Science.gov

Sample records for active drug levels

  1. Drug levels, immunogenicity and assessment of active sacroiliitis in patients with axial spondyloarthritis under biologic tapering strategy.

    PubMed

    Almirall, Miriam; Gimeno, Ramón; Salman-Monte, Tarek Carlos; Iniesta, Silvia; Lisbona, Maria Pilar; Maymó, Joan

    2016-04-01

    The aim of the study was to assess drug levels, immunogenicity and sacroiliitis on MRI in patients with axial spondyloarthritis under biologic tapering strategy. Consecutive patients with axial spondyloarthritis who remained in low disease activity more than 1 year after dose tapering of infliximab and adalimumab were included. Plasma drug concentrations of TNF inhibitors and anti-drug antibodies were determined, and MRI of sacroiliac joints was evaluated. Of twenty patients included, eighteen had therapeutic drug levels, no patient had anti-drug antibodies, and no patient had active sacroiliitis on MRI. These data could support the biologic tapering strategy and their maintenance over time.

  2. Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite.

    PubMed

    Agarwal, Varsha; Kommaddi, Reddy P; Valli, Khader; Ryder, Daniel; Hyde, Thomas M; Kleinman, Joel E; Strobel, Henry W; Ravindranath, Vijayalakshmi

    2008-06-11

    Cytochrome P450 (P450) is a super-family of drug metabolizing enzymes. P450 enzymes have dual function; they can metabolize drugs to pharmacologically inactive metabolites facilitating their excretion or biotransform them to pharmacologically active metabolites which may have longer half-life than the parent drug. The variable pharmacological response to psychoactive drugs typically seen in population groups is often not accountable by considering dissimilarities in hepatic metabolism. Metabolism in brain specific nuclei may play a role in pharmacological modulation of drugs acting on the CNS and help explain some of the diverse response to these drugs seen in patient population. P450 enzymes are also present in brain where drug metabolism can take place and modify therapeutic action of drugs at the site of action. We have earlier demonstrated an intrinsic difference in the biotransformation of alprazolam (ALP) in brain and liver, relatively more alpha-hydroxy alprazolam (alpha-OHALP) is formed in brain as compared to liver. In the present study we show that recombinant CYP3A43 metabolizes ALP to both alpha-OHALP and 4-hydroxy alprazolam (4-OHALP) while CYP3A4 metabolizes ALP predominantly to its inactive metabolite, 4-OHALP. The expression of CYP3A43 mRNA in human brain samples correlates with formation of relatively higher levels of alpha-OH ALP indicating that individuals who express higher levels of CYP3A43 in the brain would generate larger amounts of alpha-OHALP. Further, the expression of CYP3A43 was relatively higher in brain as compared to liver across different ethnic populations. Since CYP3A enzymes play a prominent role in the metabolism of drugs, the higher expression of CYP3A43 would generate metabolite profile of drugs differentially in human brain and thus impact the pharmacodynamics of psychoactive drugs at the site of action.

  3. Therapeutic drug levels

    MedlinePlus

    ... Principles of drug therapy. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine . 25th ed. Philadelphia, PA: ... Ford MD. Acute poisoning. In: Goldman L, Schafer AI, eds. Goldman-Cecil Medicine . 25th ed. Philadelphia, PA: ...

  4. Decreased glutathione levels and impaired antioxidant enzyme activities in drug-naive first-episode schizophrenic patients

    PubMed Central

    2011-01-01

    Background The aim of this study was to determine glutathione levels and antioxidant enzyme activities in the drug-naive first-episode patients with schizophrenia in comparison with healthy control subjects. Methods It was a case-controlled study carried on twenty-three patients (20 men and 3 women, mean age = 29.3 ± 7.5 years) recruited in their first-episode of schizophrenia and 40 healthy control subjects (36 men and 9 women, mean age = 29.6 ± 6.2 years). In patients, the blood samples were obtained prior to the initiation of neuroleptic treatments. Glutathione levels: total glutathione (GSHt), reduced glutathione (GSHr) and oxidized glutathione (GSSG) and antioxidant enzyme activities: superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) were determined by spectrophotometry. Results GSHt and reduced GSHr were significantly lower in patients than in controls, whereas GSSG was significantly higher in patients. GPx activity was significantly higher in patients compared to control subjects. CAT activity was significantly lower in patients, whereas the SOD activity was comparable to that of controls. Conclusion This is a report of decreased plasma levels of GSHt and GSHr, and impaired antioxidant enzyme activities in drug-naive first-episode patients with schizophrenia. The GSH deficit seems to be implicated in psychosis, and may be an important indirect biomarker of oxidative stress in schizophrenia early in the course of illness. Finally, our results provide support for further studies of the possible role of antioxidants as neuroprotective therapeutic strategies for schizophrenia from early stages. PMID:21810251

