction prior to mass analysis have been used for the rapid analysis of pharmaceutical tablets and ointments. These methods were (i) the novel direct analysis in real time (DART), (ii) desorption electrospray ionisation (DESI), and (iii) desorption atmospheric pressure chemical ionisation (DAPCI). The performance of the three techniques was investigated for a number of common drugs. Significant differences between these approaches were observed. For compounds of moderate to low polarity DAPCI produced more effective ionisation. Accurate DESI and DAPCI tandem mass spectra were obtained and these greatly enhance the selectivity and information content of the experiment. The detection from human skin of the active ingredients from ointments is reported together with the detection of ibuprofen metabolites in human urine. Copyright 2006 John Wiley & Sons, Ltd.

  16. Sedative/hypnotic dependence: patient stabilization, tolerance testing, and withdrawal.

    Science.gov (United States)

    Perry, P J; Alexander, B

    1986-01-01

    Physical dependence to sedative/hypnotic drugs is not an uncommon clinical problem. The withdrawal syndrome is analogous to alcohol withdrawal, except the duration of the syndrome occurs over a longer period of time with the symptoms being less intense than generally encountered with alcohol. The potential for withdrawal reactions is probably greater for the shorter-acting agents than the longer-acting drugs. Potentially dependent sedative/hypnotic users require stabilization of their symptoms initially, followed by tolerance testing. If tolerant, the patients should be withdrawn using either a long-acting sedative/hypnotic (e.g., diazepam) or phenobarbital. Compared to other benzodiazepines and barbiturates, diazepam appears to be the drug of choice for treating dependent patients. Diazepam is rapidly absorbed and distributed to the brain and therefore useful for stabilization and tolerance testing. It is metabolized on chronic administration to a long-acting metabolite, desmethyldiazepam, which makes the drug ideal for a tapered withdrawal schedule.

  17. Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

    Science.gov (United States)

    Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

    2015-01-01

    Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

  18. Fast mouse PK (Fast PK): a rapid screening method to increase pharmacokinetic throughput in pre-clinical drug discovery.

    Science.gov (United States)

    Reddy, Jitendar; Madishetti, Sreedhar; Vachaspati, Prakash R

    2012-09-29

    We describe a rapid screening methodology for performing pharmacokinetic (PK) studies in mice called Fast PK. In this Fast PK method, two mice were used per compound and four blood samples were collected from each mouse. The sampling times were staggered (sparse sampling) between the two mice, thus yielding complete PK profile in singlicate across eight time points. The plasma PK parameters from Fast PK were comparable to that obtained from conventional PK methods. This method has been used to rapidly screen compounds in the early stages of drug discovery and about 600 compounds have been profiled in the last 3 years, which has resulted in reduction in the usage of mice by 800 per year in compliance with the 3R principles of animal ethics. In addition, this Fast PK method can also help in evaluating the PK parameters from the same set of animals used in safety/toxicology/efficacy studies without the need for satellite groups. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Polypyrrole solid phase microextraction: A new approach to rapid sample preparation for the monitoring of antibiotic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Szultka, Malgorzata [Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus, Copernicus University, Gagarin 7, 87-100 Torun (Poland); Kegler, Ricarda [Institute of Clinical Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock (Germany); Fuchs, Patricia [Department of Anaesthesia and Intensive Care, University of Rostock, Schillingallee 35, D-18057 Rostock (Germany); Olszowy, Pawel [Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus, Copernicus University, Gagarin 7, 87-100 Torun (Poland); Miekisch, Wolfram; Schubert, Jochen K. [Department of Anaesthesia and Intensive Care, University of Rostock, Schillingallee 35, D-18057 Rostock (Germany); Buszewski, Boguslaw [Department of Environmental Chemistry and Bioanalytics, Faculty of Chemistry, Nicolaus, Copernicus University, Gagarin 7, 87-100 Torun (Poland); Mundkowski, Ralf G., E-mail: ralf.mundkowski@med.uni-rostock.de [Institute of Clinical Pharmacology, University of Rostock, Schillingallee 70, D-18057 Rostock (Germany)

    2010-05-14

    Simple or even rapid bioanalytical methods are rare, since they generally involve complicated, time-consuming sample preparation from the biological matrices like LLE or SPE. SPME provides a promising approach to overcome these limitations. The full potential of this innovative technique for medical diagnostics, pharmacotherapy or biochemistry has not been tapped yet. In-house manufactured SPME probes with polypyrrole (PPy) coating were evaluated using three antibiotics of high clinical relevance - linezolid, daptomycin, and moxifloxacin - from PBS, plasma, and whole blood. The PPy coating was characterised by scanning electron microscopy. Influences of pH, inorganic salt, and blood anticoagulants were studied for optimum performance. Extraction yields were determined from stagnant media as well as re-circulating human blood using the heart-and-lung machine model system. The PPy-SPME fibres showed high extraction yields, particularly regarding linezolid. The reproducibility of the method was optimised to achieve RSDs of 9% or 17% and 7% for SPME from stagnant or re-circulating blood using fresh and re-used fibres, respectively. The PPy-SPME approach was demonstrated to meet the requirements of therapeutic monitoring of the drugs tested, even from re-circulating blood at physiological flow rates. SPME represents a rapid and simple dual-step procedure with potency to significantly reduce the effort and expenditure of complicated sample preparations in biomedical analysis.

  20. Causes of Rapid Carrion Beetle (Coleoptera: Silphidae) Death in Flooded Pitfall Traps, Response to Soil Flooding, Immersion Tolerance, and Swimming Behavior.

    Science.gov (United States)

    Cavallaro, Michael C; Barnhart, M Christopher; Hoback, W Wyatt

    2017-04-01

    Terrestrial insects in water can often delay or escape drowning by floating and swimming. However, we observed that flooding of pitfall traps baited with rotting carrion results in high overnight mortality of captured beetles and reasoned that this risk may be enhanced by microbial respiration. By assessing carrion beetle (Coleoptera: Silphidae) response to flooding, tolerance to immersion, and swimming behavior, we offer insights to this cause of death and beetle behavioral physiology. Response of buried Nicrophorus orbicollis Say to soil flooding resulted in beetles moving to the soil surface. The lethal time to 50% mortality (LT50 (immersion); mean ± 95% CI) for Nicrophorus investigator Zetterstedt, Nicrophorus marginatus F., Necrodes surinamensis F., and Thanatophilus lapponicus Herbst was 14.8 ± 2.3, 9.0 ± 3.3, 3.2 ± 1.1, and 12.1 ± 2.5 h, respectively. Swimming behavior and survival time of N. investigator was tested using yeast:sucrose (Y:S) solutions to create a eutrophic, severely hypoxic aqueous environment. LT50 (swimming) for N. investigator was 7.5 ± 1.4, 6.0 ± 1.7, and 4.2 ± 1.2 h for the low, medium, and high Y:S solutions, respectively, and >24.0 h in control treatments. Nicrophorus investigator survived nearly twice as long when completely immersed in deoxygenated water, as might occur in flooded burrows, than when swimming on the surface. We document for the first time, the rapid induction of hypoxic coma and death for a terrestrial insect from enhanced microbial activity and CO2 production of an aqueous environment, as well as suggestions on trapping protocols related to the federally endangered Nicrophorus americanus Olivier. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Designing and comparison study of rapid detection methods of resistance to injectable drugs in clinical strains of Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Fatemeh Salehi

    2012-01-01

    Full Text Available Introduction: In this study, some molecular methods were designed for rapid detection of resistance to kanamycin and amikacin.Materials and methods: Among 120 clinical isolates of mycobacterium tuberculosis, 70 strains were selected for evaluation of possible mutations. A PCR-RFLP method was designed for detection of wild type (using enzyme ajii and mutant from (BstFNI enzyme of the isolates. Furthermore, allele specific method (as PCR was designed for detection mutations in codons 1401 and 1402 gene rrs. Some selected isolates were sequenced.Results: In PCR-RFLP method, among the 70 strains examined by BstFNI enzyme, could detect 17 mutant strains among 24 phenotypicaly resistant and 44 non-mutant isolates from 46 susceptible isolates. The sensitivity of this method was %70.83 and specificity was %95.65 on the other hand, 12 mutant from 20 resistant strains and 29 non-mutant strains from 32 susceptible strains were detected by AjiI enzyme. The sensitivity and specificity of this method was 60 and %90.62, respectively. In MAS PCR, 3 mutants from 6 resistant strains and 12 non-mutants from 17 resistant strains were detected. The sensitivity of this method was 50 and specificity was 70.58. Results of sequencing method confirmed the results of molecular methods.Discussion and conclusion: PCR-RFLP method by BstFNI enzyme was the best method for rapid detection of Mycobacterium tuberculosis resistant to second-line injectable drugs and was recommended for routine use.

  2. The effects of horizontal body casting on blood volume, drug responsiveness, and +Gz tolerance in the rhesus monkey

    Science.gov (United States)

    Dickey, D. T.; Billman, G. E.; Teoh, K.; Sandler, H.; Stone, H. L.

    1982-01-01

    To simulate the weightless condition, eight rhesus monkeys, instrumented with solid-state pressure transducers, were horizontally restrained in body casts for 28 days. Blood volume decreased an average of 13% after 14 days of restraint, due mainly to a drop in plasma volume. Aortic pressure and heart rate responses to norepinephrine and phenylephrine decreased after 14 days of restraint. The monkeys did not show a statistically significant decreased tolerance to a 90 deg sudden upright tilt after horizontal restraint. During the fifth week of casting, four animals were subjected to +Gz acceleration tests on a centrifuge. The acceleration tolerance of the casted monkeys was significantly reduced compared to four similarly instrumented control animals. These findings indicate that the cardiovascular deconditioning associated with simulated weightlessness results from an inability to maintain central blood volume during orthostatic stress.

  3. Tolerância a agente curarizante provocada pela administração repetida da droga Tolerance to curarizing drug induced by chronic administration: an experimental study

    Directory of Open Access Journals (Sweden)

    Antonio Carlos Zanini

    1974-03-01

    effective dose of DMT was determined by a "third part blind" when a 80% block was attained. When only 10 high frequency stimuli were applied to the nerve, a significant difference (p<0.05 in response was observed: Group I, 46.50 ± 20.00 g+; Group II, 55.25 ± 11.33 g+; Group III, 37.25 ± 10.77 g+; Group IV, 37.00 ± 12.74 g+. Significant differences in muscular force were also observed with sustained tetanus: Group I, 79.00 ± 16.21 g+; Group II, 76.75 ± 15.23 g+; Group III, 59.12 ± 17.38 g+; Group IV, 61.62 ± 14.74 g. Significant higher doses of curare i.v. were necessary in the group injected daily with the highest dose of curare than in any other group (p < 0.01: Group I, 3.62 ± 1.17 mcg/kg; Group II, 3.69 ± 1.21 mcg/kg; Group III, 4.01 ± 0.80 mcg/kg; Group IV, 5.48 ± 1.40. These results show that chronic administration of curare leads to physical weakness and hyposensitivity to the drug, thus suggesting that although the existence of a curarizing drug in the human blood may in fact contribute for the muscular weakness of the myasthenic patient, the blood curare does not play a major role in the pathogenesis of the syndrome since the myasthenic patient is highly sensitive to the injection of any curare.

  4. Country-wide surveillance of molecular markers of antimalarial drug resistance in Senegal by use of positive Malaria Rapid Diagnostic Tests

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Sow, Doudou; Nag, Sidsel

    2017-01-01

    of drug resistance. Therefore, surveillance of drug resistance in the malaria parasites is essential. The objective of this pilot study was to test the feasibility of routinely sampled malaria rapid diagnostic tests (RDTs) at a national scale to assess the temporal changes in the molecular profiles...... of antimalarial drug resistance markers of Plasmodium falciparum parasites. Overall, 9,549 positive malaria RDTs were collected from 14 health facilities across the country. A limited random set of RDTs were analyzed regarding Pfcrt gene polymorphisms at codon 72-76. Overall, a high but varied prevalence (> 50...

  5. [Telbivudine for prevention of perinatal transmission in pregnant women infected with hepatitis B virus in immune-tolerant phase: a study of efficacy and safety of drug withdrawal].

    Science.gov (United States)

    Sheng, Q J; Ding, Y; Li, B J; Bai, H; Zhang, C; Han, C; Fan, Y X; Li, Y W; Dou, X G

    2016-04-01

    To observe the success rate of telbivudine (LdT) for the prevention of perinatal transmission of hepatitis B virus (HBV) and the incidence of alanine aminotransferase (ALT) elevation during LdT treatment and after LdT withdrawal in HBV-infected pregnant woman with high viremia in immune-tolerant phase and receiving LdT treatment at the end of pregnancy, and to evaluate the efficacy of LdT in the prevention of perinatal transmission and the safety for pregnant women. Pregnant women infected with HBV in immune-tolerant phase who had normal ALT levels (≤40 U/L) and high viremia (HBV DNA ≥6 log10 IU/ml) with positive HBeAg were enrolled as subjects. All pregnant women received antiviral treatment with LdT at the end of pregnancy to prevent perinatal transmission of HBV. All infants received standard combined immunoprophylaxis. Failure for prevention of perinatal transmission of HBV was defined as positive HBsAg or HBV DNA in infants 7 months of age (or at one month after the third injection of hepatitis B vaccine). Liver function, HBV DNA, and HBV serological markers were evaluated at baseline, after 1 month of treatment, before childbirth, and 1, 3, and 6 months after drug withdrawal. SPSS 16.0 software was used to analyze the data. Between-group comparison of continuous data was made by t test, and comparison of categorical data was made by chi-square test. One hundred and four pregnant women (treatment group) received oral administration of 600 mg LdT once a day, and 25 pregnant women (observation group) did not receive any antiviral therapy. The success rate for the prevention of perinatal transmission was significantly higher in the treatment group than in the observation group (100% vs 89.47%, χ (2) = 9.862, P = 0.028). There was no significant difference in the incidence of ALT elevation during treatment and within 6 months after drug withdrawal between the treatment group and the observation group (4.81% (5/104) vs 4.00% (1/25), χ (2) = 0.030, P = 1

  6. Tolerance to coxibs in patients with intolerance to non-steroidal anti-inflammatory drugs (NSAIDs): a systematic structured review of the literature.

    Science.gov (United States)

    Weberschock, Tobias Bernd; Müller, Sylke-Monina; Boehncke, Sandra; Boehncke, Wolf-Henning

    2007-07-01

    Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966-2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966-2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous.

  7. Major reduction in anti-malarial drug consumption in Senegal after nation-wide introduction of malaria rapid diagnostic tests.

    Directory of Open Access Journals (Sweden)

    Sylla Thiam

    Full Text Available BACKGROUND: While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. METHODS AND FINDINGS: Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases. An estimated 516,576 courses of inappropriate ACT prescription were averted. CONCLUSIONS: The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were

  8. Major reduction in anti-malarial drug consumption in Senegal after nation-wide introduction of malaria rapid diagnostic tests.

    Science.gov (United States)

    Thiam, Sylla; Thior, Moussa; Faye, Babacar; Ndiop, Médoune; Diouf, Mamadou Lamine; Diouf, Mame Birame; Diallo, Ibrahima; Fall, Fatou Ba; Ndiaye, Jean Louis; Albertini, Audrey; Lee, Evan; Jorgensen, Pernille; Gaye, Oumar; Bell, David

    2011-04-06

    While WHO recently recommended universal parasitological confirmation of suspected malaria prior to treatment, debate has continued as to whether wide-scale use of rapid diagnostic tests (RDTs) can achieve this goal. Adherence of health service personnel to RDT results has been poor in some settings, with little impact on anti-malarial drug consumption. The Senegal national malaria control programme introduced universal parasite-based diagnosis using malaria RDTs from late 2007 in all public health facilities. This paper assesses the impact of this programme on anti-malarial drug consumption and disease reporting. Nationally-collated programme data from 2007 to 2009 including malaria diagnostic outcomes, prescription of artemisinin-based combination therapy (ACT) and consumption of RDTs in public health facilities, were reviewed and compared. Against a marked seasonal variation in all-cause out-patient visits, non-malarial fever and confirmed malaria, parasite-based diagnosis increased nationally from 3.9% of reported malaria-like febrile illness to 86.0% over a 3 year period. The prescription of ACT dropped throughout this period from 72.9% of malaria-like febrile illness to 31.5%, reaching close equivalence to confirmed malaria (29.9% of 584,873 suspect fever cases). An estimated 516,576 courses of inappropriate ACT prescription were averted. The data indicate high adherence of anti-malarial prescribing practice to RDT results after an initial run-in period. The large reduction in ACT consumption enabled by the move from symptom-based to parasite-based diagnosis demonstrates that effective roll-out and use of malaria RDTs is achievable on a national scale through well planned and structured implementation. While more detailed information on management of parasite-negative cases is required at point of care level to assess overall cost-benefits to the health sector, considerable cost-savings were achieved in ACT procurement. Programmes need to be allowed

  9. The epigenetic drug Trichostatin A ameliorates experimental autoimmune encephalomyelitis via T cell tolerance induction and impaired influx of T cells into the spinal cord.

    Science.gov (United States)

    Jayaraman, Arathi; Soni, Advait; Prabhakar, Bellur S; Holterman, Mark; Jayaraman, Sundararajan

    2017-12-01

    Multiple sclerosis is a T cell mediated chronic demyelinating disease of the central nervous system. Although currently available therapies reduce relapses, they do not facilitate tolerization of myelin antigen-specific T lymphocytes to ensure prolonged protection against multiple sclerosis. Here, we show that treatment of NOD mice with the histone deacetylase inhibitor, Trichostatin A affords robust protection against myelin peptide induced experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Protection was accompanied by histone hyperacetylation, and reduced inflammation and axonal damage in the spinal cord. Drug treatment diminished the generation of CD4+ memory T cells and induced tolerance in CD4+ T cells recognizing the immunizing myelin peptide. During the early immunization period, CD4+ T cells producing GM-CSF+IFN-γ, GM-CSF+IL-17A, as well as those expressing both IL-17A+IFN-γ (double-producers) were detected in the secondary lymphoid organs followed by the appearance of cells producing IFN-γ and GM-CSF. On the other hand, IFN-γ producing Th1 cells appear first in the spinal cord followed by cells producing IL-17A and GM-CSF. Treatment with Trichostatin A substantially reduced the frequencies of all T cells secreting various lymphokines both in the periphery and in the spinal cord. These data indicate that epigenetic modifications induced by histone hyperacetylation facilitates T cell tolerance induction in the periphery leading to reduced migration of T cells to the spinal cord and mitigation of neuronal damage and improved clinical outcome. These results suggest that epigenetic modulation of the genome may similarly offer benefits to multiple sclerosis patients via abrogating the function of encephalitogenic T lymphocytes without exerting severe side effects associated with currently used disease-modifying therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Fabrication and characterization of a rapid prototyped tissue engineering scaffold with embedded multicomponent matrix for controlled drug release

    DEFF Research Database (Denmark)

    Chen, Muwan; Le, Dang Q S; Hein, San

    2012-01-01

    showed that the scaffold was osteoinductive. The drug-release kinetics was investigated by loading doxorubicin into the scaffold. The scaffolds comprising nanoclay released up to 45% of the drug for up to 2 months, while the scaffold without nanoclay released 95% of the drug within 4 days. Therefore...

  11. 76 FR 16290 - Tolerances for Residues of New Animal Drugs in Food; 2-Acetylamino-5-Nitrothiazole; Buquinolate...

    Science.gov (United States)

    2011-03-23

    ...; Ethylenediamine; Florfenicol; Flunixin; Furazolidone; Hydrocortisone; Methylparaben; Methylprednisolone... reference an approved combination drug injectable solution containing florfenicol and flunixin (75 FR 1274... of flunixin meglumine. This action is being taken to comply with section. 512(i) of the FD&C Act and...

  12. Curling of flap tips in HIV-1 protease as a mechanism for substrate entry and tolerance of drug resistance.

    Science.gov (United States)

    Scott, W R; Schiffer, C A

    2000-12-15

    The human immunodeficiency virus type 1 (HIV-1) protease is an essential viral protein that is a major drug target in the fight against Acquired Immune Deficiency Syndrome (AIDS). Access to the active site of this homodimeric enzyme is gained when two large flaps, one from each monomer, open. The flap movements are therefore central to the function of the enzyme, yet determining how these flaps move at an atomic level has not been experimentally possible. In the present study, we observe the flaps of HIV-1 protease completely opening during a 10 ns solvated molecular dynamics simulation starting from the unliganded crystal structure. This movement is on the time scale observed by Nuclear Magnetic Resonance (NMR) relaxation data. The highly flexible tips of the flaps, with the sequence Gly-Gly-Ile-Gly-Gly, are seen curling back into the protein and thereby burying many hydrophobic residues. This curled-in conformational change has never been previously described. Previous models of this movement, with the flaps as rigid levers, are not consistent with the experimental data. The residues that participate in this hydrophobic cluster as a result of the conformational change are highly sensitive to mutation and often contribute to drug resistance when they do change. However, several of these residues are not part of the active site cavity, and their essential role in causing drug resistance could possibly be rationalized if this conformational change actually occurs. Trapping HIV-1 protease in this inactive conformation would provide a unique opportunity for future drug design.

  13. Simultaneous Rapid Determination of the Solubility and Diffusion Coefficients of a Poorly Water-Soluble Drug Based on a Novel UV Imaging System.

    Science.gov (United States)

    Lu, Yan; Li, Mingzhong

    2016-01-01

    The solubility and diffusion coefficient are two of the most important physicochemical properties of a drug compound. In practice, both have been measured separately, which is time consuming. This work utilizes a novel technique of UV imaging to determine the solubility and diffusion coefficients of poorly water-soluble drugs simultaneously. A 2-step optimal method is proposed to determine the solubility and diffusion coefficients of a poorly water-soluble pharmaceutical substance based on the Fick's second law of diffusion and UV imaging measurements. Experimental results demonstrate that the proposed method can be used to determine the solubility and diffusion coefficients of a drug with reasonable accuracy, indicating that UV imaging may provide a new opportunity to accurately measure the solubility and diffusion coefficients of a poorly water-soluble drug simultaneously and rapidly. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  14. Pharmacokinetics and Tolerance of the Phage Endolysin-Based Candidate Drug SAL200 after a Single Intravenous Administration among Healthy Volunteers.

    Science.gov (United States)

    Jun, Soo Youn; Jang, In Jin; Yoon, Seonghae; Jang, Kyungho; Yu, Kyung-Sang; Cho, Joo Youn; Seong, Moon-Woo; Jung, Gi Mo; Yoon, Seong Jun; Kang, Sang Hyeon

    2017-06-01

    This study was a phase 1, single-center, randomized, double-blind, placebo-controlled, single-dosing, and dose-escalating study of intravenous SAL200. It is a new candidate drug for the treatment of antibiotic-resistant staphylococcal infections based on a recombinant form of the phage endolysin SAL-1. The study evaluated the pharmacokinetics, pharmacodynamics, and tolerance among healthy male volunteers after the intravenous infusion of single ascending doses of SAL200 (0.1, 0.3, 1, 3, and 10 mg/kg of body weight). SAL200 was well tolerated, and no serious adverse events (AEs) were observed in this clinical study. Most AEs were mild, self-limiting, and transient. The AEs reported in more than three participants were fatigue, rigors, headache, and myalgia. No clinically significant values with respect to the findings of clinical chemistry, hematology, and coagulation analyses, urinalysis, vital signs, and physical examinations were observed, and no notable trends in our electrocardiogram (ECG) results for any tested dose were noticed. A greater-than-dose-proportional increase with regard to systemic exposure and the maximum serum concentration was observed when the SAL200 dose was increased from 0.1 mg/kg to 10 mg/kg. This investigation constitutes the first-in-human phase 1 study of an intravenously administered, phage endolysin-based drug. (This study has been registered at ClinicalTrials.gov under identifier NCT01855048 and at the Clinical Research Information Service [https://cris.nih.go.kr/cris/] under identifier KCT0000968.). Copyright © 2017 Jun et al.

  15. Rapid confirmatory analysis of non-steroidal anti-inflammatory drugs in bovine milk by rapid resolution liquid chromatography tandem mass spectrometry.

    Science.gov (United States)

    Dowling, Geraldine; Gallo, Pasquale; Malone, Edward; Regan, Liam

    2009-11-13

    A rapid method has been developed to analyse carprofen (CPF), diclofenac (DCF), mefenamic acid (MFN), niflumic acid (NIFLU), naproxen (NAP), oxyphenylbutazone (OXYPHEN), phenylbutazone (PBZ) and suxibuzone (SUXI) residues in bovine milk. Milk samples are extracted with acetonitrile and sample extracts were purified on Evolute ABN solid phase extraction cartridges. Aliquots were analysed by rapid resolution liquid chromatography tandem mass spectrometry (RRLC-MS/MS) with a runtime of 6.5 min. The method was validated in bovine milk, according to the criteria defined in Commission Decision 2002/657/EC. CCalpha values of 0.46, 1.08, 0.92, 1.26, 1.29, 2.12, 0.55 and 2.86 ng mL(-1) were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. CCbeta values of 0.79, 1.85, 1.56, 2.15, 2.19, 3.62, 0.94 and 4.87 ng mL(-1) were determined for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI, respectively. The measurement uncertainty of the method was estimated at 9, 28, 28, 45, 46, 45, 10 and 39% for CPF, DCF, MFN, NIFLU, NAP, OXYPHEN, PBZ and SUXI. Fortifying bovine milk samples (n=18) in three separate assays, show the accuracy of the method to be between 82 and 108%. The precision of the method, expressed as RSD values for the within-lab reproducibility at the three levels of fortification (5, 7.5 and 10 ng mL(-1)) was less than 16%, respectively. The advantage of the method is that low ng mL(-1) levels can be detected and quantitatively confirmed rapidly in milk and that 3 batches of samples can be analysed within a single day using RRLC-MS/MS with a runtime of 6.5 min.

  16. Fully validated method for rapid and simultaneous measurement of six antiepileptic drugs in serum and plasma using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry.

    Science.gov (United States)

    Kuhn, Joachim; Knabbe, Cornelius

    2013-06-15

    Therapeutic drug monitoring (TDM) may be very useful in the clinical management of antiepileptic drug therapy for multiple reasons, such as individual variability, metabolism, genetic factors or drug-drug or drug-food interactions. In addition, TDM is helpful to study the variation in pharmacokinetics that occurs between individuals. Here, we describe a rapid assay using ultra-performance liquid chromatography-electrospray ionization tandem mass spectrometry to measure the antiepileptic drugs lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. After the addition of internal standards (ISs) and protein precipitation of serum or plasma, 1 μl of sample was separated on a 2.1×50 mm reverse phase column (Waters, Acquity UPLC BEH Phenyl, 1.7 μm). Analytes were then ionized and detected by electrospray ionization mass spectrometry with multiple reaction monitoring. Runtime was 2.5 min per injection. Matrix effects were investigated by systematical ion suppression and in-source fragmentation experiments. The calibration curves of the 6 antiepileptic drugs were linear over the working range between 0.05 and 50 mg/L (r>0.99). The limit of detection (LOD) was measured in the assay. The intraassay and interassay coefficients of variation for all compounds were 1.0 mg/L). Mean recoveries were between 87.8 and 98.6% for all drugs. There were no significant ion suppressions detected at the elution times of the analytes. The mean differences between serum and heparinized plasma values were less than 6% for the 6 antiepileptic drugs. All drugs were stable in serum at -20°C, 4°C, and even at RT for at least 1 month. In summary, a specific and sensitive stable isotope dilution UPLC-MS/MS method was developed and validated for routine clinical monitoring of lacosamide, lamotrigine, levetiracetam, primidone, topiramate, and zonisamide. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Development of an Antivirulence Drug against Streptococcus mutans: Repression of Biofilm Formation, Acid Tolerance, and Competence by a Histidine Kinase Inhibitor, Walkmycin C ▿

    Science.gov (United States)

    Eguchi, Yoko; Kubo, Norihiro; Matsunaga, Hiroko; Igarashi, Masayuki; Utsumi, Ryutaro

    2011-01-01

    Two-component signal transduction systems (TCSs) in prokaryotes often regulate gene clusters that induce pathogenicity, and thus they have frequently been proposed as potential drug targets for attenuating the virulence of pathogens. The pathogenic potential of Streptococcus mutans, the major etiological pathogen of dental caries, is also regulated by its TCSs. The object of this study was to evaluate the effect of a histidine kinase (HK) inhibitor against two major virulence factors of S. mutans: biofilm formation and acid tolerance. Walkmycin C (WKM C), an HK inhibitor isolated from the screening of inhibitors against WalK HK in Bacillus subtilis, inhibited the in vitro autophosphorylation activity of three purified S. mutans HKs, i.e., VicK, CiaH, and LiaS. Although S. mutans does not have any essential HK but only an essential response regulator, VicR, WKM C showed an MIC of 6.25 μg/ml. This inhibitory effect of WKM C suggests that blocking the autophosphorylation of multiple HKs may inhibit phosphotransfer to VicR from VicK and other HKs. When WKM C was added at sub-MIC levels, the cells formed abnormal biofilms and also showed a defect in competence. When the cells were pretreated with WKM C, an increase in acid sensitivity was observed. Our results show that WKM C represses two pathogenic phenotypes of S. mutans, indicating the possibility of developing histidine kinase inhibitors into antivirulence drugs. PMID:21282451

  18. A randomised trial to compare the safety, tolerability and efficacy of three drug combinations for intermittent preventive treatment in children.

    Directory of Open Access Journals (Sweden)

    Kalifa Bojang

    Full Text Available BACKGROUND: Results from trials of intermittent preventive treatment (IPT in infants and children have shown that IPT provides significant protection against clinical malaria. Sulfadoxine-pyrimethamine (SP given alone or in combination with other drugs has been used for most IPT programmes. However, SP resistance is increasing in many parts of Africa. Thus, we have investigated whether SP plus AQ, SP plus piperaquine (PQ and dihydroartemisinin (DHA plus PQ might be equally safe and effective when used for IPT in children in an area of seasonal transmission. METHODS: During the 2007 malaria transmission season, 1008 Gambian children were individually randomized to receive SP plus amodiaquine (AQ, SP plus piperaquine (PQ or dihydroartemisinin (DHA plus PQ at monthly intervals on three occasions during the peak malaria transmission season. To determine the risk of side effects following drug administration, participants in each treatment group were visited at home three days after the start of each round of drug administration and a side effects questionnaire completed. To help establish whether adverse events were drug related, the same questionnaire was administered to 286 age matched control children recruited from adjacent villages. Morbidity was monitored throughout the malaria transmission season and study children were seen at the end of the malaria transmission season. RESULTS: All three treatment regimens showed good safety profiles. No severe adverse event related to IPT was reported. The most frequent adverse events reported were coughing, diarrhoea, vomiting, abdominal pain and loss of appetite. Cough was present in 15.2%, 15.4% and 18.7% of study subjects who received SP plus AQ, DHA plus PQ or SP plus PQ respectively, compared to 19.2% in a control group. The incidence of malaria in the DHA plus PQ, SP plus AQ and SP plus PQ groups were 0.10 cases per child year (95% CI: 0.05, 0.22, 0.06 (95% CI: 0.022, 0.16 and 0.06 (95% CI: 0.02, 0

  19. Efficiency and tolerance of sustained-release valproate sodium (Depakine®ChronosphereТМ as the drug of the first choice in the treatment of adult epilepsy

    Directory of Open Access Journals (Sweden)

    E. D. Belousova

    2013-01-01

    Full Text Available Objective: to obtain additional Russian data on the efficacy of Depakine®ChronosphereTMas a first-line agent for monotherapy in the treatment of adult epilepsy.Patients and methods. The short-term open-label prospective observational study that maximally approximated to routine clinical practice was conducted. The follow-up of patients lasted 2 months. The study included 494 patients over 18 years of age (mean age 30.2±14.1 years with different types of epilepsy. Symptomatic focal epilepsies were noted in 52% of all cases, presumably symptomatic and idiopathic generalized epilepsies in 16.8 and 29.8%, respectively; unspecified ones in 1.4% of cases. The patients received Depakine Chronosphere in an average daily dose of 18.58±5.53 mg/kg. The efficacy of the drug was evaluated from the change in the number of seizures; moreover, subjective assessments of therapeutic effectiveness were made by a physician and a patient. The safety was estimated from patients' reports on adverse reactions during the follow-up. Results. More than 90% of all the patients responded to Depakine Chronosphere positively (seizures ceased or decreased in number. Seizures completely disappeared in 64.6% of the patients. The drug was proven to be effective in different types of epilepsy (both partial and generalized ones. Depakine Chronosphere was well tolerated in this study. Adverse events were observed in 15.7% of the patients, but they gave grounds to discontinue the drug only in 0.8% of all cases. The physicians and patients unanimously assessed the efficiency of therapy as very good and good in over 90% of cases. The good efficacy and tolerance of the agent are supported by the data of an analysis using the global clinical rating scale: during the treatment, there was a marked improvement and no side effects in 61.1% and a marked improvement and mild side effects in 17%. Conclusion. The study has indicated that Depakine Chronosphere monotherapy for adult

  20. Rapid determination of yunaconitine and related alkaloids in aconites and aconite-containing drugs by ultra high-performance liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Song, Long; Zhang, Hong; Liu, Xin; Zhao, Zhi-Li; Chen, Shi-Lin; Wang, Zheng-Tao; Xu, Hong-Xi

    2012-12-01

    Yunaconitine (YAC) is a toxic aconite alkaloid that is considered to be a hidden aconite poison since it is frequently found in body fluids from aconite poisoning patients, but has not been well studied in commonly used herbal drugs. In this paper, a rapid and sensitive ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) detection combined with microwave-assisted extraction (MAE) was developed for high throughput simultaneous determination of YAC and six other toxic aconite alkaloids in 31 samples of crude, processed aconites and aconite-containing drugs. The optimized method showed excellent linearity, precision, accuracy and recovery for all target compounds with short run time. YAC was detected in some samples with contents from 0.015 to 10.41 mg/g. This is the first report on the determination of YAC in Radix Aconiti, Radix Aconiti Kusnezoffii and aconite-containing drugs. This newly developed method facilitates the rapid screening of YAC and related toxic aconite alkaloids and allows YAC to be used as a chemical marker for the quality control of aconites and aconite-containing drugs. Copyright © 2012 John Wiley & Sons, Ltd.

  1. A quantitative high-resolution genetic profile rapidly identifies sequence determinants of hepatitis C viral fitness and drug sensitivity.

    Directory of Open Access Journals (Sweden)

    Hangfei Qi

    2014-04-01

    Full Text Available Widely used chemical genetic screens have greatly facilitated the identification of many antiviral agents. However, the regions of interaction and inhibitory mechanisms of many therapeutic candidates have yet to be elucidated. Previous chemical screens identified Daclatasvir (BMS-790052 as a potent nonstructural protein 5A (NS5A inhibitor for Hepatitis C virus (HCV infection with an unclear inhibitory mechanism. Here we have developed a quantitative high-resolution genetic (qHRG approach to systematically map the drug-protein interactions between Daclatasvir and NS5A and profile genetic barriers to Daclatasvir resistance. We implemented saturation mutagenesis in combination with next-generation sequencing technology to systematically quantify the effect of every possible amino acid substitution in the drug-targeted region (domain IA of NS5A on replication fitness and sensitivity to Daclatasvir. This enabled determination of the residues governing drug-protein interactions. The relative fitness and drug sensitivity profiles also provide a comprehensive reference of the genetic barriers for all possible single amino acid changes during viral evolution, which we utilized to predict clinical outcomes using mathematical models. We envision that this high-resolution profiling methodology will be useful for next-generation drug development to select drugs with higher fitness costs to resistance, and also for informing the rational use of drugs based on viral variant spectra from patients.

  2. Rapid in situ detection of street samples of drugs of abuse on textile substrates using microRaman spectroscopy

    Science.gov (United States)

    Ali, Esam M. A.; Edwards, Howell G. M.; Scowen, Ian J.

    2011-10-01

    Trace amounts of street samples of cocaine hydrochloride and N-methyl-3,4-methylenedioxy-amphetamine (MDMA) on natural and synthetic textiles were successfully detected in situ using confocal Raman microscopy. The presence of some excipient bands in the spectra of the drugs did not prevent the unambiguous identification of the drugs. Raman spectra of the drugs were readily obtained without significant interference from the fibre substrates. Interfering bands arising from the fibre natural or synthetic polymer structure and/or dye molecules did not overlap with the characteristic Raman bands of the drugs. If needed, interfering bands could be successfully removed by spectral subtraction. Also, Raman spectra could be acquired from drug particles trapped between the fibres of highly fluorescent textile specimens. The total acquisition time of the spectra of the drug particles was 90 s accomplished non-destructively and without detachment from their substrates. Sample preparation was not required and spectra of the drugs could be obtained non-invasively preserving the integrity of the evidential material for further analysis.

  3. Magnetically optimized SERS assay for rapid detection of trace drug-related biomarkers in saliva and fingerprints.

    Science.gov (United States)

    Yang, Tianxi; Guo, Xiaoyu; Wang, Hui; Fu, Shuyue; Wen, Ying; Yang, Haifeng

    2015-06-15

    New developments in the fields of human healthcare and social security call for the exploration of an easy and on-field method to detect drug-related biomarkers. In this paper, Au nanoparticles dotted magnetic nanocomposites (AMN) modified with inositol hexakisphosphate (IP6) were used as surface-enhanced Raman scattering (SERS) substrate to quickly monitor trace drug-related biomarkers in saliva and to on-site screen a trace drug biomarker in fingerprints. Due to inducing with an external magnet, such substrate presented a huge SERS activity, which has met the sensitivity requirement for assay to detect the drug biomarkers in saliva from the U.S. Substance Abuse and Mental Health Services Administration, and also the limit of detection for drug biomarker in fingerprint reached 100 nM. In addition, this AMN-based SERS assay was successfully conducted using a portable Raman spectrometer, which could be used to on-site and accurately differentiate between the smokers and drug addicts in near future. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Influence of epipregnanolone on the modulation of rapid tolerance to ethanol by neurosteroids Influência da epipregnanolona sobre a modulação da tolerância rápida ao etanol pelos neuroesteróides

    Directory of Open Access Journals (Sweden)

    Adriana Dias Elpo Barbosa

    2007-12-01

    Full Text Available OBJECTIVE: The objective of the present study was to investigate the effect of epipregnanolone on the influence of neurosteroids on the development of rapid tolerance to the motor impairing and hypothermic effects of ethanol. METHOD: Experiment 1: on Day 1 groups of mice were pretreated with saline or with epipregnanolone. After 30 min each group was further divided in subgroups that received ethanol or saline. Thirty, 60 and 90 min after the injections the animals were tested on the rota-rod or the body temperature was measured. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. Experiment 2 and 3: On Day 1 groups of mice were treated with epipregnanolone and after 15 min each group was divided into three groups in order to receive pregnenolone sulfate, dehydroepiandrosterone sulfate or saline. Thirty minutes later, each group was further divided into two subgroups in order to receive ethanol or saline, respectively, and 30, 60 and 90 min later the animals were tested as in the experiment 1. On Day 2 all groups received ethanol and a similar procedure was followed to evaluate rapid tolerance. RESULTS: Pretreatment with epipregnanolone (0.10-0.30 mg/kg significantly blocked the development of tolerance to the motor impairing and hypothermic effects induced by ethanol in mice. Considering tolerance to ethanol-induced motor impairment, epipregnanolone (0.15 mg/kg reversed the stimulatory action of dehydroepiandrosterone sulfate (0.15 mg/kg, but did not affect the actions of pregnenolone sulfate (0.08 mg/kg. Moreover, epipregnanolone prevented the inhibitory action of allotetrahydrodeoxycorticosterone (0.10 mg/kg. In relation to ethanol-induced hypothermia, the results showed that pretreatment with epipregnanolone (0.30 mg/kg significantly prevented the stimulatory action of dehydroepiandrosterone sulfate and pregnenolone sulfate, as well as the inhibitory action of

  5. A multi-site validation in India of the line probe assay for the rapid diagnosis of multi-drug resistant tuberculosis directly from sputum specimens.

    Science.gov (United States)

    Raizada, Neeraj; Sachdeva, K S; Chauhan, D S; Malhotra, Bharti; Reddy, Kishore; Dave, P V; Mundade, Yamuna; Patel, Pranav; Ramachandran, Ranjani; Das, Ram; Solanki, Rajesh; Wares, Douglas Fraser; Sahu, Suvanand; O'Brien, Rick; Paramasivan, C N; Dewan, Puneet K

    2014-01-01

    Rifampicin (R) and isoniazid (H) are key first-line anti-tuberculosis drugs. Failure to detect resistance to these two drugs early results in treatment failure and poor clinical outcomes. The study purpose was to validate the use of the GenoType MTBDRplus line probe assay (LPA) to detect resistance to R and H in Mycobacterium tuberculosis strains directly from smear-positive sputum samples in India. Smear positive sputum specimens from 320 patients were subjected to LPA and results compared against those from conventional Lowenstein Jensen (LJ) culture and drug susceptibility testing (C&DST). All specimens with discordant R DST results were subjected to either sequencing of the rpoB gene and/or repeat DST on liquid culture (MGIT 960) at a National Reference Laboratory. Significantly higher proportion of interpretable results were observed with LPA compared to LJ C&DST (94% vs. 80%, p-value turnaround testing time, including specimen transportation time, on LPA was 11 days as compared with 89 days for LJ C&DST. LPA proved highly accurate in the rapid detection of R resistance. The reduction in time to diagnosis may potentially enable earlier commencement of the appropriate drug therapy, leading to some reduction of transmission of drug-resistant strains.