  5. Correlations between immunogenicity, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab.

    PubMed

    Benucci, Maurizio; Meacci, Francesca; Grossi, Valentina; Infantino, Maria; Manfredi, Mariangela; Bellio, Emanuele; Bellio, Valerio; Li Gobbi, Francesca; Bazzichi, Laura; Moscato, Paolo; Caputo, Dario; Saviola, Gianantonio; Talotta, Rossella; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola

    2016-01-01

    The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59±12 years, range 26-83; mean disease duration 11±5 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6±1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4±1.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of >3.2, an erythrocyte sedimentation rate (ESR) of >30 mm/hour, and CRP levels of >1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-α; and IL-6. TCZ and anti-TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of <10 µg/mL were considered low and >10 µg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of <10 µg/mL and the 42 with TCZ levels of >10 µg/mL showed the following differences: DAS28: 3.09±1.32 vs 2.78±1.32, P=0.0005; ESR: 27±14.8 vs 14±12 mm/hour, P=0.0001; CRP: 1.47±1.05 vs 0.65±0.80 mg/dL, P=0.0086; TNF-α: 10.2±1.2 vs 9.9±1.1 pg/mL, P=0.999; IL-6: 3.65±4.75 vs 3.62±4.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2±93.7 vs 86.7±90.3 IU/mL, P=0.94; RF IgM: 72.4±62.7 vs 68.3±61.6 IU/mL, P=0.754; RF IgA: 41.7±36.4 vs 47.8±42.1 U/mL, P=0.449; and RF IgG: 46.4±46.1 vs 59.3±58.2 U/mL, P=0.212. These findings show

  6. Correlations between immunogenicity, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab

    PubMed Central

    Benucci, Maurizio; Meacci, Francesca; Grossi, Valentina; Infantino, Maria; Manfredi, Mariangela; Bellio, Emanuele; Bellio, Valerio; Li Gobbi, Francesca; Bazzichi, Laura; Moscato, Paolo; Caputo, Dario; Saviola, Gianantonio; Talotta, Rossella; Sarzi-Puttini, Piercarlo; Atzeni, Fabiola

    2016-01-01

    The aim of this study was to evaluate the real-life immunogenicity of anti-drug antibodies, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab (TCZ). We evaluated 126 TCZ-treated patients with rheumatoid arthritis (16 males and 110 females; mean age 59±12 years, range 26–83; mean disease duration 11±5 years) with inadequate 12-week response to any synthetic and biological disease-modifying anti-rheumatic drugs, in a retrospective analysis. One-hundred and seven patients were treated with methotrexate mean dose 12.6±1.3 mg/week in combination with TCZ, 13 received TCZ monotherapy, and six received leflunomide 20 mg/day plus TCZ; all patients were treated with prednisone mean dose 6.4±1.2 mg/day. They had a 28-joint Disease Activity Score (DAS28) of >3.2, an erythrocyte sedimentation rate (ESR) of >30 mm/hour, and CRP levels of >1.0 mg/dL. We evaluated at baseline and after 6 months of treatment: DAS28; rheumatoid factor (RF) IgM, IgA, and IgG; anti-citrullinated peptide antibody; ESR; CRP; TNF-α; and IL-6. TCZ and anti-TCZ antibodies were detected using LISA-TRACKER Duo TCZ. TCZ levels of <10 µg/mL were considered low and >10 µg/mL high. After 6 months of treatment only one patient was positive for anti-TCZ antibodies. There were correlations between DAS28, ESR, and CRP and IL-6 levels in all patients. Comparison of the 84 patients with TCZ levels of <10 µg/mL and the 42 with TCZ levels of >10 µg/mL showed the following differences: DAS28: 3.09±1.32 vs 2.78±1.32, P=0.0005; ESR: 27±14.8 vs 14±12 mm/hour, P=0.0001; CRP: 1.47±1.05 vs 0.65±0.80 mg/dL, P=0.0086; TNF-α: 10.2±1.2 vs 9.9±1.1 pg/mL, P=0.999; IL-6: 3.65±4.75 vs 3.62±4.41 pg/mL, P=0.97; anti-citrullinated peptide antibody: 85.2±93.7 vs 86.7±90.3 IU/mL, P=0.94; RF IgM: 72.4±62.7 vs 68.3±61.6 IU/mL, P=0.754; RF IgA: 41.7±36.4 vs 47.8±42.1 U/mL, P=0.449; and RF IgG: 46.4±46.1 vs 59.3±58.2 U/mL, P=0.212. These findings show

  7. P450 inhibitor ketoconazole increased the intratumor drug levels and antitumor activity of fenretinide in human neuroblastoma xenograft models.

    PubMed

    Lopez-Barcons, Lluis; Maurer, Barry J; Kang, Min H; Reynolds, C Patrick

    2017-03-24

    We previously reported that concurrent ketoconazole, an oral anti-fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4-HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4-HPR cytotoxic dose-response in four neuroblastoma (NB) cell lines in vitro and on 4-HPR activity against two cell line-derived, subcutaneous NB xenografts (CDX) and three patient-derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay. Xenografted animals were treated with 4-HPR/LXS (240 mg/kg/day) + ketoconazole (38 mg/kg/day) in divided oral doses in cycles of five continuous days a week. In one model, intratumoral levels of 4-HPR and metabolites were assessed by HPLC assay, and in two models intratumoral apoptosis was assessed by TUNEL assay, on Day 5 of the first cycle. Antitumor activity was assessed by Kaplan-Meier event-free survival (EFS). The in vitro cytotoxicity of 4-HPR was not affected by ketoconazole (P ≥ 0.06). Ketoconazole increased intratumoral levels of 4-HPR (P = 0.02), of the active 4-oxo-4-HPR metabolite (P = 0.04), and intratumoral apoptosis (P ≤ 0.002), compared to 4-HPR/LXS-alone. Concurrent ketoconazole increased EFS in both CDX models compared to 4-HPR/LXS-alone (P ≤ 0.01). 4-HPR + ketoconazole also increased EFS in PDX models compared to controls (P ≤ 0.03). Thus, concurrent ketoconazole decreased 4-HPR metabolism with resultant increases of plasma and intratumoral drug levels and antitumor effects in neuroblastoma murine xenografts. These results support the clinical testing of concurrent ketoconazole and oral fenretinide in neuroblastoma. This article is protected by copyright. All rights reserved.

  8. Investigational small-molecule drug selectively suppresses constitutive CYP2B6 activity at the gene transcription level: physiologically based pharmacokinetic model assessment of clinical drug interaction risk.

    PubMed

    Zamek-Gliszczynski, Maciej J; Mohutsky, Michael A; Rehmel, Jessica L F; Ke, Alice B

    2014-06-01

    The glycogen synthase kinase-3 inhibitor LY2090314 specifically impaired CYP2B6 activity during in vitro evaluation of cytochrome P450 (P450) enzyme induction in human hepatocytes. CYP2B6 catalytic activity was significantly decreased following 3-day incubation with 0.1-10 μM LY2090314, on average by 64.3% ± 5.0% at 10 μM. These levels of LY2090314 exposure were not cytotoxic to hepatocytes and did not reduce CYP1A2 and CYP3A activities. LY2090314 was not a time-dependent CYP2B6 inhibitor, did not otherwise inhibit enzyme activity at concentrations ≤10 μM, and was not metabolized by CYP2B6. Thus, mechanism-based inactivation or other direct interaction with the enzyme could not explain the observed reduction in CYP2B6 activity. Instead, LY2090314 significantly reduced CYP2B6 mRNA levels (Imax = 61.9% ± 1.4%; IC50 = 0.049 ± 0.043 μM), which were significantly correlated with catalytic activity (r(2) = 0.87, slope = 0.77; Imax = 57.0% ± 10.8%, IC50 = 0.057 ± 0.027 μM). Direct inhibition of constitutive androstane receptor by LY2090314 is conceptually consistent with the observed CYP2B6 transcriptional suppression (Imax = 100.0% ± 10.8% and 57.1% ± 2.4%; IC50 = 2.5 ± 1.2 and 2.1 ± 0.4 μM for isoforms 1 and 3, respectively) and may be sufficiently extensive to overcome the weak but potent activation of pregnane X receptor by ≤10 μM LY2090314 (19.3% ± 2.2% of maximal rifampin response, apparent EC50 = 1.2 ± 1.1 nM). The clinical relevance of these findings was evaluated through physiologically based pharmacokinetic model simulations. CYP2B6 suppression by LY2090314 is not expected clinically, with a projected <1% decrease in hepatic enzyme activity and <1% decrease in hydroxybupropion exposure following bupropion coadministration. However, simulations showed that observed CYP2B6 suppression could be clinically relevant for a drug with different pharmacokinetic properties from LY2090314.

  9. Plasma level monitoring of antipsychotic drugs.

    PubMed

    Cooper, T B

    1978-01-01

    Psychotic patients treated with identical doses of antipsychotic drugs have been shown to have great interindividual differences in their steady state plasma concentration. Therefore, monitoring treatment by dosage adjustment alone is of little value. If antipsychotic blood levels can be related to clinical response then their routine measurement may well result in well defined guidelines to individualised optimal dosage. Despite the considerable effort expended in this field and the many interesting testable hypotheses generated, little substantive evidence for an acceptable plasma level monitoring guide has been reported to date. Work on metabolite level profiles, intra- and extracellular drug concentration differences, more detailed clinical rating scales, and improved experimental design, all show great promise for the future. Investigation of the pharmacokinetics and the elucidation of the often complex metabolic pathways of individual antipsychotic drugs are generating the data base required for the rational pharmacotherapy of these most severely ill patients. Until more data are available, routine monitoring of antipsychotic drug plasma levels remains of research interest.