  6. Preparation of multilocation reduction-sensitive core crosslinked folate-PEG-coated micelles for rapid release of doxorubicin and tariquidar to overcome drug resistance

    Science.gov (United States)

    Yi, Xiaoqing; Zhao, Dan; Zhang, Quan; Xu, Jiaqi; Yuan, Gongdao; Zhuo, Renxi; Li, Feng

    2017-02-01

    Herein, we prepared folate-targeting core crosslinked polymeric micelles (CCL/FA) containing multiple disulfide bonds located at the interface and core of the micelles to co-deliver doxorubicin (DOX) and the P-glycoprotein (P-gp) inhibitor tariquidar (TQR) for reversing drug resistance. The stability and redox-responsive behavior of the CCL/FA micelles was evaluated through the changes in morphology, molecular weight and hydrodynamic size. On the one hand, the micelles possessed good stability, which led to the suppression of drug release from the CCL micelles in the physiological environment. On the other hand, under reductive conditions, the CCL micelles collapsed rapidly and accelerated drug release markedly. In vitro cytotoxicity measurements, combined with confocal laser scanning microscopy (CLSM) and flow cytometry, confirmed that the dual-drug-loaded micelles exhibited obviously higher cytotoxicity to MCF-7/ADR-resistant cells than free DOX · HCl, single-drug loaded CCL micelles and nontargeted CCL micelles. The results imply that co-delivering DOX and TQR by CCL/FA micelles may be a promising way of overcoming multidrug resistance in tumor treatments.

  7. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono District, Uganda.

    Science.gov (United States)

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony; Clarke, Sian; Cundill, Bonnie; Magnussen, Pascal; Yeung, Shunmay

    2013-03-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years as a tool to improve malaria diagnosis, since they have proved accurate and easy to perform with minimal training. Although RDTs could feasibly be performed by drug shop vendors, it is not known how much customers would be willing to pay for an RDT if offered in these settings. We conducted a contingent valuation survey among drug shop customers in Mukono District, Uganda. Exit interviews were undertaken with customers aged 15 years and above after leaving a drug shop having purchased an antimalarial and/or paracetamol. The bidding game technique was used to elicit the willingness-to-pay (WTP) for an RDT and a course of artemisinin-based combination therapy (ACT) with and without RDT confirmation. Factors associated with WTP were investigated using linear regression. The geometric mean WTP for an RDT was US$0.53, US$1.82 for a course of ACT and US$2.05 for a course of ACT after a positive RDT. Factors strongly associated with a higher WTP for these commodities included having a higher socio-economic status, no fever/malaria in the household in the past 2 weeks and if a malaria diagnosis had been obtained from a qualified health worker prior to visiting the drug shop. The findings further suggest that the WTP for an RDT and a course of ACT among drug shop customers is considerably lower than prevailing and estimated end-user prices for these commodities. Increasing the uptake of ACTs in drug shops and restricting the sale of ACTs to parasitologically confirmed malaria will therefore require additional measures.

  8. Tailor-Made pH-Responsive Poly(choline phosphate) Prodrug as a Drug Delivery System for Rapid Cellular Internalization.

    Science.gov (United States)

    Wang, Wenliang; Wang, Bo; Ma, Xiaojing; Liu, Sanrong; Shang, Xudong; Yu, Xifei

    2016-06-13

    Rapid cellular uptake and efficient drug release in tumor cells are two of the major challenges for cancer therapy. Herein, we designed and synthesized a novel pH-responsive polymer-drug conjugate system poly(2-(methacryloyloxy)ethyl choline phosphate)-b-poly(2-methoxy-2-oxoethyl methacrylate-hydrazide-doxorubicin) (PCP-Dox) to overcome these two challenges simultaneously. It has been proved that PCP-Dox can be easily and rapidly internalized by various cancer cells due to the strong interaction between multivalent choline phosphate (CP) groups and cell membranes. Furthermore, Dox, linked to the polymer carrier via acid-labile hydrazone bond, can be released from carriers due to the increased acidity in lysosome/endosome (pH 5.0-5.5) after the polymer prodrug was internalized into the cancer cells. The cell viability assay demonstrated that this novel polymer prodrug has shown enhanced cytotoxicity in various cancer cells, indicating its great potential as a new drug delivery system for cancer therapy.

  9. Use of peak decay analysis and affinity microcolumns containing silica monoliths for rapid determination of drug-protein dissociation rates.

    Science.gov (United States)

    Yoo, Michelle J; Hage, David S

    2011-04-15

    This report examined the use of silica monoliths in affinity microcolumns containing human serum albumin (HSA) to measure the dissociation rates for various drugs from this protein. Immobilized HSA and control monolith columns with dimensions of 1 mm × 4.6 mm i.d. were prepared for this work and used with a noncompetitive peak decay method. Several drugs known to bind HSA were examined, such as warfarin, diazepam, imipramine, acetohexamide, and tolbutamide. Items that were studied and optimized in this method included the sample volume, sample concentration, and elution flow rate. It was found that flow rates up to 10 mL/min could be used in this approach. Work with HSA silica monoliths at these high flow rates made it possible to provide dissociation rate constants for drugs such as warfarin in less than 40s. The dissociation rate constants that were measured gave good agreement with values reported in the literature or that had been obtained with other solutes that had similar binding affinities for HSA. This approach is a general one that should be useful in examining the dissociation of other drugs from HSA and in providing a high-throughput method for screening drug-protein interactions. Copyright © 2010 Elsevier B.V. All rights reserved.

  10. Collective antibiotic tolerance: mechanisms, dynamics and intervention.

    Science.gov (United States)

    Meredith, Hannah R; Srimani, Jaydeep K; Lee, Anna J; Lopatkin, Allison J; You, Lingchong

    2015-03-01

    Bacteria have developed resistance against every antibiotic at a rate that is alarming considering the timescale at which new antibiotics are developed. Thus, there is a critical need to use antibiotics more effectively, extend the shelf life of existing antibiotics and minimize their side effects. This requires understanding the mechanisms underlying bacterial drug responses. Past studies have focused on survival in the presence of antibiotics by individual cells, as genetic mutants or persisters. Also important, however, is the fact that a population of bacterial cells can collectively survive antibiotic treatments lethal to individual cells. This tolerance can arise by diverse mechanisms, including resistance-conferring enzyme production, titration-mediated bistable growth inhibition, swarming and interpopulation interactions. These strategies can enable rapid population recovery after antibiotic treatment and provide a time window during which otherwise susceptible bacteria can acquire inheritable genetic resistance. Here, we emphasize the potential for targeting collective antibiotic tolerance behaviors as an antibacterial treatment strategy.

  11. The protease inhibitors ritonavir and saquinavir influence lipid metabolism: a pig model for the rapid evaluation of new drugs

    DEFF Research Database (Denmark)

    Petersen, E.; Mu, Huiling; Porsgaard, Trine

    2010-01-01

    Background: Studies of the effects of antiretroviral drugs on lipid metabolism are limited by the availability of suitable models. We have thus developed an animal model utilising Gottingen mini-pigs. The normal lipid metabolism of mini-pigs closely reflects that of humans and they are expected t...

  12. Rapid determination of furosemide in drug and blood plasma of wrestlers by a carboxyl-MWCNT sensor.

    Science.gov (United States)

    Heidarimoghadam, Rashid; Farmany, Abbas

    2016-01-01

    A novel method is developed for the quantification of furosemide in biological fluids. The method is based on the electro-reduction of Zn(II)-furosemide complex at carboxyl-MWCNT modified glassy carbon electrode. It is shown that, in Britton-Robinson buffer (pH5.7) the reduction peak of Zn(II)-furosemide complex formed at -1.0 V (versus, Ag/AgCl). The increment of current signal obtained from the reduction peak current of the Zn(II)-furosemide complex was rectilinear with furosemide concentration in the range of 0.03 to 140.0 μg ml(-1), with a detection limit of 0.007 μg ml(-1). The drug recovery ranged between 97.8% and 100.8% and the mean drug recovery was 98.89%. The accuracies (relative error% and RSD%) were less than 15% and are acceptable according to the US FDA guideline for bioanalytical method validation. The sensor was used for quantification of furosemide in drug and biological fluid samples. The data of drug analysis were compared with the standard method. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Willingness-to-pay for a rapid malaria diagnostic test and artemisinin-based combination therapy from private drug shops in Mukono district, Uganda

    DEFF Research Database (Denmark)

    Hansen, Kristian Schultz; Pedrazzoli, Debora; Mbonye, Anthony

    2013-01-01

    In Uganda, as in many parts of Africa, the majority of the population seek treatment for malaria in drug shops as their first point of care; however, parasitological diagnosis is not usually offered in these outlets. Rapid diagnostic tests (RDTs) for malaria have attracted interest in recent years...... and a course of artemisinin-based combination therapy (ACT) with and without RDT confirmation. Factors associated with WTP were investigated using linear regression. The geometric mean WTP for an RDT was US$0.53, US$1.82 for a course of ACT and US$2.05 for a course of ACT after a positive RDT. Factors strongly...

  14. A rapid and low-cost microscopic observation drug susceptibility assay for detecting TB and MDR-TB among individuals infected by HIV in South India

    Directory of Open Access Journals (Sweden)

    S Solomon

    2013-01-01

    Full Text Available Background: The converging epidemics of HIV and tuberculosis (TB pose one of the greatest public health challenges of our time. Rapid diagnosis of TB is essential in view of its infectious nature, high burden of cases, and emergence of drug resistance. Objective: The purpose of this present study was to evaluate the feasibility of implementing the microscopic observation drug susceptibility (MODS assay, a novel assay for the diagnosis of TB and multi-drug-resistant tuberculosis (MDR-TB directly from sputum specimens, in the Indian setting. Materials and Methods: This study involved a cross-sectional, blinded assessment of the MODS assay on 1036 suspected cases of pulmonary TB in HIV-positive and HIV-negative patients against the radiometric method, BD-BACTEC TB 460 system. Results: Overall, the sensitivity, specificity, positive predictive value, and negative predictive value of the MODS assay in detecting MTB among TB suspected patients were 89.1%, 99.1%, 94.2%, 95.8%, respectively. In addition, in the diagnosis of drug-resistant TB, the MODS assay was 84.2% sensitive for those specimens reporting MDR, 87% sensitivity for those specimens reporting INH mono-resistance, and 100% sensitive for specimens reporting RIF mono-resistance. The median time to detection of TB in the MODS assay versus BACTEC was 9 versus 21 days (P < 0.001. Conclusion: Costing 5 to 10 times lesser than the automated culture methods, the MODS assay has the potential clinical utility as a simple and rapid method. It could be effectively used as an alternative method for diagnosing TB and detection of MDR-TB in a timely and affordable way in resource-limited settings.

  15. Catheter ablation and antiarrhythmic drugs for haemodynamically tolerated post-infarction ventricular tachycardia; long-term outcome in relation to acute electrophysiological findings.

    Science.gov (United States)

    Della Bella, P; De Ponti, R; Uriarte, J A S; Tondo, C; Klersy, C; Carbucicchio, C; Storti, C; Riva, S; Longobardi, M

    2002-03-01

    Radiofrequency catheter ablation is effective at terminating ventricular tachycardia, but the overall clinical role of the technique in patients with a prior myocardial infarction is still debated, due to the uncertainties of the long-term reliability of the procedure. The purpose of this study was to prospectively investigate the relationship between acute results obtained by catheter ablation and long-term outcome in a homogeneous population of patients with post-myocardial infarction ventricular tachycardia. One hundred and twenty-four consecutive patients with recurrent, drug-refractory, haemodynamically tolerated ventricular tachycardia were included in the study. This population accounted for 30% of the patients with post-myocardial infarction ventricular tachycardia admitted between April 1992 and September 1997 to the investigating centres. The ablation was successful in eliminating sustained ventricular tachycardia in 91 of them (73%); a partial result was obtained in 21 (17%) and failure in 12 (10%). Low dose amiodarone and/or beta-blockers were maintained in 86% of the patients. Over a median follow-up of 41.5 months (interquartile range 30.5-59.5 months), there were 15 deaths (12%), three of which were sudden (2.4%); the 12 remaining patients died of heart failure. Event-free survival analysis showed a significantly lower ventricular tachycardia recurrence rate in patients with a successful procedure as compared to those with failure or a partial result (19% vs 53% at one year and 27% vs 60% at 3 years, P=0.003). A repeat procedure was performed in 15 patients with early recurrences and was followed in all by long-term success. Of those who submitted to a second procedure, 93/124 patients (75%) are free of ventricular tachycardia recurrences. An implantable cardioverter-defibrillator (ICD), following procedure failure, was implanted in 13 patients (11%) of the study population. Radiofrequency catheter ablation is effective in a wide population of

  16. Rapid generation of drug-resistance alleles at endogenous loci using CRISPR-Cas9 indel mutagenesis.

    Directory of Open Access Journals (Sweden)

    Jonathan J Ipsaro

    Full Text Available Genetic alterations conferring resistance to the effects of chemical inhibitors are valuable tools for validating on-target effects in cells. Unfortunately, for many therapeutic targets such alleles are not available. To address this issue, we evaluated whether CRISPR-Cas9-mediated insertion/deletion (indel mutagenesis can produce drug-resistance alleles at endogenous loci. This method takes advantage of the heterogeneous in-frame alleles produced following Cas9-mediated DNA cleavage, which we show can generate rare alleles that confer resistance to the growth-arrest caused by chemical inhibitors. We used this approach to identify novel resistance alleles of two lysine methyltransferases, DOT1L and EZH2, which are each essential for the growth of MLL-fusion leukemia cells. We biochemically characterized the DOT1L mutation, showing that it is significantly more active than the wild-type enzyme. These findings validate the on-target anti-leukemia activities of existing DOT1L and EZH2 inhibitors and reveal a simple method for deriving drug-resistance alleles for novel targets, which may have utility during early stages of drug development.

  17. A multi-site validation in India of the line probe assay for the rapid diagnosis of multi-drug resistant tuberculosis directly from sputum specimens.

    Directory of Open Access Journals (Sweden)

    Neeraj Raizada

    Full Text Available Rifampicin (R and isoniazid (H are key first-line anti-tuberculosis drugs. Failure to detect resistance to these two drugs early results in treatment failure and poor clinical outcomes. The study purpose was to validate the use of the GenoType MTBDRplus line probe assay (LPA to detect resistance to R and H in Mycobacterium tuberculosis strains directly from smear-positive sputum samples in India.Smear positive sputum specimens from 320 patients were subjected to LPA and results compared against those from conventional Lowenstein Jensen (LJ culture and drug susceptibility testing (C&DST. All specimens with discordant R DST results were subjected to either sequencing of the rpoB gene and/or repeat DST on liquid culture (MGIT 960 at a National Reference Laboratory.Significantly higher proportion of interpretable results were observed with LPA compared to LJ C&DST (94% vs. 80%, p-value <0.01. A total of 248 patients had both LJ and LPA DST results available; 232 (93.5% had concordant R DST results. Among the 16 discordant R DST results, 13 (81% were resolved in agreement with LPA results. Final LPA performance characteristics were sensitivity 96% (CI: 90%-98%, specificity 99% (CI: 95%-99%, positive predictive value 99% (CI: 95%-99%, and negative predictive value 95% (CI: 89%-98%. The median turnaround testing time, including specimen transportation time, on LPA was 11 days as compared with 89 days for LJ C&DST.LPA proved highly accurate in the rapid detection of R resistance. The reduction in time to diagnosis may potentially enable earlier commencement of the appropriate drug therapy, leading to some reduction of transmission of drug-resistant strains.

  18. Multicentre laboratory validation of the colorimetric redox indicator (CRI) assay for the rapid detection of extensively drug-resistant (XDR) Mycobacterium tuberculosis.

    Science.gov (United States)

    Martin, Anandi; Paasch, Fabienne; Docx, Sven; Fissette, Krista; Imperiale, Belen; Ribón, Wellman; González, Liliana Andrea; Werngren, Jim; Engström, Anna; Skenders, Girts; Juréen, Pontus; Hoffner, Sven; Del Portillo, Patricia; Morcillo, Nora; Palomino, Juan Carlos

    2011-04-01

    To perform a multicentre study to evaluate the performance of the colorimetric redox indicator (CRI) assay and to establish the MICs and critical concentrations of rifampicin, isoniazid, ofloxacin, kanamycin and capreomycin. The study was carried out in two phases. Phase I determined the MIC of each drug. Phase II established critical concentrations for the five drugs tested by the CRI assay compared with the conventional proportion method. Phase I: a strain was considered resistant by the CRI assay if the MIC was ≥0.5 mg/L for rifampicin, ≥0.25 mg/L for isoniazid, ≥4.0 mg/L for ofloxacin and ≥5.0 mg/L for kanamycin and capreomycin. Sensitivity was 99.1% for isoniazid and 100% for the other drugs and specificity was 97.9% for capreomycin and 100% for the other drugs. Phase II: the critical concentration was 0.5 mg/L for rifampicin, 0.25 mg/L for isoniazid, 2.0 mg/L for ofloxacin and 2.5 mg/L for kanamycin and capreomycin giving an overall accuracy of 98.4%, 96.6%, 96.7%, 98.3% and 90%, respectively. Results demonstrate that the CRI assay is an accurate method for the rapid detection of XDR Mycobacterium tuberculosis. The CRI assay is faster than the conventional drug susceptibility testing method using solid medium, has the same turnaround time as the BACTEC MGIT 960 system, but is less expensive, and could be an adequate method for low-income countries.

  19. Assessment of maximum tolerated dose of a new herbal drug, Semelil (ANGIPARSTM in patients with diabetic foot ulcer: A Phase I clinical trial

    Directory of Open Access Journals (Sweden)

    Heshmat R

    2008-04-01

    Full Text Available Background and the purpose of the study: In many cases of diabetic foot ulcer (DFU management, wound healing is incomplete, and wound closure and epithelial junctional integrity are rarely achieved. Our aim was to evaluate the maximum tolerated dose (MTD and dose-limiting toxicity (DLT of Semelil (ANGIPARSTM, a new herbal compound for wound treatment in a Phase I clinical trial.Methods: In this open label study, six male diabetic patients with a mean age of 57±7.6 years were treated with escalating intravenous doses of Semelil, which started at 2 cc/day to 13.5 cc/day for 28 days. Patients were assessed with a full physical exam; variables which analyzed included age, past history of diabetes and its duration, blood pressure, body temperature, weight, characteristics of DFU, Na, K, liver function test, Complete Blood Count and Differential(CBC & diff, serum amylase, HbA1c, PT, PTT, proteinuria, hematuria, and side effects were recorded. All the measurements were taken at the beginning of treatment, the end of week 2 and week 4. We also evaluated Semelil's side effects at the end of weeks 4 and 8 after ending therapy.Results and major conclusions: Up to the drug dose of 10 cc/day foot ulcer dramatically improved. We did not observe any clinical or laboratory side effects at this or lower dose levels in diabetic patients. With daily dose of 13.5 cc of Semelil we observed phlebitis at the infusion site, which was the only side effect. Therefore, in this study we determined the MTD of Semelil at 10 cc/day, and the only DLT was phlebitis in injection vein. The recommended dose of Semelil I.V. administration for Phase II studies was 4 cc/day.

  20. SAFETY AND TOLERABILITY OF ANTIEPILEPTIC DRUGS AT WOMEN WITH EPILEPSY (DATA OF SVT. LUKA’S INSTITUTE OF CHILD NEUROLOGY AND EPILEPSY

    Directory of Open Access Journals (Sweden)

    K. Yu. Мukhin

    2015-01-01

    Full Text Available Women with epilepsy are referred to the special risk group due to the development of side effects of antiepileptic drugs (АED. Women’s neuroendocrinal disorders can be caused by the disease itself-epilepsy, as well as by the undertaken therapy. We have carried out a retrospective research in order to assess the safety and the tolerance of different AED at young girls and women of reproductive age. Was analyzed the data base of patients of Svt. Luka’s Institute of Child Neurology and Epilepsy, comprising all patients, who have been monitored in the period between 2000 and 2014 inclusive at the age between 15–40 years (n = 301. The research included patients, with different diagnosed forms of focal or generalized epilepsy, who were taking AED both during mono and polytherapy. Were analyzed all cases of neuroendocrinal, especially reproductive disorders, including the considerable gain of weight, menstrual disorder, sterility at AED background. Also was analyzed the result of all registered pregnancies at women with epilepsy (at the background of the antiepileptic therapy, as well as without treatment during pregnancy. The retrospective data analysis has revealed 51 сase (17 % in the group under review of expressed neuroendocrinal, reproductive and cosmetic side effects (including the menstrual disorder: dysmenorrhea, opsomenorrhea, amenorrhea, anovulatory cycles, sterility, unfavorable pregnancy outcomes, as well as cosmetic endocrinal side effects: obesity, hirsutism, hair loss. Most patients have got such combined side effects. Our research results show, that in most cases the pregnancy at women with epilepsy ends by birth of a healthy child, the pregnancy outcome depends on many factors, it also differs according to applied AED. Valproic acid drugs show the highest teratogenic risk. Also at the back ground of the therapy with valproic acid have been registered most cases of neuroendocrinal reproductive diseases at women

  1. Novel ultra-rapid freezing particle engineering process for enhancement of dissolution rates of poorly water-soluble drugs.

    Science.gov (United States)

    Overhoff, Kirk A; Engstrom, Josh D; Chen, Bo; Scherzer, Brian D; Milner, Thomas E; Johnston, Keith P; Williams, Robert O

    2007-01-01

    An ultra-rapid freezing (URF) technology has been developed to produce high surface area powders composed of solid solutions of an active pharmaceutical ingredient (API) and a polymer stabilizer. A solution of API and polymer excipient(s) is spread on a cold solid surface to form a thin film that freezes in 50 ms to 1s. This study provides an understanding of how the solvent's physical properties and the thin film geometry influence the freezing rate and consequently the final physico-chemical properties of URF-processed powders. Theoretical calculations of heat transfer rates are shown to be in agreement with infrared images with 10ms resolution. Danazol (DAN)/polyvinylpyrrolidone (PVP) powders, produced from both acetonitrile (ACN) and tert-butanol (T-BUT) as the solvent, were amorphous with high surface areas (approximately 28-30 m2/g) and enhanced dissolution rates. However, differences in surface morphology were observed and attributed to the cooling rate (film thickness) as predicted by the model. Relative to spray-freezing processes that use liquid nitrogen, URF also offers fast heat transfer rates as a result of the intimate contact between the solution and cold solid surface, but without the complexity of cryogen evaporation (Leidenfrost effect). The ability to produce amorphous high surface area powders with submicron primary particles with a simple ultra-rapid freezing process is of practical interest in particle engineering to increase dissolution rates, and ultimately bioavailability.

  2. Rapid wide-scope screening of drugs of abuse, prescription drugs with potential for abuse and their metabolites in influent and effluent urban wastewater by ultrahigh pressure liquid chromatography-quadrupole-time-of-flight-mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Hernandez, Felix, E-mail: felix.hernandez@qfa.uji.es [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain); Bijlsma, Lubertus, E-mail: bijlsma@guest.uji.es [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain); Sancho, Juan V.; Diaz, Ramon; Ibanez, Maria [Research Institute for Pesticides and Water, University Jaume I, Avda. Sos Baynat s/n, E-12071 Castellon (Spain)

    2011-01-17

    This work illustrates the potential of hybrid quadrupole-time-of-flight mass spectrometry (QTOF MS) coupled to ultrahigh pressure liquid chromatography (UHPLC) to investigate the presence of drugs of abuse in wastewater. After solid-phase extraction with Oasis MCX cartridges, seventy-six illicit drugs, prescription drugs with potential for abuse, and metabolites were investigated in the samples by TOF MS using electrospray interface under positive ionization mode, with MS data acquired over an m/z range of 50-1000 Da. For 11 compounds, reference standards were available, and experimental data (e.g., retention time and fragmentation data) could be obtained, facilitating a more confident identification. The use of a QTOF instrument enabled the simultaneous application of two acquisition functions with different collision energies: a low energy (LE) function, where none or poor fragmentation took place, and a high energy (HE) function, where fragmentation in the collision cell was promoted. This approach, known as MS{sup E}, enabled the simultaneous acquisition of full-spectrum accurate mass data of both protonated molecules and fragment ions in a single injection, providing relevant information that facilitates the rapid detection and reliable identification of these emerging contaminants in the sample matrices analyzed. In addition, isomeric compounds, like the opiates, morphine and norcodeine, could be discriminated by their specific fragments observed in HE TOF MS spectra, without the need of reference standards. UHPLC-QTOF MS was proven to be a powerful and efficient technique for rapid wide-scope screening and identification of many relevant drugs in complex matrices, such as influent and effluent urban wastewater.

  3. A microstructural study of sleep instability in drug-naive patients with schizophrenia and healthy controls: sleep spindles, rapid eye movements, and muscle atonia.

    Science.gov (United States)

    Guénolé, Fabian; Chevrier, Elyse; Stip, Emmanuel; Godbout, Roger

    2014-05-01

    This study aimed at characterizing the functional stability of sleep in schizophrenia by quantifying dissociated stages of sleep (DSS), and to explore their correlation with psychopathology. The sleep of 10 first-break, drug-naive young adults with schizophrenia and 10 controls was recorded. Four basic DSS patterns were scored: 1) the transitional EEG-mixed intermediate stage (EMIS); 2) Rapid-eye-movement (REM) sleep without rapid eye movement (RSWR); 3) REM sleep without atonia (RSWA); and 4) non-REM sleep with rapid eye movements. An intermediate sleep (IS) score was calculated by summing EMIS and RSWR scores, and the durations of intra-REM sleep periods IS (IRSPIS) and IS scored "at the expense" of REM sleep (ISERS) were determined. Patients were administered the Brief Psychiatric Rating Scale (BPRS) at the time of recording. Proportions of each DSS variables over total sleep time and proportions of IRSPIS and ISERS over REM sleep duration were compared between patients and controls. Correlation coefficients between DSS variables and BPRS total scores were calculated. The proportion of total DSS did not differ between patients and controls. Among DSS subtypes, RSWA was significantly increased in patients while other comparisons showed no significant differences. Significant positive correlations were found between BPRS scores and proportions of DSS, IS, RSWR, IRSPIS and ISERS over total sleep and REM sleep durations. These results demonstrate the functional instability of REM sleep in first-break, drug naive young adults with schizophrenia and unveil a pattern reminiscent of REM sleep behavior disorder. The significant correlation suggests that schizophrenia and REM sleep share common neuronal control mechanisms. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Efficacy and tolerability of urate-lowering drugs in gout : a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol

    NARCIS (Netherlands)

    Reinders, Mattheus; van Roon, E.N.; Jansen, T.L.; Delsing, J.; Griep, E.N.; Hoekstra, M.; van de Laar, M.F.; Brouwers, J.R.

    Objectives: To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout, and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment. Methods: Prospective, multicentre, open-label, two-stage randomised

  5. Optimization of Sample Preparation and Instrumental Parameters for the Rapid Analysis of Drugs of Abuse in Hair samples by MALDI-MS/MS Imaging

    Science.gov (United States)

    Flinders, Bryn; Beasley, Emma; Verlaan, Ricky M.; Cuypers, Eva; Francese, Simona; Bassindale, Tom; Clench, Malcolm R.; Heeren, Ron M. A.

    2017-08-01

    Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) has been employed to rapidly screen longitudinally sectioned drug user hair samples for cocaine and its metabolites using continuous raster imaging. Optimization of the spatial resolution and raster speed were performed on intact cocaine contaminated hair samples. The optimized settings (100 × 150 μm at 0.24 mm/s) were subsequently used to examine longitudinally sectioned drug user hair samples. The MALDI-MS/MS images showed the distribution of the most abundant cocaine product ion at m/z 182. Using the optimized settings, multiple hair samples obtained from two users were analyzed in approximately 3 h: six times faster than the standard spot-to-spot acquisition method. Quantitation was achieved using longitudinally sectioned control hair samples sprayed with a cocaine dilution series. A multiple reaction monitoring (MRM) experiment was also performed using the `dynamic pixel' imaging method to screen for cocaine and a range of its metabolites, in order to differentiate between contaminated hairs and drug users. Cocaine, benzoylecgonine, and cocaethylene were detectable, in agreement with analyses carried out using the standard LC-MS/MS method. [Figure not available: see fulltext.

  6. Two functionally distinct members of the MATE (multi-drug and toxic compound extrusion) family of transporters potentially underlie two major aluminum tolerance QTLs in maize.

    Science.gov (United States)

    Maron, Lyza G; Piñeros, Miguel A; Guimarães, Claudia T; Magalhaes, Jurandir V; Pleiman, Jennifer K; Mao, Chuanzao; Shaff, Jon; Belicuas, Silvia N J; Kochian, Leon V

    2010-03-01

    Crop yields are significantly reduced by aluminum (Al) toxicity on acidic soils, which comprise up to 50% of the world's arable land. Al-activated release of ligands (such as organic acids) from the roots is a major Al tolerance mechanism in plants. In maize, Al-activated root citrate exudation plays an important role in tolerance. However, maize Al tolerance is a complex trait involving multiple genes and physiological mechanisms. Recently, transporters from the MATE family have been shown to mediate Al-activated citrate exudation in a number of plant species. Here we describe the cloning and characterization of two MATE family members in maize, ZmMATE1 and ZmMATE2, which co-localize to major Al tolerance QTL. Both genes encode plasma membrane proteins that mediate significant anion efflux when expressed in Xenopus oocytes. ZmMATE1 expression is mostly concentrated in root tissues, is up-regulated by Al and is significantly higher in Al-tolerant maize genotypes. In contrast, ZmMATE2 expression is not specifically localized to any particular tissue and does not respond to Al. [(14)C]-citrate efflux experiments in oocytes demonstrate that ZmMATE1 is a citrate transporter. In addition, ZmMATE1 expression confers a significant increase in Al tolerance in transgenic Arabidopsis. Our data suggests that ZmMATE1 is a functional homolog of the Al tolerance genes recently characterized in sorghum, barley and Arabidopsis, and is likely to underlie the largest maize Al tolerance QTL found on chromosome 6. However, ZmMATE2 most likely does not encode a citrate transporter, and could be involved in a novel Al tolerance mechanism.

  7. Rapid on-site TLC-SERS detection of four antidiabetes drugs used as adulterants in botanical dietary supplements.

    Science.gov (United States)

    Zhu, Qingxia; Cao, Yongbing; Cao, Yingying; Chai, Yifeng; Lu, Feng

    2014-03-01

    A novel facile method has been established for rapid on-site detection of antidiabetes chemicals used to adulterate botanical dietary supplements (BDS) for diabetes. Analytes and components of pharmaceutical matrices were separated by thin-layer chromatography (TLC) then surface-enhanced Raman spectroscopy (SERS) was used for qualitative identification of trace substances on the HPTLC plate. Optimization and standardization of the experimental conditions, for example the method used for preparation of silver colloids, the mobile phase, and the concentration of colloidal silver, resulted in a very robust and highly sensitive method which enabled successful detection when the amount of adulteration was as low as 0.001 % (w/w). The method was also highly selective, enabling successful identification of some chemicals in extremely complex herbal matrices. The established TLC-SERS method was used for analysis of real BDS used to treat diabetes, and the results obtained were verified by liquid chromatography-triple quadrupole mass spectrometry (LC-MS-MS). The study showed that TLC-SERS could be used for effective separation and detection of four chemicals used to adulterate BDS, and would have good prospects for on-site qualitative screening of BDS for adulterants.

  8. The non-benzodiazepine anxiolytic drug etifoxine causes a rapid, receptor-independent stimulation of neurosteroid biosynthesis.

    Directory of Open Access Journals (Sweden)

    Jean Luc do Rego

    Full Text Available Neurosteroids can modulate the activity of the GABAA receptors, and thus affect anxiety-like behaviors. The non-benzodiazepine anxiolytic compound etifoxine has been shown to increase neurosteroid concentrations in brain tissue but the mode of action of etifoxine on neurosteroid formation has not yet been elucidated. In the present study, we have thus investigated the effect and the mechanism of action of etifoxine on neurosteroid biosynthesis using the frog hypothalamus as an experimental model. Exposure of frog hypothalamic explants to graded concentrations of etifoxine produced a dose-dependent increase in the biosynthesis of 17-hydroxypregnenolone, dehydroepiandrosterone, progesterone and tetrahydroprogesterone, associated with a decrease in the production of dihydroprogesterone. Time-course experiments revealed that a 15-min incubation of hypothalamic explants with etifoxine was sufficient to induce a robust increase in neurosteroid synthesis, suggesting that etifoxine activates steroidogenic enzymes at a post-translational level. Etifoxine-evoked neurosteroid biosynthesis was not affected by the central-type benzodiazepine (CBR receptor antagonist flumazenil, the translocator protein (TSPO antagonist PK11195 or the GABAA receptor antagonist bicuculline. In addition, the stimulatory effects of etifoxine and the triakontatetraneuropeptide TTN, a TSPO agonist, were additive, indicating that these two compounds act through distinct mechanisms. Etifoxine also induced a rapid stimulation of neurosteroid biosynthesis from frog hypothalamus homogenates, a preparation in which membrane receptor signalling is disrupted. In conclusion, the present study demonstrates that etifoxine stimulates neurosteroid production through a membrane receptor-independent mechanism.

  9. Fabrication of novel Si-doped hydroxyapatite/gelatine scaffolds by rapid prototyping for drug delivery and bone regeneration.

    Science.gov (United States)

    Martínez-Vázquez, F J; Cabañas, M V; Paris, J L; Lozano, D; Vallet-Regí, M

    2015-03-01

    Porous 3-D scaffolds consisting of gelatine and Si-doped hydroxyapatite were fabricated at room temperature by rapid prototyping. Microscopic characterization revealed a highly homogeneous structure, showing the pre-designed porosity (macroporosity) and a lesser in-rod porosity (microporosity). The mechanical properties of such scaffolds are close to those of trabecular bone of the same density. The biological behavior of these hybrid scaffolds is greater than that of pure ceramic scaffolds without gelatine, increasing pre-osteoblastic MC3T3-E1 cell differentiation (matrix mineralization and gene expression). Since the fabrication process of these structures was carried out at mild conditions, an antibiotic (vancomycin) was incorporated in the slurry before the extrusion of the structures. The release profile of this antibiotic was measured in phosphate-buffered saline solution by high-performance liquid chromatography and was adjusted to a first-order release kinetics. Vancomycin released from the material was also shown to inhibit bacterial growth in vitro. The implications of these results for bone tissue engineering applications are discussed. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  10. Rapid in situ repeatable analysis of drugs in powder form using reflectance near-infrared spectroscopy and multivariate calibration.

    Science.gov (United States)

    Melucci, Dora; Monti, Dario; D'Elia, Marcello; Luciano, Giorgio

    2012-01-01

    This study takes the first step toward in situ analysis of powder drugs which does not require any alteration of the samples. A fast, inexpensive analytical method based on reflectance near-infrared (NIR) spectrometry and multivariate calibration was applied. A diode-array fiber-optic portable spectrometer in the 900-1700 nm range was employed. Samples were laboratory-prepared ternary powders (diacetylmorphine, caffeine, and paracetamol). Partial least squares regression was applied. The choice of the standard samples for calibration and validation was performed through a D-optimal experimental design. The explained variance was higher than 90%, and the relative root mean square errors were <2%. The number of principal components (6) was very low when compared with the number of raw variables (356 absorbance values). Response plots showed slopes and intercepts were very close to optimal values. Correlation coefficients ranged between 0.909 and 0.989. The method here proposed proved to be competitive with Fourier transform NIR spectrometry. © 2011 American Academy of Forensic Sciences.

  11. How a microbial drug transporter became essential for crop cultivation on acid soils: aluminium tolerance conferred by the multidrug and toxic compound extrusion (MATE) family.

    Science.gov (United States)

    Magalhaes, Jurandir V

    2010-07-01

    Aluminium (Al) toxicity is a major agricultural constraint for crop cultivation on acid soils, which comprise a large portion of the world's arable land. One of the most widely accepted mechanisms of Al tolerance in plants is based on Al-activated organic acid release into the rhizosphere, with organic acids forming stable, non-toxic complexes with Al. This mechanism has recently been validated by the isolation of bona-fide Al-tolerance genes in crop species, which encode membrane transporters that mediate Al-activated organic acid release leading to Al exclusion from root apices. In crop species such as sorghum and barley, members in the multidrug and toxic compound extrusion (MATE) family underlie Al tolerance by a mechanism based on Al-activated citrate release. The study of Al tolerance in plants as conferred by MATE family members is in its infancy. Therefore, much is yet to be discovered about the functional diversity and evolutionary dynamics that led MATE proteins to acquire transport properties conducive to Al tolerance in plants. In this paper we review the major characteristics of transporters in the MATE family and will relate this knowledge to Al tolerance in plants. The MATE family is clearly extremely flexible with respect to substrate specificity, which raises the possibility that Al tolerance as encoded by MATE proteins may not be restricted to Al-activated citrate release in plant species. There are also indications that regulatory loci may be of pivotal importance to fully explore the potential for Al-tolerance improvement based on MATE genes.

  12. Costly tolerance

    African Journals Online (AJOL)

    2016-07-08

    Jul 8, 2016 ... It shows how this decision is related to the broader context of early twentieth century political life in the Netherlands. (the 'Pacification of 1917'), and it concludes with some thoughts on the costliness of true tolerance. Costly tolerance. Read online: Scan this QR code with your smart phone or mobile device.

  13. Rapid detection by direct analysis in real time-mass spectrometry (DART-MS) of psychoactive plant drugs of abuse: the case of Mitragyna speciosa aka "Kratom".

    Science.gov (United States)

    Lesiak, Ashton D; Cody, Robert B; Dane, A John; Musah, Rabi A

    2014-09-01

    Mitragyna speciosa, also known commonly as "Kratom" or "Ketum", is a plant with psychoactive properties that have been attributed to the presence of various indole alkaloids such as mitragynine and 7-hydroxymitragynine. M. speciosa use is gaining popularity internationally as a natural and legal alternative to narcotics. As a drug of abuse, its detection and identification are not straightforward, since M. speciosa plant material is not particularly distinctive. Here, we show that direct analysis in real time-mass spectrometry (DART-MS) can be used not only to rapidly identify M. speciosa plant material and distinguish it from other plants, but also to distinguish between M. speciosa plant varieties, based on differences between their chemical profiles. The method is rapid and the analysis expeditious. Plant material such as that found at a crime scene can be analyzed directly with no sample pre-preparation steps. Furthermore, we show that the basis set of principal components that permit characterization of the plant material can be used to positively identify M. speciosa. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Rapid acquisition and modulation of colistin-resistance by an extensively drug-resistant Acinetobacter baumannii: case report and review of current literature

    Directory of Open Access Journals (Sweden)

    Jari Intra

    2016-10-01

    Full Text Available Acinetobacter baumannii has emerged as a major cause of healthcare-associated infections. It commonly expresses clinical resistance to multiple antimicrobial agents, and hence, it is considered the paradigm of an extensively drug-resistant (XDR bacterium. XDR A. baumannii is a rapidly emerging pathogen, especially in the intensive care unit (ICU, causing nosocomial infections including sepsis, ventilatorassociated pneumonia, meningitis, peritonitis, urinary tract infection, and central venous catheter-related infection. In the present report, we described an in vivo evolution of A. baumannii strain from a colistinsusceptibility to a colistin-resistance state. A 65-year-old male, who suffered a duodenal ulcer, two days after hospitalization and during the stay in ICU, contracted a pneumonia and peritoneal infection by a carbapenem-resistant A. baumannii strain. After a combination treatment with colistin, vancomycin plus imipenem, and within seven days, the pathogen rapidly evolved in seven days to a pandrug-resistant phenotype. As the antimicrobial treatment was stopped, the A. baumannii isolate changed another time its profile to colistin, becoming newly susceptible, showing a very high level of adaptability to external conditions. We also have reviewed here the current literature on this worryingly public health threat.

  15. Real-Time PCR and High-Resolution Melt Analysis for Rapid Detection of Mycobacterium leprae Drug Resistance Mutations and Strain Types

    Science.gov (United States)

    Li, Wei; Matsuoka, Masanori; Kai, Masanori; Thapa, Pratibha; Khadge, Saraswoti; Hagge, Deanna A.; Brennan, Patrick J.

    2012-01-01

    Drug resistance surveillance and strain typing of Mycobacterium leprae are necessary to investigate ongoing transmission of leprosy in regions of endemicity. To enable wider implementation of these molecular analyses, novel real-time PCR–high-resolution melt (RT-PCR-HRM) assays without allele-specific primers or probes and post-PCR sample handling were developed. For the detection of mutations within drug resistance-determining regions (DRDRs) of folP1, rpoB, and gyrA, targets for dapsone, rifampin, and fluoroquinolones, real-time PCR-HRM assays were developed. Wild-type and drug-resistant mouse footpad-derived strains that included three folP1, two rpoB, and one gyrA mutation types in a reference panel were tested. RT-PCR-HRM correctly distinguished the wild type from the mutant strains. In addition, RT-PCR-HRM analyses aided in recognizing samples with mixed or minor alleles and also a mislabeled sample. When tested in 121 sequence-characterized clinical strains, HRM identified all the folP1 mutants representing two mutation types, including one not within the reference panel. The false positives (PCR inhibition. A second set of RT-PCR-HRM assays for identification of three previously reported single nucleotide polymorphisms (SNPs) that have been used for strain typing were developed and validated in 22 reference and 25 clinical strains. Real-time PCR-HRM is a sensitive, simple, rapid, and high-throughput tool for routine screening known DRDR mutants in new and relapsed cases, SNP typing, and detection of minor mutant alleles in the wild-type background at lower costs than current methods and with the potential for quality control in leprosy investigations. PMID:22170923

  16. Discrimination and quantification of two isomeric antineoplastic drugs by rapid and non-invasive analytical control using a handheld Raman spectrometer.

    Science.gov (United States)

    Lê, L M M; Tfayli, A; Zhou, J; Prognon, P; Baillet-Guffroy, A; Caudron, E

    2016-12-01

    Raman spectroscopy is a rapid, non-destructive and non-invasive method that is a promising tool for real-time analytical control of drug concentrations. This study evaluated a handheld Raman device to discriminate and quantify two isomeric drugs used to treat cancer. Doxorubicin (DOXO) and epirubicin (EPIR) samples were analyzed at therapeutic concentrations from 0.1 to 2mg/mL (n=90) and 0.08-2mg/mL (n=90) by non-invasive measurements using a portable Raman spectrometer. The discrimination of these two molecules was demonstrated for all concentrations (n=180) by qualitative analysis using partial least square discriminant analysis (PLS-DA) with 100% classification accuracy, sensitivity and specificity and 0% error rate. For each molecule, quantitative analyses were performed using PLS regression. The validity of the model was evaluated using root mean square error of cross validation (RMSECV) and prediction (RMSEP) that furnished 0.05 and 0.02mg/mL for DOXO and 0.17 and 0.16mg/mL for EPIR after pretreatment optimization. Based on the accuracy profile, the linearity range was from 1.256 to 2.000mg/mL for DOXO (R2=0.9988) and from 0.553 to 2.000mg/Ml for EPIR (R2=0.9240) and repeatability (CV% max of 1.8% for DOXO and 3.2% for EPIR) and intermediate precision (CV% max of 2.8% for DOXO and 4.5% for EPIR) were both acceptable. Despite the narrow validated concentration range for quantitative analysis, this study shows the potential of a handheld Raman spectrometer coupled to chemometric approaches for real-time quantification of cytotoxic drugs, as well for discriminating between two drugs with similar UV absorption profiles. Finally, the use of a handheld spectrometer with the possibility of a direct measurement of substances in containers is a potentially valuable tool for combining patient safety with security of healthcare workers. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Crafting tolerance

    DEFF Research Database (Denmark)

    Kirchner, Antje; Freitag, Markus; Rapp, Carolin

    2011-01-01

    Ongoing changes in social structures, orientation, and value systems confront us with the growing necessity to address and understand transforming patterns of tolerance as well as specific aspects, such as social tolerance. Based on hierarchical analyses of the latest World Values Survey (2005–08...... results show that specific institutional qualities, which reduce status anxiety, such as inclusiveness, universality, and fairness, prevail over traditional socio-economic, societal, cultural, and democratic explanations.......–08) and national statistics for 28 countries, we assess both individual and contextual aspects that influence an individual's perception of different social groupings. Using a social tolerance index that captures personal attitudes toward these groupings, we present an institutional theory of social tolerance. Our...

  18. Om tolerance

    DEFF Research Database (Denmark)

    Huggler, Jørgen

    2007-01-01

    Begrebet tolerance og dets betydninger diskuteres med henblik på en tydeliggørelse af begrebets forbindelse med stat, religion, ytringsfrihed, skeptisk erkendelsesteori, antropologi og pædagogik.......Begrebet tolerance og dets betydninger diskuteres med henblik på en tydeliggørelse af begrebets forbindelse med stat, religion, ytringsfrihed, skeptisk erkendelsesteori, antropologi og pædagogik....

  19. Drug allergy

    Directory of Open Access Journals (Sweden)

    Warrington Richard

    2011-11-01

    Full Text Available Abstract Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. This type of adverse drug reaction (ADR not only affects patient quality of life, but may also lead to delayed treatment, unnecessary investigations, and even mortality. Given the myriad of symptoms associated with the condition, diagnosis is often challenging. Therefore, referral to an allergist experienced in the identification, diagnosis and management of drug allergy is recommended if a drug-induced allergic reaction is suspected. Diagnosis relies on a careful history and physical examination. In some instances, skin testing, graded challenges and induction of drug tolerance procedures may be required. The most effective strategy for the management of drug allergy is avoidance or discontinuation of the offending drug. When available, alternative medications with unrelated chemical structures should be substituted. Cross-reactivity among drugs should be taken into consideration when choosing alternative agents. Additional therapy for drug hypersensitivity reactions is largely supportive and may include topical corticosteroids, oral antihistamines and, in severe cases, systemic corticosteroids. In the event of anaphylaxis, the treatment of choice is injectable epinephrine. If a particular drug to which the patient is allergic is indicated and there is no suitable alternative, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug. This article provides a backgrounder on drug allergy and strategies for the diagnosis and management of some of the most common drug-induced allergic reactions, such allergies to penicillin, sulfonamides, cephalosporins, radiocontrast media, local anesthetics, general anesthetics, acetylsalicylic acid (ASA and non-steroidal anti-inflammatory drugs.

  20. Design and baseline findings of a large-scale rapid response to an HIV outbreak in people who inject drugs in Athens, Greece: the ARISTOTLE programme.

    Science.gov (United States)

    Hatzakis, Angelos; Sypsa, Vana; Paraskevis, Dimitrios; Nikolopoulos, Georgios; Tsiara, Chrissa; Micha, Katerina; Panopoulos, Anastasios; Malliori, Meni; Psichogiou, Mina; Pharris, Anastasia; Wiessing, Lucas; van de Laar, Marita; Donoghoe, Martin; Heckathorn, Douglas D; Friedman, Samuel R; Des Jarlais, Don C

    2015-09-01

    To (i) describe an intervention implemented in response to the HIV-1 outbreak among people who inject drugs (PWIDs) in Greece (ARISTOTLE programme), (ii) assess its success in identifying and testing this population and (iii) describe socio-demographic characteristics, risk behaviours and access to treatment/prevention, estimate HIV prevalence and identify risk factors, as assessed at the first participation of PWIDs. A 'seek, test, treat, retain' intervention employing five rounds of respondent-driven sampling. Athens, Greece (2012-13). A total of 3320 individuals who had injected drugs in the past 12 months. ARISTOTLE is an intervention that involves reaching out to high-risk, hard-to-reach PWIDs ('seek'), engaging them in HIV testing and providing information and materials to prevent HIV ('test') and initiating and maintaining anti-retroviral and opioid substitution treatment for those testing positive ('treat' and 'retain'). Blood samples were collected for HIV testing and personal interviews were conducted. ARISTOTLE recruited 3320 PWIDs during the course of 13.5 months. More than half (54%) participated in multiple rounds, resulting in 7113 visits. HIV prevalence was 15.1%. At their first contact with the programme, 12.5% were on opioid substitution treatment programmes and the median number of free syringes they had received in the preceding month was 0. In the multivariable analysis, apart from injection-related variables, homelessness was a risk factor for HIV infection in male PWIDs [odds ratio (OR) yes versus no = 1.89, 95% confidence interval (CI) = 1.41, 2.52] while, in female PWIDS, the number of sexual partners (OR for > 5 versus one partner in the past year = 4.12, 95% CI = 1.93, 8.77) and history of imprisonment (OR yes versus no = 2.76, 95% CI = 1.43, 5.31) were associated with HIV. In Athens, Greece, the ARISTOTLE intervention for identifying HIV-positive people among people who inject drugs (PWID) facilitated rapid

  1. Large volume sample stacking for rapid and sensitive determination of antidiabetic drug metformin in human urine and serum by capillary electrophoresis with contactless conductivity detection.

    Science.gov (United States)

    Tůma, Petr

    2014-06-06

    Two CE methods with contactless conductivity detection have been developed for determining the oral antidiabetic drug metformin in human urine and blood. The determination of metformin is performed on a separation capillary with an effective length of 14 cm, using a maximum voltage of 30 kV and with a small injection of 50-fold diluted urine into the capillary. Under these conditions, the migration time of metformin is 35s and the LOD is 0.3 μM. Large-volume sample stacking was used to determine low metformin levels in serum. The injection of a sample of serum deproteinized with acetonitrile was 10 times greater compared to the injected amount of urine. This enabled reduction of the LOD to 0.03 μM and the metformin migration time equalled 86 s. The undesirable solvent from sample zone was forced out of the capillary to ensure rapidity and good repeatability of the determination. The RSD values for the migration time are 0.1% for urine and 0.7% for serum; RSD for the peak areas equalled 1.4% for urine and 2.6% for serum. The developed CE technique was tested on performance of routine analyses of metformin in the urine and serum of patients suffering from type II diabetes mellitus. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Soil transmitted helminths and scabies in Zanzibar, Tanzania following mass drug administration for lymphatic filariasis - a rapid assessment methodology to assess impact

    Directory of Open Access Journals (Sweden)

    Mohammed Khalfan A

    2012-12-01

    Full Text Available Abstract Background Ivermectin and albendazole are used in annual mass drug administration (MDA for the lymphatic filariasis elimination programmes in African countries co-endemic for onchocerciasis, but have additional impact on soil transmitted helminths and the ectoparasitic mite which causes scabies. Assessing these collateral impacts at scale is difficult due to the insensitivity of available parasite detection techniques. Methods The numbers of cases diagnosed with intestinal helminths and scabies and who received prescriptions for treatment were evaluated in 50 health centres in Zanzibar. Records were examined from 2000, prior to the initiation of MDA to 2005, after six rounds of MDA for lymphatic filariasis had taken place. Results Health centre records showed a consistent decline in the number of cases of intestinal helminths and scabies diagnosed by community health workers in Zanzibar and the number of prescriptions issued across five age groups. A 90-98% decline in soil transmitted helminths and 68-98% decline in scabies infections were recorded. Poisson regression models aggregated to both the island-level and district-level indicated that the decline was statistically significant. Conclusions The described method of examining health centre records has the potential for use on a large scale, despite limitations, as a rapid method to evaluate the impacts resulting from both lymphatic filariasis and onchocerciasis MDA. This would result in a reduction in the need for parasitological evaluations to determine prevalence and intensity.

  3. Efficacy and tolerability of EPs 7630 in children and adolescents with acute bronchitis - a randomized, double-blind, placebo-controlled multicenter trial with a herbal drug preparation from Pelargonium sidoides roots.

    Science.gov (United States)

    Kamin, W; Maydannik, V; Malek, F A; Kieser, M

    2010-03-01

    The study aim was to demonstrate the efficacy and to investigate the tolerability of EPs 7630, a herbal drug preparation from Pelargonium sidoides roots, in the treatment of patients (1 - 18 years) with acute bronchitis outside the strict indication for antibiotics. A total of 200 patients were randomized to receive either active drug containing EPs 7630 (1 - 6 years: 3 x 10 drops/d; > 6 - 12 years: 3 x 20 drops/d; > 12 - 18 years: 3 x 30 drops/d) or placebo for 7 consecutive days. change in the total score of bronchitis-specific symptoms (BSS) from Day 0 to Day 7. Main secondary outcome measures: treatment outcome, patients' satisfaction with treatment, onset of effect, bed rest. From baseline to Day 7, the mean BSS score improved significantly more for EPs 7630 compared with placebo (3.4 +/- 1.8 vs. 1.2 +/- 1.8 points, p acute bronchitis in children and adolescents outside the strict indication for antibiotics with patients treated with EPs 7630 perceiving a more favorable course of the disease and a good tolerability as compared with placebo.

  4. Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol.

    Science.gov (United States)

    Reinders, M K; van Roon, E N; Jansen, T L Th A; Delsing, J; Griep, E N; Hoekstra, M; van de Laar, M A F J; Brouwers, J R B J

    2009-01-01

    To investigate the efficacy and tolerability of allopurinol as the first-choice antihyperuricaemic treatment for gout, and compare the efficacy and tolerability of benzbromarone and probenecid as second-choice treatment. Prospective, multicentre, open-label, two-stage randomised controlled trial in gout patients with normal renal function. Enrolled patients were given 300 mg allopurinol for 2 months (stage 1). Those patients who could not tolerate allopurinol or who did not attain the target serum urate concentration (sUr) probenecid 2 g/day for another 2 months (stage 2). 96 patients were enrolled in stage 1. 82 patients (85%) were eligible for the analysis at the end of stage 1: there was a mean (SD) decrease in sUr concentration of 35 (11)% from baseline; 20 patients (24%) attained target sUr probenecid (4 patients not eligible for analysis). Treatment with benzbromarone was successful in 22/24 patients (92%) and with probenecid in 20/31 patients (65%) (p = 0.03 compared with benzbromarone). Compared with baseline values, there was a mean (SD) decrease of sUr concentration of 64 (9)% with benzbromarone and 50 (7)% with probenecid (pprobenecid 2 g/day.

  5. Pesticide Tolerances

    Science.gov (United States)

    EPA regulates pesticides used to protect crops and sets limits on the amount of pesticide remaining in or on foods in the U.S. The limits on pesticides on foods are called tolerances in the U.S. (maximum residue limits (MRLs) in many other countries).

  6. Towards Tolerance

    NARCIS (Netherlands)

    Lisette Kuyper; Jurjen Iedema; Saskia Keuzenkamp

    2013-01-01

    Across Europe, public attitudes towards lesbian, gay and bisexual (LGB) individuals range from broad tolerance to widespread rejection. Attitudes towards homosexuality are more than mere individual opinions, but form part of the social and political structures which foster or hinder the equality

  7. Repressive Tolerance

    DEFF Research Database (Denmark)

    Pedersen, Morten Jarlbæk

    2017-01-01

    to an administrative culture of repressive tolerance of organised interests: authorities listen but only reacts in a very limited sense. This bears in it the risk of jeopardising the knowledge transfer from societal actors to administrative ditto thus harming the consultation institutions’ potential for strengthening...

  8. Tolerance Geometry.

    Science.gov (United States)

    Roberts, Fred S.

    The author cites work on visual perception which indicates that in order to study perception it is necessary to replace such classical geometrical notions as betweeness, straightness, perpendicularity, and parallelism with more general concepts. The term tolerance geometry is used for any geometry when primitive notions are obtained from the…

  9. Rapid discrimination and determination of antibiotics drugs in plastic syringes using near infrared spectroscopy with chemometric analysis: Application to amoxicillin and penicillin.

    Science.gov (United States)

    Lê, Laetitia Minh Mai; Eveleigh, Luc; Hasnaoui, Ikram; Prognon, Patrice; Baillet-Guffroy, Arlette; Caudron, Eric

    2017-05-10

    The aim of this study was to investigate near infrared spectroscopy (NIRS) combined to chemometric analysis to discriminate and quantify three antibiotics by direct measurement in plastic syringes.Solutions of benzylpenicillin (PENI), amoxicillin (AMOX) and amoxicillin/clavulanic acid (AMOX/CLAV) were analyzed at therapeutic concentrations in glass vials and plastic syringes with NIR spectrometer by direct measurement. Chemometric analysis using partial least squares regression and discriminative analysis was conducted to develop qualitative and quantitative calibration models. Discrimination of the three antibiotics was optimal for concentrated solutions with 100% of accuracy. For quantitative analysis, the three antibiotics furnished a linear response (R²>0.9994) for concentrations ranging from 0.05 to 0.2 g/mL for AMOX, 0.1 to 1.0 MUI/mL for PENI and 0.005 to 0.05 g/mL for AMOX/CLAV with excellent repeatability (maximum 1.3%) and intermediate precision (maximum of 3.2%). Based on proposed models, 94.4% of analyzed AMOX syringes, 80.0% of AMOX/CLAV syringes and 85.7% of PENI syringes were compliant with a relative error including the limit of ± 15%.NIRS as rapid, non-invasive and non-destructive analytical method represents a potentially powerful tool to further develop for securing the drug administration circuit of healthcare institutions to ensure that patients receive the correct product at the right dose. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Identification of Staphylococcus aureus α-hemolysin as a protein drug that is secreted by anticancer bacteria and rapidly kills cancer cells.

    Science.gov (United States)

    Swofford, Charles A; St Jean, Adam T; Panteli, Jan T; Brentzel, Zachary J; Forbes, Neil S

    2014-06-01

    Targeted bacterial delivery of anticancer proteins has the ability to overcome therapeutic resistance in tumors that limits the efficacy of chemotherapeutics. The ability of bacteria to specifically target tumors allows for delivery of aggressive proteins that directly kill cancer cells and cannot be administered systemically. However, few proteins have been tested for this purpose. To identify effective molecules, we systematically sorted proteins that have been shown to cause mammalian cell death. The genes for five proteins were selected and cloned into Escherichia coli and Salmonella. Supernatant from cultures of the transformed bacteria was applied to flasks of MCF-7 mammary carcinoma cells to identify proteins that (1) were expressed, (2) secreted, and (3) rapidly killed cancer cells. Time-lapse images were taken to visualize mammalian cell morphology. Of the investigated proteins, α-hemolysin from Staphylococcus aureus (SAH) was the most promising because it was secreted, caused trauma to cellular membranes, and induced oncosis in 18 min. After exposure for 6 h, SAH decreased cell viability by 90%. In comparison, the positive control, Pseudomonas aeruginosa exotoxin A (PEA), required 11 days to achieve a similar effect, when administered at 3,000 times its LC50 . The maximum death rate induced by SAH was calculated to be a reduction in cell viability of 7.1% per min, which was 200-fold faster than the PEA control. Two proteins, Dermonecrotic Toxin and Phospholipase C were active when extracted from the bacterial cytoplasm but were not secreted. This investigation revealed for the first time SAH as a potent anticancer drug for delivery by bacteria because of its ability to be secreted in a fully functional form and aggressively kill cancer cells. © 2014 Wiley Periodicals, Inc.

  11. Drug induced aseptic meningitis

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-09-29

    Sep 29, 2013 ... Drug induced aseptic meningitis can mimic an infectious process as well as meningitis secondary to systemic disorders for which treatment of these drugs were used. 6,9,10. Drug-induced aseptic meningitis may develop in a pa- tient who initially was able to tolerate the causative drug. The patients in our ...

  12. Plasmodium falciparum in vitro continuous culture conditions: A comparison of parasite susceptibility and tolerance to anti-malarial drugs throughout the asexual intra-erythrocytic life cycle.

    Science.gov (United States)

    Duffy, Sandra; Avery, Vicky M

    2017-12-01

    The continuous culture of Plasmodium falciparum is often seen as a means to an end, that end being to probe the biology of the parasite in question, and ultimately for many in the malaria drug discovery arena, to identify means of killing the parasite in order to treat malaria. In vitro continuous culture of Plasmodium falciparum is a fundamental requirement when undertaking malaria research where the primary objectives utilise viable parasites of a desired lifecycle stage. This investigation, and resulting data, compared the impact culturing Plasmodium falciparum long term (4 months) in different environmental conditions had on experimental outcomes and thus conclusions. The example presented here focused specifically on the effect culture conditions had on the in vitro tolerance of Plasmodium falciparum to standard anti-malarial drugs, including artemisinin and lumefantrine. Historical data from an independent experiment for 3D7-ALB (5% O 2 ) was also compared with that obtained from this study. We concluded that parasites cultured for several months in media supplemented with a serum substitute such as Albumax II ® or within hyperoxic conditions (21% O 2 ), demonstrate highly variable responses to artemisinin and lumefantrine but not all anti-malarial drugs, when compared to those cultured in human serum in combination with Albumax II ® under normoxic conditions (5% O 2 ) for the parasite. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  13. Efficacy and tolerability of EPs 7630 tablets in patients with acute bronchitis: a randomised, double-blind, placebo-controlled dose-finding study with a herbal drug preparation from Pelargonium sidoides.

    Science.gov (United States)

    Matthys, H; Lizogub, V G; Malek, F A; Kieser, M

    2010-06-01

    Acute bronchitis is one of the most frequent health complaints for which patients seek medical advice. Although viral infections prevail, antibiotics are commonly prescribed. In this study, the efficacy and tolerability of EPs 7630 tablets, a herbal drug preparation from the roots of Pelargonium sidoides, were investigated in adults with acute bronchitis outside the strict indication for antibiotics. In this randomised, double-blind, placebo-controlled, multicentre dose-finding trial using an adaptive group-sequential design, 406 patients were randomly assigned to one of four parallel treatment groups (10 mg EPs 7630 tablets three times a day (30-mg group), 20 mg EPs 7630 tablets three times a day (60-mg group), 30 mg EPs 7630 tablets three times a day (90-mg group) or placebo three times a day) for a treatment period of 7 days. Primary endpoint was the change in the total score of bronchitis-specific symptoms (BSS) from baseline to day 7. Between day 0 and day 7, the mean BSS score decreased by 2.7 +/- 2.3 (placebo), 4.3 +/- 1.9 (30-mg group), 6.1 +/- 2.1 (60-mg group), and 6.3 +/- 2.0 points (90-mg group), respectively. The differences between the EPs 7630 groups and placebo were statistically significant (p < 0.0001, each). The secondary endpoints showed comparable results. EPs 7630 was well-tolerated. All documented adverse events were of mild to moderate intensity; their frequency was dose-dependent. No serious adverse events were reported. This study demonstrated statistically significant and clinically relevant superiority of all three tested dosages of EPs 7630 over placebo. All dosages of EPs 7630 were well-tolerated. Taking into account both efficacy and safety, the results of this study indicate that the 20 mg tablets of EPs 7630 taken three times daily constitute the optimal dose with respect to the benefit-risk ratio.

  14. A field evaluation of the Hardy TB MODS Kit™ for the rapid phenotypic diagnosis of tuberculosis and multi-drug resistant tuberculosis.

    Directory of Open Access Journals (Sweden)

    Laura Martin

    Full Text Available Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA with PATH (Seattle, WA, USA to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory.2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ, conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct DST and proportion method (indirect DST. 778 samples (31.8% were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals of the MODS Kit were 99.3% (98.3-99.8%, 98.3% (97.5-98.8%, 95.8% (94.0-97.1%, and 99.7% (99.3-99.9%. Median (interquartile ranges time to culture-positivity (and rifampicin and isoniazid DST was 10 (9-13 days for conventional MODS and 8.5 (7-11 for MODS Kit (p<0.01. Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples and reference indirect DST (97.9% agreement, 687/702 evaluable samples.MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked, readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of

  15. A systematic study of the effect of low pH acid treatment on anti-drug antibodies specific for a domain antibody therapeutic: Impact on drug tolerance, assay sensitivity and post-validation method assessment of ADA in clinical serum samples.

    Science.gov (United States)

    Kavita, Uma; Duo, Jia; Crawford, Sean M; Liu, Rong; Valcin, Joan; Gleason, Carol; Dong, Huijin; Gadkari, Snaehal; Dodge, Robert W; Pillutla, Renuka C; DeSilva, Binodh S

    2017-09-01

    We developed a homogeneous bridging anti-drug antibody (ADA) assay on an electro chemiluminescent immunoassay (ECLIA) platform to support the immunogenicity evaluation of a dimeric domain antibody (dAb) therapeutic in clinical studies. During method development we evaluated the impact of different types of acid at various pH levels on polyclonal and monoclonal ADA controls of differing affinities and on/off rates. The data shows for the first time that acids of different pH can have a differential effect on ADA of various affinities and this in turn impacts assay sensitivity and drug tolerance as defined by these surrogate controls. Acid treatment led to a reduction in signal of intermediate and low affinity ADA, but not high affinity or polyclonal ADA. We also found that acid pretreatment is a requisite for dissociation of drug bound high affinity ADA, but not for low affinity ADA-drug complexes. Although we were unable to identify an acid that would allow a 100% retrieval of ADA signal post-treatment, use of glycine pH3.0 enabled the detection of low, intermediate and high affinity antibodies (Abs) to various extents. Following optimization, the ADA assay method was validated for clinical sample analysis. Consistencies within various parameters of the clinical data such as dose dependent increases in ADA rates and titers were observed, indicating a reliable ADA method. Pre- and post-treatment ADA negative or positive clinical samples without detectable drug were reanalyzed in the absence of acid treatment or presence of added exogenous drug respectively to further assess the effectiveness of the final acid treatment procedure. The overall ADA results indicate that assay conditions developed and validated based on surrogate controls sufficed to provide a reliable clinical data set. The effect of low pH acid treatment on possible pre-existing ADA or soluble multimeric target in normal human serum was also evaluated, and preliminary data indicate that acid type and

  16. Rapid small lot manufacturing

    Energy Technology Data Exchange (ETDEWEB)

    Harrigan, R.W.

    1998-05-09

    The direct connection of information, captured in forms such as CAD databases, to the factory floor is enabling a revolution in manufacturing. Rapid response to very dynamic market conditions is becoming the norm rather than the exception. In order to provide economical rapid fabrication of small numbers of variable products, one must design with manufacturing constraints in mind. In addition, flexible manufacturing systems must be programmed automatically to reduce the time for product change over in the factory and eliminate human errors. Sensor based machine control is needed to adapt idealized, model based machine programs to uncontrolled variables such as the condition of raw materials and fabrication tolerances.

  17. Country-wide surveillance of molecular markers of antimalarial drug resistance in Senegal by use of positive Malaria Rapid Diagnostic Tests

    DEFF Research Database (Denmark)

    Ndiaye, Magatte; Sow, Doudou; Nag, Sidsel

    2017-01-01

    In Senegal, antimalarial drugs used in treatment and prevention of malaria are one of the main reasons for the current success in controlling malaria. However, the successful control of malaria is highly dependent on continued effectiveness of these drugs which may be compromised by the spread of...

  18. Development of a high-throughput in vitro intestinal lipolysis model for rapid screening of lipid-based drug delivery systems

    DEFF Research Database (Denmark)

    Mosgaard, Mette D; Sassene, Philip; Mu, Huiling

    2015-01-01

    (DIVL) model with regard to the extent of lipid digestion and drug distribution of two poorly soluble model drugs (cinnarizine and danazol), during digestion of three LbDDS (LbDDS I-III). RESULT: The HTP model was able to maintain pH around 6.5 during digestion, without the addition of NaOH...

  19. Using the Slug Mucosal Irritation Assay to Investigate the Tolerability of Tablet Excipients on Human Skin in the Context of the Use of a Nipple Shield Delivery System.

    Science.gov (United States)

    Kendall, Richard; Lenoir, Joke; Gerrard, Stephen; Scheuerle, Rebekah L; Slater, Nigel K H; Tuleu, Catherine

    2017-04-01

    Neonates are particularly challenging to treat. A novel patented drug delivery device containing a rapidly disintegrating tablet held within a modified nipple shield (NSDS) was designed to deliver medication to infants during breastfeeding. However concerns exist around dermatological nipple tolerability with no pharmaceutical safety assessment guidance to study local tissue tolerance of the nipple and the areola. This is the first Slug Mucosal Irritation (SMI) study to evaluate irritancy potential of GRAS excipients commonly used to manufacture rapidly disintegrating immediate release solid oral dosage form METHODS: Zinc sulphate selected as the antidiarrheal model drug that reduces infant mortality, was blended with functional excipients at traditional levels [microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, magnesium stearate]. Slugs were exposed to blends slurried in human breast milk to assess their stinging, itching or burning potential, using objective values such as mucus production to categorize irritation potency RESULTS: Presently an in vivo assay, previously validated for prediction of ocular and nasal irritation, was used as an alternative to vertebrate models to anticipate the potential maternal dermatological tolerability issues to NSDS tablet components. The excipients did not elicit irritancy. However, mild irritancy was observed when zinc sulphate was present in blends. These promising good tolerability results support the continued investigation of these excipients within NSDS rapidly disintegrating tablet formulations. Topical local tolerance effects being almost entirely limited to irritation, the slug assay potentially adds to the existing preformulation toolbox, and may sit in between the in vitro and existing in vivo assays.

  20. Enhancing TB case detection: experience in offering upfront Xpert MTB/RIF testing to pediatric presumptive TB and DR TB cases for early rapid diagnosis of drug sensitive and drug resistant TB.

    Science.gov (United States)

    Raizada, Neeraj; Sachdeva, Kuldeep Singh; Nair, Sreenivas Achuthan; Kulsange, Shubhangi; Gupta, Radhey Shayam; Thakur, Rahul; Parmar, Malik; Gray, Christen; Ramachandran, Ranjani; Vadera, Bhavin; Ekka, Shobha; Dhawan, Shikha; Babre, Ameet; Ghedia, Mayank; Alavadi, Umesh; Dewan, Puneet; Khetrapal, Mini; Khanna, Ashwini; Boehme, Catharina; Paramsivan, Chinnambedu Nainarappan

    2014-01-01

    Diagnosis of pulmonary tuberculosis (PTB) in children is challenging due to difficulties in obtaining good quality sputum specimens as well as the paucibacillary nature of disease. Globally a large proportion of pediatric tuberculosis (TB) cases are diagnosed based only on clinical findings. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents the results from pediatric groups taking part in a large demonstration study wherein Xpert MTB/RIF testing replaced smear microscopy for all presumptive PTB cases in public health facilities across India. The study covered a population of 8.8 million across 18 programmatic sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each study TU. Pediatric presumptive PTB cases (both TB and Drug Resistant TB (DR-TB)) accessing any public health facilities in study area were prospectively enrolled and tested on Xpert MTB/RIF following a standardized diagnostic algorithm. 4,600 pediatric presumptive pulmonary TB cases were enrolled. 590 (12.8%, CI 11.8-13.8) pediatric PTB were diagnosed. Overall 10.4% (CI 9.5-11.2) of presumptive PTB cases had positive results by Xpert MTB/RIF, compared with 4.8% (CI 4.2-5.4) who had smear-positive results. Upfront Xpert MTB/RIF testing of presumptive PTB and presumptive DR-TB cases resulted in diagnosis of 79 and 12 rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high (98%, CI 90.1-99.9), with no statistically significant variation with respect to past history of treatment. Upfront access to Xpert MTB/RIF testing in pediatric presumptive PTB cases was associated with a two-fold increase in bacteriologically-confirmed PTB, and increased detection of rifampicin-resistant TB cases under routine operational conditions across India. These results suggest that routine Xpert MTB/RIF testing is a promising solution to

  1. Disposition and tolerance of suxibuzone in horses.

    Science.gov (United States)

    Jaraiz, M V; Rodriguez, C; San Andres, M D; Gonzalez, F; San Andres, M I

    1999-09-01

    Suxibuzone (SBZ), a nonsteroidal anti-inflammatory drug, was administered to 6 horses at a dose rate of 7.5 mg/kg bwt by intravenous (i.v.) route. Plasma and synovial fluid concentrations of suxibuzone and its main active metabolites, phenylbutazone (PBZ) and oxyphenbutazone (OPBZ), were measured simultaneously by a sensitive and specific high-performance liquid chromatographic method. The pharmacokinetic parameters were determined by noncompartmental analysis. Plasma SBZ concentrations rapidly decreased and were not detectable beyond 20 min after treatment. The parent drug was not detected in any synovial fluid samples. Average maximum plasma concentrations of PBZ (16.43 microg/ml) and OPBZ (2.37 microg/ml) were attained at 0.76 and 7.17 h, respectively. The mean residence time (MRT) of PBZ was 6.96 h in plasma. Oxyphenbutazone plasma concentrations were below those reached by phenylbutazone during the first 12 h after suxibuzone administration, even though its values were detectable for at least 24 h (MRT = 10.65 h). Plasma concentrations of PBZ and OPBZ exceeding EC50 and IC50 of TXB2 and PGE2 were reached by at least 12 h. Synovial fluid concentrations of PBZ and OPBZ were 2.87+/-0.37 microg/ml and 0.97+/-0.08 microg/ml at 9 h after suxibuzone administration and exceeded IC50 of PGE2 for at least this time. In the present study, suxibuzone was well tolerated following i.v. injection.

  2. Macroevolutionary patterns of salt tolerance in angiosperms

    Science.gov (United States)

    Bromham, Lindell

    2015-01-01

    Background Halophytes are rare, with only 0·25 % of angiosperm species able to complete their life cycle in saline conditions. This could be interpreted as evidence that salt tolerance is difficult to evolve. However, consideration of the phylogenetic distribution of halophytes paints a different picture: salt tolerance has evolved independently in many different lineages, and halophytes are widely distributed across angiosperm families. In this Viewpoint, I will consider what phylogenetic analysis of halophytes can tell us about the macroevolution of salt tolerance. Hypothesis Phylogenetic analyses of salt tolerance have shown contrasting patterns in different families. In some families, such as chenopods, salt tolerance evolved early in the lineage and has been retained in many lineages. But in other families, including grasses, there have been a surprisingly large number of independent origins of salt tolerance, most of which are relatively recent and result in only one or a few salt-tolerant species. This pattern of many recent origins implies either a high transition rate (salt tolerance is gained and lost often) or a high extinction rate (salt-tolerant lineages do not tend to persist over macroevolutionary timescales). While salt tolerance can evolve in a wide range of genetic backgrounds, some lineages are more likely to produce halophytes than others. This may be due to enabling traits that act as stepping stones to developing salt tolerance. The ability to tolerate environmental salt may increase tolerance of other stresses or vice versa. Conclusions Phylogenetic analyses suggest that enabling traits and cross-tolerances may make some lineages more likely to adapt to increasing salinization, a finding that may prove useful in assessing the probable impact of rapid environmental change on vegetation communities, and in selecting taxa to develop for use in landscape rehabilitation and agriculture. PMID:25452251

  3. CONFLICT TOLERANCE OF A TEACHER: DIAGNOSIS AND DEVELOPMENT

    OpenAIRE

    Koryakovtseva, Olga; Yuferova, Marina; Bugaychuk, Tatiana

    2017-01-01

    In today's rapidly developing society conflict tolerance is an important quality of professionals in different areas. The question of the teacher’s tolerance to conflict has not been studies well enough. The results of this research disclose relationships between indicators general adaptability and components of conflict tolerance of future teachers, which is important in the formation and development of conflict tolerance of a teacher

  4. Drugs and drug policy in the Netherlands

    NARCIS (Netherlands)

    Leuw, Ed.

    1991-01-01

    The Dutch parliament enacted the revised Opium Act in 1976. This penal law is part of the Dutch drug policy framework that includes tolerance for nonconforming lifestyles, risk reduction in regard to the harmful health and social consequences of drug taking, and penal measures directed against

  5. Rapid manufacturing for microfluidics

    CSIR Research Space (South Africa)

    Land, K

    2012-10-01

    Full Text Available . Microfluidics is at the forefront of developing solutions for drug discovery, diagnostics (from glucose tests to malaria and TB testing) and environmental diagnostics (E-coli monitoring of drinking water). In order to quickly implement new designs, a rapid...

  6. Allergen Immunotherapy and Tolerance

    Directory of Open Access Journals (Sweden)

    Tomokazu Matsuoka

    2013-01-01

    Full Text Available Successful allergen-specific immunotherapy (AIT is associated with a marked decrease in symptoms on allergen exposure, a reduced requirement for 'rescue' anti-allergic drugs and improvement in patients' quality of life. These benefits persist for at least several years following discontinuation of immunotherapy - the hallmark of clinical and immunological tolerance. AIT has been shown to modulate both innate and adaptive immunological responses. Early suppression of innate effector cells of allergic inflammation (mast cells, basophils, regulation of pro-allergic T helper 2 type (Th 2 responses and IgE+ B cell responses have been shown to occur both in the tissue and in the peripheral blood during AIT. The allergen-tolerant state is associated with local and systemic induction of distinct populations of allergen-specific T regulatory cells including IL-10+ Tregs (Tr1 cells, TGF-P+ Tregs and FoxP3+ memory T regs. B cells are switched in favour of producing IgG (particularly IgG4 antibodies and associated blocking activity for IgE-dependent events, including basophil activation and IgE-facilitated allergen binding to B cells. An induction of IL-10+ B regulatory cells and alterations in dendritic cell subsets have also recently been described. These events are followed by the induction of T regulatory cells, suppression of allergen-specific T cell proliferation and immune deviation from Th2 in favour of Th1 responses. Alternative mechanisms of tolerance include apoptosis/deletion of antigen-specific memory Th2 cells and/or a failure of co-stimulation leading to T cell anergy.

  7. Differential development of antinociceptive tolerance to morphine and fentanyl is not linked to efficacy in the ventrolateral periaqueductal gray of the rat

    Science.gov (United States)

    Bobeck, Erin N.; Haseman, Rachel A.; Hong, Dana; Ingram, Susan L.; Morgan, Michael M.

    2012-01-01

    Systemic administration of morphine typically produces greater tolerance than higher efficacy mu-opioid receptor (MOPr) agonists, such as fentanyl. The objective of the present study was to test this relationship by measuring antinociceptive efficacy and tolerance to morphine and fentanyl microinjected into the ventrolateral periaqueductal gray (vlPAG). MOPr agonist efficacy was evaluated by microinjecting the irreversible opioid receptor antagonist β-funaltrexamine hydrochloride (β-FNA) into the vlPAG prior to a dose-response analysis of morphine and fentanyl antinociception. In contrast to systemic administration of morphine and fentanyl, microinjection of these drugs into the vlPAG had similar efficacy as measured by similar reductions in maximal antinociception following β-FNA administration. Analysis of tolerance revealed a rightward shift in the dose-response curve to a single pretreatment with morphine, but not fentanyl. Moreover, the magnitude of tolerance to morphine was comparable following one, four, or eight pretreatments. Tolerance to fentanyl also was evident following four or eight microinjections. These data are surprising in that antinociceptive efficacy appears to vary depending on the site of administration. Moreover, the similar efficacy following microinjection of morphine and fentanyl into the vlPAG was associated with comparable tolerance, with the one exception of no tolerance to acute administration of fentanyl. Perspective These data reveal that antinociceptive tolerance following vlPAG administration of opioids develops rapidly, is evident with both morphine and fentanyl, and the magnitude is relatively consistent regardless of the number of pretreatments. PMID:22766006

  8. Use of Optical Imaging Technology in the Validation of a New, Rapid, Cost-Effective Drug Screen as Part of a Tiered In Vivo Screening Paradigm for Development of Drugs To Treat Cutaneous Leishmaniasis.

    Science.gov (United States)

    Caridha, Diana; Parriot, Sandi; Hudson, Thomas H; Lang, Thierry; Ngundam, Franklyn; Leed, Susan; Sena, Jenell; Harris, Michael; O'Neil, Michael; Sciotti, Richard; Read, Lisa; Lecoeur, Herve; Hickman, Mark; Grogl, Max

    2017-04-01

    In any drug discovery and development effort, a reduction in the time of the lead optimization cycle is critical to decrease the time to license and reduce costs. In addition, ethical guidelines call for the more ethical use of animals to minimize the number of animals used and decrease their suffering. Therefore, any effort to develop drugs to treat cutaneous leishmaniasis requires multiple tiers of in vivo testing that start with higher-throughput efficacy assessments and progress to lower-throughput models with the most clinical relevance. Here, we describe the validation of a high-throughput, first-tier, noninvasive model of lesion suppression that uses an in vivo optical imaging technology for the initial screening of compounds. A strong correlation between luciferase activity and the parasite load at up to 18 days postinfection was found. This correlation allows the direct assessment of the effects of drug treatment on parasite burden. We demonstrate that there is a strong correlation between drug efficacy measured on day 18 postinfection and the suppression of lesion size by day 60 postinfection, which allows us to reach an accurate conclusion on drug efficacy in only 18 days. Compounds demonstrating a significant reduction in the bioluminescence signal compared to that in control animals can be tested in lower-throughput, more definitive tests of lesion cure in BALB/c mice and Golden Syrian hamsters (GSH) using Old World and New World parasites. Copyright © 2017 Caridha et al.

  9. AN OPEN-LABEL MULTICENTER OBSERVATIONAL STUDY OF THE EFFICACY, TOLERABILITY, AND SAFETY OF THE NONSTEROIDAL ANTI-INFLAMMATORY DRUG AMTOLMETIN GUACIL IN PATIENTS WITH KNEE OSTEOARTHRITIS AND DYSPEPSIA

    Directory of Open Access Journals (Sweden)

    E. S. Tsvetkova

    2016-01-01

    Full Text Available Objective: to investigate the efficacy and tolerability of amtolmetin guacil (AMG; Niselat®, Dr. Reddy's Laboratories Ltd, India versus previous therapy with nonsteroidal anti-inflammatory drugs (NSAIDs in patients with knee osteoarthritis (OA and signs of dyspepsia.Subjects and methods. The open-label observational study included 220 patients aged 30–65 years who suffered from knee OA and intense pain during NSAID intake and had symptoms of dyspepsia in the absence of contraindications to the use of AMG. Among the comorbidities that generally occurred in 68% of the patients, there was a preponderance of hypertension (42%, lower extremity varicose veins (6.4%, and diabetes mellitus (6%. Treatment efficacy was evaluated using three domains of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, by also taking into account pain intensity and general health assessment on the visual analogue scale. A Severity of Dyspepsia Assessment (SODA scale was used to rate dyspepsia.Results and discussion. AMG had a marked analgesic effect confirmed by 40% or more pain reduction that occurred in 72.5% of the patients. The high analgesic effect of AMG was confirmed by a statistically significant (p <0.001 reduction in the WOMAC index (pain and stiffness and by an increase in functional activity. There was a significant decrease in painless and painful signs of dyspepsia, as well as positive changes in the measures “overall assessment of dyspepsia severity” (p < 0.001 and “satisfaction with treatment”. Overall assessment of AMG tolerability was only positive: excellent (33%, good (56%, and satisfactory (11%. There were no serious adverse events (AE. AE were graded as moderate and mild in 8 and 82% of cases, respectively. AE were recorded in 7.7% of the patients. Conclusion. The findings suggest that AMG offers good prospects for knee OA treatment.

  10. Development of a lateral-flow assay for rapid screening of the performance-enhancing sympathomimetic drug clenbuterol used in animal production; food safety assessments.