  10. Contraband drug surface chemistry at nanogram levels

    NASA Astrophysics Data System (ADS)

    Homstead, Juliana; Poziomek, Edward J.

    1997-02-01

    The surface chemistry of contraband drugs is very important in many detection techniques. It is also important in choosing materials for sampling and sample handling. The chemical nature of surfaces may facilitate drug decomposition or serve to stabilize the drugs. We have developed a simple technique to study the chemistry of contraband drugs such as cocaine HCl at nanogram levels. The normal operating modes of an IONSCAN 400 ion mobility spectrometer were adjusted to allow the chemistry of the drugs to be examined in the sample chamber of the spectrometer. For example, a membrane with deposited drug is held in the sample chamber at a specified temperature up to 20 seconds with no air flow. An ON-OFF valve was placed in- line just before the carrier gas enters the desorption chamber where samples are heated. This modification allows the gas flow to be manually turned off while the sample is being heated. We have used this technique to examine the pyrolysis of cocaine hydrochloride under a variety of conditions. At the end of the designated reaction time, the air flow is turned on allowing the reaction products and any starting materials to flow into the spectrometer for analysis. This technique has allowed studies of the stability of the drugs at various temperatures on different surfaces. For example, evidence was obtained of cocaine HCl decomposition at 75 degrees for 5 seconds using Teflon as the support material. The use of this technique has also assisted us in choosing materials for pyrolysis studies in which the goal is the decompose target drugs quickly and efficiently for detection applications.

  11. Social Disorganization, Drug Market Activity, and Neighborhood Violent Crime

    PubMed Central

    Martínez, Ramiro; Rosenfeld, Richard; Mares, Dennis

    2009-01-01

    Although illicit drug activity occurs within local communities, past quantitative research on drug markets and violent crime in the United States has been conducted mainly at the city level. The authors use neighborhood-level data from the city of Miami to test hypotheses regarding the effect of drug activity and traditional indicators of social disorganization on rates of aggravated assault and robbery. The results show that drug activity has robust effects on violent crime that are independent of other disorganization indicators. The authors also find that drug activity is concentrated in neighborhoods with low rates of immigration, less linguistic isolation and ethnic heterogeneity, and where nondrug accidental deaths are prevalent. The authors find no independent effect of neighborhood racial composition on drug activity or violent crime. The results suggest that future neighborhood-level research on social disorganization and violent crime should devote explicit attention to the disorganizing and violence-producing effects of illicit drug activity. PMID:19655037

  12. 10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites...

  13. 10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites...

  14. 10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites...

  15. 10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites...

  16. 10 CFR 26.133 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Cutoff levels for drugs and drug metabolites. 26.133... § 26.133 Cutoff levels for drugs and drug metabolites. Subject to the provisions of § 26.31(d)(3)(iii), licensees and other entities may specify more stringent cutoff levels for drugs and drug metabolites...

  17. [Level of evidence for therapeutic drug monitoring of itraconazole].

    PubMed

    Charles, Marie; Le Guellec, Chantal; Richard, Damien; Libert, Frédéric

    2011-01-01

    Itraconazole is a triazole antifungal agent that is active against Aspergillus, histoplasmosis, and rare fungal infections. Itraconazole exhibit marked variability in drug concentration as a result of inconsistent absorption, metabolism, or interaction with concomitant medications. Preclinical and clinical data have exhibited a relationship between serum concentrations and treatment efficacy or toxicity, thus therapeutic drug monitoring (TDM) of itraconazole is largely used to optimise therapy. The analysis of bibliographic data demonstrate that, even if the utility of itraconazole's TDM has not been proved by randomized controlled trial or pharmaco-economics studies, it could be useful for managing an absence of response or a drug-drug interactions, or interpreting an adverse effect. However, the interest of this monitoring was proved only in some populations of patients (neutropenics or AIDS patients) so its level of proof varies between levels "potentially useful" and "recommended".

  18. 10 CFR 26.163 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Cutoff levels for drugs and drug metabolites. 26.163... the Department of Health and Human Services § 26.163 Cutoff levels for drugs and drug metabolites. (a) Initial drug testing. (1) HHS-certified laboratories shall apply the following cutoff levels for...

  19. 10 CFR 26.163 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 1 2012-01-01 2012-01-01 false Cutoff levels for drugs and drug metabolites. 26.163... the Department of Health and Human Services § 26.163 Cutoff levels for drugs and drug metabolites. (a) Initial drug testing. (1) HHS-certified laboratories shall apply the following cutoff levels for...

  20. 10 CFR 26.163 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 1 2011-01-01 2011-01-01 false Cutoff levels for drugs and drug metabolites. 26.163... the Department of Health and Human Services § 26.163 Cutoff levels for drugs and drug metabolites. (a) Initial drug testing. (1) HHS-certified laboratories shall apply the following cutoff levels for...