    Science.gov (United States)

    Lai, Weihua; Xu, Yang; Fung, Daniel Y C; Xiong, Yonghua

    2007-01-01

    A lateral-flow assay that could provide visual evidence of the presence of clenbuterol in swine urine was developed. Colloidal gold was prepared and conjugated with anti-clenbuterol monoclonal antibody. Immunochromatographic test strips were produced, and then, 210 samples were tested on these strips. Analysis was completed in 10 min. Detection limit was 3 ppb of clenbuterol. Parallel GC-MS data indicated that clenbuterol rapid detection strip had no false negative. The false positive rate was 4.4%. Immunochromatographic strip has great applied value in the food safety field because it possesses benefits of sensitivity, stability, reproducibility, ease of use and inexpensive.

  11. Rapid detection of extensively drug-resistant (XDR-TB) strains from multidrug-resistant tuberculosis (MDR-TB) cases isolated from smear-negative pulmonary samples in an Intermediate Reference Laboratory in India.

    Science.gov (United States)

    Vashistha, Himanshu; Hanif, M; Saini, Sanjeev; Khanna, Ashwani; Sharma, Srashty; Sidiq, Zeeshan; Ahmed, Vasim; Dubey, Manoj; Chopra, K K; Shrivastava, Divya

    2016-07-01

    Direct sputum smear microscopy is commonly used for diagnosing tuberculosis (TB). The objectives of the study were first, to determine the recovery of Mycobacterium tuberculosis in smear-negative sputum samples through liquid culture (using MGIT 960) and solid culture (using LJ slant) and second, to screen multidrug-resistant isolates through line probe assay and further third, to identify XDR isolates through MGIT second-line DST from these positive MDR cultures in Delhi region. In this study, the sample size was 717 (sputum smear AFB negative and culture positive for M. tuberculosis complex by both solid and liquid culture methods) MDRTB suspects who were enrolled from January 2014 to December 2014 at the Intermediate Reference Laboratory in New Delhi Tuberculosis Centre, New Delhi. Rapid line probe assay was performed on all culture-positive samples, which were direct smear-negative specimens, and LPA-confirmed MDR samples were tested on MGIT 960 second-line DST for identification of XDR strains. An overall increase in the culture positivity (9.4%) among these smear-negative cases shows a good sign of recovery from M. tuberculosis infection in these samples. 717 (9.4%) positive cultures (MGIT+LJ) were subjected to line probe assay. Out of these 717 cultures, 9 (1.2%) were confirmed as NTM, 50 (7%) were MDR, 4 (0.6%) were mono-rifampicin resistant and 654 (91.2%) cultures were sensitive to both drugs Rif and Inh, respectively. Out of these 54 (50 MDR +4 mono-RIF resistant) cultures as screened by LPA, 1 (1.8%) was XDR, 10 (18.6%) were mono-ofloxacin resistant and 1 (1.8%) was mono-Kanamycin resistant. Sensitivity to both drugs KAN and OFX was seen in 42 (77.8%) cultures. Since the bacterial load in direct smear-negative suspected MDR samples is less, it is important to recover mycobacteria by rapid liquid culture method in such samples. Initial screening for MDRTB is to be done in such cases by performing rapid molecular genotypic drug susceptibility test such as

  12. A novel UV-photolysis approach with acetone and isopropyl alcohol for the rapid determination of fluoride in organofluorine-containing drugs by spectrophotometry

    Directory of Open Access Journals (Sweden)

    Venkata Balarama Krishna Mullapudi

    2018-01-01

    Full Text Available A UV photolysis decomposition (UVPD method for the determination of fluoride in fluorine containing pharmaceuticals by spectrophotometry is reported. It is based on the use of high intensity UV-irradiation in the presence of a digesting solution comprising a mixture of acetone and isopropanol. For the optimization of the UVPD procedure, three bulk drugs (levofloxacin, nebivolol and efavirenz were chosen as representatives of three diverse compounds containing a single fluorine atom, two fluorine atoms, and trifluoromethyl groups respectively. Operational conditions of the UVPD method, such as concentration and volume of reagents (acetone and isopropyl alcohol, and UV irradiation time (1–6 minutes were optimized. The efficiency of digestion was evaluated by the determination of fluoride in sample digests. Using the developed method, it was possible for complete conversion of the organofluoride to free fluoride ion for its subsequent determination by spectrophotometry based on bleaching of Zr–xylenol orange-color complex. Quantitative recovery (>98% of the fluorine in the drug samples could be achieved using a mixture of 2% acetone + 2% isopropyl alcohol + 0.003% Na2CO3 in just 5 minutes of UV irradiation, which can be considered an important aspect considering the difficulties involved in the cleavage of the CF bond. Accuracy was evaluated by comparison of results obtained by the UVPD method with the values estimated using formula weight of the compound and no statistical difference was observed between the results. Therefore, the proposed method is suitable for application in routine analysis of fluoride in organofluorine-containing drugs.

  13. Measuring enzymatic HIV-1 susceptibility to two reverse transcriptase inhibitors as a rapid and simple approach to HIV-1 drug-resistance testing.

    Directory of Open Access Journals (Sweden)

    Dieter Hoffmann

    Full Text Available Simple and cost-effective approaches for HIV drug-resistance testing are highly desirable for managing increasingly expanding HIV-1 infected populations who initiate antiretroviral therapy (ART, particularly in resource-limited settings. Non-nucleoside reverse trancriptase inhibitor (NNRTI-based regimens with an NRTI backbone containing lamivudine (3TC or emtricitabine (FTC are preferred first ART regimens. Failure with these drug combinations typically involves the selection of NNRTI- and/or 3TC/FTC-resistant viruses. Therefore, the availability of simple assays to measure both types of drug resistance is critical. We have developed a high throughput screening test for assessing enzymatic resistance of the HIV-1 RT in plasma to 3TC/FTC and NNRTIs. The test uses the sensitive "Amp-RT" assay with a newly-developed real-time PCR format to screen biochemically for drug resistance in single reactions containing either 3TC-triphosphate (3TC-TP or nevirapine (NVP. Assay cut-offs were defined based on testing a large panel of subtype B and non-subtype B clinical samples with known genotypic profiles. Enzymatic 3TC resistance correlated well with the presence of M184I/V, and reduced NVP susceptibility was strongly associated with the presence of K103N, Y181C/I, Y188L, and G190A/Q. The sensitivity and specificity for detecting resistance were 97.0% and 96.0% in samples with M184V, and 97.4% and 96.2% for samples with NNRTI mutations, respectively. We further demonstrate the utility of an HIV capture method in plasma by using magnetic beads coated with CD44 antibody that eliminates the need for ultracentifugation. Thus our results support the use of this simple approach for distinguishing WT from NNRTI- or 3TC/FTC-resistant viruses in clinical samples. This enzymatic testing is subtype-independent and can assist in the clinical management of diverse populations particularly in resource-limited settings.

  14. From Fault-tolerance to Attack Tolerance

    Science.gov (United States)

    2011-04-02

    AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Means to build fault - tolerant ...bottlenecks. We also implemented a distributed storage service that uses Byzantine Quo- rum Systems (rather than state machine replication) and employs...From Fault - tolerance to Attack Tolerance AFOSR Grant F9550-06-1-0019 Final Report 1 December 2005 – 30 November 2010 Fred B. Schneider Computer

  15. A rapid, high-throughput viability assay for Blastocystis spp. reveals metronidazole resistance and extensive subtype-dependent variations in drug susceptibilities.

    Science.gov (United States)

    Mirza, Haris; Teo, Joshua D W; Upcroft, Jacqui; Tan, Kevin S W

    2011-02-01

    Blastocystis is an emerging protistan parasite of controversial pathogenesis. Although metronidazole (Mz) is standard therapy for Blastocystis infections, there have been accumulating reports of treatment failure, suggesting the existence of drug-resistant isolates. Furthermore, very little is known about Blastocystis susceptibility to standard antimicrobials. In the present study, we established resazurin and XTT viability microassays for Blastocystis spp. belonging to subtypes 4 and 7, both of which have been suggested to represent pathogenic zoonotic subtypes. The optimized resazurin assay was used to screen a total of 19 compounds against both subtypes. Interestingly, subtype 7 parasites were resistant to Mz, a 1-position-substituted 5-nitroimidazole (5-NI), while subtype 4 parasites were sensitive. Some cross-resistance was observed to tinidazole, another 1-position 5-NI. Conversely, subtype 4 parasites were resistant to emetine, while subtype 7 parasites were sensitive. Position 2 5-NIs were effective against both subtypes, as were ornidazole, nitazoxanide, furazolidone, mefloquine, quinicrine, quinine, cotrimoxazole (trimethoprim-sulfamethoxazole), and iodoacetamide. Both subtypes were resistant to chloroquine, doxycycline, paromomycin, ampicillin, and pyrimethamine. This is the first study to report extensive variations in drug sensitivities among two clinically important subtypes. Our study highlights the need to reevaluate established treatment regimens for Blastocystis infections and offers clear new treatment options for Mz treatment failures.

  16. A simple and rapid LC-MS/MS method for therapeutic drug monitoring of cetuximab: a GPCO-UNICANCER proof of concept study in head-and-neck cancer patients.

    Science.gov (United States)

    Becher, François; Ciccolini, Joseph; Imbs, Diane-Charlotte; Marin, Clémence; Fournel, Claire; Dupuis, Charlotte; Fakhry, Nicolas; Pourroy, Bertrand; Ghettas, Aurélie; Pruvost, Alain; Junot, Christophe; Duffaud, Florence; Lacarelle, Bruno; Salas, Sebastien

    2017-06-02

    Administration of first-in-class anti-EGFR monoclonal antibody cetuximab is contingent upon extensive pharmacogenomic testing. However in addition to tumor genomics, drug exposure levels could play a critical, yet largely underestimated role, because several reports have demonstrated that cetuximab pharmacokinetic parameters, in particular clearance values, were associated with survival in patients. Here, we have developed an original bioanalytical method based upon the use of LC-MS/MS technology and a simplified sample preparation procedure to assay cetuximab in plasma samples from patients, thus meeting the requirements of standard Therapeutic Drug Monitoring in routine clinical practice. When tested prospectively in a pilot study in 25 head-and-neck cancer patients, this method showed that patients with clinical benefit had cetixumab residual concentrations higher than non-responding patients (i.e., 49 ± 16.3 µg/ml VS. 25.8 ± 17 µg/ml, p < 0.01 t test). Further ROC analysis showed that 33.8 µg/ml was the Cmin threshold predictive of response with an acceptable sensitivity (87%) and specificity (78%). Mass spectrometry-based therapeutic drug monitoring of cetuximab in head-and-neck cancer patients could therefore help to rapidly predict cetuximab efficacy and to adapt dosing if required.

  17. Rapid, Sensitive, and Accurate Evaluation of Drug Resistant Mutant (NS5A-Y93H Strain Frequency in Genotype 1b HCV by Invader Assay.

    Directory of Open Access Journals (Sweden)

    Satoshi Yoshimi

    Full Text Available Daclatasvir and asunaprevir dual oral therapy is expected to achieve high sustained virological response (SVR rates in patients with HCV genotype 1b infection. However, presence of the NS5A-Y93H substitution at baseline has been shown to be an independent predictor of treatment failure for this regimen. By using the Invader assay, we developed a system to rapidly and accurately detect the presence of mutant strains and evaluate the proportion of patients harboring a pre-treatment Y93H mutation. This assay system, consisting of nested PCR followed by Invader reaction with well-designed primers and probes, attained a high overall assay success rate of 98.9% among a total of 702 Japanese HCV genotype 1b patients. Even in serum samples with low HCV titers, more than half of the samples could be successfully assayed. Our assay system showed a better lower detection limit of Y93H proportion than using direct sequencing, and Y93H frequencies obtained by this method correlated well with those of deep-sequencing analysis (r = 0.85, P <0.001. The proportion of the patients with the mutant strain estimated by this assay was 23.6% (164/694. Interestingly, patients with the Y93H mutant strain showed significantly lower ALT levels (p=8.8 x 10-4, higher serum HCV RNA levels (p=4.3 x 10-7, and lower HCC risk (p=6.9 x 10-3 than those with the wild type strain. Because the method is both sensitive and rapid, the NS5A-Y93H mutant strain detection system established in this study may provide important pre-treatment information valuable not only for treatment decisions but also for prediction of disease progression in HCV genotype 1b patients.

  18. Rapid screening and confirmation of drugs and toxic compounds in biological specimens using liquid chromatography/ion trap tandem mass spectrometry and automated library search.

    Science.gov (United States)

    Liu, Hsiu-Chuan; Liu, Ray H; Lin, Dong-Liang; Ho, Hsiu-O

    2010-01-01

    Recent advances in liquid chromatography/tandem mass spectrometry (LC/MS/MS) technology have provided an opportunity for the development of more specific approaches to achieve the 'screen' and 'confirmation' goals in a single analytical step. For this purpose, this study adapts the electrospray ionization ion trap LC/MS/MS instrumentation (LC/ESI-MS/MS) for the screening and confirmation of over 800 drugs and toxic compounds in biological specimens. Liquid-liquid and solid-phase extraction protocols were coupled to LC/ESI-MS/MS using a 1.8-microm particle size analytical column operated at 50 degrees C. Gradient elution of the analytes was conducted using a solvent system composed of methanol and water containing 0.1% formic acid. Positive-ion ESI-MS/MS spectra and retention times for each of the 800 drugs and toxic compounds were first established using 1-10 microg/mL standard solutions. This spectra and retention time information was then transferred to the library and searched by the identification algorithm for the confirmation of compounds found in test specimens - based on retention time matches and scores of fit, reverse fit, and purity resulting from the searching process. The established method was found highly effective when applied to the analyses of postmortem specimens (blood, urine, and hair) and external proficiency test samples provided by the College of American Pathology (CAP). The development of this approach has significantly improved the efficiency of our routine laboratory operation that was based on a two-step (immunoassay and GC/MS) approach in the past. Copyright 2009 John Wiley & Sons, Ltd.

  19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    Science.gov (United States)

    Bridle, C; Palmer, S; Bagnall, A-M; Darba, J; Duffy, S; Sculpher, M; Riemsma, R

    2004-05-01

    To evaluate the clinical and cost-effectiveness of quetiapine, olanzapine and valproate semisodium in the treatment of mania associated with bipolar disorder. Electronic databases; industry submissions made to the National Institute for Clinical Excellence. Randomised trials and economic evaluations that evaluated the effectiveness of quetiapine, olanzapine or valproate semisodium in the treatment of mania associated with bipolar disorder were selected for inclusion. Data were extracted by one reviewer into a Microsoft Access database and checked for quality and accuracy by a second. The quality of the cost-effectiveness studies was assessed using a checklist updated from that developed by Drummond and colleagues. Relative risk and mean difference data were presented as Forest plots but only pooled where this made sense clinically and statistically. Studies were grouped by drug and, within each drug, by comparator used. Chi-squared tests of heterogeneity were performed for the outcomes if pooling was indicated. A probabilistic model was developed to estimate costs from the perspective of the NHS, and health outcomes in terms of response rate, based on an improvement of at least 50% in a patient's baseline manic symptoms derived from an interview-based mania assessment scale. The model evaluated the cost-effectiveness of the alternative drugs when used as part of treatment for the acute manic episode only. Eighteen randomised trials met the inclusion criteria. Aspects of three of the quetiapine studies were commercial-in-confidence. The quality of the included trials was limited and overall, key methodological criteria were not met in most trials. Quetiapine, olanzapine and valproate semisodium appear superior to placebo in reducing manic symptoms, but may cause side-effects. There appears to be little difference between these treatments and lithium in terms of effectiveness, but quetiapine is associated with somnolence and weight gain, whereas lithium is associated

  20. Evaluation of an automated rapid diagnostic assay for detection of Gram-negative bacteria and their drug-resistance genes in positive blood cultures.

    Directory of Open Access Journals (Sweden)

    Masayoshi Tojo

    Full Text Available We evaluated the performance of the Verigene Gram-Negative Blood Culture Nucleic Acid Test (BC-GN; Nanosphere, Northbrook, IL, USA, an automated multiplex assay for rapid identification of positive blood cultures caused by 9 Gram-negative bacteria (GNB and for detection of 9 genes associated with β-lactam resistance. The BC-GN assay can be performed directly from positive blood cultures with 5 minutes of hands-on and 2 hours of run time per sample. A total of 397 GNB positive blood cultures were analyzed using the BC-GN assay. Of the 397 samples, 295 were simulated samples prepared by inoculating GNB into blood culture bottles, and the remaining were clinical samples from 102 patients with positive blood cultures. Aliquots of the positive blood cultures were tested by the BC-GN assay. The results of bacterial identification between the BC-GN assay and standard laboratory methods were as follows: Acinetobacter spp. (39 isolates for the BC-GN assay/39 for the standard methods, Citrobacter spp. (7/7, Escherichia coli (87/87, Klebsiella oxytoca (13/13, and Proteus spp. (11/11; Enterobacter spp. (29/30; Klebsiella pneumoniae (62/72; Pseudomonas aeruginosa (124/125; and Serratia marcescens (18/21; respectively. From the 102 clinical samples, 104 bacterial species were identified with the BC-GN assay, whereas 110 were identified with the standard methods. The BC-GN assay also detected all β-lactam resistance genes tested (233 genes, including 54 bla(CTX-M, 119 bla(IMP, 8 bla(KPC, 16 bla(NDM, 24 bla(OXA-23, 1 bla(OXA-24/40, 1 bla(OXA-48, 4 bla(OXA-58, and 6 blaVIM. The data shows that the BC-GN assay provides rapid detection of GNB and β-lactam resistance genes in positive blood cultures and has the potential to contributing to optimal patient management by earlier detection of major antimicrobial resistance genes.

  1. Evaluation of an automated rapid diagnostic assay for detection of Gram-negative bacteria and their drug-resistance genes in positive blood cultures.

    Science.gov (United States)

    Tojo, Masayoshi; Fujita, Takahiro; Ainoda, Yusuke; Nagamatsu, Maki; Hayakawa, Kayoko; Mezaki, Kazuhisa; Sakurai, Aki; Masui, Yoshinori; Yazaki, Hirohisa; Takahashi, Hiroshi; Miyoshi-Akiyama, Tohru; Totsuka, Kyoichi; Kirikae, Teruo; Ohmagari, Norio

    2014-01-01

    We evaluated the performance of the Verigene Gram-Negative Blood Culture Nucleic Acid Test (BC-GN; Nanosphere, Northbrook, IL, USA), an automated multiplex assay for rapid identification of positive blood cultures caused by 9 Gram-negative bacteria (GNB) and for detection of 9 genes associated with β-lactam resistance. The BC-GN assay can be performed directly from positive blood cultures with 5 minutes of hands-on and 2 hours of run time per sample. A total of 397 GNB positive blood cultures were analyzed using the BC-GN assay. Of the 397 samples, 295 were simulated samples prepared by inoculating GNB into blood culture bottles, and the remaining were clinical samples from 102 patients with positive blood cultures. Aliquots of the positive blood cultures were tested by the BC-GN assay. The results of bacterial identification between the BC-GN assay and standard laboratory methods were as follows: Acinetobacter spp. (39 isolates for the BC-GN assay/39 for the standard methods), Citrobacter spp. (7/7), Escherichia coli (87/87), Klebsiella oxytoca (13/13), and Proteus spp. (11/11); Enterobacter spp. (29/30); Klebsiella pneumoniae (62/72); Pseudomonas aeruginosa (124/125); and Serratia marcescens (18/21); respectively. From the 102 clinical samples, 104 bacterial species were identified with the BC-GN assay, whereas 110 were identified with the standard methods. The BC-GN assay also detected all β-lactam resistance genes tested (233 genes), including 54 bla(CTX-M), 119 bla(IMP), 8 bla(KPC), 16 bla(NDM), 24 bla(OXA-23), 1 bla(OXA-24/40), 1 bla(OXA-48), 4 bla(OXA-58), and 6 blaVIM. The data shows that the BC-GN assay provides rapid detection of GNB and β-lactam resistance genes in positive blood cultures and has the potential to contributing to optimal patient management by earlier detection of major antimicrobial resistance genes.

  2. The dlt genes play a role in antimicrobial tolerance of Streptococcus mutans biofilms

    DEFF Research Database (Denmark)

    Nilsson, Carl Martin Peter; Rybtke, Morten; Givskov, Michael

    2016-01-01

    Microbial biofilms are tolerant to antibiotic treatment and therefore cause problematic infections. Knowledge about the molecular mechanisms underlying biofilm-associated antimicrobial tolerance will aid the development of antibiofilm drugs. Screening of a Streptococcus mutans transposon mutant...

  3. Rapid detection of Gram-negative bacteria and their drug resistance genes from positive blood cultures using an automated microarray assay.

    Science.gov (United States)

    Han, Eunhee; Park, Dong-Jin; Kim, Yukyoung; Yu, Jin Kyung; Park, Kang Gyun; Park, Yeon-Joon

    2015-03-01

    We evaluated the performance of the Verigene Gram-negative blood culture (BC-GN) assay (CE-IVD version) for identification of Gram-negative (GN) bacteria and detection of resistance genes. A total of 163 GN organisms (72 characterized strains and 91 clinical isolates from 86 patients) were tested; among the clinical isolates, 86 (94.5%) isolates were included in the BC-GN panel. For identification, the agreement was 98.6% (146/148, 95% confidence interval [CI], 92.1-100) and 70% (7/10, 95% CI, 53.5-100) for monomicrobial and polymicrobial cultures, respectively. Of the 48 resistance genes harbored by 43 characterized strains, all were correctly detected. Of the 19 clinical isolates harboring resistance genes, 1 CTX-M-producing Escherichia coli isolated in polymicrobial culture was not detected. Overall, BC-GN assay provides acceptable accuracy for rapid identification of Gram-negative bacteria and detection of resistance genes, compared with routine laboratory methods despite that it has limitations in the number of genus/species and resistance gene included in the panel and it shows lower sensitivity in polymicrobial cultures. Copyright © 2015. Published by Elsevier Inc.

  4. Ensembling and filtering: an effective and rapid in silico multitarget drug-design strategy to identify RIPK1 and RIPK3 inhibitors.

    Science.gov (United States)

    Fayaz, S M; Rajanikant, G K

    2015-12-01

    Necroptosis, a programmed necrosis pathway, is witnessed in diverse human diseases and is primarily regulated by receptor-interacting serine/threonine protein kinase 1 (RIPK1) and RIPK3. Ablation or inhibition of these individual proteins, or both, has been shown to be protective in various in vitro and in vivo disease models involving necroptosis. In this study, we propose an effective and rapid virtual screening strategy to identify multitarget inhibitors of both RIPK1 and RIPK3. It involves ensemble pharmacophore-based screening (EPS) of a compound database, post-EPS filtration (PEPSF) of the ligand hits, and multiple dockings. Structurally diverse inhibitors were identified through ensemble pharmacophore features, and the speed of this process was enhanced by filtering out the compounds containing cross-features. The stability of these inhibitors with both of the proteins was verified by means of molecular dynamics (MD) simulation. Graphical Abstract A generalized workflow employed in this study. Subsequent utilization of EPS and PEPSF might lead to reduced computational time and load.

  5. Methodology for Rapid Measures of Glutamate Release in Rat Brain Slices Using Ceramic-Based Microelectrode Arrays: Basic Characterization and Drug Pharmacology

    Science.gov (United States)

    Quintero, Jorge E.; Pomerleau, François; Huettl, Peter; Johnson, Kirk W.; Offord, James; Gerhardt, Greg A.

    2011-01-01

    Excessive excitability or hyperexcitability of glutamate-containing neurons in the brain has been proposed as a possible explanation for anxiety, stress-induced disorders, epilepsy, and some neurodegenerative diseases. However, direct measurement of glutamate on a rapid time scale has proven to be difficult. Here we adapted enzyme-based microelectrode arrays (MEA) capable of detecting glutamate in vivo, to assess the effectiveness of hyperexcitability modulators on glutamate release in brain slices of the rat neocortex. Using glutamate oxidase coated ceramic MEAs coupled with constant voltage amperometry, we measured resting glutamate levels and synaptic overflow of glutamate after K+ stimulation in brain slices. MEAs reproducibly detected glutamate on a second-by-second time scale in the brain slice preparation after depolarization with high K+ to evoke glutamate release. This stimulus-evoked glutamate release was robust, reproducible, and calcium dependent. The K+-evoked glutamate release was modulated by ligands to the a2δ subunit of voltage sensitive calcium channels (PD-0332334 and PD-0200390). Meanwhile, agonists to Group II metabotropic glutamate (mGlu) receptors (LY379268 and LY354740), which are known to alter hyperexcitability of glutamate neurons, attenuated K+-evoked glutamate release but did not alter resting glutamate levels. This new MEA technology provides a means of directly measuring the chemical messengers involved in glutamate neurotransmission and thereby helping to reveal the role multiple glutamatergic system components have on glutamate signaling. PMID:21664606

  6. Electromembrane-surrounded solid-phase microextraction coupled to ion mobility spectrometry for the determination of nonsteroidal anti-inflammatory drugs: A rapid screening method in complicated matrices.

    Science.gov (United States)

    Abedi, Hamid; Ebrahimzadeh, Homeira

    2015-05-01

    A new robust method of electromembrane-surrounded solid-phase microextraction coupled to ion mobility mass spectrometry was applied for nonsteroidal anti-inflammatory drugs determination in complex matrices. This is the first time that a graphene/polyaniline composite coating is applied in electromembrane-surrounded solid-phase microextraction method. The homemade graphene/polyaniline composite is characterized by a high electrical conductivity and thermal stability. The variables affecting electromembrane-surrounded solid-phase microextraction, including extraction time; applied voltage and pH were optimized through chemometric methods, central composite design, and response surface methodology. Under the optimized conditions, limits of detection of 0.04 and 0.05 ng/mL were obtained for mefenamic acid and ibuprofen, respectively. The feasibility of electromembrane-surrounded solid-phase microextraction followed by ion mobility mass spectrometry was successfully confirmed by the extraction and determination of low levels of ibuprofen and mefenamic acid in human urine and plasma samples and satisfactory results were obtained. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Evaluation of Microscopic Observation Drug Susceptibility (MODS) and the string test for rapid diagnosis of pulmonary tuberculosis in HIV/AIDS patients in Bolivia.

    Science.gov (United States)

    Lora, Meredith H; Reimer-McAtee, Melissa J; Gilman, Robert H; Lozano, Daniel; Saravia, Ruth; Pajuelo, Monica; Bern, Caryn; Castro, Rosario; Espinoza, Magaly; Vallejo, Maya; Solano, Marco; Challapa, Roxana; Torrico, Faustino

    2015-06-06

    Tuberculosis (TB) is the most common opportunistic infection and the leading cause of death in HIV-positive people worldwide. Diagnosing TB is difficult, and is more challenging in resource-scarce settings where culture-based diagnostic methods rely on poorly sensitive smear microscopy by Ziehl-Neelsen stain (ZN). We performed a cross-sectional study examining the diagnostic utility of Microscopic Observation Drug Susceptibility liquid culture (MODS) versus traditional Ziehl-Neelsen staining (ZN) and Lowenstein Jensen culture (LJ) of pulmonary tuberculosis (TB) and multidrug-resistant tuberculosis (MDRTB) in HIV-infected patients in Bolivia. For sputum scarce individuals we assessed the value of the string test and induced sputum for TB diagnosis. The presence of Mycobacterium tuberculosis (Mtb) in the sputum of 107 HIV-positive patients was evaluated by ZN, LJ, and MODS. Gastric secretion samples obtained by the string test were evaluated by MODS in 102 patients. The TB-HIV co-infection rate of HIV patients with respiratory symptoms by sputum sample was 45 % (48/107); 46/48 (96 %) were positive by MODS, 38/48 (79 %) by LJ, and 30/48 (63 %) by ZN. The rate of MDRTB was 9 % (4/48). Median time to positive culture was 10 days by MODS versus 34 days by LJ (p Bolivia.

  8. Nest-representable tolerances

    OpenAIRE

    Lipparini, Paolo

    2017-01-01

    We introduce the notion of a nest-representable tolerance and show that some results from our former paper "From congruence identities to tolerance identities" [CT] can be extended to this more general setting.

  9. Software fault tolerance

    OpenAIRE

    Kazinov, Tofik Hasanaga; Mostafa, Jalilian Shahrukh

    2009-01-01

    Because of our present inability to produce errorfree software, software fault tolerance is and will contiune to be an important consideration in software system. The root cause of software design errors in the complexity of the systems. This paper surveys various software fault tolerance techniquest and methodologies. They are two gpoups: Single version and Multi version software fault tolerance techniques. It is expected that software fault tolerance research will benefit from this research...

  10. 21 CFR 109.30 - Tolerances for polychlorinated biphenyls (PCB's).

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Tolerances for polychlorinated biphenyls (PCB's). 109.30 Section 109.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN..., principally those of animal and marine origin, contain PCB's as unavoidable, environmental contaminants. PCB's...

  11. EFFICACY AND TOLERABILITY OF LACOSAMIDE (VIMPAT FOR TREATMENT OF EPILEPSY IN ADULTS (A REVIEW

    Directory of Open Access Journals (Sweden)

    O. A. Pylaeva

    2014-01-01

    Full Text Available In spite of the significant progress achieved in epileptology, resistant forms of epilepsy comprise about 30 % of all cases of epilepsy. The articles reviews modern concepts and basic mechanisms of pharmacoresistance, as well as the ways to overcome them. The authors presented a detailed review of modern literature devoted to studies of efficacy, safety, and tolerability of the new antiepileptic drug (AED lacosamide (Vimpat® with uncontrolled epilepsy. Lacosamidе is registered in Russia for additional therapy of patients of 16 y.o. and older with focal seizures with or without secondary generalization. The drug is a functionalized amino acid. The assumed action mechanism differs from that of other AEDs: this drug selectively lowers the pathological hyperactivity of neurons without affecting their physiological activity, decreases abnormal epileptogenic neuronal excitability, selectively enhances slow inactivation of sodium channels without affecting rapid inactivation. Lacosamidе has the following pharmacokinetic advantages: linear kinetics; the drug is a weak inducer of liver enzymes (CYP and, therefore, does not alter the metabolism of other AEDs and is only slightly bound to plasma proteins (< 15 %. Clinical studies have shown the efficacy and good tolerability of lacosamidе by patients with focal seizures; the dosage of the drug of 400 mg/day was assessedto be optimal. Efficacy and good tolerability of lacosamidе has been confirmed by postmarketing studies after beginning of its broad use in clinical practice. Frequent side effects associated with the therapy ( 15 % include dizziness, headache, drowsiness, nausea, and diplopia. Concurrent intake of other AEDs that block sodium channels statistically significantly increased the risk of arising of side effects associated with the therapy. Pharmacoeconomic analysis of several studies showed favorable indicator of lacosamidе regarding the cost/efficacy criterion for treatment

  12. RAPID3? Aptly named!

    Science.gov (United States)

    Berthelot, J-M

    2014-01-01

    The RAPID3 score is the sum of three 0-10 patient self-report scores: pain, functional impairment on MDHAQ, and patient global estimate. It requires 5 seconds for scoring and can be used in all rheumatologic conditions, although it has mostly been used in rheumatoid arthritis where cutoffs for low disease activity (12/30) have been set. A RAPID3 score of ≤ 3/30 with 1 or 0 swollen joints (RAPID3 ≤ 3 + ≤ SJ1) provides remission criteria comparable to Boolean, SDAI, CDAI, and DAS28 remission criteria, in far less time than a formal joint count. RAPID3 performs as well as the DAS28 in separating active drugs from placebos in clinical trials. RAPID3 also predicts subsequent structural disease progression. RAPID3 can be determined at short intervals at home, allowing the determination of the area under the curve of disease activity between two visits and flare detection. However, RAPID3 should not be seen as a substitute for DAS28 and face to face visits in routine care. Monitoring patient status with only self-report information without a rheumatologist's advice (including joints and physical examination, and consideration of imaging and laboratory tests) may indeed be as undesirable for most patients than joint examination without a patient questionnaire. Conversely, combining the RAPID3 and the DAS28 may consist in faster or more sensitive confirmation that a medication is effective. Similarly, better enquiring of most important concerns of patients (pain, functional status and overall opinion on their disorder) should reinforces patients' confidence in their rheumatologist and treatments.

  13. Rapid decline in HCV incidence among people who inject drugs associated with national scale-up in coverage of a combination of harm reduction interventions.

    Science.gov (United States)

    Palmateer, Norah E; Taylor, Avril; Goldberg, David J; Munro, Alison; Aitken, Celia; Shepherd, Samantha J; McAllister, Georgina; Gunson, Rory; Hutchinson, Sharon J

    2014-01-01

    Government policy has precipitated recent changes in the provision of harm reduction interventions - injecting equipment provision (IEP) and opiate substitution therapy (OST) - for people who inject drugs (PWID) in Scotland. We sought to examine the potential impact of these changes on hepatitis C virus (HCV) transmission among PWID. We used a framework to triangulate different types of evidence: 'group-level/ecological' and 'individual-level'. Evidence was primarily generated from bio-behavioural cross-sectional surveys of PWID, undertaken during 2008-2012. Individuals in the window period (1-2 months) where the virus is present, but antibodies have not yet been formed, were considered to have recent infection. The survey data were supplemented with service data on the provision of injecting equipment and OST. Ecological analyses examined changes in intervention provision, self-reported intervention uptake, self-reported risk behaviour and HCV incidence; individual-level analyses investigated relationships within the pooled survey data. Nearly 8,000 PWID were recruited in the surveys. We observed a decline in HCV incidence, per 100 person-years, from 13.6 (95% CI: 8.1-20.1) in 2008-09 to 7.3 (3.0-12.9) in 2011-12; a period during which increases in the coverage of OST and IEP, and decreases in the frequency of injecting and sharing of injecting equipment, were observed. Individual-level evidence demonstrated that combined high coverage of needles/syringes and OST were associated with reduced risk of recent HCV in analyses that were unweighted (AOR 0.29, 95%CI 0.11-0.74) and weighted for frequency of injecting (AORw 0.05, 95%CI 0.01-0.18). We estimate the combination of harm reduction interventions may have averted 1400 new HCV infections during 2008-2012. This is the first study to demonstrate that impressive reductions in HCV incidence can be achieved among PWID over a relatively short time period through high coverage of a combination of interventions.

  14. Rapid decline in HCV incidence among people who inject drugs associated with national scale-up in coverage of a combination of harm reduction interventions.

    Directory of Open Access Journals (Sweden)

    Norah E Palmateer

    Full Text Available BACKGROUND: Government policy has precipitated recent changes in the provision of harm reduction interventions - injecting equipment provision (IEP and opiate substitution therapy (OST - for people who inject drugs (PWID in Scotland. We sought to examine the potential impact of these changes on hepatitis C virus (HCV transmission among PWID. METHODS AND FINDINGS: We used a framework to triangulate different types of evidence: 'group-level/ecological' and 'individual-level'. Evidence was primarily generated from bio-behavioural cross-sectional surveys of PWID, undertaken during 2008-2012. Individuals in the window period (1-2 months where the virus is present, but antibodies have not yet been formed, were considered to have recent infection. The survey data were supplemented with service data on the provision of injecting equipment and OST. Ecological analyses examined changes in intervention provision, self-reported intervention uptake, self-reported risk behaviour and HCV incidence; individual-level analyses investigated relationships within the pooled survey data. Nearly 8,000 PWID were recruited in the surveys. We observed a decline in HCV incidence, per 100 person-years, from 13.6 (95% CI: 8.1-20.1 in 2008-09 to 7.3 (3.0-12.9 in 2011-12; a period during which increases in the coverage of OST and IEP, and decreases in the frequency of injecting and sharing of injecting equipment, were observed. Individual-level evidence demonstrated that combined high coverage of needles/syringes and OST were associated with reduced risk of recent HCV in analyses that were unweighted (AOR 0.29, 95%CI 0.11-0.74 and weighted for frequency of injecting (AORw 0.05, 95%CI 0.01-0.18. We estimate the combination of harm reduction interventions may have averted 1400 new HCV infections during 2008-2012. CONCLUSIONS: This is the first study to demonstrate that impressive reductions in HCV incidence can be achieved among PWID over a relatively short time period through

  15. Mechanical tolerance stackup and analysis

    CERN Document Server

    Fischer, Bryan R

    2004-01-01

    BackgroundDimensioning and TolerancingTolerance Format and Decimal PlacesConverting Plus/Minus Dimensions and Tolerances into Equal Bilaterally Toleranced DimensionsVariation and Sources of VariationTolerance AnalysisWorst-case Tolerance StackupsStatistical Tolerance StackupsGeometric Dimensioning and Tolerancing (GD&T)Converting Plus/Minus Tolerancing to Positional Tolerancing and Projected Tolerance ZonesDiametral and Radial Tolerance StackupsSpecifying Material Condition Modifiers and Their Effect on Tolerance Stackups The Tolerance Stackup SketchThe Tolerance Stackup Report FormTolerance S

  16. Effectiveness and tolerability of second-line treatment with vildagliptin versus other oral drugs for type 2 diabetes in a real-world setting in the Middle East: results from the EDGE study

    Directory of Open Access Journals (Sweden)

    Saab C

    2015-02-01

    assessed. Results: Of the 4,780 patients enrolled in the Middle East, 2,513 received vildagliptin and 2,267 received other OADs. Overall, the mean (± standard deviation age at baseline was 52.1±10.2 years, mean HbA1c was 8.5%±1.3%, and mean T2DM duration was 4.2±4.0 years. The proportion of patients achieving the primary (76.1% versus 61.6%, P<0.0001 and secondary (54.8% versus 29.9%, P<0.0001 endpoints was higher with vildagliptin than with the comparator OADs. The unadjusted odds ratios for the primary and secondary endpoints were 1.98 (95% confidence interval 1.75–2.25 and 2.8 (95% confidence interval 2.5–3.2, respectively, in favor of vildagliptin. Vildagliptin achieved a numerically greater reduction in HbA1c (1.7% from baseline versus comparator OADs (1.4%. The overall incidence of adverse events was comparable between studied cohorts. Conclusion: In real life, treatment with vildagliptin was associated with a higher proportion of patients with T2DM achieving better glycemic control without tolerability issues in the Middle East. Keywords: dipeptidyl peptidase-4, Middle East, oral antidiabetic drugs, real world, type 2 diabetes mellitus, vildagliptin

  17. 78 FR 40017 - Ethalfluralin; Pesticide Tolerances

    Science.gov (United States)

    2013-07-03

    ... Number 4 (IR-4) requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES...), 1200 Pennsylvania Ave. NW., Washington, DC 20460-0001. Hand Delivery: To make special arrangements for... of this action. EPA has sufficient data to assess the hazards of and to make a determination on...

  18. 77 FR 63745 - Buprofezin; Pesticide Tolerances

    Science.gov (United States)

    2012-10-17

    .... The acute dietary food exposure assessment was performed based on 100 PCT and a conservative estimate... Nichino America Inc. requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA... affected by this action if you are an agricultural producer, food manufacturer, or pesticide manufacturer...

  19. 76 FR 82157 - Difenoconazole; Pesticide Tolerances

    Science.gov (United States)

    2011-12-30

    ... to understate the residues in food commodities. EPA also made conservative (protective) assumptions... tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This regulation is effective...? You may be potentially affected by this action if you are an agricultural producer, food manufacturer...

  20. 77 FR 42654 - Trifloxystrobin; Pesticide Tolerance

    Science.gov (United States)

    2012-07-20

    .../risks from residues in food will not be underestimated. EPA made conservative (protective) assumptions... or on artichoke, globe. Bayer CropScience requested these tolerances under the Federal Food, Drug... producer, food manufacturer, or pesticide manufacturer. Potentially affected entities may include, but are...

  1. 76 FR 61592 - Isopyrazam; Pesticide Tolerances

    Science.gov (United States)

    2011-10-05

    ... occurring as a result of a 1-day or single exposure. A conservative acute dietary (food only) exposure... banana. Syngenta Crop Protection, Inc., requested this tolerance under the Federal Food, Drug, and... are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected...

  2. 75 FR 5518 - Dithianon; Pesticide Tolerances

    Science.gov (United States)

    2010-02-03

    ... NOAEL in the toxicology study identified as appropriate for use in risk assessment. However, if a NOAEL... grapes that are imported. BASF requested this tolerance under the Federal Food, Drug, and Cosmetic Act... are an agricultural producer, food manufacturer, or pesticide manufacturer. Potentially affected...

  3. 76 FR 18895 - Hexythiazox; Pesticide Tolerances

    Science.gov (United States)

    2011-04-06

    ..., including acute and subchronic neurotoxicity studies and an immunotoxicity study. However, the toxicology.... Gowan Company requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES..., food manufacturer, or pesticide manufacturer. Potentially affected entities may include, but are not...

  4. 75 FR 81878 - Imazosulfuron; Pesticide Tolerances

    Science.gov (United States)

    2010-12-29

    ... for a food-use pesticide, if a toxicological study has indicated the possibility of an effect of... toxicity accompanied by body weight and food consumption effects is seen throughout the toxicology database... tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This regulation is effective...

  5. 75 FR 22252 - Cyromazine; Pesticide Tolerances

    Science.gov (United States)

    2010-04-28

    ... cyromazine based on a chronic dog study. Decrease in body weight and food consumption are also common effects... highest dose at which no adverse effects are observed (the NOAEL) in the toxicology study identified as... these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This regulation is...