  1. 10 CFR 26.163 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 1 2013-01-01 2013-01-01 false Cutoff levels for drugs and drug metabolites. 26.163... the Department of Health and Human Services § 26.163 Cutoff levels for drugs and drug metabolites. (a) Initial drug testing. (1) HHS-certified laboratories shall apply the following cutoff levels for...

  2. 10 CFR 26.163 - Cutoff levels for drugs and drug metabolites.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 1 2014-01-01 2014-01-01 false Cutoff levels for drugs and drug metabolites. 26.163... the Department of Health and Human Services § 26.163 Cutoff levels for drugs and drug metabolites. (a) Initial drug testing. (1) HHS-certified laboratories shall apply the following cutoff levels for...

  3. 32 CFR 637.7 - Drug enforcement activities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Drug enforcement activities. 637.7 Section 637.7... CRIMINAL INVESTIGATIONS MILITARY POLICE INVESTIGATION Investigations § 637.7 Drug enforcement activities. Provost marshals and U.S. Army law enforcement supervisors at all levels will ensure that active...

  4. 32 CFR 637.7 - Drug enforcement activities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Drug enforcement activities. 637.7 Section 637.7... CRIMINAL INVESTIGATIONS MILITARY POLICE INVESTIGATION Investigations § 637.7 Drug enforcement activities. Provost marshals and U.S. Army law enforcement supervisors at all levels will ensure that active...

  5. Stress Levels of Recovering Drug Addicts.

    ERIC Educational Resources Information Center

    LaMon, Brent C.; Alonzo, Anthony

    It appears that chronic drug use may develop as a means of coping in which individuals use self-medication to produce a more desirable state of being. Because drugs are often used to cope with stress, this study examined stress among recovering male drug addicts (N=23) from an urban substance abuse program by administering a self-report inventory…

  6. Systems Level Neuroplasticity in Drug Addiction

    PubMed Central

    Feltenstein, Matthew W.

    2013-01-01

    Drug addiction is a chronic relapsing disorder for which research has been dedicated to understand the various factors that contribute to development, loss of control, and persistence of compulsive addictive behaviors. In this review, we provide a broad overview of various theories of addiction, drugs of abuse, and the neurobiology involved across the addiction cycle. Specific focus is devoted to the role of the mesolimbic pathway in acute drug reinforcement and occasional drug use, the mesocortical pathway and associated areas (e.g., the dorsal striatum) in escalation/dependence, and the involvement of these pathways and associated circuits in mediating conditioned responses, drug craving, and loss of behavioral control thought to underlie withdrawal and relapse. With a better understanding of the neurobiological factors that underlie drug addiction, continued preclinical and clinical research will aid in the development of novel therapeutic interventions that can serve as effective long-term treatment strategies for drug-dependent individuals. PMID:23580792

  7. [Level of evidence for therapeutic drug monitoring for docetaxel].

    PubMed

    Gerritsen-van Schieveen, Pauline; Royer, Bernard

    2010-01-01

    Pharmacokinetic properties of docetaxel, an anticancer drug, are though to be interesting for therapeutic drug monitoring: high inter- and intra-variability, relationship between exposure and efficacy and especially toxicity. Moreover, the 3-weekly administration, which is the more effective scheme, is also the more toxic. However, neutropenia can be modeled and be efficiently predicted without needing plasma drug concentrations. The level evidence of therapeutic drug monitoring is thus weak regarding the possibility to adapt dose regimen without drug concentrations.

  8. The effect of antidepressant drugs on the HPA axis activity, glucocorticoid receptor level and FKBP51 concentration in prenatally stressed rats.

    PubMed

    Szymańska, Magdalena; Budziszewska, Bogusława; Jaworska-Feil, Lucylla; Basta-Kaim, Agnieszka; Kubera, Marta; Leśkiewicz, Monika; Regulska, Magdalena; Lasoń, Władysław

    2009-07-01

    Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity is thought to be an important factor in pathogenesis of depression. In animals, stress or glucocorticoids given in prenatal period lead to long-lasting behavioral and neuroendocrine changes similar to those observed in depressed patients. However, molecular basis for HPA disturbances in animals exposed to prenatal stress - a model of depression - have been only partially recognized. Therefore, in the present study we investigated the effect of prenatal stress on behavioral changes, blood corticosterone level, concentrations of glucocorticoid receptor (GR) and its cochaperone, FKBP51, in the hippocampus and frontal cortex in adult rats. It has been found that prenatally stressed rats display high level of immobility in the Porsolt test and anxiety-like behavior. The HPA axis hyperactivity in theses animals was evidenced by corticosterone hypersecretion at the end of the light phase and 1h following acute stress. Western blot study revealed that GR level was significantly elevated in the hippocampus but not in the frontal cortex of prenatally stressed rats, whereas concentration of FKBP51 was decreased only in the former brain structure. Chronic treatment with imipramine, fluoxetine, mirtazapine and tianeptine have diminished both behavioral and biochemical alterations observed in this animal model of depression. These data indicate that the increase in hippocampal GR level and low concentration of FKBP51 in the frontal cortex may be responsible for enhanced glucocorticoid action in depression.