  6. 77 FR 43524 - Acetamiprid; Pesticide Tolerances

    Science.gov (United States)

    2012-07-25

    ... that reduced maternal body weight and food consumption. In the reproduction study, decreased body... are performed for a food-use pesticide, if a toxicological study has indicated the possibility of an... Project Number 4 (IR-4) requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA...

  7. 76 FR 70896 - Polyethylene Glycol; Tolerance Exemption

    Science.gov (United States)

    2011-11-16

    ... chemical formulation. Clariant Corporation submitted a petition to EPA under the Federal Food, Drug, and Cosmetic Act (FFDCA), requesting an exemption from the requirement of a tolerance. This regulation... pesticide inert ingredient in pesticide formulations as a solubilizer without limitations. That notice...

  8. 78 FR 13264 - Acetochlor; Pesticide Tolerances

    Science.gov (United States)

    2013-02-27

    .... Monsanto Company requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES...), 21 U.S.C. 346a(d)(3), announcing the filing of a pesticide petition (PP 2F7996) by Monsanto Company... summary of the petition prepared by Monsanto Company, the registrant, which is available in the docket...

  9. 76 FR 38033 - Cloquintocet-mexyl; Pesticide Tolerances

    Science.gov (United States)

    2011-06-29

    ... ingredient (safener) in pesticide formulations containing the active ingredient, dicamba. BASF Corporation requested this tolerance amendment under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES: This... formulation with the active ingredient, dicamba. No numerical change to the tolerances for the specific wheat...

  10. Multi-class, multi-residue analysis of trace veterinary drugs in milk by rapid screening and quantification using ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry.

    Science.gov (United States)

    Zhang, Yaqian; Li, Xiang; Liu, Xiaomao; Zhang, Jinjie; Cao, Yanzhong; Shi, Zhihong; Sun, Hanwen

    2015-12-01

    A simple and rapid multi-class multi-residue analytical method was developed for the screening and quantification of veterinary drugs in milk by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). A total of 90 veterinary drugs investigated belonged to almost 20 classes including lincomycins, macrolides, sulfonamides, quinolones, tetracyclines, β-agonists, β-lactams, sedatives, β-receptor antagonists, sex hormones, glucocorticoids, nitroimidazoles, benzimidazoles, nitrofurans, and some others. A modified quick, easy, cheap, effective, rugged, and safe (QuEChERS) procedure was developed for the sample preparation without the solid-phase extraction step. The linearity, sensitivity, accuracy, repeatability, and reproducibility of the method were fully validated. The response of the detector was linear for each target compound in a wide concentration range with a correlation coefficient (R(2)) of 0.9973 to 0.9999 (among them R(2)>0.999 for 73 of 90 analytes). The range of the limit of quantification for these compounds in the milk ranged from 0.10 to 17.30μg/kg. The repeatability and reproducibility were in the range of 2.11 to 9.62% and 2.76 to 13.9%, respectively. The average recoveries ranged from 72.62 to 122.2% with the RSD (n=6) of 1.30 to 9.61% at 3 concentration levels. For the screening method, the data of the precursor and product ions of the target analytes were simultaneously acquired under the all ions MS/MS mode in a single run. An accurate mass database for the confirmation and identification of the target compounds was established. The applicability of the screening method was verified by applying to real milk samples. The proposed analytical method allows the identification and confirmation of the target veterinary drugs at trace levels employing quick analysis time. Certain veterinary drugs were detected in some cases. Copyright © 2015 American Dairy Science Association. Published by

  11. Toleration out of respect?

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2014-01-01

    be based on a modus vivendi designed to secure peaceful co-existence, but should be based on moral reasons. Forst therefore advances what he calls the ‘respect conception’ of toleration as an in itself morally desirable type of relationship, which is furthermore the only conception of toleration......Under conditions of pluralism different cultures, interests or values can come into conflict, which raises the problem of how to secure peaceful co-existence. The idea of toleration historically emerged as an answer to this problem. Recently Rainer Forst has argued that toleration should not just...... that avoids various so-called ‘paradoxes of toleration’. The paper first examines whether Forst’s respect conception can be applied descriptively to distinguish between actual patterns of behaviour and classify different acts of toleration. Then the focus is shifted to toleration out of respect as a normative...

  12. Rapid Prototyping

    Science.gov (United States)

    1999-01-01

    Javelin, a Lone Peak Engineering Inc. Company has introduced the SteamRoller(TM) System as a commercial product. The system was designed by Javelin during a Phase II NASA funded small commercial product. The purpose of the invention was to allow automated-feed of flexible ceramic tapes to the Laminated Object Manufacturing rapid prototyping equipment. The ceramic material that Javelin was working with during the Phase II project is silicon nitride. This engineered ceramic material is of interest for space-based component.

  13. Evaluation of two line probe assays for rapid detection of Mycobacterium tuberculosis, tuberculosis (TB) drug resistance, and non-TB Mycobacteria in HIV-infected individuals with suspected TB.

    Science.gov (United States)

    Luetkemeyer, Anne F; Kendall, Michelle A; Wu, Xingye; Lourenço, Maria Cristina; Jentsch, Ute; Swindells, Susan; Qasba, Sarojini S; Sanchez, Jorge; Havlir, Diane V; Grinsztejn, Beatriz; Sanne, Ian M; Firnhaber, Cynthia

    2014-04-01

    Limited performance data from line probe assays (LPAs), nucleic acid tests used for the rapid diagnosis of tuberculosis (TB), nontuberculosis mycobacteria (NTM), and Mycobacterium tuberculosis drug resistance are available for HIV-infected individuals, in whom paucibacillary TB is common. In this study, the strategy of testing sputum with GenoType MTBDRplus (MTBDR-Plus) and GenoType Direct LPA (Direct LPA) was compared to a gold standard of one mycobacterial growth indicator tube (MGIT) liquid culture. HIV-positive (HIV(+)) individuals with suspected TB from southern Africa and South America with tuberculosis culture positive, of which 276 (72.8%) were acid-fast bacillus (AFB) smear positive. MTBDR-Plus had a sensitivity of 81.0% and a specificity of 100%, with sensitivities of 44.1% in AFB smear-negative versus 94.6% in AFB smear-positive specimens. For specimens that were positive for M. tuberculosis by MTBDR-Plus, the sensitivity and specificity for rifampin resistance were 91.7% and 96.6%, respectively, and for isoniazid (INH) they were 70.6% and 99.1%. The Direct LPA had a sensitivity of 88.4% and a specificity of 94.6% for M. tuberculosis detection, with a sensitivity of 72.5% in smear-negative specimens. Ten of 639 MGIT cultures grew Mycobacterium avium complex or Mycobacterium kansasii, half of which were detected by Direct LPA. Both LPA assays performed well in specimens from HIV-infected individuals, including in AFB smear-negative specimens, with 72.5% sensitivity for M. tuberculosis identification with the Direct LPA and 44.1% sensitivity with MTBDR-Plus. LPAs have a continued role for use in settings where rapid identification of INH resistance and clinically relevant NTM are priorities.

  14. Recognition and Toleration

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2010-01-01

    Recognition and toleration are ways of relating to the diversity characteristic of multicultural societies. The article concerns the possible meanings of toleration and recognition, and the conflict that is often claimed to exist between these two approaches to diversity. Different forms or inter......Recognition and toleration are ways of relating to the diversity characteristic of multicultural societies. The article concerns the possible meanings of toleration and recognition, and the conflict that is often claimed to exist between these two approaches to diversity. Different forms...

  15. Sulfur tolerant anode materials

    Energy Technology Data Exchange (ETDEWEB)

    1987-02-01

    The goal of this program is the development of a molten carbonate fuel cell (MCFC) anode which is more tolerant of sulfur contaminants in the fuel than the current state-of-the-art nickel-based anode structures. This program addresses two different but related aspects of the sulfur contamination problem. The primary aspect is concerned with the development of a sulfur tolerant electrocatalyst for the fuel oxidation reaction. A secondary issue is the development of a sulfur tolerant water-gas-shift reaction catalyst and an investigation of potential steam reforming catalysts which also have some sulfur tolerant capabilities. These two aspects are being addressed as two separate tasks.

  16. Toleration, Groups, and Multiculturalism

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2014-01-01

    to the political and social relationship between the subject and the objects of toleration. Finally, toleration is often argued to be a normative requirement on the basis of the way it affects the object or receiver of toleration, e.g. on the basis of the good of or right to freedom from non-interference which....... The chapter relates the different possible meanings of groups toleration to widespread criticisms of multiculturalism for being excessively 'groupist' (e.g. to essentialise or reify groups), to promote group rights over individual rights, or to deny or ignore the internal heterogeneity of groups...

  17. Methods and means for determining and conferring stress tolerance in plants

    NARCIS (Netherlands)

    Wordragen, van M.F.; Balk, P.A.; Geest, van der A.H.M.

    2006-01-01

    The current invention provides a method for rapid testing of stress tolerance in a plant and a method of producing plants with enhanced stress tolerance, in particular cold and/or drought tolerance. Such a method may be applied in breeding and selection programs for this trait, or for determining

  18. Artesunate Tolerance in Transgenic Plasmodium falciparum Parasites Overexpressing a Tryptophan-Rich Protein▿†

    Science.gov (United States)

    Deplaine, Guillaume; Lavazec, Catherine; Bischoff, Emmanuel; Natalang, Onguma; Perrot, Sylvie; Guillotte-Blisnick, Micheline; Coppée, Jean-Yves; Pradines, Bruno; Mercereau-Puijalon, Odile; David, Peter H.

    2011-01-01

    Due to their rapid, potent action on young and mature intraerythrocytic stages, artemisinin derivatives are central to drug combination therapies for Plasmodium falciparum malaria. However, the evidence for emerging parasite resistance/tolerance to artemisinins in southeast Asia is of great concern. A better understanding of artemisinin-related drug activity and resistance mechanisms is urgently needed. A recent transcriptome study of parasites exposed to artesunate led us to identify a series of genes with modified levels of expression in the presence of the drug. The gene presenting the largest mRNA level increase, Pf10_0026 (PArt), encoding a hypothetical protein of unknown function, was chosen for further study. Immunodetection with PArt-specific sera showed that artesunate induced a dose-dependent increase of the protein level. Bioinformatic analysis showed that PArt belongs to a Plasmodium-specific gene family characterized by the presence of a tryptophan-rich domain with a novel hidden Markov model (HMM) profile. Gene disruption could not be achieved, suggesting an essential function. Transgenic parasites overexpressing PArt protein were generated and exhibited tolerance to a spike exposure to high doses of artesunate, with increased survival and reduced growth retardation compared to that of wild-type-treated controls. These data indicate the involvement of PArt in parasite defense mechanisms against artesunate. This is the first report of genetically manipulated parasites displaying a stable and reproducible decreased susceptibility to artesunate, providing new possibilities to investigate the parasite response to artemisinins. PMID:21464256

  19. Digital Direct-to-Consumer Advertising: A Perfect Storm of Rapid Evolution and Stagnant Regulation; Comment on “Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters”

    Directory of Open Access Journals (Sweden)

    Tim K. Mackey

    2016-04-01

    Full Text Available The adoption and use of digital forms of direct-to-consumer advertising (also known as “eDTCA” is on the rise. At the same time, the universe of eDTCA is expanding, as technology on Internet-based platforms continues to evolve, from static websites, to social media, and nearly ubiquitous use of mobile devices. However, little is known about how this unique form of pharmaceutical marketing impacts consumer behavior, public health, and overall healthcare utilization. The study by Kim analyzing US Food and Drug Administration (FDA notices of violations (NOVs and warning letters regarding online promotional activities takes us in the right direction, but study results raise as many questions as it does answers. Chief among these are unanswered concerns about the unique regulatory challenges posed by the “disruptive” qualities of eDTCA, and whether regulators have sufficient resources and oversight powers to proactively address potential violations. Further, the globalization of eDTCA via borderless Internet-based technologies raises larger concerns about the potential global impact of this form of health marketing unique to only the United States and New Zealand. Collectively, these challenges make it unlikely that regulatory science will be able to keep apace with the continued rapid evolution of eDTCA unless more creative policy solutions are explored.

  20. Digital Direct-to-Consumer Advertising: A Perfect Storm of Rapid Evolution and Stagnant Regulation Comment on "Trouble Spots in Online Direct-to-Consumer Prescription Drug Promotion: A Content Analysis of FDA Warning Letters".

    Science.gov (United States)

    Mackey, Tim K

    2016-02-03

    The adoption and use of digital forms of direct-to-consumer advertising (also known as "eDTCA") is on the rise. At the same time, the universe of eDTCA is expanding, as technology on Internet-based platforms continues to evolve, from static websites, to social media, and nearly ubiquitous use of mobile devices. However, little is known about how this unique form of pharmaceutical marketing impacts consumer behavior, public health, and overall healthcare utilization. The study by Kim analyzing US Food and Drug Administration (FDA) notices of violations (NOVs) and warning letters regarding online promotional activities takes us in the right direction, but study results raise as many questions as it does answers. Chief among these are unanswered concerns about the unique regulatory challenges posed by the "disruptive" qualities of eDTCA, and whether regulators have sufficient resources and oversight powers to proactively address potential violations. Further, the globalization of eDTCA via borderless Internet-based technologies raises larger concerns about the potential global impact of this form of health marketing unique to only the United States and New Zealand. Collectively, these challenges make it unlikely that regulatory science will be able to keep apace with the continued rapid evolution of eDTCA unless more creative policy solutions are explored. © 2016 by Kerman University of Medical Sciences.

  1. Drugs + HIV, Learn the Link

    Medline Plus

    Full Text Available ... WMATA) Dallas Area Rapid Transit (DART) NY Metropolitan Transportation Authority (MTA) Titan Worldwide Hestia International Panasonic Times ... Education Projects National Drug & Alcohol Facts Week NIDA ...

  2. Remember Tolerance Differently

    DEFF Research Database (Denmark)

    Tønder, Lars

    2012-01-01

    This essay questions the linear conception of history which often accompanies the way contemporary democratic theory tends to disavow tolerance's discontinuities and remainders. In the spirit of Foucault's genealogy of descent, the idea is to develop a new sense of tolerance's history, not by inv...

  3. Toleration out of respect?

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2013-01-01

    Under conditions of pluralism different cultures, interests or values can come into conflict, which raises the problem of how to secure peaceful co-existence. The idea of toleration historically emerged as an answer to this problem. Recently Rainer Forst has argued that toleration should not just...

  4. Tolerances in micro manufacturing

    DEFF Research Database (Denmark)

    Hansen, Hans Nørgaard; Zhang, Yang; Islam, Aminul

    2017-01-01

    This paper describes a method for analysis of tolerances in micro manufacturing. It proposes a mapping oftolerances to dimensions and compares this with current available international standards. The analysisdocuments that tolerances are not scaled down as the absolute dimension. In practice...

  5. Tolerances in micro manufacturing

    DEFF Research Database (Denmark)

    Hansen, Hans Nørgaard; Zhang, Yang; Islam, Aminul

    This paper describes a method for analysis of tolerances in micro manufacturing. It proposes a mapping oftolerances to dimensions and compares this with current available international standards. The analysisdocuments that tolerances are not scaled down as the absolute dimension. In practice...

  6. Fault Tolerant Feedback Control

    DEFF Research Database (Denmark)

    Stoustrup, Jakob; Niemann, H.

    2001-01-01

    An architecture for fault tolerant feedback controllers based on the Youla parameterization is suggested. It is shown that the Youla parameterization will give a residual vector directly in connection with the fault diagnosis part of the fault tolerant feedback controller. It turns out that there...

  7. Recognition and Toleration

    DEFF Research Database (Denmark)

    Lægaard, Sune

    2010-01-01

    Recognition and toleration are ways of relating to the diversity characteristic of multicultural societies. The article concerns the possible meanings of toleration and recognition, and the conflict that is often claimed to exist between these two approaches to diversity. Different forms or inter...

  8. Student-on-Student Harassment and Zero Tolerance: Achieving a Delicate Balance

    Science.gov (United States)

    Essex, Nathan L.

    2009-01-01

    Zero tolerance policy. Most school districts have a zero tolerance policy in place for drug use, weapons on campus, sexual harassment, or all of the above. At their very core, zero tolerance policies make schools safer. However, a one-size-fits-all approach does not work well in all situations involving student misconduct. This article outlines…

  9. Cancer Nanomedicines Stabilized by π-π Stacking between Heterodimeric Prodrugs Enable Exceptionally High Drug Loading Capacity and Safer Delivery of Drug Combinations.

    Science.gov (United States)

    Wang, Hangxiang; Chen, Jianmei; Xu, Chang; Shi, Linlin; Tayier, Munire; Zhou, Jiahui; Zhang, Jun; Wu, Jiaping; Ye, Zhijian; Fang, Tao; Han, Weidong

    2017-01-01

    Combination therapy using distinct mode-of-action drugs has sparked a rapidly growing interest because this paradigm holds promise for improving the therapeutic efficacy of anticancer therapy. However, the current drug combination therapy refers to administering individual drugs together, which is far from a perfect regimen for cancer patients. The aim of this work was to demonstrate that synergistic delivery of two chemotherapeutic drugs in a single nanoparticle reservoir could be achieved through the rational chemical ligation of the drugs followed by supramolecular nano-assembly via blending of the drugs with a minimal amount of matrix. Choosing 7-ethyl-10-hydroxycamptothecin and taxanes, which are rich in aromatic structures, as model compounds, we show that the heterodimeric conjugates of the two agents are miscible with lipids to form systemically injectable nanomedicines. The compatibility between the prodrug conjugates and lipid carriers is substantially augmented by the intermolecular π-π stacking and alleviated polarity, thus enabling an exceptionally high drug loading (DL) capacity (~92%) and a gratifyingly long drug retention time within the micellar core. We further observed superior therapeutic outcomes in a mouse tumor model without detecting accompanying systemic toxicity. This structure-based, self-assembled cancer nanomedicine increased the potency and drug tolerability in animals and thus offers a robust strategy for simultaneously formulating two or more drugs in single nanovehicles.

  10. Assessment of heat production, heat loss, and core temperature during nitrous oxide exposure: a new paradigm for studying drug effects and opponent responses.

    Science.gov (United States)

    Kaiyala, Karl J; Ramsay, Douglas S

    2005-03-01

    Studies using core temperature (T(c)) have contributed greatly to theoretical explanations of drug tolerance and its relationship to key features of addiction, including dependence, withdrawal, and relapse. Many theoretical accounts of tolerance propose that a given drug-induced psychobiological disturbance elicits opponent responses that contribute to tolerance development. This proposal and its theoretical extensions (e.g., conditioning as a mechanism of chronic tolerance) have been inferred from dependent variables, such as T(c), which represent the summation of multiple underlying determinants. Direct measurements of determinants could increase the understanding of opponent processes in tolerance, dependence, and withdrawal. The proximal determinants of T(c) are metabolic heat production (HP) and heat loss (HL). We developed a novel system for simultaneously quantifying HP (indirect calorimetry), HL (direct gradient layer calorimetry), and T(c) (telemetry) during steady-state administrations of nitrous oxide (N(2)O), an inhalant with abuse potential that has been previously used to study acute and chronic tolerance development to its hypothermia-inducing property. Rats were administered 60% N(2)O (n = 18) or placebo gas (n = 16) for 5 h after a 2-h placebo baseline exposure. On average, N(2)O rapidly but transiently lowered HP and increased HL, each by approximately 16% (P HL) after becoming hypothermic such that acute tolerance developed, i.e., T(c) rose despite continued drug administration. This work is the first to directly quantify the thermal determinants of T(c) during administration of a drug of abuse and establishes a new paradigm for studying opponent processes involved in acute and chronic hypothermic tolerance development.

  11. Insights into immune tolerance from AIRE deficiency.

    Science.gov (United States)

    Proekt, Irina; Miller, Corey N; Lionakis, Michail S; Anderson, Mark S

    2017-12-01

    AIRE is a well-established master regulator of central tolerance. It plays an essential role in driving expression of tissue-specific antigens in the thymus and shaping the development of positively selected T-cells. Humans and mice with compromised or absent AIRE function have markedly variable phenotypes that include a range of autoimmune manifestations. Recent evidence suggests that this variability stems from cooperation of autoimmune susceptibilities involving both central and peripheral tolerance checkpoints. Here we discuss the broadening understanding of the factors that influence Aire expression, modify AIRE function, and the impact and intersection of AIRE with peripheral immunity. This rapidly expanding body of knowledge will force a reexamination of the definition and clinical management of APS-1 patients as well as provide a foundation for the development of immunomodulatory strategies targeting central tolerance. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. GTB - an online genome tolerance browser.

    Science.gov (United States)

    Shihab, Hashem A; Rogers, Mark F; Ferlaino, Michael; Campbell, Colin; Gaunt, Tom R

    2017-01-06

    Accurate methods capable of predicting the impact of single nucleotide variants (SNVs) are assuming ever increasing importance. There exists a plethora of in silico algorithms designed to help identify and prioritize SNVs across the human genome for further investigation. However, no tool exists to visualize the predicted tolerance of the genome to mutation, or the similarities between these methods. We present the Genome Tolerance Browser (GTB, http://gtb.biocompute.org.uk ): an online genome browser for visualizing the predicted tolerance of the genome to mutation. The server summarizes several in silico prediction algorithms and conservation scores: including 13 genome-wide prediction algorithms and conservation scores, 12 non-synonymous prediction algorithms and four cancer-specific algorithms. The GTB enables users to visualize the similarities and differences between several prediction algorithms and to upload their own data as additional tracks; thereby facilitating the rapid identification of potential regions of interest.

  13. Drug Facts

    Medline Plus

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

  14. Antimicrobial Tolerance in Biofilms

    Science.gov (United States)

    Stewart, Philip S.

    2015-01-01

    The tolerance of microorganisms in biofilms to antimicrobial agents is examined through a meta-analysis of literature data. A numerical tolerance factor comparing the rates of killing in the planktonic and biofilm states is defined to provide a quantitative basis for the analysis. Tolerance factors for biocides and antibiotics range over three orders of magnitude. This variation is not explained by taking into account the molecular weight of the agent, the chemistry of the agent, the substratum material, or the speciation of the microorganisms. Tolerance factors do depend on the areal cell density of the biofilm at the time of treatment and on the age of the biofilm as grown in a particular experimental system. This suggests that there is something that happens during biofilm maturation, either physical or physiological, that is essential for full biofilm tolerance. Experimental measurements of antimicrobial penetration times in biofilms range over orders of magnitude, with slower penetration (>12 min) observed for reactive oxidants and cationic molecules. These agents are retarded through the interaction of reaction, sorption, and diffusion. The specific physiological status of microbial cells in a biofilm contributes to antimicrobial tolerance. A conceptual framework for categorizing physiological cell states is discussed in the context of antimicrobial susceptibility. It is likely that biofilms harbor cells in multiple states simultaneously (e.g., growing, stress-adapted, dormant, inactive) and that this physiological heterogeneity is an important factor in the tolerance of the biofilm state. PMID:26185072

  15. [Drug therapy for benign prostatic syndrome (BPS)].

    Science.gov (United States)

    Berges, R

    2006-09-01

    Alpha1-receptor blockers (alfuzosin, doxazosin, tamsulosin and terazosin), 5alpha-reductase inhibitors (dutasteride and finasteride) and combinations thereof are used in the drug treatment of benign prostatic syndrome. As before, there is still no evidence supporting the use of plant extracts, the use of anticholinergic substances alone or in combination with other BPS drugs is currently under investigation and should not be attempted outside of clinical trials. For all drugs the placebo effect is considerable. Accordingly, deviations from the recommended doses are rapidly associated with an activity loss over that of placebo. alpha1-Receptor blockers show a rapid onset of action and are slightly superior to 5alpha-reductase inhibitors with regard to the relief of symptoms. All alpha1-receptor blockers are similarly effective at adequate doses, however, quantitative differences are seen in the side effect profiles. 5alpha-reductase inhibitors also provide relief from BPS-associated symptoms with the relief being volume-dependent. Prostate volume-dependent complications of BPS (operation risk and risk of acute urine retention) can be reduced by 5alpha-reductase inhibitors. Long-term drug studies have demonstrated the superiority of combination therapies over monotherapies with alpha1-receptor blockers and 5alpha-reductase inhibitors in patients with a high risk for progression. This superiority is accompanied by a combination of the respective side-effect profiles and their absolute increase. Besides poorer tolerability, combination therapies also result in higher costs. Thus, it is important to decide at an early stage which patients are to be treated with drugs and which by surgery.

  16. Engineering antigen-specific immunological tolerance.

    Energy Technology Data Exchange (ETDEWEB)

    Kontos, Stephan; Grimm, Alizee J.; Hubbell, Jeffrey A.

    2015-05-01

    Unwanted immunity develops in response to many protein drugs, in autoimmunity, in allergy, and in transplantation. Approaches to induce immunological tolerance aim to either prevent these responses or reverse them after they have already taken place. We present here recent developments in approaches, based on engineered peptides, proteins and biomaterials, that harness mechanisms of peripheral tolerance both prophylactically and therapeutically to induce antigenspecific immunological tolerance. These mechanisms are based on responses of B and T lymphocytes to other cells in their immune environment that result in cellular deletion or ignorance to particular antigens, or in development of active immune regulatory responses. Several of these approaches are moving toward clinical development, and some are already in early stages of clinical testing.

  17. Improving uptake and use of malaria rapid diagnostic tests in the context of artemisinin drug resistance containment in eastern Myanmar: an evaluation of incentive schemes among informal private healthcare providers.

    Science.gov (United States)

    Aung, Tin; White, Christopher; Montagu, Dominic; McFarland, Willi; Hlaing, Thaung; Khin, Hnin Su Su; San, Aung Kyaw; Briegleb, Christina; Chen, Ingrid; Sudhinaraset, May

    2015-03-06

    As efforts to contain artemisinin resistance and eliminate Plasmodium falciparum intensify, the accurate diagnosis and prompt effective treatment of malaria are increasingly needed in Myanmar and the Greater Mekong Sub-region (GMS). Rapid diagnostic tests (RDTs) have been shown to be safe, feasible, and effective at promoting appropriate treatment for suspected malaria, which are of particular importance to drug resistance containment. The informal private sector is often the first point of care for fever cases in malaria endemic areas across Myanmar and the GMS, but there is little published information about informal private provider practices, quality of service provision, or potential to contribute to malaria control and elimination efforts. This study tested different incentives to increase RDT use and improve the quality of care among informal private healthcare providers in Myanmar. The study randomized six townships in the Mon and Shan states of rural Myanmar into three intervention arms: 1) RDT price subsidies, 2) price subsidies with product-related financial incentives, and 3) price subsidies with intensified information, education and counselling (IEC). The study assessed the uptake of RDT use in the communities by cross-sectional surveys of 3,150 households at baseline and six months post-intervention (6,400 households total, 832 fever cases). The study also used mystery clients among 171 providers to assess quality of service provision across intervention arms. The pilot intervention trained over 600 informal private healthcare providers. The study found a price subsidy with intensified IEC, resulted in the highest uptake of RDTs in the community, as compared to subsidies alone or merchandise-related financial incentives. Moreover, intensified IEC led to improvements in the quality of care, with mystery client surveys showing almost double the number of correct treatment following diagnostic test results as compared to a simple subsidy. Results show

  18. A rapid method for simultaneous detection of phenotypic resistance to inhibitors of protease and reverse transcriptase in recombinant human immunodeficiency virus type 1 isolates from patients treated with antiretroviral drugs.

    Science.gov (United States)

    Hertogs, K; de Béthune, M P; Miller, V; Ivens, T; Schel, P; Van Cauwenberge, A; Van Den Eynde, C; Van Gerwen, V; Azijn, H; Van Houtte, M; Peeters, F; Staszewski, S; Conant, M; Bloor, S; Kemp, S; Larder, B; Pauwels, R

    1998-02-01

    Combination therapy with protease (PR) and reverse transcriptase (RT) inhibitors can efficiently suppress human immunodeficiency virus (HIV) replication, but the emergence of drug-resistant variants correlates strongly with therapeutic failure. Here we describe a new method for high-throughput analysis of clinical samples that permits the simultaneous detection of HIV type 1 (HIV-1) phenotypic resistance to both RT and PR inhibitors by means of recombinant virus assay technology. HIV-1 RNA is extracted from plasma samples, and a 2.2-kb fragment containing the entire HIV-1 PR- and RT-coding sequence is amplified by nested reverse transcription-PCR. The pool of PR-RT-coding sequences is then cotransfected into CD4+ T lymphocytes (MT4) with the pGEMT3deltaPRT plasmid from which most of the PR (codons 10 to 99) and RT (codons 1 to 482) sequences are deleted. Homologous recombination leads to the generation of chimeric viruses containing PR- and RT-coding sequences derived from HIV-1 RNA in plasma. The susceptibilities of the chimeric viruses to all currently available RT and/or PR inhibitors is determined by an MT4 cell-3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-based cell viability assay in an automated system that allows high sample throughput. The profile of resistance to all RT and PR inhibitors is displayed graphically in a single PR-RT-Antivirogram. This assay system facilitates the rapid large-scale phenotypic resistance determinations for all RT and PR inhibitors in one standardized assay.

  19. Inequality, Tolerance, and Growth

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    2004-01-01

    This paper argues for the importance of individuals' tolerance of inequality for economic growth. By using the political ideology of governments as a measure of revealed tolerance of inequality, the paper shows that controlling for ideology improves the accuracy with which the effects of inequali...... are measured. Results show that inequality reduces growth but more so in societies where people perceive it as being relatively unfair. Further results indicate that legal quality and social trust are likely transmission channels for the effects of inequality.......This paper argues for the importance of individuals' tolerance of inequality for economic growth. By using the political ideology of governments as a measure of revealed tolerance of inequality, the paper shows that controlling for ideology improves the accuracy with which the effects of inequality...

  20. Inequality, Tolerance, and Growth

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    This paper argues for the importance of individuals' tolerance of inequality for economic growth. By using the political ideology of governments as a measure of revealed tolerance of inequality, the paper shows that controlling for ideology improves the accuracy with which the effects of inequali...... are measured. Results show that inequality reduces growth but more so in societies where people perceive it as being relatively unfair. Further results indicate that legal quality and social trust are likely transmission channels for the effects of inequality.......This paper argues for the importance of individuals' tolerance of inequality for economic growth. By using the political ideology of governments as a measure of revealed tolerance of inequality, the paper shows that controlling for ideology improves the accuracy with which the effects of inequality...

  1. [INABILITY TO TOLERATE COSMETICS].

    Science.gov (United States)

    Piérard, G E; Piérard-Franchimont, C

    2016-05-01

    Inability to tolerate cosmetics can result from distinct mechanisms which appear as the so-called sensitive skin corresponding to one aspect of invisible dermatosis, or which corresponds to manifestations of a contact allergic or irritation dermatitis.

  2. Salt Tolerance of Desorption Electrospray Ionization (DESI)

    Energy Technology Data Exchange (ETDEWEB)

    Jackson, Ayanna U. [Purdue University; Talaty, Nari [Purdue University; Cooks, R G [Purdue University; Van Berkel, Gary J [ORNL

    2007-01-01

    Suppression of ion intensity in the presence of high salt matrices is common in most mass spectrometry ionization techniques. Desorption electrospray ionization (DESI) is an ionization method that exhibits salt tolerance, and this is investigated. DESI analysis was performed on three different drug mixtures in the presence of 0, 0.2, 2, 5, 10, and 20% NaCl:KCl weight by volume from seven different surfaces. At physiological concentrations individual drugs in each mixture were observed with each surface. Collision-induced dissociation (CID) was used to provide additional confirmation for select compounds. Multiple stage experiments, to MS5, were performed for select compounds. Even in the absence of added salt, the benzodiazepine containing mixture yielded sodium and potassium adducts of carbamazepine which masked the ions of interest. These adducts were eliminated by adding 0.1% 7M ammonium acetate to the standard methanol:water (1:1) spray solvent. Comparison of the salt tolerance of DESI with that of electrospray ionization (ESI) demonstrated much better signal/noise characteristics for DESI in this study. The salt tolerance of DESI was also studied by performing limit of detection and dynamic range experiments. Even at a salt concentration significantly above physiological concentrations, select surfaces were effective in providing spectra that allowed the ready identification of the compounds of interest. The already high salt tolerance of DESI can be optimized further by appropriate choices of surface and spray solution.

  3. Fault-tolerant design

    CERN Document Server

    Dubrova, Elena

    2013-01-01

    This textbook serves as an introduction to fault-tolerance, intended for upper-division undergraduate students, graduate-level students and practicing engineers in need of an overview of the field.  Readers will develop skills in modeling and evaluating fault-tolerant architectures in terms of reliability, availability and safety.  They will gain a thorough understanding of fault tolerant computers, including both the theory of how to design and evaluate them and the practical knowledge of achieving fault-tolerance in electronic, communication and software systems.  Coverage includes fault-tolerance techniques through hardware, software, information and time redundancy.  The content is designed to be highly accessible, including numerous examples and exercises.  Solutions and powerpoint slides are available for instructors.   ·         Provides textbook coverage of the fundamental concepts of fault-tolerance; ·         Describes a variety of basic techniques for achieving fault-toleran...

  4. Targeting phenotypically tolerant Mycobacterium tuberculosis

    Science.gov (United States)

    Gold, Ben; Nathan, Carl

    2016-01-01

    While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of

  5. Sulfasalazine efficacy and tolerability in rheumatic diseases

    Directory of Open Access Journals (Sweden)

    V. V. Badokin

    2005-01-01

    Full Text Available Sulfasalazine is one of the main disease modifying drugs for the treatment of chronic inflammatory joint and spine diseases. The article describes mechanism of action of sulfasalazine and its main metabolites. Detailed information about anti-inflammatory and immunosuppressive action of the drug is presented. Results of many studies of sulfasalazine efficacy in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and reactive arthritis are discussed from the evidence based medicine point of view. Data on sulfasalazine tolerability and safety are presented with separate discussion of hypersensitivity and dose-dependent adverse reactions so as their treatment and prophylaxis.

  6. Drug Facts

    Medline Plus

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

  7. GABA-ergic drugs: exit stage left, enter stage right.

    Science.gov (United States)

    Ashton, Heather; Young, Allan H

    2003-06-01

    Drugs that enhance gamma-aminobutyric acid (GABA) activity by interacting at post-synaptic GABA(A) receptors have long been used as hypnotics, sedatives, tranquillizers and anticonvulsants. In this category, benzodiazepines rapidly gained pride of place, replacing barbiturates and becoming the most commonly prescribed of all drugs in the Western world in the 1970s. However, problems such as dependence and withdrawal reactions became apparent in the 1980s, and it seemed that the usefulness of drugs with this mode of action was limited. Recently, focus has shifted to a new group of drugs with GABA-ergic actions mediated through various mechanisms not directly involving the GABA(A) receptor. These drugs include gabapentin, vigabatrin, tiagabine, lamotrigine, pregabalin and others. Although originally developed as anticonvulsants for epilepsy, they appear to have wider applications for use in affective disorders, especially bipolar depression, anxiety disorders and pain conditions. The current information on the properties and therapeutic potential of this new generation of GABA-ergic drugs is reviewed. It remains to be seen whether long-term use leads to tolerance, dependence and withdrawal or discontinuation reactions.

  8. Ocular Insert: Dosage Form for Sustain Opthalmic Drug Delivery

    Directory of Open Access Journals (Sweden)

    Sunil Kumar

    2012-06-01

    Full Text Available Except for skin, the eye is the most easily accessible site for topical administration of a medication. Traditional topical ophthalmic formulations (eye drops and ointments have poor bioavailability because of rapid pre-corneal elimination, conjunctival absorption, solution drainage by gravity, induced lacrimation and normal tear turnover. This leads to frequent installations of concentrated medication to achieve a therapeutic effect. The typical “pulse-entry” type drug release observed with ocular aqueous solutions (eye drops, suspensions and ointments can be replaced by more controlled, sustained, and continuous drug delivery, using a controlled-release ocular drug delivery system. Ocular inserts are solid or semisolid sterile preparations, of appropriate size and shape, designed to be inserted behind the eyelid or held on the eye and to deliver drugs for topical or systemic effect. These are polymeric systems into which the drug is incorporated as a solution or dispersion. They are better tolerated as to drainage and tear flow compared with other ophthalmic formulation and produce reliable drug release in the conjunctival cul-de-sac.

  9. Efficacy and Tolerability of Malartin and Sulphadoxine-Pyrimethamine Combination against Uncomplicated Falciparum Malaria in Dibanda, Southwest Cameroon

    Directory of Open Access Journals (Sweden)

    Helen Kuokuo Kimbi

    2012-01-01

    Full Text Available Artemisinin derivatives are now the most potent and rapidly acting antimalarials. The aim of this study was to assess the in vivo efficacy and tolerability of a combination of Malartin (an artesunate and sulphadoxine-pyrimethamine (SP in the treatment of uncomplicated falciparum malaria in Dibanda, Cameroon. A total of 197 subjects were recruited into the study and administered Malartin for 3 days and SP as a single dose on day 0. Only 174 of the subjects were successfully followed up on days 3, 7, and 14. The overall success rate of the drug combination was 92.53%. Parasite density decreased during the follow-up period in different age groups, sexes, and social classes. The prevalence of anaemia decreased from 22.99% at enrolment to 9.77% on day 14, and the difference was significant (P<0.05 on all days of followup. The drug combination did not give rise to any serious side effects.

  10. The genomic landscape of rapid repeated evolutionary ...

    Science.gov (United States)

    Atlantic killifish populations have rapidly adapted to normally lethal levels of pollution in four urban estuaries. Through analysis of 384 whole killifish genome sequences and comparative transcriptomics in four pairs of sensitive and tolerant populations, we identify the aryl hydrocarbon receptor–based signaling pathway as a shared target of selection. This suggests evolutionary constraint on adaptive solutions to complex toxicant mixtures at each site. However, distinct molecular variants apparently contribute to adaptive pathway modification among tolerant populations. Selection also targets other toxicity-mediatinggenes and genes of connected signaling pathways; this indicates complex tolerance phenotypes and potentially compensatory adaptations. Molecular changes are consistent with selection on standing genetic variation. In killifish, high nucleotide diversityhas likely been a crucial substrate for selective sweeps to propel rapid adaptation. This manuscript describes genomic evaluations that contribute to our understanding of the ecological and evolutionary risks associated with chronic contaminant exposures to wildlife populations. Here, we assessed genetic patterns associated with long-term response to an important class of highly toxic environmental pollutants. Specifically, chemical-specific tolerance has rapidly and repeatedly evolved in an estuarine fish species resident to estuaries of the Atlantic U.S. coast. We used laboratory studies to ch

  11. Heat tolerance in wheat

    DEFF Research Database (Denmark)

    Sharma, Dew Kumari

    climate, wheat is sensitive to heat stress. We need to understand how our crops will perform in these changing climatic conditions and how we can develop varieties, which are more tolerant. The PhD study focussed on understanding heat tolerance in wheat with a combined approach of plant physiology...... and quantitative genetics in particular, plant phenotyping based quantitative trait loci (QTL) discovery for a physiological trait under heat stress. Chlorophyll a fluorescence trait, Fv/Fm was used as a phenotyping tool, as it reflects the effect of heat stress on maximum photochemical efficiency of photosystem...... among cultivars due to heat stress as the GD of most of them remained similar in control and stress. The second study investigated if it was possible to use detached leaves to screen for heat tolerance instead of intact plants. The previously selected 41 cultivars, known to differ in v/Fm, were used...

  12. Preventing and managing antiretroviral drug resistance.

    Science.gov (United States)

    Kuritzkes, Daniel R

    2004-05-01

    Development of resistance to antiretroviral drugs (ARVs) is a major impediment to optimum treatment of HIV-1 infection. Although resistance testing can help to select subsequent regimens when virologic failure occurs, cross-resistance, which affects all classes of ARVs, may make it more difficult to achieve optimum control of HIV. We have known for some time that our first choice of antiretroviral therapy offers the best chance to control HIV replication and that initial therapy should be selected with an eye on future options. Potency is the first line of defense against the development of resistance. Other factors that affect resistance development include: tolerability, potential for optimum adherence, and genetic and pharmacologic barriers to development of resistance. If resistance emerges, only a single drug may be affected initially, and a rapid change in ARVs may preserve the efficacy of other components. One cautionary note is that we can no longer assume that a patient's HIV is fully susceptible to all ARVs even in the initial regimen. Transmission of drug-resistant HIV means that the genetic composition may be that of an "experienced" virus with reduced susceptibility to ARVs. Resistance testing at the time of transmission is most likely to reveal this resistance, but over time the dominant genetic pattern may revert to wild-type, and be missed by resistance testing. Because "archived" resistant HIV may emerge quickly once treatment is initiated, we need to keep this in mind when selecting initial therapy.

  13. Acquired pharmaco-dynamic opioid tolerance: a concept analysis.

    Science.gov (United States)

    Middleton, Carolyn; Harden, Jane

    2014-02-01

    To report an analysis of the concept of acquired pharmaco-dynamic opioid tolerance. Acquired pharmaco-dynamic opioid tolerance is a complex and poorly understood phenomenon associated with strong opioid therapy for managing pain. Critical review of the concept provides greater clarification of the attributes, assisting healthcare professionals in addressing pain and functional management of patients, particularly those with non-malignant pain. Concept analysis. A systematic literature search was undertaken using electronic data bases: CINAHL, British Nursing Index, EMBase, Medline, Pubmed and AMED. All literature reviewed was in English and published between 1976 and 2012. The key search terms were 'chronic non-malignant pain', 'strong opioid therapy' and 'development of acquired pharmaco-dynamic opioid tolerance'; all possible variant terms were also searched. The Walker and Avant approach was used to guide the concept analysis. The concept analysis revealed four empirical referents: plasticity, drug administration, reduced analgesic efficacy and increased drug dosing. Tachyphylexia was identified as a borderline case, opioid induced hyperalgesia as a related case and pseudo-tolerance as a contrary case. The antecedent is administration of an opioid analgesic drug and the consequences, increasing opioid drug dose to maintain analgesic effect. Untangling the antecedents, empirical referents and consequences of tolerance help healthcare professionals understand its complexities. Improved knowledge may ultimately influence patient outcomes through the construction of better monitoring systems. This concept analysis may also provide insights for policy change and give empirical direction for future research. © 2013 Blackwell Publishing Ltd.