  9. Cisplatin and platinum drugs at the molecular level. (Review).

    PubMed

    Boulikas, Teni; Vougiouka, Maria

    2003-01-01

    Over twenty years of intensive work toward improvement of cisplatin, and with hundreds of platinum drugs tested, has resulted in the introduction of the widely used carboplatin and of oxaliplatin used only for a very narrow spectrum of cancers. A number of interesting platinum compounds including the orally administered platinum drug JM216, nedaplatin, the sterically hindered platinum(II) complex ZD0473, the trinuclear platinum complex BBR3464, and the liposomal forms Lipoplatin and SPI-77 are under clinical evaluation. This review summarizes the molecular mechanisms of platinum compounds for DNA damage, DNA repair and induction of apoptosis via activation or modulation of signaling pathways and explores the basis of platinum resistance. Cisplatin, carboplatin, oxaliplatin and most other platinum compounds induce damage to tumors via induction of apoptosis; this is mediated by activation of signal transduction leading to the death receptor mechanisms as well as mitochondrial pathways. Apoptosis is responsible for the characteristic nephrotoxicity, ototoxicity and most other toxicities of the drugs. The major limitation in the clinical applications of cisplatin has been the development of cisplatin resistance by tumors. Mechanisms explaining cisplatin resistance include the reduction in cisplatin accumulation inside cancer cells because of barriers across the cell membrane, the faster repair of cisplatin adducts, the modulation of apoptotic pathways in various cells, the upregulation in transcription factors, the loss of p53 and other protein functions and a higher concentration of glutathione and metallothioneins in some type of tumors. A number of experimental strategies to overcome cisplatin resistance are at the preclinical or clinical level such as introduction of the bax gene, inhibition of the JNK pathway, introduction of a functional p53 gene, treatment of tumors with aldose reductase inhibitors and others. Particularly important are combinations of platinum

  10. Taking Risks: Activities and Materials for Teaching About Alcohol, Other Drugs, and Traffic Safety. Book 2, Secondary Level (Grades 7 and 10).

    ERIC Educational Resources Information Center

    Resnik, Henry S.; And Others

    This guide is designed to help teachers instruct students in the areas of alcohol, drugs, and traffic safety. It consists of two units, targeted to seventh-grade students and the other to tenth-grade students. Each unit can be used over a two-week period. The lesson plans and related materials focus on helping students gain insight into factors…

  11. Taking Risks: Activities and Materials for Teaching About Alcohol, Other Drugs, and Traffic Safety. Book 1, Elementary Level (Grades 3 and 5).

    ERIC Educational Resources Information Center

    Resnik, Henry S.; And Others

    This guide is designed to help teachers instruct students in the areas of alcohol, drugs and traffic safety. It consists of two units targeted to third-grade students and the other to fifth-grade students. Each unit can be used over a two-week period. The lesson plans and related materials focus on helping students gain insight into factors that…

  12. Controlled prescription drug abuse at epidemic level.

    PubMed

    2006-01-01

    In July 2005, The National Center on Addiction and Substance Abuse (CASA) at Columbia University announced the results of a study indicating that the number of Americans who abuse controlled prescription drugs has nearly doubled from 7.8 million to 15.1 million from 1992 to 2003 and abuse among teens has more than tripled during that time. A summary of that study and information about the full report are presented.

  13. Computational simulation of drug delivery at molecular level.

    PubMed

    Li, Youyong; Hou, Tingjun

    2010-01-01

    The field of drug delivery is advancing rapidly. By controlling the precise level and/or location of a given drug in the body, side effects are reduced, doses are lowered, and new therapies are possible. Nonetheless, substantial challenges remain for delivering specific drugs into specific cells. Computational methods to predict the binding and dynamics between drug molecule and its carrier are increasingly desirable to minimize the investment in drug design and development. Significant progress in computational simulation is making it possible to understand the mechanism of drug delivery. This review summarizes the computational methods and progress of four categories of drug delivery systems: dendrimers, polymer micelle, liposome and carbon nanotubes. Computational simulations are particularly valuable in designing better drug carriers and addressing issues that are difficult to be explored by laboratory experiments, such as diffusion, dynamics, etc.