  14. Safety of antiobesity drugs.

    Science.gov (United States)

    Cheung, Bernard Man Yung; Cheung, Tommy Tsang; Samaranayake, Nithushi Rajitha

    2013-08-01

    Obesity is a major health problem worldwide. Although diet and physical activity are crucial in the management of obesity, the long-term success rate is low. Therefore antiobesity drugs are of great interest, especially when lifestyle modification has failed. As obesity is not an immediate life-threatening disease, these drugs are required to be safe. Antiobesity drugs that have been developed so far have limited efficacies and considerable adverse effects affecting tolerability and safety. Therefore, most antiobesity drugs have been withdrawn. Fenfluramine and dexfenfluramine were withdrawn because of the potential damage to heart valves. Sibutramine was associated with an increase in major adverse cardiovascular events in the Sibutramine Cardiovascular Outcomes (SCOUT) trial and it was withdrawn from the market in 2010. Rimonabant was withdrawn because of significant psychiatric adverse effects. Orlistat was approved in Europe and the United States for long-term treatment of obesity, but many patients cannot tolerate its gastrointestinal side effects. Phentermine and diethylpropion can only be used for less than 12 weeks because the long-term safety of these drugs is unknown. Ephedrine and caffeine are natural substances but the effects on weight reduction are modest. As a result there is a huge unmet need for effective and safe antiobesity drugs. Recently lorcaserin and topiramate plus phentermine have been approved for the treatment of obesity but long-term safety data are lacking.

  15. Drug Facts

    Medline Plus

    Full Text Available ... Treatment and Recovery Resources? Prevent Drug Use Help Children and Teens Stay Drug-Free Talking to Kids About Drugs: What to Say if You ... drug abuse, addiction, and treatment. Watch Videos Information About Drugs ...

  16. Drug Allergy

    Science.gov (United States)

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

  17. 3HP tolerance

    DEFF Research Database (Denmark)

    2014-01-01

    Cells and cell cultures are provided that have improved tolerance to 3-hydroxypropionic acid (3HP). Genetic modifications to provide a mutated or overexpressed SFA1 gene or other enhancement of 3HP detoxification via a glutathione- dependent dehydrogenase reaction, including medium supplementation...... with glutathione, may be combined with a 3HP producing metabolic pathway....

  18. COMMUNICATIVE TOLERANCE DISCOURSE

    Directory of Open Access Journals (Sweden)

    B. R. Mogilevich

    2016-01-01

    Full Text Available Tolerance, communication and theme repertoire are communicative discourse components. The dialogue relations of communicators in the process of their life activity reflect where socio-cultural specific characteristics. The speech structure of communication adherence to speech frames and the Principles of Cooperation and Politeness as indicators of tolerance and empathy. Language speakers share one discourse code as a condition of successful communication. Discourse activity represents information exchange in the process of achieving various socio-cultural and cognitive goals. Tolerance, in its term, includes communicators` mutual empathy as the main conditions of communication success. Communicative tolerance is presented as communicative behavior prescriptions, specific for various socio-cultural areas. Theme repertoire phenomenon means shared knowledge and interpretation of all social communication participants. The combination of global context and local ones acquire special significance. Contextual limitations reflect socio-cultural specifics and are determined by the existence of behavior stereotypes and their evaluation. Thus, each discourse component contributes to achieving social-communication goals. 

  19. Deconstructing tolerance with clobazam

    Science.gov (United States)

    Wechsler, Robert T.; Sankar, Raman; Montouris, Georgia D.; White, H. Steve; Cloyd, James C.; Kane, Mary Clare; Peng, Guangbin; Tworek, David M.; Shen, Vivienne; Isojarvi, Jouko

    2016-01-01

    Objective: To evaluate potential development of tolerance to adjunctive clobazam in patients with Lennox-Gastaut syndrome. Methods: Eligible patients enrolled in open-label extension study OV-1004, which continued until clobazam was commercially available in the United States or for a maximum of 2 years outside the United States. Enrolled patients started at 0.5 mg·kg−1·d−1 clobazam, not to exceed 40 mg/d. After 48 hours, dosages could be adjusted up to 2.0 mg·kg−1·d−1 (maximum 80 mg/d) on the basis of efficacy and tolerability. Post hoc analyses evaluated mean dosages and drop-seizure rates for the first 2 years of the open-label extension based on responder categories and baseline seizure quartiles in OV-1012. Individual patient listings were reviewed for dosage increases ≥40% and increasing seizure rates. Results: Data from 200 patients were included. For patients free of drop seizures, there was no notable change in dosage over 24 months. For responder groups still exhibiting drop seizures, dosages were increased. Weekly drop-seizure rates for 100% and ≥75% responders demonstrated a consistent response over time. Few patients had a dosage increase ≥40% associated with an increase in seizure rates. Conclusions: Two-year findings suggest that the majority of patients do not develop tolerance to the antiseizure actions of clobazam. Observed dosage increases may reflect best efforts to achieve seizure freedom. It is possible that the clinical development of tolerance to clobazam has been overstated. ClinicalTrials.gov identifier: NCT00518713 and NCT01160770. Classification of evidence: This study provides Class III evidence that the majority of patients do not develop tolerance to clobazam over 2 years of treatment. PMID:27683846

  20. Injection drug use and HIV/AIDS in China: Review of current situation, prevention and policy implications

    Directory of Open Access Journals (Sweden)

    Chen Huey T

    2006-02-01

    Full Text Available Abstract Illicit drug abuse and HIV/AIDS have increased rapidly in the past 10 to 20 years in China. This paper reviews drug abuse in China, the HIV/AIDS epidemic and its association with injection drug use (IDU, and Chinese policies on illicit drug abuse and prevention of HIV/AIDS based on published literature and unpublished official data. As a major drug trans-shipment country with source drugs from the "Golden Triangle" and "Gold Crescent" areas in Asia, China has also become an increasingly important drug consuming market. About half of China's 1.14 million documented drug users inject, and many share needles. IDU has contributed to 42% of cumulatively reported HIV/AIDS cases thus far. Drug trafficking is illegal in China and can lead to the death penalty. The public security departments adopt "zero tolerance" approach to drug use, which conflict with harm reduction policies of the public health departments. Past experience in China suggests that cracking down on drug smuggling and prohibiting drug use alone can not prevent or solve all illicit drug related problems in the era of globalization. In recent years, the central government has outlined a series of pragmatic policies to encourage harm reduction programs; meanwhile, some local governments have not fully mobilized to deal with drug abuse and HIV/AIDS problems seriously. Strengthening government leadership at both central and local levels; scaling up methadone substitution and needle exchange programs; making HIV voluntary counseling and testing available and affordable to both urban and rural drug users; and increasing utilization of outreach and nongovernmental organizations are offered as additional strategies to help cope with China's HIV and drug abuse problem.

  1. The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients.

    Science.gov (United States)

    Massart, Annick; Pallier, Annaïck; Pascual, Julio; Viklicky, Ondrej; Budde, Klemens; Spasovski, Goce; Klinger, Marian; Sever, Mehmet Sukru; Sørensen, Søren Schwartz; Hadaya, Karine; Oberbauer, Rainer; Dudley, Christopher; De Fijter, Johan W; Yussim, Alexander; Hazzan, Marc; Wekerle, Thomas; Berglund, David; De Biase, Consuelo; Pérez-Sáez, María José; Mühlfeld, Anja; Orlando, Giuseppe; Clemente, Katia; Lai, Quirino; Pisani, Francesco; Kandus, Aljosa; Baas, Marije; Bemelman, Frederike; Ponikvar, Jadranka Buturovic; Mazouz, Hakim; Stratta, Piero; Subra, Jean-François; Villemain, Florence; Hoitsma, Andries; Braun, Laura; Cantarell, Maria Carmen; Colak, Hulya; Courtney, Aisling; Frasca, Giovanni Maria; Howse, Matthew; Naesens, Maarten; Reischig, Tomas; Serón, Daniel; Seyahi, Nurhan; Tugmen, Cem; Alonso Hernandez, Angel; Beňa, Luboslav; Biancone, Luigi; Cuna, Vania; Díaz-Corte, Carmen; Dufay, Alexandre; Gaasbeek, André; Garnier, Arnaud; Gatault, Philippe; Gentil Govantes, Miguel Angel; Glowacki, François; Gross, Oliver; Hurault de Ligny, Bruno; Huynh-Do, Uyen; Janbon, Bénédicte; Jiménez Del Cerro, Luis Antonio; Keller, Frieder; La Manna, Gaetano; Lauzurica, Ricardo; Le Monies De Sagazan, Hervé; Thaiss, Friedrich; Legendre, Christophe; Martin, Séverine; Moal, Marie-Christine; Noël, Christian; Pillebout, Evangeline; Piredda, Gian Benedetto; Puga, Ana Ramírez; Sulowicz, Wladyslaw; Tuglular, Serhan; Prokopova, Michaela; Chesneau, Mélanie; Le Moine, Alain; Guérif, Pierrick; Soulillou, Jean-Paul; Abramowicz, Marc; Giral, Magali; Racapé, Judith; Maggiore, Umberto; Brouard, Sophie; Abramowicz, Daniel

    2016-06-01

    Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still operationally tolerant. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  2. Improving abiotic stress tolerance of quinoa

    DEFF Research Database (Denmark)

    Yang, Aizheng

    other crops, its productivity declines under severe drought, high salt conditions and harsh climate conditions. Different management approaches including water-saving irrigation methods (such as deficit irrigation, DI and alternate root-zone drying irrigation, ARD), inoculating crop seeds with plant......Global food security faces the challenges of rapid population growth and shortage of water resources. Drought, heat waves and soil salinity are becoming more frequent and extreme due to climatic changes in many regions of the world, and resulting in yield reduction of many crops. It is hypothesized...... that quinoa has the potential to grow under a range of abiotic stresses, tolerating levels regarded as stresses in other crop species. Therefore cultivation of quinoa (Chenopodium quinoa Willd.) could be an alternative option in such regions. Even though quinoa is more tolerant to abiotic stress than most...

  3. Brain targeting efficiency of antimigrain drug loaded mucoadhesive intranasal nanoemulsion.

    Science.gov (United States)

    Abdou, Ebtsam M; Kandil, Soha M; Miniawy, Hala M F El

    2017-08-30

    Zolmitriptan (ZT) is a well-tolerated drug in migraine treatment suffering from low bioavailability due to low amount of the drug that reaches the brain after oral and nasal delivery. Development of new nasal mucoadhesive nanoemulsion formulation for zolmitriptan may success in delivering the drug directly from the nose to the brain to achieve rapid onset of action and high drug concentration in the brain which is required for treatment of acute migraine. ZT mucoadhesive nanoemulsion were prepared and characterized for drug content, zeta potential, particle size, morphology, residence time and permeation through the nasal mucosa. The selected formula was tested in-vivo in mice for its pharmacokinetics in comparison with intravenous and nasal solution of zolmitriptan. Results showed that addition of chitosan as mucoadhesive agent in 0.3% concentration to the nanoemulsion enhanced its residence time and zetapotential with no significant effect on the globule size. All tested formulations showed higher permeability coefficients than the zolmitriptan solution through the nasal mucosa. In-vivo studies showed that the mucoadhesive nanoemulsion formulation of zolmitriptan has higher AUC0-8 and shorter Tmax in the brain than the intravenous or the nasal solution. This was related to the small globule size and higher permeability of the formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Alcohol-Induced Histone Acetylation Reveals a Gene Network Involved in Alcohol Tolerance

    Science.gov (United States)

    Ghezzi, Alfredo; Krishnan, Harish R.; Lew, Linda; Prado, Francisco J.; Ong, Darryl S.; Atkinson, Nigel S.

    2013-01-01

    Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol. PMID:24348266

  5. Alcohol-induced histone acetylation reveals a gene network involved in alcohol tolerance.

    Directory of Open Access Journals (Sweden)

    Alfredo Ghezzi

    Full Text Available Sustained or repeated exposure to sedating drugs, such as alcohol, triggers homeostatic adaptations in the brain that lead to the development of drug tolerance and dependence. These adaptations involve long-term changes in the transcription of drug-responsive genes as well as an epigenetic restructuring of chromosomal regions that is thought to signal and maintain the altered transcriptional state. Alcohol-induced epigenetic changes have been shown to be important in the long-term adaptation that leads to alcohol tolerance and dependence endophenotypes. A major constraint impeding progress is that alcohol produces a surfeit of changes in gene expression, most of which may not make any meaningful contribution to the ethanol response under study. Here we used a novel genomic epigenetic approach to find genes relevant for functional alcohol tolerance by exploiting the commonalities of two chemically distinct alcohols. In Drosophila melanogaster, ethanol and benzyl alcohol induce mutual cross-tolerance, indicating that they share a common mechanism for producing tolerance. We surveyed the genome-wide changes in histone acetylation that occur in response to these drugs. Each drug induces modifications in a large number of genes. The genes that respond similarly to either treatment, however, represent a subgroup enriched for genes important for the common tolerance response. Genes were functionally tested for behavioral tolerance to the sedative effects of ethanol and benzyl alcohol using mutant and inducible RNAi stocks. We identified a network of genes that are essential for the development of tolerance to sedation by alcohol.

  6. GABA(A receptor α subunits differentially contribute to diazepam tolerance after chronic treatment.

    Directory of Open Access Journals (Sweden)

    Christiaan H Vinkers

    Full Text Available Within the GABA(A-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABA(A-receptor subtypes.We investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABA(A-receptor positive allosteric modulators: diazepam (non-selective, bretazenil (partial non-selective, zolpidem (α(1 selective and TPA023 (α(2/3 selective. In-vivo binding studies with [(3H]flumazenil confirmed compounds occupied CNS GABA(A receptors.Chronic diazepam treatment resulted in tolerance to diazepam's acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam's anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam's hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam's hypothermic, anxiolytic or sedative effects.OUR DATA INDICATE THAT: (i GABA(A-α(2/α(3 subtype selective drugs might not induce tolerance; (ii in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent with clinical experience with benzodiazepines (e.g., differential tolerance to antiepileptic and anxiolytic actions; (iii tolerance to diazepam's sedative actions needs concomitant activation of GABA(A-α(1/GABA(A-α(5 receptors. Regarding mechanism, in-situ hybridization studies indicated no gross changes in expression levels of GABA(A α(1, α(2 or α(5 subunit mRNA in hippocampus or cortex. Since selective chronic activation of either GABA(A α(2, or α(3 receptors does not engender tolerance development, subtype-selective GABA(A drugs might constitute a promising class of novel drugs.

  7. GABAA Receptor α Subunits Differentially Contribute to Diazepam Tolerance after Chronic Treatment

    Science.gov (United States)

    Vinkers, Christiaan H.; van Oorschot, Ruud; Nielsen, Elsebet Ø.; Cook, James M.; Hansen, Henrik H.; Groenink, Lucianne; Olivier, Berend; Mirza, Naheed R.

    2012-01-01

    Background Within the GABAA-receptor field, two important questions are what molecular mechanisms underlie benzodiazepine tolerance, and whether tolerance can be ascribed to certain GABAA-receptor subtypes. Methods We investigated tolerance to acute anxiolytic, hypothermic and sedative effects of diazepam in mice exposed for 28-days to non-selective/selective GABAA-receptor positive allosteric modulators: diazepam (non-selective), bretazenil (partial non-selective), zolpidem (α1 selective) and TPA023 (α2/3 selective). In-vivo binding studies with [3H]flumazenil confirmed compounds occupied CNS GABAA receptors. Results Chronic diazepam treatment resulted in tolerance to diazepam's acute anxiolytic, hypothermic and sedative effects. In mice treated chronically with bretazenil, tolerance to diazepam's anxiolytic and hypothermic, but not sedative, effects was seen. Chronic zolpidem treatment resulted in tolerance to diazepam's hypothermic effect, but partial anxiolytic tolerance and no sedative tolerance. Chronic TPA023 treatment did not result in tolerance to diazepam's hypothermic, anxiolytic or sedative effects. Conclusions Our data indicate that: (i) GABAA-α2/α3 subtype selective drugs might not induce tolerance; (ii) in rodents quantitative and temporal variations in tolerance development occur dependent on the endpoint assessed, consistent with clinical experience with benzodiazepines (e.g., differential tolerance to antiepileptic and anxiolytic actions); (iii) tolerance to diazepam's sedative actions needs concomitant activation of GABAA-α1/GABAA-α5 receptors. Regarding mechanism, in-situ hybridization studies indicated no gross changes in expression levels of GABAA α1, α2 or α5 subunit mRNA in hippocampus or cortex. Since selective chronic activation of either GABAA α2, or α3 receptors does not engender tolerance development, subtype-selective GABAA drugs might constitute a promising class of novel drugs. PMID:22912786

  8. Drug Facts

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    Full Text Available ... signs and symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely ... Hard to Quit Drugs? Effects of Drugs Drug Use and Other People Drug Use and Families Drug ...

  9. Drug Facts

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

  10. Tolerability and safety aspects of mirtazapine.

    Science.gov (United States)

    Nutt, David J

    2002-06-01

    The tolerability and safety profile of the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine reflects its unique pharmacological profile. The 5-HT(2) blocking effect contributes towards its anxiolytic effects and benefits on sleep, as well as preventing the sexual dysfunction that may occur with non-specific stimulation of the serotonin system by drugs such as the selective serotonin reuptake inhibitors (SSRIs). In addition, 5-HT(3) blockade by mirtazapine helps to prevent nausea and vomiting. Weight gain is the most commonly reported side-effect of mirtazapine, although there is evidence to suggest that this is not a significant problem during long-term treatment. In conclusion, mirtazapine has a good tolerability and safety profile that demonstrates several benefits over other antidepressants. Copyright 2002 John Wiley & Sons, Ltd.

  11. Anaphylaxis to drugs.

    Science.gov (United States)

    Kuruvilla, Merin; Khan, David A

    2015-05-01

    Drug-induced anaphylaxis is a common cause of anaphylaxis and a leading cause of fatal anaphylaxis. Antibiotics, radiocontrast, and nonsteroidal anti-inflammatory drugs are commonly implicated drugs. Vocal cord dysfunction can mimic anaphylaxis and is often overlooked. β-Lactams are a common cause of anaphylaxis; however, skin testing and drug challenge can usually determine tolerability of other classes of β-lactams. Nonionic contrast agents cause anaphylaxis less frequently than ionic contrast, and immunoglobulin E-mediated mechanisms may have a role in some of these reactions. Skin testing with radiocontrast may have a role in evaluating patients with anaphylaxis to nonionic contrast. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Abuse Tolerance Improvements

    Energy Technology Data Exchange (ETDEWEB)

    Orendorff, Christopher J. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Nagasubramanian, Ganesan [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Fenton, Kyle R. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Allcorn, Eric [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-10-01

    As lithium-ion battery technologies mature, the size and energy of these systems continues to increase (> 50 kWh for EVs); making safety and reliability of these high energy systems increasingly important. While most material advances for lithium-ion chemistries are directed toward improving cell performance (capacity, energy, cycle life, etc.), there are a variety of materials advancements that can be made to improve lithium-ion battery safety. Issues including energetic thermal runaway, electrolyte decomposition and flammability, anode SEI stability, and cell-level abuse tolerance continue to be critical safety concerns. This report highlights work with our collaborators to develop advanced materials to improve lithium-ion battery safety and abuse tolerance and to perform cell-level characterization of new materials.

  13. Fault Tolerant Control Systems

    DEFF Research Database (Denmark)

    Bøgh, S.A.

    failures. It is often feasible to increase availability for these control loops by designing the control system to perform on-line detection and reconfiguration in case of faults before the safety system makes a close-down of the process. A general development methodology is given in the thesis......This thesis considered the development of fault tolerant control systems. The focus was on the category of automated processes that do not necessarily comprise a high number of identical sensors and actuators to maintain safe operation, but still have a potential for improving immunity to component...... that carried the control system designer through the steps necessary to consider fault handling in an early design phase. It was shown how an existing control loop with interface to the plant wide control system could be extended with three additional modules to obtain fault tolerance: Fault detection...

  14. Helminths and immunological tolerance

    OpenAIRE

    Johnston, Chris J C; McSorley, Henry J; Anderton, Stephen M; Wigmore, Stephen J; Maizels, Rick M

    2014-01-01

    Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunolo...

  15. Toleration, Liberty and Privileges

    DEFF Research Database (Denmark)

    Simonton, Deborah

    2017-01-01

    Guilds are usually seen as the epitome of economic regulation and organization in early modern European towns. As organisations closely tied to the nominal male lifecycle, historians of women have tended to be chary of them and identified guilds as a key mechanism for restricting women’s access t...... to trade could depend on gaining tolerations, earning the liberty of the trade and using the liberties associated with it....

  16. Drought Tolerance in Wheat

    Science.gov (United States)

    Prodhan, Zakaria Hossain; Faruq, Golam

    2013-01-01

    Drought is one of the most important phenomena which limit crops' production and yield. Crops demonstrate various morphological, physiological, biochemical, and molecular responses to tackle drought stress. Plants' vegetative and reproductive stages are intensively influenced by drought stress. Drought tolerance is a complicated trait which is controlled by polygenes and their expressions are influenced by various environmental elements. This means that breeding for this trait is so difficult and new molecular methods such as molecular markers, quantitative trait loci (QTL) mapping strategies, and expression patterns of genes should be applied to produce drought tolerant genotypes. In wheat, there are several genes which are responsible for drought stress tolerance and produce different types of enzymes and proteins for instance, late embryogenesis abundant (lea), responsive to abscisic acid (Rab), rubisco, helicase, proline, glutathione-S-transferase (GST), and carbohydrates during drought stress. This review paper has concentrated on the study of water limitation and its effects on morphological, physiological, biochemical, and molecular responses of wheat with the possible losses caused by drought stress. PMID:24319376

  17. Salinity tolerance in halophytes.

    Science.gov (United States)

    Flowers, Timothy J; Colmer, Timothy D

    2008-01-01

    Halophytes, plants that survive to reproduce in environments where the salt concentration is around 200 mm NaCl or more, constitute about 1% of the world's flora. Some halophytes show optimal growth in saline conditions; others grow optimally in the absence of salt. However, the tolerance of all halophytes to salinity relies on controlled uptake and compartmentalization of Na+, K+ and Cl- and the synthesis of organic 'compatible' solutes, even where salt glands are operative. Although there is evidence that different species may utilize different transporters in their accumulation of Na+, in general little is known of the proteins and regulatory networks involved. Consequently, it is not yet possible to assign molecular mechanisms to apparent differences in rates of Na+ and Cl- uptake, in root-to-shoot transport (xylem loading and retrieval), or in net selectivity for K+ over Na+. At the cellular level, H+-ATPases in the plasma membrane and tonoplast, as well as the tonoplast H+-PPiase, provide the trans-membrane proton motive force used by various secondary transporters. The widespread occurrence, taxonomically, of halophytes and the general paucity of information on the molecular regulation of tolerance mechanisms persuade us that research should be concentrated on a number of 'model' species that are representative of the various mechanisms that might be involved in tolerance.

  18. A microfluidic platform for drug screening in a 3D cancer microenvironment.

    Science.gov (United States)

    Pandya, Hardik J; Dhingra, Karan; Prabhakar, Devbalaji; Chandrasekar, Vineethkrishna; Natarajan, Siva Kumar; Vasan, Anish S; Kulkarni, Ashish; Shafiee, Hadi

    2017-08-15

    Development of resistance to chemotherapy treatments is a major challenge in the battle against cancer. Although a vast repertoire of chemotherapeutics is currently available for treating cancer, a technique for rapidly identifying the right drug based on the chemo-resistivity of the cancer cells is not available and it currently takes weeks to months to evaluate the response of cancer patients to a drug. A sensitive, low-cost diagnostic assay capable of rapidly evaluating the effect of a series of drugs on cancer cells can significantly change the paradigm in cancer treatment management. Integration of microfluidics and electrical sensing modality in a 3D tumour microenvironment may provide a powerful platform to tackle this issue. Here, we report a 3D microfluidic platform that could be potentially used for a real-time deterministic analysis of the success rate of a chemotherapeutic drug in less than 12h. The platform (66mm×50mm; L×W) is integrated with the microsensors (interdigitated gold electrodes with width and spacing 10µm) that can measure the change in the electrical response of cancer cells seeded in a 3D extra cellular matrix when a chemotherapeutic drug is flown next to the matrix. B16-F10 mouse melanoma, 4T1 mouse breast cancer, and DU 145 human prostate cancer cells were used as clinical models. The change in impedance magnitude on flowing chemotherapeutics drugs measured at 12h for drug-susceptible and drug tolerant breast cancer cells compared to control were 50,552±144 Ω and 28,786±233 Ω, respectively, while that of drug-susceptible melanoma cells were 40,197±222 Ω and 4069±79 Ω, respectively. In case of prostate cancer the impedance change between susceptible and resistant cells were 8971±1515 Ω and 3281±429 Ω, respectively, which demonstrated that the microfluidic platform was capable of delineating drug susceptible cells, drug tolerant, and drug resistant cells in less than 12h. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Acid tolerance mechanisms utilized by Streptococcus mutans

    Science.gov (United States)

    Matsui, Robert; Cvitkovitch, Dennis

    2010-01-01

    Since its discovery in 1924 by J Clarke, Streptococcus mutans has been the focus of rigorous research efforts due to its involvement in caries initiation and progression. Its ability to ferment a range of dietary carbohydrates can rapidly drop the external environmental pH, thereby making dental plaque inhabitable to many competing species and can ultimately lead to tooth decay. Acid production by this oral pathogen would prove suicidal if not for its remarkable ability to withstand the acid onslaught by utilizing a wide variety of highly evolved acid-tolerance mechanisms. The elucidation of these mechanisms will be discussed, serving as the focus of this review. PMID:20210551

  20. A Multirelational Account of Toleration

    DEFF Research Database (Denmark)

    Ferretti, Maria Paola; Lægaard, Sune

    2013-01-01

    be understood purely attitudinally or purely politically, we argue that the components of classical toleration are crucial elements of contemporary cases of minority accommodation. The concept of toleration is applicable to, and is an important element of descriptions of such cases, provided that one views them...... and Denmark. Finally, we propose that intersectionality is not only relevant to the descriptive concept of toleration but also captures an important aspect of normative theories of toleration. We illustrate this by discussing ideals of respect-based toleration, which we also apply to the case studies....

  1. Desensitization for drug allergy.

    Science.gov (United States)

    Castells, Mariana

    2006-12-01

    Desensitization for drug allergy is the induction of temporary clinical unresponsiveness to drug antigens. Gradual reintroduction of small doses of drug antigen at fixed time intervals allows for the delivery of full therapeutic doses, protecting patients from anaphylaxis. Rapid desensitizations permit the use of essential antibiotics in severely infected allergic patients or aspirin in aspirin-sensitive cardiac patients undergoing revascularization. We review the indications and outcomes of recent protocols for desensitization to antibiotics and aspirin. Despite the success of rapid desensitizations, the cellular and molecular inhibitory mechanisms are incompletely understood. In-vitro mast cell and basophil models implicate molecular signaling molecules syk and STAT6. Rapid desensitization protocols treat type I mast cell/IgE dependent reactions, such as anaphylaxis, as seen with sensitization to penicillin, cephalosporins, and other antibiotics. Anaphylactoid reactions induced upon initial drug exposure and with similar clinical presentation as immunoglobulin E-mediated reactions, as seen with aspirin, vancomycin and taxenes, can also be treated with rapid desensitizations. Successful rapid desensitization protocols for treating adverse reactions to antibiotics and aspirin allow for treatment of critically infected patients and aspirin-sensitive cardiac patients. Standardized protocols with high success rates should be implemented as the standard of care.

  2. A COMPARATIVE STUDY OF EFFICACY AND TOLERABILITY OF ANTIANGINAL DRUGS OF DIFFERENT GROUPS — NITROVASODILATATOR (ISOSORBIDE-5-MONONITRATE SUSTAINED RELEASE AND BETA-BLOCKER WITH VASODILATING ACTION (NEBIVOLOL — IN PATIENTS WITH STABLE ANGINA

    Directory of Open Access Journals (Sweden)

    S. Yu. Martsevich

    2011-01-01

    Full Text Available Aim. To compare the efficacy and safety of the slow-release isosorbide-5-mononitrate and of the nebivolol in patients with stable angina. Material and Methods. Patients (n=19 with ischemic heart disease (stable angina were enrolled into randomized, double-blind, placebo-controlled, crossover study. They alternatively received nebivolol 5 mg QD or slow-release isosorbide-5-mononitrate 50 mg QD. The drug efficacy was assessed by changes in symptoms, angina attack number , sublingual nitroglycerin need, and treadmill test duration. Results. Patients treated with isosorbide-5-mononitrate shown significant increase in heart rate (HR at rest in all time check-points in comparison with patients receiving placebo. HR significantly decreased 2 hours after nebivolol intake both single one and after 30 days of treatment (p<0.001. Duration of treadmill exercise significantly increased (vs placebo 2 hours after a single intake of both isosorbide-5-mononitrate (454.3±37.1 vs 310.6±13.3 s; p <0.001 and nebivolol (428.6±33.3 vs 310.6±13.3 s; p<0.01. In one month of treatment isosorbide- 5-mononitrate and nebivolol reduced a number of angina episodes vs placebo (5.6±2.1 and 4.3±1.4, respectively , vs 8.6±2.4 episodes per month; p<0.05, the need for nitroglycerin (5.5±2.6 and 3.1±1.2, respectively , vs 6.7±2.2 sublingual tablets/month; p>0.05. No significant differences of these indicators were found between studied drugs. Conclusion. Nebivolol 5 mg daily is not inferior to slow-release isosorbide-5-mononitrate 50 mg daily in antianginal efficacy , significantly reduces HR, and much less causes headache and other side effects.

  3. Cross-tolerance to cannabinoids in morphine-tolerant rhesus monkeys.

    Science.gov (United States)

    Gerak, L R; Zanettini, C; Koek, W; France, C P

    2015-10-01

    Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects limit their use. Therapeutic utility might be improved by combining opioids with other drugs to enhance analgesic effects, but only if adverse effects are not similarly changed. Cannabinoids have been shown to enhance the antinociceptive potency of opioids without increasing other effects; this study examined whether the effectiveness of cannabinoids is altered in morphine-dependent monkeys. Four monkeys received up to 10 mg/kg morphine twice daily. Changes in the antinociceptive effects of opioid receptor agonists (morphine, U50,488) and cannabinoid receptor agonists (WIN 55,212, CP 55,940, and Δ(9)-tetrahydrocannabinol [THC]) were determined by measuring the latency for monkeys to remove their tails from 40, 50, 54, and 58 °C water. Before treatment, all drugs increased tail withdrawal latency from warm (54 °C) water. Chronic morphine treatment decreased the potency of each drug; the magnitude of rightward shift in dose-effect curves was greatest for morphine, WIN 55,212 and CP 55,940 with at least sixfold shifts for each drug during treatment. Discontinuation of morphine treatment resulted in signs that are indicative of withdrawal, including increased heart rate, decreased daytime activity, and tongue movement. Tolerance developed to the antinociceptive effects of morphine and cross-tolerance developed to cannabinoids under conditions that produced modest physical dependence. Compared with the doses examined in this study, much smaller doses of opioids have antinociceptive effects when given with cannabinoids; it is possible that tolerance will not develop to chronic treatment with opioid/cannabinoid mixtures.

  4. Drug Repurposing: Far Beyond New Targets for Old Drugs

    DEFF Research Database (Denmark)

    Oprea, Tudor; Mestres, J.

    2012-01-01

    repurposing, but may limit the commercial applications by patent applications. Certain clinical applications may be more feasible for repurposing than others because of marked differences in side effect tolerance. Other factors that ought to be considered when assessing drug repurposing opportunities include...... relevance to the disease in question and the intellectual property landscape. These activities go far beyond the identification of new targets for old drugs....

  5. Urban physiology: city ants possess high heat tolerance.

    Directory of Open Access Journals (Sweden)

    Michael J Angilletta

    Full Text Available Urbanization has caused regional increases in temperature that exceed those measured on a global scale, leading to urban heat islands as much as 12 degrees C hotter than their surroundings. Optimality models predict ectotherms in urban areas should tolerate heat better and cold worse than ectotherms in rural areas. We tested these predications by measuring heat and cold tolerances of leaf-cutter ants from South America's largest city (São Paulo, Brazil. Specifically, we compared thermal tolerances of ants from inside and outside of the city. Knock-down resistance and chill-coma recovery were used as indicators of heat and cold tolerances, respectively. Ants from within the city took 20% longer to lose mobility at 42 degrees C than ants from outside the city. Interestingly, greater heat tolerance came at no obvious expense of cold tolerance; hence, our observations only partially support current theory. Our results indicate that thermal tolerances of some organisms can respond to rapid changes in climate. Predictive models should account for acclimatory and evolutionary responses during climate change.

  6. Drug Facts

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    Full Text Available ... Drug Use and Kids Drug Use and Unborn Children Drug Use and Your Health Other Effects on ... Someone Find Treatment and Recovery Resources? Prevention Help Children and Teens Stay Drug-Free Talking to Kids ...

  7. Drug Facts

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    Full Text Available ... and symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What ... Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use ...

  8. Drug Facts

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    Full Text Available ... Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & ...

  9. Drug Facts

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    Full Text Available ... Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug ...

  10. Drug Safety

    Science.gov (United States)

    ... over-the-counter drug. The FDA evaluates the safety of a drug by looking at Side effects ... clinical trials The FDA also monitors a drug's safety after approval. For you, drug safety means buying ...

  11. Drug Abuse

    Science.gov (United States)

    ... or injuries among Americans. Abused drugs include Methamphetamine Anabolic steroids Club drugs Cocaine Heroin Inhalants Marijuana Prescription drugs, including opioids Drug abuse also plays a role in many major social ...

  12. Drug Facts

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    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  13. Drug Facts

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    Full Text Available ... Where Can Someone Find Treatment and Recovery Resources? Prevent Drug Use Help Children and Teens Stay Drug- ... You Used Drugs in the Past Drug Use Prevention Phone Numbers and Websites Search Share Listen English ...

  14. Tolerability and efficacy of a three-age class dosage schedule of Diethylcarbamazine citrate (DEC) in the treatment of microfilaria carriers of Wuchereria bancrofti and its implications in mass drug administration (MDA) strategy for elimination of lymphatic filariasis (LF).

    Science.gov (United States)

    Pani, S P; Das, L K; Vanamail, P

    2005-03-01

    A six-age class dosage schedule of Diethylcarbamazine (DEC) of 50mg (1-2 years), 100mg (3-4 years), 150mg (5-8 years), 200mg (9-11 years), 250mg (12-14 years) and 300mg for above 14 years is being adopted for annual single dose MDA for LF elimination treat Wuchereria bancrofti microfilaria carriers. In order to increase the community compliance as well as to make the distribution easier during MDA, a revised 3 age class dosage schedule of 100mg (2-4 years), 200mg (5-14 years) and 300mg for above 14 years was evaluated for its tolerability and efficacy. By this change, it was observed that the 4-8 years age class is receiving 50 mg higher and 11-14 years age class is receiving 50mg lesser dose compared to the earlier class schedule. Therefore, the safety aspect in the age class of 4-8 years and efficacy component in the age class of 11-14 years were assessed. Apparently "healthy" asymptomatic microfilaraemic volunteers between the age class of 4-8 and 11-14 years were recruited for the study. The incidence of side reaction in the 4-8 years age class was 50.0% with 150mg dose and 66.7% with 200mg (P>0.05). No life threatening adverse reactions was observed in any dosage schedule. Fever, headache and myalgia, the predominant adverse reactions were mild and similar in both schedules. The mean intensity of the three major specific adverse reactions (fever, headache and myalgia) also did not differ significantly (P>0.05). For the purpose of LF elimination, efficacy in terms of reduction in mean microfilaria load is important. In the 11-14 year age class considerable reduction in the geometric mean density (GMD) was observed by day 90 and 180 post-therapy in both groups (250mg group and 200mg group) compared to pre-therapy level. By day 360 post-therapy, the difference was statistically not significant (P>0.05) (reduction of 72.2% in 250mg and 69.6% reduction in 200mg). The reductions in GMD were statistically significant when compared to pre-therapy levels in both the

  15. Tolerance of yeast biofilm cells towards systemic antifungals

    DEFF Research Database (Denmark)

    Bojsen, Rasmus Kenneth

    in an attempt to take advantage of the molecular tools available for S. cerevisiae. Mature biofilms containing mainly growth arrested cells were shown to be tolerant to three out of four tested antifungals, while all drugs had inhibitory activity against proliferating biofilm cells, demonstrating that drug......Fungal infections have become a major problem in the hospital sector in the past decades due to the increased number of immune compromised patients susceptible to mycosis. Most human infections are believed to be associated with biofilm forming cells that are up to 1000-fold more tolerant...... of this thesis has been to explore the tolerance mechanisms of yeast biofilms to systemic antifungal agents and to identify the molecular target of a novel peptidomimetic with anti-biofilm activity. The genetic tractable S. cerevisiae was used as biofilm model system for the pathogenic Candida species...

  16. AFLP marker linked to water-stress-tolerant bulks in barley (Hordeum vulgare L.

    Directory of Open Access Journals (Sweden)

    A. Altinkut

    2003-01-01

    Full Text Available The amplified fragment length polymorphism (AFLP assay is an efficient method for the identification of molecular markers, useful in the improvement of numerous crop species. Bulked Segregant Analysis (BSA was used to identify AFLP markers associated with water-stress tolerance in barley, as this would permit rapid selection of water-stress tolerant genotypes in breeding programs. AFLP markers linked to water-stress tolerance was identified in two DNA pools (tolerant and sensitive, which were established using selected F2 individuals resulting from a cross between water-stress-tolerant and sensitive barley parental genotypes, based on their paraquat (PQ tolerance, leaf size, and relative water content (RWC. All these three traits were previously shown to be associated with water-stress tolerance in segregating F2 progeny of the barley cross used in a previous study. AFLP analysis was then performed on these DNA pools, using 40 primer pairs to detect AFLP fragments that are present/absent, respectively, in the two pools and their parental lines. One separate AFLP fragment, which was present in the tolerant parent and in the tolerant bulk, but absent in the sensitive parent and in the sensitive bulk, was identified. Polymorphism of the AFLP marker was tested among tolerant and sensitive F2 individuals. The presence of this marker that is associated with water-stress tolerance will greatly enhance selection for paraquat and water-stress tolerant genotypes in future breeding programs.

  17. Cytochromes P450 and drug resistance

    NARCIS (Netherlands)

    Doehmer, J.; Goeptar, A R; Vermeulen, N P

    1993-01-01

    Cytochromes P450 are the key enzymes for activating and inactivating many drugs, in particular anticancer drugs. Therefore, individual expression levels of cytochromes P450 may play a crucial role in drug safety and drug efficacy. Overexpression of cytochrome P450 may yield rapid turnover and

  18. 76 FR 31479 - Pyraflufen-ethyl; Pesticide Tolerances

    Science.gov (United States)

    2011-06-01

    ... conservative estimate of residues in food. EPA made conservative (protective) assumptions in the ground and... America, Inc., requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA). DATES... producer, food manufacturer, or pesticide manufacturer. Potentially affected entities may include, but are...

  19. Intravenous Antiepileptic Drugs in Russia

    Directory of Open Access Journals (Sweden)

    P. N. Vlasov

    2014-01-01

    Full Text Available Launching four intravenous antiepileptic drugs: valproate (Depakene and Convulex, lacosamide (Vimpat, and levetiracetam (Keppra – into the Russian market has significantly broadened the possibilities of rendering care to patients in seizure emergency situations. The chemi- cal structure, mechanisms of action, indications/contraindications, clinical effectiveness and tolerability, advantages/disadvantages, and adverse events of using these drugs in urgent and elective neurology are discussed. 

  20. Tolerance to non-opioid analgesics is opioid-sensitive in nucleus raphe magnus

    Directory of Open Access Journals (Sweden)

    Merab G Tsagareli

    2011-07-01

    Full Text Available Repeated injection of opioid analgesics can lead to a progressive loss of its effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs in the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM in the following four days result in progressively less antinociception, i.e. produce the development of tolerance to these drugs in mail rats. Special control experiments showed that post-treatment with μ-opioid antagonist naloxone in NRM significantly decreased antinociceptive effects of NSAIDs at the first day in behavioral tail flick reflex (TF and hot plate (HP latencies. At the second day, naloxone generally had trend effects in both TF and HP tests impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion on endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

  1. Rapidly Developing Toxic Epidermal Necrolysis

    Directory of Open Access Journals (Sweden)

    Viktoria Oline Barrios Poulsen

    2013-01-01

    Full Text Available Severe cutaneous reactions with potentially fatal outcomes can have many different causes. The Stevens-Johnson syndrome (SJS and toxic epidermal necrolysis (TEN are rare. They are characterized by a low incidence but high mortality, and drugs are most commonly implicated. Urgent active therapy is required. Prompt recognition and withdrawal of suspect drug and rapid intervention can result in favourable outcome. No further international guidelines for treatment exist, and much of the treatment relies on old or experimental concepts with no scientific evidence. We report on a 54-year-old man experiencing rapidly developing drug-induced severe TEN and presented multiorgan failure involving the respiratory and circulatory system, coagulopathy, and renal insufficiency. Detachment counted 30% of total body surface area (TBSA. SCORTEN = 5, indicating a mortality rate >90%. The patient was sedated and mechanically ventilated, supported with fluids and inotropes to maintain a stable circulation. Component therapy was guided by thromboelastography (TEG. The patient received plasmapheresis, and shock reversal treatment was initiated. He was transferred to a specialized intensive care burn unit within 24 hours from admittance. The initial care was continued, and hemodialysis was started. Pulmonary, circulatory, and renal sequelae resolved with intensive care, and re-epithelialization progressed slowly. The patient was discharged home on hospital day 19.

  2. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial.

    Directory of Open Access Journals (Sweden)

    Dennis L Kelleher

    Full Text Available Umeclidinium bromide (GSK573719; UMEC, a new long-acting muscarinic receptor antagonist (LAMA, is in development with vilanterol (GW642444; VI, a selective long-acting β(2 agonist (LABA, as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD. A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD and pharmacokinetics (PK of inhaled umeclidinium (500 µg and vilanterol (50 µg when administered separately and in combination using a novel dry powder inhaler (NDPI. Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol followed by rapid elimination with median tlast of 4-5 h for umeclidinium and median tlast of 1.5-2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone.Clinicaltrials.gov NCT00976144.

  3. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial.

    Science.gov (United States)

    Kelleher, Dennis L; Mehta, Rashmi S; Jean-Francois, Bernadette M; Preece, Andrew F; Blowers, James; Crater, Glenn D; Thomas, Paul

    2012-01-01

    Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting β(2) agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4-5 h for umeclidinium and median tlast of 1.5-2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone. Clinicaltrials.gov NCT00976144.

  4. BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer

    DEFF Research Database (Denmark)

    López-García, Carlos; Sansregret, Laurent; Domingo, Enric

    2016-01-01

    Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, ...

  5. Toleration, Synthesis or Replacement?

    DEFF Research Database (Denmark)

    Holtermann, Jakob v. H.; Madsen, Mikael Rask

    2016-01-01

    , in order to answer is not yet another partisan suggestion, but rather an attempt at making intelligible both the oppositions and the possibilities of synthesis between normative and empirical approaches to law. Based on our assessment and rational reconstruction of current arguments and positions, we...... therefore outline a taxonomy consisting of the following three basic, ideal-types in terms of the epistemological understanding of the interface of law and empirical studies: toleration, synthesis and replacement. This tripartite model proves useful with a view to teasing out and better articulating...

  6. Fault Tolerant Distributive Processing

    Science.gov (United States)

    Quesnell, Harris

    1982-12-01

    A fault tolerant design used to enhanced the survivability of a distributive processing system is described. Based on physical limitations, mission duration and maintenance support, the approach has emphasized functional redundancy in place of the traditional hardware or software level redundancy. A top down architecture within the system's hierarchy allows sharing of common resources. Various techniques used to enhance the survivability of the hardware at the equipment, module and component level were analyzed. The intent of the on going work is to demonstrate the ability of a distributive processing system to maintain itself for a long period of time.

  7. Fault Tolerant Computer Architecture

    CERN Document Server

    Sorin, Daniel

    2009-01-01

    For many years, most computer architects have pursued one primary goal: performance. Architects have translated the ever-increasing abundance of ever-faster transistors provided by Moore's law into remarkable increases in performance. Recently, however, the bounty provided by Moore's law has been accompanied by several challenges that have arisen as devices have become smaller, including a decrease in dependability due to physical faults. In this book, we focus on the dependability challenge and the fault tolerance solutions that architects are developing to overcome it. The two main purposes

  8. Clinically Relevant Drug Interactions with Anti-Alzheimer's Drugs.

    Science.gov (United States)

    Caraci, Filippo; Sultana, Janet; Drago, Filippo; Spina, Edoardo

    2017-01-01

    The aging world population had led to an increase in the prevalence of Alzheimer's disease (AD). The drugs used to slow down the onset of AD, galantamine, donepezil, rivastigmine and memantine, are generally well-tolerated. However, drug interactions between these drugs and other drugs are an important aspect of patient safety that should be borne in mind, particularly given the high burden of polypharmacy in the elderly. The aim of this review is to provide an updated review of clinically significant drug-drug interactions concerning drugs approved for AD. PubMed was searched for relevant keywords. No time limit was imposed but only articles in English published in peer-reviewed journals were selected. Relevant literature was also identified from the references of identified articles. Further information was obtained from drug summary of product characteristics. The major pharmacokinetic interactions identified concerned fluoxetine, paroxetine and ketoconazole when used with galantamine or donepezil. On the other hand, the major potential pharmacodynamic interactions concerned anti-dementia drugs and general anesthesia agents, anti-cholinergic drugs, conventional antipsychotics and bradycardia-inducing drugs. In clinical practice memantine shows a lower potential for pharmacodynamic drug-drug interactions (DDIs) compared to other drug classes. The concomitant use of anti-dementia drugs with other drugs can have variable clinical effects, making appropriate prescribing of these drugs very challenging. A simple and coherent way of presenting evidence on complex drug interaction information from heterogenous sources to clinicians is needed in order for the voluminous data available to have an impact on clinical practice. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  9. Strategies for determining soil-loss tolerance

    Science.gov (United States)

    Alexander, Earl B.

    1988-11-01

    Excessive soil losses due to erosion or lateral displacement by machinery impair productivity. Some soil loss is tolerable, but not so much that plant productivity diminishes. Thus productivity is the dominant concern in determining soil-loss tolerance. The effects of soil loss on productivity, however, are difficult to determine. Therefore, two alternatives are discussed for determining the limits of soil loss, or soil-loss tolerance. These alternatives are the maintenance of soil organic matter and, for shallow and moderately deep soils, the maintenance of soil depth. They are not new strategies, but our rapidly increasing knowledge of the dynamics of soil organic matter and the rates of soil formation from bedrock or consolidated sediments warrants the reconsideration of these alternatives. Reductions in either soil organic matter or the depth of shallow or moderately deep soils will lead to declining productivity. Soil organic matter, considered to be a surrogate for productivity, is much easier to monitor than is productivity. Also, there are many computer models for predicting the effects of management on soil organic matter. Recently compiled data on rates of soil formation suggest that soil losses of 1 t/a (2.24 Mg/ha yr) are greater than the rate of replenishment by the weathering of lithic or paralithic material in all but very wet climates.

  10. Breeding of Freeze-tolerant Yeast and the Mechanisms of Stress-tolerance

    Science.gov (United States)

    Hino, Akihiro

    Frozen dough method have been adopted in the baking industry to reduce labor and to produce fresh breads in stores. New freeze-tolerant yeasts for frozen dough preparations were isolated from banana peel and identified. To obtain strains that have fermentative ability even after several months of frozen storage in fermented dough, we attempted to breed new freeze-tolerantstrain. The hybrid between S.cerevisiae, which is a isolated freeze-tolerant strain, and a strain isolated from bakers' yeast with sexual conjugation gave a good quality bread made from frozen dough method. Freeze-tolerant strains showed higher surviving and trehalose accumulating abilities than freeze-sensitive strains. The freeze tolerance of the yeasts was associated with the basal amount of intracellular trehalose after rapid degradation at the onset of the prefermentation period. The complicated metabolic pathway and the regulation system of trehalose in yeast cells are introduced. The trehalose synthesis may act as a metabolic buffer system which contribute to maintain the intracellular inorganic phosphate and as a feedback regulation system in the glycolysis. However, it is not known enough how the trehalose protects yeast cells from stress.

  11. Drugs, drugs--who has the drugs?

    Science.gov (United States)

    Blair, James

    2012-01-01

    Drug diversion, although on the increase, is not the only problem involving drugs that hospital security officials should be concerned with. Growing drug shortages, offshore production, counterfeiting, and weaknesses in the drug supply chain in case of a world-wide pandemic, are even greater causes for concern, the author claims.

  12. Helminths and immunological tolerance.

    Science.gov (United States)

    Johnston, Chris J C; McSorley, Henry J; Anderton, Stephen M; Wigmore, Stephen J; Maizels, Rick M

    2014-01-27

    Current immunosuppression regimens for solid-organ transplantation have shown disappointing efficacy in the prevention of chronic allograft rejection and carry unacceptable risks including toxicity, neoplasia, and life-threatening infection. Achievement of immunological tolerance (long-term antigen unresponsiveness in an immunocompetent host) presents the exciting prospect of freedom from immunosuppression for transplant recipients. It is now 60 years since the first demonstration of immunological tolerance in animal models of transplantation, but translation into routine clinical practice remains elusive. Helminth parasites may provide novel strategies toward achieving this goal. Helminths are remarkably successful parasites: they currently infect more than one quarter of the world's population. It is now well established that the parasites' success is the result of active immunomodulation of their hosts' immune response. Although this primarily secures ongoing survival of the parasites, helminth-induced immunomodulation can also have a number of benefits for the host. Significant reductions in the prevalence of allergy and autoimmune conditions among helminth-infected populations are well recognized and there is now a significant body of evidence to suggest that harmful immune responses to alloantigens may be abrogated as well. Here, we review all existing studies of helminth infection and transplantation, explore the mechanisms involved, and discuss possible avenues for future translation to clinical practice.

  13. Ethnopoly promotes tolerance

    CERN Multimedia

    CERN Bulletin

    2010-01-01

    On Friday 23 April, 225 primary school children from the eight schools in Meyrin-Cointrin and their accompanying adults took part in a big game of Ethnopoly. Private individuals, associations, administrations, shopkeepers and CERN all opened their doors to them to talk about their countries, their customs and what they are doing to promote tolerance and integration.   The CERN stand set up at ForumMeyrin for the Ethnopoly game. Scurrying from one place to another, the 10 and 11 year olds were made aware of the rich cultural diversity of their commune, which is home to 130 different nationalities. Physicists and engineers from CERN took up residence in the Forum Meyrin for the day in order to talk to the children about the advantages of international collaboration, a subject dear to the Organization's heart. They welcomed around fifty children in the course of the day, conveying to them a message of tolerance: despite their differences, the 10,000 scientists and other members of the CERN...

  14. Stress tolerance of Methylobacterium biofilms in bathrooms.

    Science.gov (United States)

    Yano, Takehisa; Kubota, Hiromi; Hanai, Junya; Hitomi, Jun; Tokuda, Hajime

    2013-01-01

    A comprehensive survey of microbial flora within pink biofilms in bathrooms was performed. Pink biofilms develop relatively rapidly in bathrooms, can be difficult to remove, and are quick to recur. Bacterium-sized cells were found to be predominant in 42 pink biofilms in Japan using a scanning electron microscope. Methylobacterium strains were detected from all samples in bathrooms by an isolation method. To explain this predominance, 14 biofilm samples were analyzed by fluorescence in situ hybridization. Methylobacterium was indicated to be the major genus in all biofilms. The isolated Methylobacterium survived after contact with 1.0% cleaning agents, including benzalkonium chloride for 24 h. Their tolerance did not differ under biofilm-like conditions on fiber reinforced plastics (FRP), a general material of bath tubs, floors, and walls. Also, the strains exhibited higher tolerance to desiccation than other isolated species on FRP. Some Methylobacterium survived and exhibited potential to grow after four weeks of desiccation without any nutrients. These specific characteristics could be a cause of their predominance in bathrooms, an environment with rapid flowing water, drying, low nutrients, and occasional exposure to cleaning agents.

  15. Rapid infusion of esketamine for unipolar and bipolar depression: a retrospective chart review

    Directory of Open Access Journals (Sweden)

    Correia-Melo FS

    2017-06-01

    the esketamine infusion was dissociative symptoms ranging from mild to severe, which was reported by 11.1% of patients as a very disturbing experience.Limitations: This study was done retrospectively, had a small sample size, and there was no comparative group.Conclusion: The present study demonstrates that rapid infusion of esketamine is possibly not the optimal choice to administer this drug for treatment-resistant depression due to tolerability reasons. Further controlled studies are required to investigate efficacy, safety, and tolerability profiles among the different types of ketamines and methods of using this drug in depressed patients. Keywords: tolerability, S-(+-ketamine, treatment-resistant depression, dissociative symptoms, efficacy, safety

  16. Distribution of veterinary drug residues among muscles

    Science.gov (United States)

    The U.S. Food and Drug Administration sets tolerances for veterinary drug residues in muscle, but does not specify which muscle should be sampled for analysis. The goal of this research was to determine if antibiotic residue levels are dependent on muscle type. In this study, penicillin G (Pen G) d...

  17. Commercialization of radiation tolerant camera

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Yong Bum; Choi, Young Soo; Kim, Sun Ku; Lee, Jong Min; Cha, Bung Hun; Lee, Nam Ho; Byun, Eiy Gyo; Yoo, Seun Wook; Choi, Bum Ki; Yoon, Sung Up; Kim, Hyun Gun; Sin, Jeong Hun; So, Suk Il

    1999-12-01

    In this project, radiation tolerant camera which tolerates 10{sup 6} - 10{sup 8} rad total dose is developed. In order to develop radiation tolerant camera, radiation effect of camera components was examined and evaluated, and camera configuration was studied. By the result of evaluation, the components were decided and design was performed. Vidicon tube was selected to use by image sensor and non-browning optics and camera driving circuit were applied. The controller needed for CCTV camera system, lens, light, pan/tilt controller, was designed by the concept of remote control. And two type of radiation tolerant camera were fabricated consider to use in underwater environment or normal environment. (author)

  18. Physical fault tolerance of nanoelectronics.

    Science.gov (United States)

    Szkopek, Thomas; Roychowdhury, Vwani P; Antoniadis, Dimitri A; Damoulakis, John N

    2011-04-29

    The error rate in complementary transistor circuits is suppressed exponentially in electron number, arising from an intrinsic physical implementation of fault-tolerant error correction. Contrariwise, explicit assembly of gates into the most efficient known fault-tolerant architecture is characterized by a subexponential suppression of error rate with electron number, and incurs significant overhead in wiring and complexity. We conclude that it is more efficient to prevent logical errors with physical fault tolerance than to correct logical errors with fault-tolerant architecture.

  19. The molecular pathways underlying host resistance and tolerance to pathogens

    Directory of Open Access Journals (Sweden)

    Elizabeth Janet Glass

    2012-12-01

    Full Text Available Breeding livestock that are better able to withstand the onslaught of endemic and exotic pathogens is high on the wish list of breeders and farmers world-wide. However the defence systems in both pathogens and their hosts are complex and the degree of genetic variation in resistance and tolerance will depend on the trade-offs that they impose on host fitness as well as their life-histories. The genes and pathways underpinning resistance and tolerance traits may be distinct or intertwined as the outcome of any infection is a result of a balance between collateral damage of host tissues and control of the invading pathogen. Genes and molecular pathways associated with resistance are mainly expressed in the mucosal tract and the innate immune system and control the very early events following pathogen invasion. Resistance genes encode receptors involved in uptake of pathogens, as well as pattern recognition receptors (PRR such as the toll-like receptor family as well as molecules involved in strong and rapid inflammatory responses which lead to rapid pathogen clearance yet do not lead to immunopathology. In contrast tolerance genes and pathways play a role in reducing immunopathology or enhancing the host’s ability to protect against pathogen associated toxins. Candidate tolerance genes may include cytosolic PRRs and unidentified sensors of pathogen growth, perturbation of host metabolism and intrinsic danger or damage associated molecules. In addition, genes controlling regulatory pathways, tissue repair and resolution are also tolerance candidates. The identities of distinct genetic loci for resistance and tolerance to infectious pathogens in livestock species remain to be determined. A better understanding of the mechanisms involved and phenotypes associated with resistance and tolerance should ultimately help to improve livestock health and welfare.

  20. The molecular pathways underlying host resistance and tolerance to pathogens.

    Science.gov (United States)

    Glass, Elizabeth J

    2012-01-01

    Breeding livestock that are better able to withstand the onslaught of endemic- and exotic pathogens is high on the wish list of breeders and farmers world-wide. However, the defense systems in both pathogens and their hosts are complex and the degree of genetic variation in resistance and tolerance will depend on the trade-offs that they impose on host fitness as well as their life-histories. The genes and pathways underpinning resistance and tolerance traits may be distinct or intertwined as the outcome of any infection is a result of a balance between collateral damage of host tissues and control of the invading pathogen. Genes and molecular pathways associated with resistance are mainly expressed in the mucosal tract and the innate immune system and control the very early events following pathogen invasion. Resistance genes encode receptors involved in uptake of pathogens, as well as pattern recognition receptors (PRR) such as the toll-like receptor family as well as molecules involved in strong and rapid inflammatory responses which lead to rapid pathogen clearance, yet do not lead to immunopathology. In contrast tolerance genes and pathways play a role in reducing immunopathology or enhancing the host's ability to protect against pathogen associated toxins. Candidate tolerance genes may include cytosolic PRRs and unidentified sensors of pathogen growth, perturbation of host metabolism and intrinsic danger or damage associated molecules. In addition, genes controlling regulatory pathways, tissue repair and resolution are also tolerance candidates. The identities of distinct genetic loci for resistance and tolerance to infectious pathogens in livestock species remain to be determined. A better understanding of the mechanisms involved and phenotypes associated with resistance and tolerance should ultimately help to improve livestock health and welfare.

  1. Polyjet technology applications for rapid tooling

    Directory of Open Access Journals (Sweden)

    Udroiu Razvan

    2017-01-01

    Full Text Available Polymer Jetting (PolyJet has proved to be one of the most accurate additive manufacturing technologies, in order to manufacture rapid tools. Rapid Tooling (RT is different from conventional tooling as follow: manufacturing time is shorter, the cost is much less, but the tool life is shorter and tolerances are wider. The purpose of this paper is to make a comparative study between the soft tools (silicon moulds and hard tools (acrylic thermoplastic moulds based on the Polymer Jetting technology. Thus, two types of moulds have been made in order to manufacture a test part. Reaction injection moulding (RIM and casting techniques were used to fill these moulds with resins that simulate the plastic injection materials. Rapid tooling applications, such as indirect tooling and direct tooling, based on PolyJet technology were experimentally investigated.

  2. Drug Facts

    Medline Plus

    Full Text Available ... some signs and symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What ... Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use ...

  3. Delay tolerant networks

    CERN Document Server

    Gao, Longxiang; Luan, Tom H

    2015-01-01

    This brief presents emerging and promising communication methods for network reliability via delay tolerant networks (DTNs). Different from traditional networks, DTNs possess unique features, such as long latency and unstable network topology. As a result, DTNs can be widely applied to critical applications, such as space communications, disaster rescue, and battlefield communications. The brief provides a complete investigation of DTNs and their current applications, from an overview to the latest development in the area. The core issue of data forward in DTNs is tackled, including the importance of social characteristics, which is an essential feature if the mobile devices are used for human communication. Security and privacy issues in DTNs are discussed, and future work is also discussed.

  4. Manufacturing tolerant topology optimization

    DEFF Research Database (Denmark)

    Sigmund, Ole

    2009-01-01

    In this paper we present an extension of the topology optimization method to include uncertainties during the fabrication of macro, micro and nano structures. More specifically, we consider devices that are manufactured using processes which may result in (uniformly) too thin (eroded) or too thick...... (dilated) structures compared to the intended topology. Examples are MEMS devices manufactured using etching processes, nano-devices manufactured using e-beam lithography or laser micro-machining and macro structures manufactured using milling processes. In the suggested robust topology optimization...... that the method provides manufacturing tolerant designs with little decrease in performance. As a positive side effect the robust design formulation also eliminates the longstanding problem of one-node connected hinges in compliant mechanism design using topology optimization....

  5. Sex Differences in Drug Abuse

    Science.gov (United States)

    Becker, Jill B.; Hu, Ming

    2008-01-01

    Sex differences are present for all of the phases of drug abuse (initiation, escalation of use, addiction, and relapse following abstinence). While there are some differences among specific classes of abused drugs, the general pattern of sex differences is the same for all drugs of abuse. Females begin regularly self-administering licit and illicit drugs of abuse at lower doses than do males, use escalates more rapidly to addiction, and females are at greater risk for relapse following abstinence. In this review, sex differences in drug abuse are discussed for humans and in animal models. The possible neuroendocrine mechanisms mediating these sex differences are discussed. PMID:17904621

  6. 75 FR 33317 - Antibacterial Resistance and Diagnostic Device and Drug Development Research for Bacterial...

    Science.gov (United States)

    2010-06-11

    ... HUMAN SERVICES Food and Drug Administration Antibacterial Resistance and Diagnostic Device and Drug... resistance, rapid diagnostic device development for bacterial diseases, and antibacterial drug development. The workshop will address antibacterial drug resistance, mechanisms of resistance, epidemiology of...

  7. Investigational drugs for hyperuricemia.

    Science.gov (United States)

    Shahid, Hania; Singh, Jasvinder A

    2015-01-01

    The unmet need and the growing prevalence of hyperuricemia and its complications worldwide have pushed investigators to identify new agents to manage hyperuricemia. This review discusses the drugs in preclinical and early clinical trials for hyperuricemia, their mechanisms of action and available results. This article reviews a total of 10 novel agents: i) drugs in Phase II/III trials - arhalofenate (MBX201), AC201, RDEA group of drugs (including lesinurad), tranilast, ulodesine (BCX4208); and ii) drugs in Phase I trials, including levotofisopam, UR1102, KX1151, LC350189 and Marine Active. The goal of emerging therapies is to address the unsatisfactory control of serum uric acid in patients with symptomatic hyperuricemia such as those with gout, to provide better tolerability compared to traditional agents and minimize the risk of adverse events, especially in patients with comorbidities and the elderly. Some drugs like arhalofenate, ulodesine (BCX-4208) and lesinurad are in or have completed Phase II and Phase III trials. The growing knowledge about the urate transporters in the kidney have advanced our knowledge of pathophysiology of hyperuricemia and have led to the development of several new potential treatment options. Availability of new drugs will lead to better management and address the unmet need in patients with symptomatic hyperuricemia in the coming years.

  8. Drug Facts

    Medline Plus

    Full Text Available ... to main content Easy-to-Read Drug Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts ... Past Drug Use Prevention Phone Numbers and Websites Search Share Government Shutdown Because of a lapse in ...

  9. Drug Facts

    Medline Plus

    Full Text Available ... time to find drug treatment centers near you. I want my daughter to avoid drugs. "Debbie" has ... addiction. Counseling is very helpful to her. All I wanted was more of the drug. "Max" was ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So ...

  11. Rapid shift in thermal resistance between generations through maternal heat exposure

    NARCIS (Netherlands)

    Zizzari, Z.V.; Ellers, J.

    2014-01-01

    Given the current rapid climate change, understanding the mechanisms underlying heat tolerance and its plasticity is an important goal of global change biology. Soil fauna communities are especially vulnerable because of their limited dispersal ability. It is generally recognized that

  12. The genomic landscape of rapid repeated evolutionary adaptation to toxic pollution in wild fish

    Science.gov (United States)

    Atlantic killifish populations have rapidly adapted to normally lethal levels of pollution in four urban estuaries. Through analysis of 384 whole killifish genome sequences and comparative transcriptomics in four pairs of sensitive and tolerant populations, we identify the aryl h...

  13. Legal Quality, Inequality, and Tolerance

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    2004-01-01

    Previous findings suggest that income inequality leads to lower legal quality. This paper argues that voters' tolerance of inequality exerts an additional influence. Empirical findings suggest that inequality leads to lower legal quality due to its effect on trust while the tolerance of inequality...

  14. Legal Quality, Inequality, and Tolerance

    DEFF Research Database (Denmark)

    Bjørnskov, Christian

    Previous findings suggest that income inequality leads to lower legal quality. This paper argues that voters' tolerance of inequality exerts an additional influence. Empirical findings suggest that inequality leads to lower legal quality due to its effect on trust while the tolerance of inequality...

  15. Tolerance Issue in Kazakh Culture

    Science.gov (United States)

    Aubakirova, Saltanat S.; Ismagambetova, Zukhra N.; Karabayeva, Aliya G.; Rysbekova, Shamshiya S.; Mirzabekova, Alma Sh.

    2016-01-01

    In this article the authors reveal the basic cultural mechanisms that influence the formation of the tolerance strategy in Kazakh and Kazakhstan society, show its basic directions, as well as its importance for the modern Kazakhstan society and the formation of intercultural communication with foreign countries. Tolerance is a necessary element of…

  16. Glucose tolerance test - non-pregnant

    Science.gov (United States)

    Oral glucose tolerance test - non-pregnant; OGTT - non-pregnant; Diabetes - glucose tolerance test; Diabetic - glucose tolerance test ... The most common glucose tolerance test is the oral glucose tolerance test (OGTT). Before the test begins, a sample of blood will be ...

  17. Tolerability, adverse events and compliance to glatiramer acetate in 28 patients with multiple sclerosis using the drug continuously for at least six months Tolerabilidade, eventos adversos e aderência ao acetato de glatiramer em 28 pacientes com esclerose múltipla usando a droga continuamente por pelo menos seis meses

    Directory of Open Access Journals (Sweden)

    Ana Patricia Perez Fiore

    2005-09-01

    Full Text Available AIM: To assess tolerability, adverse events and compliance to treatment with glatiramer acetate in multiple sclerosis. METHOD: Review of patient records and individual interviews. RESULTS: 30 individuals residing in the coastal region of the State of São Paulo who had been in use of glatiramer acetate for at least 6 months were identified. From this group, 28 individuals came to regular consultations and were individually assessed, their complaints being noted down in confidential records. Ten patients reported systemic reactions to the drug. Four of them stopped the medication due to such reactions. Eight patients reported local reactions to the injections. Compliance with injections was achieved, although three patients reported forgetting the injection on a few days. CONCLUSION: We noticed a higher level of systemic adverse events in our patients than in reports in the literature.OBJETIVO: Avaliar tolerância, eventos adversos e aderência ao tratamento com acetato de glatiramer em esclerose múltipla. MÉTODO:Revisão de prontuários de pacientes e entrevistas individuais. RESULTADOS: 30 indivíduos residentes na região do litoral do Estado de São Paulo, que fizeram tratamento com acetato de glatirâmer por pelo menos 6 meses foram identificados. Deste grupo, 28 indivíduos compareceram a consultas regulares e foram avaliados individualmente, sendo suas queixas anotadas em prontuário confidencial. Dez pacientes relataram reações sistêmicas à droga. Quatro deles suspenderam o tratamento devido às reações. Oito pacientes relataram reação local às injeções. Aderência às injeções foi obtida, embora três pacientes admitam ter esquecido a injeção alguns poucos dias. CONCLUSÃO: Observamos um índice maior de reações sistêmicas em nossos pacientes do que o relatado na literatura.

  18. A rapid mitochondrial toxicity assay utilizing rapidly changing cell energy metabolism.

    Science.gov (United States)

    Sanuki, Yosuke; Araki, Tetsuro; Nakazono, Osamu; Tsurui, Kazuyuki

    2017-01-01

    Drug-induced liver injury is a major cause of safety-related drug-marketing withdrawals. Several drugs have been reported to disrupt mitochondrial function, resulting in hepatotoxicity. The development of a simple and effective in vitro assay to identify the potential for mitochondrial toxicity is thus desired to minimize the risk of causing hepatotoxicity and subsequent drug withdrawal. An in vitro test method called the "glucose-galactose" assay is often used in drug development but requires prior-culture of cells over several passages for mitochondrial adaptation, thereby restricting use of the assay. Here, we report a rapid version of this method with the same predictability as the original method. We found that replacing the glucose in the medium with galactose resulted in HepG2 cells immediately shifting their energy metabolism from glycolysis to oxidative phosphorylation due to drastic energy starvation; in addition, the intracellular concentration of ATP was reduced by mitotoxicants when glucose in the medium was replaced with galactose. Using our proposed rapid method, mitochondrial dysfunction in HepG2 cells can be evaluated by drug exposure for one hour without a pre-culture step. This rapid assay for mitochondrial toxicity may be more suitable for high-throughput screening than the original method at an early stage of drug development.

  19. The beginning of clinical tolerance in solid organ allografts.

    Science.gov (United States)

    Monaco, Anthony P

    2004-06-01

    Development of effective multidrug immunosuppressive regimens and improvements in the management of chronically immunosuppressed patients have produced extraordinary patient and allograft survival in clinical organ transplantation. Unfortunately, significant problems of morbidity and mortality related to chronic immunosuppression remain. Thus, there is an enormous motivation and interest in inducing specific unresponsiveness (tolerance) to clinical solid organ allografts. Operational clinical tolerance may be defined as stable, normal graft function in the total absence of a requirement for maintenance immunosuppression. Alternatively, the concept of employing tolerogenic strategies to permit graft acceptance with dramatically reduced immunosuppression requirements is referred to as prope' or minimal immunosuppression tolerance. There have been isolated examples of clinical tolerance, usually in the context of spontaneous or induced donor chimerism, excellent HLA matching, and/or drug weaning or patient noncompliance. The various attempts that are currently being employed to induce some type of clinical tolerance are reviewed in this manuscript. Strategies in which all immunosuppression was to be withdrawn from the recipient (donor-specific unresponsiveness) are first discussed. These include strategies that utilize initial immunoablation with varying doses of irradiation and/or lymphocytic antibodies with or without donor-specific bone marrow infusion and short-term standard immunosuppressive therapy. Strategies to induce prope' or minimal immunosuppression tolerance that utilize induction lymphoablation with polyclonal or monoclonal antilymphocyte antibodies, with or without donor bone marrow infusion, followed by limited low-dose immunosuppressive therapy are also discussed. The ethical considerations in testing clinical tolerance strategies and protocols are discussed in detail. The limited number of clinical tolerance studies already available affirms that

  20. General tolerances - Part 1: Tolerances for linear and angular dimensions without individual tolerance indications

    CERN Document Server

    International Organization for Standardization. Geneva

    1989-01-01

    This part is intended to simplify drawing indications and specifies general tolerances in four tolerance classes. It applies to the dimensions of workpieces that are produced by metal removal or are formed from sheet metal. It contains three tables and an informative annex with regard to concepts behind general tolerancing of dimensions.

  1. General tolerances -- Part 2: Geometrical tolerances for features without individual tolerance indications

    CERN Document Server

    International Organization for Standardization. Geneva

    1989-01-01

    This part is intended to simplify drawing indications and specifies general tolerances in three tolerance classes. It mainly applies to features which are produced by removal of material. It contains tour tables and an informative annex A with regard to concepts behind general tolerancing of dimensions, as well as an informative annex B with further information.

  2. Uso de analgésicos e antiinflamatórios em pacientes portadores de polipose nasossinusal eosinofílica tolerantes e intolerantes à aspirina Use of analgesics and anti-inflammatory drugs in patients with eosinophilic nasal polyposis tolerant and intolerant to aspirin

    Directory of Open Access Journals (Sweden)

    Helena M. G. Becker

    2003-06-01

    dipirona e ao álcool, respectivamente, em quase metade e um terço destes pacientes.Following aspirin introduction as medicine, several reports were described concerning adverse reactions after its ingestion. Widal et al. (1922¹ were the first investigators to associate Aspirin intolerance (AI with asthma and nasal polyps (NP followed by Samter & Beers (1967². Such intolerance was manifested mainly by nasal obstruction and/or bronchospasm related to the cyclooxygenase-1 (COX-1 inhibition and consequent overproduction of leukotrienes. This might also be triggered by the administration of other non-steroid anti-inflammatory drugs, acetaminophen, food dyes and additives and alcohol. AIM: To analyze the risks of the analgesics and anti-inflammatory drugs use in patients with eosinophilic nasal polyposis tolerant and intolerant to aspirin. STUDY DESIGN: Transversal cohort study. MATERIAL AND METHOD: 45 patients were selected # 15 suffering from eosinophilic nasosinusal polyposis, tolerant to aspirin (group TA; other 15 with eosinophilic nasosinusal polyposis associated with aspirin intolerance (group AI, and 15 patients without nasosinusal polyposis with septal deviation (control group. The presence of reaction to aspirin, dipyrone, acetaminophen, other non-steroids anti-inflammatory drugs, food dyes and additives, other drugs or chemical substances was detected by inquiry. To exclude aspirin intolerance in TA and control groups, oral provocation test with aspirin was carried out. RESULTS: Bronchospasm was the main aspirin reaction in patients suffering from eosinophilic nasosinusal polyposis and which also showed with ingestion of acetaminophen (20%, alcohol (27%, non-steroids anti-inflammatory drugs (60% and dipyrone (47%. CONCLUSION: In patients with eosinophilic nasosinusal polyposis associated with aspirin intolerance it is important to do the diagnosis of intolerance to other drugs. The use of dipyrone and alcohol is worth attention, once its intolerance was observed

  3. Modifying Yeast Tolerance to Inhibitory Conditions of Ethanol Production Processes

    DEFF Research Database (Denmark)

    Caspeta, Luis; Castillo, Tania; Nielsen, Jens

    2015-01-01

    Saccharomyces cerevisiae strains having a broad range of substrate utilization, rapid substrate consumption, and conversion to ethanol, as well as good tolerance to inhibitory conditions are ideal for cost-competitive ethanol production from lignocellulose. A major drawback to directly design S....... cerevisiae tolerance to inhibitory conditions of lignocellulosic ethanol production processes is the lack of knowledge about basic aspects of its cellular signaling network in response to stress. Here, we highlight the inhibitory conditions found in ethanol production processes, the targeted cellular...... functions, the key contributions of integrated -omics analysis to reveal cellular stress responses according to these inhibitors, and current status on design-based engineering of tolerant and efficient S. cerevisiae strains for ethanol production from lignocellulose....

  4. Modifying yeast tolerance to inhibitory conditions of ethanol production processes

    Directory of Open Access Journals (Sweden)

    Luis eCaspeta

    2015-11-01

    Full Text Available Saccharomyces cerevisiae strains having a broad range of substrate utilization, rapid substrate consumption and conversion to ethanol, as well as good tolerance to inhibitory conditions are ideal for cost-competitive ethanol production from lignocellulose. A major drawback to directly design S. cerevisiae tolerance to inhibitory conditions of lignocellulosic ethanol production processes is the lack of knowledge about basic aspects of its cellular signaling network in response to stress. Here we highlight the inhibitory conditions found in ethanol production processes, the targeted cellular functions, the key contributions of integrated –omics analysis to reveal cellular stress responses according to these inhibitors, and current status on design-based engineering of tolerant and efficient S. cerevisiae strains for ethanol production from lignocellulose.

  5. Effect of Anionic Polymers on Drug Loading and Release from ...

    African Journals Online (AJOL)

    or sodium alginate as anionic polymers for the delivery of clindamycin phosphate as a model hydrophilic cationic ... Controlled drug delivery, enhanced bioavailability of entrapped drugs [5], and/or improved tissue distribution, good tolerability, and drug targeting have been ... certain types of bacterial infections, including.

  6. Drug Facts

    Medline Plus

    Full Text Available ... Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? ...

  7. Brain enhancing drugs

    OpenAIRE

    Hili, Alexander

    2016-01-01

    This is a murky area to discuss. Cognitive-Enhancing drugs are usually used to treat conditions such as sleeping disorders and ADHD. However, if taken by a person (and we do not recommend these pills) without these conditions, they can enhance the brain for a short time. But no gain comes without pain. Side effects are a problem. Take coffee, a weak stimulant that increases focus for a short period. A person slowly builds up tolerance and an addiction to the effect of caffeine. The ability to...

  8. 21 CFR 509.30 - Temporary tolerances for polychlorinated biphenyls (PCB's).

    Science.gov (United States)

    2010-04-01

    ... (PCB's). 509.30 Section 509.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND....30 Temporary tolerances for polychlorinated biphenyls (PCB's). (a) Polychlorinated biphenyls (PCB's..., PCB's have become a persistent and ubiquitous contaminant in the environment. As a result, certain...

  9. Multifunctional High Drug Loading Nanocarriers for Cancer Drug Delivery

    Science.gov (United States)

    Jin, Erlei

    2011-12-01

    Most anticancer drugs have poor water-solubility, rapid blood clearance, low tumor-selectivity and severe systemic toxicity to healthy tissues. Thus, polymeric nanocarriers have been widely explored for anticancer drugs to solve these problems. However, polymer nanocarriers developed to date still suffer drawbacks including low drug loading contents, premature drug release, slow cellular internalization, slow intracellular drug release and thereby low therapeutic efficiency in cancer thermotherapy. Accordingly, in this dissertation, functional nanocapsules and nanoparticles including high drug loading liposome-like nanocapsules, high drug loading phospholipid-mimic nanocapsules with fast intracellular drug release, high drug loading charge-reversal nanocapsules, TAT based long blood circulation nanoparticles and charge-reversal nuclear targeted nanoparticles are designed and synthesized. These functional carriers have advantages such as high drug loading contents without premature drug release, fast cellular internalization and intracellular drug release, nuclear targeted delivery and long blood circulation. As a result, all these drug carriers show much higher in vitro and in vivo anti-cancer activities.

  10. Rapid Prototyping Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — The ARDEC Rapid Prototyping (RP) Laboratory was established in December 1992 to provide low cost RP capabilities to the ARDEC engineering community. The Stratasys,...

  11. Mechanical tolerance stackup and analysis

    CERN Document Server

    Fischer, Bryan R

    2011-01-01

    Use Tolerance Analysis Techniques to Avoid Design, Quality, and Manufacturing Problems Before They Happen Often overlooked and misunderstood, tolerance analysis is a critical part of improving products and their design processes. Because all manufactured products are subject to variation, it is crucial that designers predict and understand how these changes can affect form, fit, and function of parts and assemblies--and then communicate their findings effectively. Written by one of the developers of ASME Y14.5 and other geometric dimension and tolerancing (GD&T) standards, Mechanical Tolerance

  12. Advanced cloud fault tolerance system

    Science.gov (United States)

    Sumangali, K.; Benny, Niketa

    2017-11-01

    Cloud computing has become a prevalent on-demand service on the internet to store, manage and process data. A pitfall that accompanies cloud computing is the failures that can be encountered in the cloud. To overcome these failures, we require a fault tolerance mechanism to abstract faults from users. We have proposed a fault tolerant architecture, which is a combination of proactive and reactive fault tolerance. This architecture essentially increases the reliability and the availability of the cloud. In the future, we would like to compare evaluations of our proposed architecture with existing architectures and further improve it.

  13. A review of the tolerability and safety of levocabastine eye drops and nasal spray. Implications for patient management

    Directory of Open Access Journals (Sweden)

    Peter H. Howarth

    1995-01-01

    Full Text Available Levocabastine is a highly potent and selective H1-receptor antagonist specifically developed for topical administration by ocular and nasal routes. The clinical effects of levocabastine occur rapidly and are predominantly due to local antihistaminic effects at the site of application. Clinically, levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate and placebo. As might be expected from the route of drug administration, local irritation is the most frequent adverse event seen with levocabastine eye drops and nasal spray with an incidence comparable with that in placebo-treated controls. Intranasal application of levocabastine has been shown to have no adverse effect on ciliary activity both in vitro and in vivo, while ocular administration has not been shown to have any significant or consistent adverse effect in both animal and human studies. At therapeutic doses, levocabastine appears to be devoid of significant systemic activity producing no apparent effects on cardiovascular, psychomotor and cognitive function. Since levocabastine undergoes little hepatic metabolism, and only low plasma levels of the drug are attained following topical administration, drug interactions are unlikely.

  14. Freeze-Tolerant Condensers

    Science.gov (United States)

    Crowley, Christopher J.; Elkouhk, Nabil

    2004-01-01

    Two condensers designed for use in dissipating heat carried by working fluids feature two-phase, self-adjusting configurations such that their working lengths automatically vary to suit their input power levels and/or heat-sink temperatures. A key advantage of these condensers is that they can function even if the temperatures of their heat sinks fall below the freezing temperatures of their working fluids and the fluids freeze. The condensers can even be restarted from the frozen condition. The top part of the figure depicts the layout of the first condenser. A two-phase (liquid and vapor) condenser/vapor tube is thermally connected to a heat sink typically, a radiatively or convectively cooled metal panel. A single-phase (liquid) condensate-return tube (return artery) is also thermally connected to the heat sink. At intervals along their lengths, the condenser/vapor tube and the return artery are interconnected through porous plugs. This condenser configuration affords tolerance of freezing, variable effective thermal conductance (such that the return temperature remains nearly constant, independently of the ultimate sink temperature), and overall pressure drop smaller than it would be without the porous interconnections. An additional benefit of this configuration is that the condenser can be made to recover from the completely frozen condition either without using heaters, or else with the help of heaters much smaller than would otherwise be needed. The second condenser affords the same advantages and is based on a similar principle, but it has a different configuration that affords improved flow of working fluid, simplified construction, reduced weight, and faster recovery from a frozen condition.

  15. The evolution of ecological tolerance in prokaryotes

    Science.gov (United States)

    Knoll, A. H.; Bauld, J.

    1989-01-01

    The ecological ranges of Archaeobacteria and Eubacteria are constrained by a requirement for liquid water and the physico-chemical stability limits of biomolecules, but within this broad envelope, prokaryotes have evolved adaptations that permit them to tolerate a remarkable spectrum of habitats. Laboratory experiments indicate that prokaryotes can adapt rapidly to novel environmental conditions, yet geological studies suggest early diversification and long-term stasis within the prokaryotic kingdoms. These apparently contradictory perspectives can be reconciled by understanding that, in general, rates and patterns of prokaryotic evolution reflect the developmental history of the Earth's surface environments. Our understanding of modern microbial ecology provides a lens through which our accumulating knowledge of physiology, molecular phylogeny and the Earth's history can be integrated and focussed on the phenomenon of prokaryotic evolution.