  14. Discovering New Drugs on the Cellular Level

    NASA Technical Reports Server (NTRS)

    2005-01-01

    With the Vision for Space Exploration calling for a sustained human presence in space, astronauts will need to grow plants, while in orbit, for nourishment that they will not receive from only consuming dehydrated foods. As a potential source of food for long-duration missions, space-grown plants could also give astronauts an important psychological boost, as fresh vegetables could serve as a welcomed change from monotonous meals consisting of reconstituted foods in plastic bags. Even more, these plants could likely aid in the recycling of air and wastewater on spacecraft. With a helping hand from a company by the name of Biolog, Inc., NASA is studying the impacts of decreased gravity and spaceborne bacteria on the plants being grown for food in space. With a helping hand from NASA, this very same company is creating powerful new cell- and bacteria-analysis tools for use in discovering and developing new drugs on Earth.

  15. [Level of evidence for therapeutic drug monitoring for paclitaxel].

    PubMed

    Gerritsen-van Schieveen, Pauline; Royer, Bernard

    2010-01-01

    Paclitaxel is an anticancer drug which displays pharmacokinetic properties which can lead to therapeutic drug monitoring requirement. The most effective pharmacokinetic parameter seems to be the time during which the plasma concentration is over 0.05 micromol/L. However, this target needs to be validated with new weekly schedules of administration. These reasons lead to consider the level of evidence of therapeutic drug monitoring of paclitaxel as potentially useful.

  16. Airborne drug levels in a laminar-flow hood

    SciTech Connect

    Kleinberg, M.L.; Quinn, M.J.

    1981-09-01

    The airborne levels of fluorouracil and cefazolin sodium injections after manipulation of these drug products inside a horizontal laminar-flow hood were measured. The Biotest RCS Centrifugal Air Sampler, generally used to measure microbial levels in air, was adapted with a paper filter to measure drug levels in air. In each of nine trials, five ampuls of fluorouracil were opened in the hood and transferred to empty vials. Likewise, in each of nine trials, 50 vials of cefazolin sodium 1 g were reconstituted and transferred to small-volume i.v. solutions. Drug manipulations were performed between the hood's filter and the Biotest, which was placed inside the hood. Drug collected on the filter in the Biotest was assayed with ultraviolet spectrophotometry after extraction. The range of fluorouracil collected by the Biotest was from 0 to 14 microgram, corresponding to 0-0.07 microgram/liter of sample air. Recovered cefazolin sodium ranged from 28 to 131 microgram, or 0.02-0.11 microgram/liter of sampled air. Following routine manipulation of drug products in a laminar-flow hood, the drug can contaminate, the air flowing over the product.

  17. Airborne drug levels in a laminar-flow hood.

    PubMed

    Kleinberg, M L; Quinn, M J

    1981-09-01

    The airborne levels of fluorouracil and cefazolin sodium injections after manipulation of these drug products inside a horizontal laminar-flow hood were measured. The Biotest RCS Centrifugal Air Sampler, generally used to measure microbial levels in air, was adapted with a paper filter to measure drug levels in air. In each of nine trials, five ampuls of fluorouracil were opened in the hood and transferred to empty vials. Likewise, in each of nine trials, 50 vials of cefazolin sodium 1 g were reconstituted and transferred to small-volume i.v. solutions. Drug manipulations were performed between the hood's filter and the Biotest, which was placed inside the hood. Drug collected on the filter in the Biotest was assayed with ultraviolet spectrophotometry after extraction. The range of fluorouracil collected by the Biotest was from 0 to 14 microgram, corresponding to 0-0.07 microgram/liter of sample air. Recovered cefazolin sodium ranged from 28 to 131 microgram, or 0.02-0.11 microgram/liter of sampled air. Following routine manipulation of drug products in a laminar-flow hood, the drug can contaminate, the air flowing over the product.

  18. Plasma drug activity assay for treatment optimization in tuberculosis patients.

    PubMed

    Heysell, Scott K; Mtabho, Charles; Mpagama, Stellah; Mwaigwisya, Solomon; Pholwat, Suporn; Ndusilo, Norah; Gratz, Jean; Aarnoutse, Rob E; Kibiki, Gibson S; Houpt, Eric R

    2011-12-01

    Low antituberculosis (TB) drug levels are common, but their clinical significance remains unclear, and methods of measurement are resource intensive. Subjects initiating treatment for sputum smear-positive pulmonary TB were enrolled from Kibong'oto National TB Hospital, Tanzania, and levels of isoniazid, rifampin, ethambutol, and pyrazinamide were measured at the time of typical peak plasma concentration (C(2 h)). To evaluate the significance of the effect of observed drug levels on Mycobacterium tuberculosis growth, a plasma TB drug activity (TDA) assay was developed using the Bactec MGIT system. Time to detection of plasma-cocultured M. tuberculosis versus time to detection of control growth was defined as a TDA ratio. TDA assays were later performed using the subject's own M. tuberculosis isolate and C(2 h) plasma from the Tanzanian cohort and compared to drug levels and clinical outcomes. Sixteen subjects with a mean age of 37.8 years ± 10.7 were enrolled. Fourteen (88%) had C(2 h) rifampin levels and 11 (69%) had isoniazid levels below 90% of the lower limit of the expected range. Plasma spiked with various concentrations of antituberculosis medications found TDA assay results to be unaffected by ethambutol or pyrazinamide. Yet with a range of isoniazid and rifampin concentrations, TDA exhibited a statistically significant correlation with drug level and drug MIC, and a TDA of ~1.0 indicated the presence of multidrug-resistant TB. In Tanzania, low (≤ 2.0) TDA was significantly associated with both lower isoniazid and rifampin C(2 h) levels, and very low (≤ 1.5) TDA corresponded to a trend toward lack of cure. Study of TDA compared to additional clinical outcomes and as a therapeutic management tool is warranted.