  16. Tolerance of pollination networks to species extinctions.

    Science.gov (United States)

    Memmott, Jane; Waser, Nickolas M.; Price, Mary V.

    2004-01-01

    Mutually beneficial interactions between flowering plants and animal pollinators represent a critical 'ecosystem service' under threat of anthropogenic extinction. We explored probable patterns of extinction in two large networks of plants and flower visitors by simulating the removal of pollinators and consequent loss of the plants that depend upon them for reproduction. For each network, we removed pollinators at random, systematically from least-linked (most specialized) to most-linked (most generalized), and systematically from most- to least-linked. Plant species diversity declined most rapidly with preferential removal of the most-linked pollinators, but declines were no worse than linear. This relative tolerance to extinction derives from redundancy in pollinators per plant and from nested topology of the networks. Tolerance in pollination networks contrasts with catastrophic declines reported from standard food webs. The discrepancy may be a result of the method used: previous studies removed species from multiple trophic levels based only on their linkage, whereas our preferential removal of pollinators reflects their greater risk of extinction relative to that of plants. In both pollination networks, the most-linked pollinators were bumble-bees and some solitary bees. These animals should receive special attention in efforts to conserve temperate pollination systems. PMID:15615687

  17. Tolerance of pollination networks to species extinctions.

    Science.gov (United States)

    Memmott, Jane; Waser, Nickolas M; Price, Mary V

    2004-12-22

    Mutually beneficial interactions between flowering plants and animal pollinators represent a critical 'ecosystem service' under threat of anthropogenic extinction. We explored probable patterns of extinction in two large networks of plants and flower visitors by simulating the removal of pollinators and consequent loss of the plants that depend upon them for reproduction. For each network, we removed pollinators at random, systematically from least-linked (most specialized) to most-linked (most generalized), and systematically from most- to least-linked. Plant species diversity declined most rapidly with preferential removal of the most-linked pollinators, but declines were no worse than linear. This relative tolerance to extinction derives from redundancy in pollinators per plant and from nested topology of the networks. Tolerance in pollination networks contrasts with catastrophic declines reported from standard food webs. The discrepancy may be a result of the method used: previous studies removed species from multiple trophic levels based only on their linkage, whereas our preferential removal of pollinators reflects their greater risk of extinction relative to that of plants. In both pollination networks, the most-linked pollinators were bumble-bees and some solitary bees. These animals should receive special attention in efforts to conserve temperate pollination systems.

  18. Antibiotic tolerance and microbial biofilms

    DEFF Research Database (Denmark)

    Folkesson, Anders

    Increased tolerance to antimicrobial agents is thought to be an important feature of microbes growing in biofilms. We study the dynamics of antibiotic action within hydrodynamic flow chamber biofilms of Escherichia coli and Pseudomonas aeruginosa using isogenic mutants and fluorescent gene...... expression reporters and we address the question of how biofilm organization affects antibiotic susceptibility. The dynamics of microbial killing is monitored by viable count determination, and confocal laser microscopy. Our work shows that the apparent increased antibiotic tolerance is due to the formation...... of antibiotic tolerant subpopulations within the biofilm. The formation of these subpopulations is highly variable and dependent on the antibiotic used, the biofilm structural organization and the induction of specific tolerance mechanisms....

  19. [Antidepressant and tolerance: Determinants and management of major side effects].

    Science.gov (United States)

    David, D J; Gourion, D

    2016-12-01

    need to take into account the key role of the nocebo effect in the occurrence of adverse effects. The next generation of antidepressant would aim to have a rapid efficacy in patients unresponsive or resistant to drugs currently available while improving certain effects of tolerance through an optimization of their psychopharmacological properties leading to a reduction of their side effects. Copyright © 2016 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

  20. Allergy to cloxacillin with normal tolerance to amoxicillin and cefuroxime.

    Science.gov (United States)

    Domínguez-Ortega, J; Martínez-Alonso, J C; Marcos-Pérez, M C; Kindelan, C; Frades, A

    2006-01-01

    Cloxacillin is a semisynthetic penicillin widely used in nonmethicillin resistant Staphylococcus aureus infections. Several hypersensitivity reactions to cloxacillin have been reported, although IgE-mediated allergic reactions to the drug are rare and there is little information about possible tolerance to other semisynthetic penicillins or cephalosporins in patients with cloxacillin allergy. We present 2 patients with demonstrated IgE-mediated allergy to cloxacillin and tolerance to amoxicillin and cefuroxime. Case 1. A 47-year-old woman began treatment with cloxacillin due to acute cellulitis. After ingesting 500 mg of the drug, she experience generalized maculopapular eruption and facial angioedema. Case 2. A 55-year-old woman presented an episode of acute urticaria and labial angioedema 60 minutes after ingesting 500 mg of cloxacillin for a skin abscess. Skin prick tests were positive to cloxacillin in case 1 and negative in case 2. However, an intradermal test was positive to cloxacillin (2 mg/ml) in case 2. Simple-blind oral challenge tests with amoxicillin (1 g) and cefuroxime (500 mg) were well-tolerated by both patients. We present 2 patients allergic to cloxacillin with normal tolerance to other betalactam antibiotics, confirming that cross-reactivity among these antibiotics seems to be uncommon. Complete allergy study, including an oral challenge test, should be considered in these patients.

  1. Women’s G Tolerance

    Science.gov (United States)

    1986-08-01

    for the groups matched by age (70 pairs), weight sickness, uncomfortable feelings of distension in arms (26 pairs), and act~vity status (84 pairs...mass-spring-damper) s ,stem Straining G tolerance, being dpendent on skeletal having a resonant frequency above about I Hz. As muscular strength and...of the women’s G tolerance stud\\ scclic variations in muscular strength and endurance. was below 0.1 Hz (11), the production of any significant

  2. Behavioral Tolerance to Anticholinergic Agents

    Science.gov (United States)

    1986-11-20

    Medicine , 47, 137-141. 7. Kurtz, P.J. (1977) Behavioral and biochemical effects of the carbamate insecticide, mobam. Pharmacology Biochemistry & Behavior...tolerance to marihuana in rats. Pharmacology Biochemistry and Behavior, 1, 73-76. 43 40. Olson, J. and Carder, B. (1974) Behavioral tolerance to... marihuana as a function of amount of prior training. Pharmacology Biochemistry and Behavior, 2, 243-247. 41. Sidman, M. (1960) Tactics of Scientific

  3. Drug resistance mechanisms and novel drug targets for tuberculosis therapy.

    Science.gov (United States)

    Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu

    2017-01-20

    Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance. Copyright © 2016 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.

  4. 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

  5. NEW ANTIPLATELET DRUGS (PART 1

    Directory of Open Access Journals (Sweden)

    A. B. Sumarokov

    2016-01-01

    Full Text Available Antiplatelet agents are a necessary component of modern atherosclerosis therapy. The difficulties of antiplatelet treatment lie in the balance between the necessary therapeutic effect of the drug and the risk of excessive action leading to the bleeding. Possibility to control pharmacodynamics effects of antiplatelet agents is still very limited. Pharmacology of antiplatelet drugs is growing rapidly. Some of new antiplatelet drugs are on their way to clinical application — prasugrel, ticagrelor, elinogrel, inhibitors of thromboxane and thrombin receptors. Clinical pharmacology of these drugs is different. This requires a doctor's good knowledge of their identity to avoid the development of iatrogenic complications.

  6. NEW ANTIPLATELET DRUGS (PART 1

    Directory of Open Access Journals (Sweden)

    A. B. Sumarokov

    2011-01-01

    Full Text Available Antiplatelet agents are a necessary component of modern atherosclerosis therapy. The difficulties of antiplatelet treatment lie in the balance between the necessary therapeutic effect of the drug and the risk of excessive action leading to the bleeding. Possibility to control pharmacodynamics effects of antiplatelet agents is still very limited. Pharmacology of antiplatelet drugs is growing rapidly. Some of new antiplatelet drugs are on their way to clinical application — prasugrel, ticagrelor, elinogrel, inhibitors of thromboxane and thrombin receptors. Clinical pharmacology of these drugs is different. This requires a doctor's good knowledge of their identity to avoid the development of iatrogenic complications.

  7. Youth, drugs, and biopolitics

    Directory of Open Access Journals (Sweden)

    Alcides Jose Sanches Vergara

    2011-07-01

    Full Text Available In this article, we tackle the issue of youth and drugs as something linked to biopower and biopolitics, both concepts developed by Michael Foucault. Youth and drugs are taken and analyzed in situations involving the management of crime linked to the risks and deviations from the law, abuse and dependence. The youth; irreverent, courageous, healthy, idealistic, and that wanted to change the world for the better as we have seen in the past, is now strongly related to violence, dangerous activities, moral and social risks, drug addiction, criminality, and others negative images. To deal with these young people, tolerance and small punishments of yore are not enough anymore. The young people emerge as a segment of the population subject to various actions and programs. The drugs now are seen as matters of security and public health. There is a shifting and repositioning in the discourse about the young - from minor, drugged, and criminal to lawbreaker, user and drug addict. The change is subtle, but represents a modulation in the devices of social control. Beyond the consent of the young to get rid of drugs, there is a search for the creation of a wide area of monitoring of their behavior through the activation of community protection networks. The belief that the young are more impressionable and vulnerable, and that action on the cause of the problem or risk reduction are the most efficient ways of management, taking responsibility away from personal and family sphere and transferring it to the State, contributes to the increasing control of young people nowadays.

  8. Anti-hyperglycemic effect and glucose tolerance of guajava (Psidium guajava L.) leaf ethanol extract in diabetic rats

    Science.gov (United States)

    Yanis Musdja, Muhammad; Mahendra, Feizar; Musir, Ahmad

    2017-12-01

    Traditionally guava (Psidium guajava L) leaf is used for treatment of various ailments like diarrhea, wounds, rheumatism, anti-allergy, ant-spasmodic, etc, as folk medicine. The aim of this research is to know the effect of hypoglycemia and glucose tolerance of ethanol extract of guava leaf against male white rat. The guajava leaf was obtained from Balitro Bogor. Preparation of guajava leaf extract was done by cold maceration extraction technique using ethanol 70%. Male albino rats were made into diabetics using the alloxan method. Rats were divided into 6 groups, as a comparative drug for anti-hyperglycemic used glibenclamid and as a comparative drug for glucose tolerance used acarbose. The result of blood glucometer test showed that ethanol extract 70% of guajava leaf had effect as anti-hyperglycemic and glucose tolerance with no significant difference with glibenclamid drug as anti-hyperglycemic and acarbose as glucose tolerance drug.

  9. Rapid Airplane Parametric Input Design (RAPID)

    Science.gov (United States)

    Smith, Robert E.

    1995-01-01

    RAPID is a methodology and software system to define a class of airplane configurations and directly evaluate surface grids, volume grids, and grid sensitivity on and about the configurations. A distinguishing characteristic which separates RAPID from other airplane surface modellers is that the output grids and grid sensitivity are directly applicable in CFD analysis. A small set of design parameters and grid control parameters govern the process which is incorporated into interactive software for 'real time' visual analysis and into batch software for the application of optimization technology. The computed surface grids and volume grids are suitable for a wide range of Computational Fluid Dynamics (CFD) simulation. The general airplane configuration has wing, fuselage, horizontal tail, and vertical tail components. The double-delta wing and tail components are manifested by solving a fourth order partial differential equation (PDE) subject to Dirichlet and Neumann boundary conditions. The design parameters are incorporated into the boundary conditions and therefore govern the shapes of the surfaces. The PDE solution yields a smooth transition between boundaries. Surface grids suitable for CFD calculation are created by establishing an H-type topology about the configuration and incorporating grid spacing functions in the PDE equation for the lifting components and the fuselage definition equations. User specified grid parameters govern the location and degree of grid concentration. A two-block volume grid about a configuration is calculated using the Control Point Form (CPF) technique. The interactive software, which runs on Silicon Graphics IRIS workstations, allows design parameters to be continuously varied and the resulting surface grid to be observed in real time. The batch software computes both the surface and volume grids and also computes the sensitivity of the output grid with respect to the input design parameters by applying the precompiler tool

  10. Drug Facts

    Medline Plus

    Full Text Available ... Search form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) ... Facts Tobacco and Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and ...

  11. Drug Facts

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    Full Text Available ... Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) ... treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice ( ...

  12. Drug Facts

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    Full Text Available ... call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I ... The National Institute on Drug Abuse (NIDA) is part of the National Institutes of Health (NIH) , the ...

  13. Drug Facts

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    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...

  14. Study Drugs

    Science.gov (United States)

    ... What Are Study Drugs? Doctors prescribe medicines like Adderall and Ritalin to treat conditions like attention deficit ... stimulants are used as study drugs: amphetamines like Adderall, Dexedrine, or Vyvanse methylphenidates like Ritalin or Concerta ...

  15. Drug Facts

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    Full Text Available ... symptoms of someone with a drug use problem? How Does Drug Use Become an Addiction? What Makes ... Options? What Is Recovery? What Is a Relapse? How Can Friends and Family Help? Where Can Someone ...

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  17. Drug Testing

    Science.gov (United States)

    ... or slurred speech Dilated or small pupils Agitation Panic Paranoia Delirium Difficulty breathing Nausea Changes in blood ... MedlinePlus Health Topics Drug Abuse Opioid Abuse and Addiction Prescription Drug Abuse The medical information provided is ...

  18. Drug Facts

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    Full Text Available ... Numbers and Websites Search Share Listen English Español Information about this page Click on the button that ... about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana ...

  19. Drug Facts

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    Full Text Available ... Link Between Drug Use and HIV/AIDS Treatment & Recovery Why Does a Person Need Treatment? Does Drug ... Work? What Are the Treatment Options? What Is Recovery? What Is a Relapse? How Can Friends and ...

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    Full Text Available ... centers near you. I want my daughter to avoid drugs. "Debbie" has been drug-free for years. ... life. I need different people around me. To stop using marijuana, "Cristina" is making positive changes in ...

  1. Drug Facts

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    Full Text Available ... to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  2. Drug Facts

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    ... to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  3. Drug Facts

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    Full Text Available ... Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts ... Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs ...

  4. Club Drugs

    Science.gov (United States)

    ... To Treat Methamphetamine Addiction, Part 2 ( April 2016 ) Narrative of Discovery: In Search ... on Drug Abuse - National Library of Medicine, NIH www.abovetheinfluence.com - Office of National Drug ...

  5. Drug Facts

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    Full Text Available ... the Past Drug Use Prevention Phone Numbers and Websites Search Share Listen English Español Information about this ... computer will read the text to you. This website talks about drug abuse, addiction, and treatment. Watch ...

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    Full Text Available ... Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and symptoms of someone ... use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted ...

  7. Drug Facts

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    Full Text Available ... Does a Person Need Treatment? Does Drug Treatment Work? What Are the Treatment Options? What Is Recovery? What Is a Relapse? How Can Friends and Family Help? Where Can Someone Find Treatment and Recovery Resources? Prevent Drug Use Help Children and Teens Stay Drug-Free Talking to Kids ...

  8. Drug Metabolism

    Indian Academy of Sciences (India)

    IAS Admin

    functional groups on which different reactions take place in the body. We have covered the detoxification pathways of drug metabolism; however, we still have to understand the toxic effects of drug metabolism via bioactivation process. 3.3 Bioactivation Reactions:Chemistry of Reactive Metabolites and Adverse Drug Effects.

  9. Drug Facts

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    Full Text Available ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs ... adicción. English Español About the National Institute on Drug Abuse (NIDA) | About This Website Tools and Resources | Contact ...

  10. Drug Facts

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    Full Text Available ... Makes Someone More Likely to Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard ... the text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol ...

  11. Drug Facts

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    Full Text Available ... Search form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts ... text to you. This website talks about drug abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain ...

  12. Drug Facts

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    Full Text Available ... to main content Easy-to-Read Drug Facts Search form Search Menu Home Drugs That People Abuse Alcohol Facts ... Past Drug Use Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page ...

  13. Drug allergies

    Science.gov (United States)

    ... reaction to a drug (medicine). Causes A drug allergy involves an immune response in the body that produces an allergic reaction ... the use of a drug that causes an allergy if you are first treated with ... These include corticosteroids (such as prednisone) and antihistamines. ...

  14. Tolerance and acculturation

    Directory of Open Access Journals (Sweden)

    Ursula Småland Goth

    2014-12-01

    study shows a varied pattern of use of GP services among the diverse groups of foreign-born residents. Results suggest that immigrants are more likely to use emergency-room services during the first few years after arrival. Results also indicate that information about the patient-list system does not always reach newly arrived immigrants. Contrary to general understanding, non-visible immigrants (when considering factors such as skin color and clothing diverge the most from the pattern of the majority. Immigrants originating from European countries, such as Sweden and Poland, use the emergency room most frequently. From the qualitative aspects of the study, we have also found that primary health care services are not perceived as equitable.Conclusion: Recently arrived immigrants’ utilization of primary health care services shows an unfavorable pattern. The choice of primary health care service providers is dependent on the individual’s preferences, expectations, experiences and/or actual obstacles. The observed utilization of services provided at emergency rooms is one more reason for monitoring and increasing tolerance and cultural sensitivity in primary health care.

  15. Rapid shallow breathing

    Science.gov (United States)

    ... the smallest air passages of the lungs in children ( bronchiolitis ) Pneumonia or other lung infection Transient tachypnea of the newborn Anxiety and panic Other serious lung disease Home Care Rapid, shallow breathing should not be treated at home. It is ...

  16. Rapid Strep Test

    Science.gov (United States)

    ... worse than normal. Your first thoughts turn to strep throat. A rapid strep test in your doctor’s office ... your suspicions.Viruses cause most sore throats. However, strep throat is an infection caused by the Group A ...

  17. Selective labelling and eradication of antibiotic-tolerant bacterial populations in Pseudomonas aeruginosa biofilms

    Science.gov (United States)

    Chua, Song Lin; Yam, Joey Kuok Hoong; Hao, Piliang; Adav, Sunil S.; Salido, May Margarette; Liu, Yang; Givskov, Michael; Sze, Siu Kwan; Tolker-Nielsen, Tim; Yang, Liang

    2016-01-01

    Drug resistance and tolerance greatly diminish the therapeutic potential of antibiotics against pathogens. Antibiotic tolerance by bacterial biofilms often leads to persistent infections, but its mechanisms are unclear. Here we use a proteomics approach, pulsed stable isotope labelling with amino acids (pulsed-SILAC), to quantify newly expressed proteins in colistin-tolerant subpopulations of Pseudomonas aeruginosa biofilms (colistin is a ‘last-resort' antibiotic against multidrug-resistant Gram-negative pathogens). Migration is essential for the formation of colistin-tolerant biofilm subpopulations, with colistin-tolerant cells using type IV pili to migrate onto the top of the colistin-killed biofilm. The colistin-tolerant cells employ quorum sensing (QS) to initiate the formation of new colistin-tolerant subpopulations, highlighting multicellular behaviour in antibiotic tolerance development. The macrolide erythromycin, which has been previously shown to inhibit the motility and QS of P. aeruginosa, boosts biofilm eradication by colistin. Our work provides insights on the mechanisms underlying the formation of antibiotic-tolerant populations in bacterial biofilms and indicates research avenues for designing more efficient treatments against biofilm-associated infections. PMID:26892159

  18. New drugs of abuse.

    Science.gov (United States)

    Rech, Megan A; Donahey, Elisabeth; Cappiello Dziedzic, Jacqueline M; Oh, Laura; Greenhalgh, Elizabeth

    2015-02-01

    Drug abuse is a common problem and growing concern in the United States, and over the past decade, novel or atypical drugs have emerged and have become increasingly popular. Recognition and treatment of new drugs of abuse pose many challenges for health care providers due to lack of quantitative reporting and routine surveillance, and the difficulty of detection in routine blood and urine analyses. Furthermore, street manufacturers are able to rapidly adapt and develop new synthetic isolates of older drugs as soon as law enforcement agencies render them illegal. In this article, we describe the clinical and adverse effects and purported pharmacology of several new classes of drugs of abuse including synthetic cannabinoids, synthetic cathinones, salvia, desomorphine, and kratom. Because many of these substances can have severe or life-threatening adverse effects, knowledge of general toxicology is key in recognizing acute intoxication and overdose; however, typical toxidromes (e.g., cholinergic, sympathomimetic, opioid, etc.) are not precipitated by many of these agents. Medical management of patients who abuse or overdose on these drugs largely consists of supportive care, although naloxone may be used as an antidote for desomorphine overdose. Symptoms of aggression and psychosis may be treated with sedation (benzodiazepines, propofol) and antipsychotics (haloperidol or atypical agents such as quetiapine or ziprasidone). Other facets of management to consider include treatment for withdrawal or addiction, nutrition support, and potential for transmission of infectious diseases. © 2014 Pharmacotherapy Publications, Inc.

  19. Multiperspective analysis of erosion tolerance

    Directory of Open Access Journals (Sweden)

    Sparovek Gerd

    2003-01-01

    Full Text Available Erosion tolerance is the most multidisciplinary field of soil erosion research. Scientists have shown lack in ability to adequately analyze the huge list of variables that influence soil loss tolerance definitions. For these the perspectives of erosion made by farmers, environmentalists, society and politicians have to be considered simultaneously. Partial and biased definitions of erosion tolerance may explain not only the polemic nature of the currently suggested values but also, in part, the nonadoption of the desired levels of erosion control. To move towards a solution, considerable changes would have to occur on how this topic is investigated, especially among scientists, who would have to change methods and strategies and extend the perspective of research out of the boundaries of the physical processes and the frontiers of the academy. A more effective integration and communication with the society and farmers, to learn about their perspective of erosion and a multidisciplinary approach, integrating soil, social, economic and environmental sciences are essential for improved erosion tolerance definitions. In the opinion of the authors, soil erosion research is not moving in this direction and a better understanding of erosion tolerance is not to be expected in the near future.

  20. A Novel Two-Step Method for Screening Shade Tolerant Mutant Plants via Dwarfism

    Science.gov (United States)

    Li, Wei; Katin-Grazzini, Lorenzo; Krishnan, Sanalkumar; Thammina, Chandra; El-Tanbouly, Rania; Yer, Huseyin; Merewitz, Emily; Guillard, Karl; Inguagiato, John; McAvoy, Richard J.; Liu, Zongrang; Li, Yi

    2016-01-01

    When subjected to shade, plants undergo rapid shoot elongation, which often makes them more prone to disease and mechanical damage. Shade-tolerant plants can be difficult to breed; however, they offer a substantial benefit over other varieties in low-light areas. Although perennial ryegrass (Lolium perenne L.) is a popular species of turf grasses because of their good appearance and fast establishment, the plant normally does not perform well under shade conditions. It has been reported that, in turfgrass, induced dwarfism can enhance shade tolerance. Here we describe a two-step procedure for isolating shade tolerant mutants of perennial ryegrass by first screening for dominant dwarf mutants, and then screening dwarf plants for shade tolerance. The two-step screening process to isolate shade tolerant mutants can be done efficiently with limited space at early seedling stages, which enables quick and efficient isolation of shade tolerant mutants, and thus facilitates development of shade tolerant new cultivars of turfgrasses. Using the method, we isolated 136 dwarf mutants from 300,000 mutagenized seeds, with 65 being shade tolerant (0.022%). When screened directly for shade tolerance, we recovered only four mutants from a population of 150,000 (0.003%) mutagenized seeds. One shade tolerant mutant, shadow-1, was characterized in detail. In addition to dwarfism, shadow-1 and its sexual progeny displayed high degrees of tolerance to both natural and artificial shade. We showed that endogenous gibberellin (GA) content in shadow-1 was higher than wild-type controls, and shadow-1 was also partially GA insensitive. Our novel, simple and effective two-step screening method should be applicable to breeding shade tolerant cultivars of turfgrasses, ground covers, and other economically important crop plants that can be used under canopies of existing vegetation to increase productivity per unit area of land. PMID:27752260

  1. A novel two-step method for screening shade tolerant mutant plants via dwarfism

    Directory of Open Access Journals (Sweden)

    Wei Li

    2016-10-01

    Full Text Available When subjected to shade, plants undergo rapid shoot elongation, which often makes them more prone to disease and mechanical damage. Shade-tolerant plants can be difficult to breed; however, they offer a substantial benefit over other varieties in low-light areas. Although perennial ryegrass (Lolium perenne L. is a popular species of turf grasses because of their good appearance and fast establishment, the plant normally does not perform well under shade conditions. It has been reported that, in turfgrass, induced dwarfism can enhance shade tolerance. Here we describe a two-step procedure for isolating shade tolerant mutants of perennial ryegrass by first screening for dominant dwarf mutants, and then screening dwarf plants for shade tolerance. The two-step screening process to isolate shade tolerant mutants can be done efficiently with limited space at early seedling stages, which enables quick and efficient isolation of shade tolerant mutants, and thus facilitates development of shade tolerant new cultivars of turfgrasses. Using the method, we isolated 136 dwarf mutants from 300,000 mutagenized seeds, with 65 being shade tolerant (0.022%. When screened directly for shade tolerance, we recovered only four mutants from a population of 150,000 (0.003% mutagenized seeds. One shade tolerant mutant, shadow-1, was characterized in detail. In addition to dwarfism, shadow-1 and its sexual progeny displayed high degrees of tolerance to both natural and artificial shade. We showed that endogenous gibberellin (GA content in shadow-1 was higher than wild-type controls, and shadow-1 was also partially GA insensitive. Our novel, simple and effective two-step screening method should be applicable to breeding shade tolerant cultivars of turfgrasses, ground covers, and other economically important crop plants that can be used under canopies of existing vegetation to increase productivity per unit area of land.

  2. Combination of antiarrhythmic drugs.

    Science.gov (United States)

    Lüderitz, B; Mletzko, R; Jung, W; Manz, M

    1991-01-01

    Antiarrhythmic treatment with single agents is often ineffective and can be limited by dose-dependent side effects. Therefore, combinations of antiarrhythmic drugs in smaller and well-tolerated doses are advocated in cases refractory to single antiarrhythmic drugs. Basically, substances belonging to the same electrophysiologic class should not be combined. However, drugs of different subsets of class I may be combined. Agents that have pharmacokinetic interactions, such as quinidine and amiodarone, should not be given together because this combination may be associated with a considerable proarrhythmic effect. A combination of beta-adrenoreceptor blockers with class I antiarrhythmic drugs may be effective, mainly in cases in which the arrhythmia is dependent on adrenergic stimulation. The combination of class III and IB substances can be useful in some cases, from the electrophysiological and clinical point of view. Among the successful combinations of this type are amiodarone and mexiletine, sotalol and mexiletine, or sotalol and tocainide. In 34 patients, the reduction of ventricular premature beats by sotalol alone was 28%, and by sotalol plus mexiletine or tocainide was 79%. Complex ventricular arrhythmias were suppressed by sotalol alone by less than 40% and by sotalol plus mexiletine or tocainide by more than 80%. There was no difference in the effectiveness of mexiletine and tocainide (both of them being class IB drugs) in this combination. However, mexiletine was associated with fewer adverse effects than was tocainide. In patients refractory to amiodarone alone or to a combination with mexiletine, the combined treatment with amiodarone and class IC drugs such as flecainide and encainide prolongs the cycle length of ventricular tachycardia, but does not suppress induction of ventricular tachycardia during programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Ontogenetic variation in cold tolerance plasticity in Drosophila: is the Bogert effect bogus?

    Science.gov (United States)

    Mitchell, Katherine A.; Sinclair, Brent J.; Terblanche, John S.

    2013-03-01

    Ontogenetic variation in plasticity is important to understanding mechanisms and patterns of thermal tolerance variation. The Bogert effect postulates that, to compensate for their inability to behaviourally thermoregulate, less-mobile life stages of ectotherms are expected to show greater plasticity of thermal tolerance than more-mobile life stages. We test this general prediction by comparing plasticity of thermal tolerance (rapid cold-hardening, RCH) between mobile adults and less-mobile larvae of 16 Drosophila species. We find an RCH response in adults of 13 species but only in larvae of four species. Thus, the Bogert effect is not as widespread as expected.

  4. Eslicarbazepine Acetate: A New Improvement on a Classic Drug Family for the Treatment of Partial-Onset Seizures.

    Science.gov (United States)

    Galiana, Graciana L; Gauthier, Angela C; Mattson, Richard H

    2017-09-01

    Eslicarbazepine acetate is a new anti-epileptic drug belonging to the dibenzazepine carboxamide family that is currently approved as adjunctive therapy and monotherapy for partial-onset (focal) seizures. The drug enhances slow inactivation of voltage-gated sodium channels and subsequently reduces the activity of rapidly firing neurons. Eslicarbazepine acetate has few, but some, drug-drug interactions. It is a weak enzyme inducer and it inhibits cytochrome P450 2C19, but it affects a smaller assortment of enzymes than carbamazepine. Clinical studies using eslicarbazepine acetate as adjunctive treatment or monotherapy have demonstrated its efficacy in patients with refractory or newly diagnosed focal seizures. The drug is generally well tolerated, and the most common side effects include dizziness, headache, and diplopia. One of the greatest strengths of eslicarbazepine acetate is its ability to be administered only once per day. Eslicarbazepine acetate has many advantages over older anti-epileptic drugs, and it should be strongly considered when treating patients with partial-onset epilepsy.

  5. Drug Resistance Mechanisms in Mycobacterium tuberculosis.

    Science.gov (United States)

    Palomino, Juan Carlos; Martin, Anandi

    2014-07-02

    Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative agent of the disease. In recent years, even more serious forms of drug resistance have been reported. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. This review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular basis of drug resistance in M. tuberculosis.

  6. Fault-Tolerant Heat Exchanger

    Science.gov (United States)

    Izenson, Michael G.; Crowley, Christopher J.

    2005-01-01

    A compact, lightweight heat exchanger has been designed to be fault-tolerant in the sense that a single-point leak would not cause mixing of heat-transfer fluids. This particular heat exchanger is intended to be part of the temperature-regulation system for habitable modules of the International Space Station and to function with water and ammonia as the heat-transfer fluids. The basic fault-tolerant design is adaptable to other heat-transfer fluids and heat exchangers for applications in which mixing of heat-transfer fluids would pose toxic, explosive, or other hazards: Examples could include fuel/air heat exchangers for thermal management on aircraft, process heat exchangers in the cryogenic industry, and heat exchangers used in chemical processing. The reason this heat exchanger can tolerate a single-point leak is that the heat-transfer fluids are everywhere separated by a vented volume and at least two seals. The combination of fault tolerance, compactness, and light weight is implemented in a unique heat-exchanger core configuration: Each fluid passage is entirely surrounded by a vented region bridged by solid structures through which heat is conducted between the fluids. Precise, proprietary fabrication techniques make it possible to manufacture the vented regions and heat-conducting structures with very small dimensions to obtain a very large coefficient of heat transfer between the two fluids. A large heat-transfer coefficient favors compact design by making it possible to use a relatively small core for a given heat-transfer rate. Calculations and experiments have shown that in most respects, the fault-tolerant heat exchanger can be expected to equal or exceed the performance of the non-fault-tolerant heat exchanger that it is intended to supplant (see table). The only significant disadvantages are a slight weight penalty and a small decrease in the mass-specific heat transfer.

  7. What is Fault Tolerant Control

    DEFF Research Database (Denmark)

    Blanke, Mogens; Frei, C. W.; Kraus, K.

    2000-01-01

    availability and reduce the risk of safety hazards. Its aim is to prevent that simple faults develop into serious failure. Fault-tolerant control merges several disciplines to achieve this goal, including on-line fault diagnosis, automatic condition assessment and calculation of remedial actions when a fault......Faults in automated processes will often cause undesired reactions and shut-down of a controlled plant, and the consequences could be damage to the plant, to personnel or the environment. Fault-tolerant control is the synonym for a set of recent techniques that were developed to increase plant...

  8. Selective labelling and eradication of antibiotic-tolerant bacterial populations in Pseudomonas aeruginosa biofilms

    DEFF Research Database (Denmark)

    Chua, Song Lin; Yam, Joey Kuok Hoong; Hao, Piliang

    2016-01-01

    Drug resistance and tolerance greatly diminish the therapeutic potential of antibiotics against pathogens. Antibiotic tolerance by bacterial biofilms often leads to persistent infections, but its mechanisms are unclear. Here we use a proteomics approach, pulsed stable isotope labelling with amino...... research avenues for designing more efficient treatments against biofilm-associated infections....... development. The macrolide erythromycin, which has been previously shown to inhibit the motility and QS of P. aeruginosa, boosts biofilm eradication by colistin. Our work provides insights on the mechanisms underlying the formation of antibiotic-tolerant populations in bacterial biofilms and indicates...

  9. Tolerating extremism : to what extent should intolerance be tolerated?

    NARCIS (Netherlands)

    Guiora, Amos Neuser

    2013-01-01

    In discussing extremism, the key questions are: to whom is a duty owed and what are the limits of intolerance that are to be tolerated? Answering these questions requires examining limits and rights; analyzing them in the context of extremism is the ‘core’ of this book. While freedom of speech and

  10. Ocular tolerance in rabbits after intracameral administration of a fixed combination of tropicamide, phenylephrine, and lidocaine with and without rinsing.

    Science.gov (United States)

    Nuijts, Rudy M M A; Mencucci, Rita; Viaud-Quentric, Karen; Elena, Pierre-Paul; Olmière, Céline; Behndig, Anders

    2017-05-01

    To evaluate the safety and tolerability of a single intracameral administration of a combined mydriatic (tropicamide and phenylephrine) and anesthetic (lidocaine) formulation (Mydrane) with or without rinsing. Iris Pharma, La Gaude, France. Experimental study. Sixty pigmented rabbits received 100 μL or 200 μL of the combination product or a placebo (sodium chloride 0.9%) by intracameral injection. For the combination product, separate groups were included with and without rinsing after administration. From day 1 day to day 7, assessments included general clinical and ocular observations, pupil diameter measurements, corneal assessments, confocal microscopy, and electroretinography (ERG). Necropsy examinations were performed at study completion at day 8. Rapid mydriasis, stable 24 minutes after injection and returning to baseline levels by day 1, was induced in all groups that received the combination mydriatic and anesthetic drug. Rinsing had no effect. The combination product induced no adverse effects on the anterior or posterior segment of the eye (ie, no increased corneal thickness and endothelial cell loss, no abnormalities in ERG). Slitlamp examination showed slightly increased anterior chamber inflammation with rinsing in both the study group and placebo group. This observation was not confirmed by aqueous flare examination. No toxic effects of the products were found on histological evaluation. The combination mydriatic and anesthetic drug administered to pigmented rabbits as a single intracameral injection at volumes of 100 μL and 200 μL was well tolerated with no ocular adverse effects and no effect on the corneal endothelium. Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  11. Drug allergy.

    Science.gov (United States)

    Kim, K; Evans, R; Mahr, T A

    1990-01-01

    Undesirable or adverse drug effects occur with 1-15% of drug doses. The mechanisms of these reactions are not always known; however, 5-10% are immunologically mediated allergic reactions. Risk factors for allergic drug reactions include age, type of drug, degree of exposure, and route of administration. Penicillin allergy is the most common example of classical drug allergy. Skin test reagents are available which identify the patient at risk of anaphylaxis from penicillin. These patients can be given penicillin in a carefully monitored desensitization protocol. It is essential to establish first the absolute requirement for the drug in the patient sensitive to it. There are also established methods for administration to the sensitive patient: local anesthetics, measles vaccines, and sulfamethoxazole.

  12. [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.

  13. Hyperspectral imaging to identify salt-tolerant wheat lines

    Science.gov (United States)

    Moghimi, Ali; Yang, Ce; Miller, Marisa E.; Kianian, Shahryar; Marchetto, Peter

    2017-05-01

    In order to address the worldwide growing demand for food, agriculture is facing certain challenges and limitations. One of the important threats limiting crop productivity is salinity. Identifying salt tolerate varieties is crucial to mitigate the negative effects of this abiotic stress in agricultural production systems. Traditional measurement methods of this stress, such as biomass retention, are labor intensive, environmentally influenced, and often poorly correlated to salinity stress alone. In this study, hyperspectral imaging, as a non-destructive and rapid method, was utilized to expedite the process of identifying relatively the most salt tolerant line among four wheat lines including Triticum aestivum var. Kharchia, T. aestivum var. Chinese Spring, (Ae. columnaris) T. aestivum var. Chinese Spring, and (Ae. speltoides) T. aestivum var. Chinese Spring. To examine the possibility of early detection of a salt tolerant line, image acquisition was started one day after stress induction and continued on three, seven, and 12 days after adding salt. Simplex volume maximization (SiVM) method was deployed to detect superior wheat lines in response to salt stress. The results of analyzing images taken as soon as one day after salt induction revealed that Kharchia and (columnaris)Chinese Spring are the most tolerant wheat lines, while (speltoides) Chinese Spring was a moderately susceptible, and Chinese Spring was a relatively susceptible line to salt stress. These results were confirmed with the measuring biomass performed several weeks later.

  14. Rapid Cycling and Its Treatment

    Science.gov (United States)

    ... Announcements Public Service Announcements Partnering with DBSA Rapid Cycling and its Treatment What is bipolar disorder? Bipolar ... to Depression and Manic Depression . What is rapid cycling? Rapid cycling is defined as four or more ...

  15. Evolutionary potential of upper thermal tolerance: biogeographic patterns and expectations under climate change.

    Science.gov (United States)

    Diamond, Sarah E

    2017-02-01

    How will organisms respond to climate change? The rapid changes in global climate are expected to impose strong directional selection on fitness-related traits. A major open question then is the potential for adaptive evolutionary change under these shifting climates. At the most basic level, evolutionary change requires the presence of heritable variation and natural selection. Because organismal tolerances of high temperature place an upper bound on responding to temperature change, there has been a surge of research effort on the evolutionary potential of upper thermal tolerance traits. Here, I review the available evidence on heritable variation in upper thermal tolerance traits, adopting a biogeographic perspective to understand how heritability of tolerance varies across space. Specifically, I use meta-analytical models to explore the relationship between upper thermal tolerance heritability and environmental variability in temperature. I also explore how variation in the methods used to obtain these thermal tolerance heritabilities influences the estimation of heritable variation in tolerance. I conclude by discussing the implications of a positive relationship between thermal tolerance heritability and environmental variability in temperature and how this might influence responses to future changes in climate. © 2016 New York Academy of Sciences.

  16. "Zero Tolerance" for Free Speech.

    Science.gov (United States)

    Hils, Lynda

    2001-01-01

    Argues that school policies of "zero tolerance" of threatening speech may violate a student's First Amendment right to freedom of expression if speech is less than a "true threat." Suggests a two-step analysis to determine if student speech is a "true threat." (PKP)

  17. Fault Tolerance Using Group Communication

    NARCIS (Netherlands)

    Kaashoek, M.F.; Tanenbaum, A.S.

    We propose group communication as an efficient mechanism to support fault tolerance. Our approach is based on an efficient reliable broadcast protocol that requires on average only two messages per broadcast. To illustrate our approach we will describe how the task bag model can be made

  18. New fault tolerant matrix converter

    Energy Technology Data Exchange (ETDEWEB)

    Ibarra, Edorta; Andreu, Jon; Kortabarria, Inigo; Ormaetxea, Enekoitz; Alegria, Inigo Martinez de; Martin, Jose Luis [Department of Electronics and Telecommunications, University of the Basque Country, Alameda de Urquijo s/n, E-48013 Bilbao (Spain); Ibanez, Pedro [TECNALIA, Energy Unit, Parque Tecnologico de Zamudio, E-48170 Bizkaia (Spain)

    2011-02-15

    The matrix converter (MC) presents a promising topology that will have to overcome certain barriers (protection systems, durability, the development of converters for real applications, etc.) in order to gain a foothold in the industry. In some applications, where continuous operation must be insured in the case of a system failure, improved reliability of the converter is of particular importance. In this sense, this article focuses on the study of a fault tolerant MC. The fault tolerance of a converter is characterized by its total or partial response in the case of a breakage of any of its components. Taking into consideration that virtually no work has been done on fault tolerant MCs, this paper describes the most important studies in this area. Moreover, a new method is proposed for detecting the breakage of MC semiconductors. Likewise, a new variation of SVM modulation with failure tolerance capacity is presented. This guarantees the continuous operation of the converter and the pseudo-optimum control of a PMSM. This paper also proposes a novel MC topology, which allows the flexible reconfiguration of this converter, when one or several of its semiconductors are damaged. In this way, the MC can continue operating at 100% of its performance without having to double its resources. In this way, it can be said that the solution described in this article represents a step forward towards the development of reliable matrix converters for real applications. (author)

  19. When Should Sects be Tolerated?

    DEFF Research Database (Denmark)

    Hvithamar, Annika

    2009-01-01

    Jehovas vidners kontroverser med majoritetssamfundet gør dem til et godt test-case for tolerance. I artiklen bruges udviklingen af bevægelsens syn på blodstransfusioner til at diskutere, hvordan institutionaliseringen af en minoritetsbevægelse får kontroversernes styrke til at mindskes, men også ...

  20. ORAL GLUCOSE TOLERANCE TEST REVISITED

    African Journals Online (AJOL)

    0 Abnormal previous glucose result of either impaired fasting plasma glucose ... Population studies for epidemiological data are known indications for oral ... Table I : Factors other than diabetes that may influence oral glucose tolerance test 1. Patient's preparation. 0 Duration of fast. Prior carbohydrate intake. Medications.