  19. 32 CFR 637.7 - Drug enforcement activities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CRIMINAL INVESTIGATIONS MILITARY POLICE INVESTIGATION Investigations § 637.7 Drug enforcement activities... initial, interim and final military police reports concerning drug investigations will be provided to...

  20. 32 CFR 637.7 - Drug enforcement activities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... CRIMINAL INVESTIGATIONS MILITARY POLICE INVESTIGATION Investigations § 637.7 Drug enforcement activities... initial, interim and final military police reports concerning drug investigations will be provided to...

  1. 32 CFR 637.7 - Drug enforcement activities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... CRIMINAL INVESTIGATIONS MILITARY POLICE INVESTIGATION Investigations § 637.7 Drug enforcement activities... initial, interim and final military police reports concerning drug investigations will be provided to...

  2. High Levels of Transmitted HIV Drug Resistance in a Study in Papua New Guinea

    PubMed Central

    Lavu, Evelyn; Kave, Ellan; Mosoro, Euodia; Markby, Jessica; Aleksic, Eman; Gare, Janet; Elsum, Imogen A.; Nano, Gideon; Kaima, Petronia; Dala, Nick; Gurung, Anup; Bertagnolio, Silvia; Crowe, Suzanne M.; Myatt, Mark

    2017-01-01

    Introduction Papua New Guinea is a Pacific Island nation of 7.3 million people with an estimated HIV prevalence of 0.8%. ART initiation and monitoring are guided by clinical staging and CD4 cell counts, when available. Little is known about levels of transmitted HIV drug resistance in recently infected individuals in Papua New Guinea. Methods Surveillance of transmitted HIV drug resistance in a total of 123 individuals recently infected with HIV and aged less than 30 years was implemented in Port Moresby (n = 62) and Mount Hagen (n = 61) during the period May 2013-April 2014. HIV drug resistance testing was performed using dried blood spots. Transmitted HIV drug resistance was defined by the presence of one or more drug resistance mutations as defined by the World Health Organization surveillance drug resistance mutations list. Results The prevalence of non-nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 16.1% (95% CI 8.8%-27.4%) and 8.2% (95% CI 3.2%-18.2%) in Port Moresby and Mount Hagen, respectively. The prevalence of nucleoside reverse transcriptase inhibitor transmitted HIV drug resistance was 3.2% (95% CI 0.2%-11.7%) and 3.3% (95% CI 0.2%-11.8%) in Port Moresby and Mount Hagen, respectively. No protease inhibitor transmitted HIV drug resistance was observed. Conclusions The level of non-nucleoside reverse transcriptase inhibitor drug resistance in antiretroviral drug naïve individuals recently infected with HIV in Port Moresby is amongst the highest reported globally. This alarming level of transmitted HIV drug resistance in a young sexually active population threatens to limit the on-going effective use of NNRTIs as a component of first-line ART in Papua New Guinea. To support the choice of nationally recommended first-line antiretroviral therapy, representative surveillance of HIV drug resistance among antiretroviral therapy initiators in Papua New Guinea should be urgently implemented. PMID:28146591

  3. Antiplatelet activity of flavonoid and coumarin drugs.

    PubMed

    Zaragozá, Cristina; Monserrat, Jorge; Mantecón, Carolina; Villaescusa, Lucinda; Zaragozá, Francisco; Álvarez-Mon, Melchor

    2016-12-01

    Polyphenols are used as phlebotonic drugs, but their mechanism of action remains unknown. Since platelet activity and platelet-endothelial cell interactions are involved in the pathogenesis of cardiovascular disease, this work examines whether different flavonoid and coumarin drugs are able to inhibit platelet aggregation. This specific case of coumarins, the antiplatelet effect is not linked with a possible interaction over blood coagulation since this effect only dicoumarols have it. The antiplatelet capacity of polyphenols was assayed using peripheral blood platelets from healthy controls. The distribution of the different platelets subsets was quantified by flow cytometry, using the calcium ionophore as a pro-aggregant. The number of GPIIb/IIIa receptors occupied by the drugs was assayed by flow cytometry using two CD61 surface fluorescein antibodies. All the polyphenols tested inhibited platelet aggregation. A percentage antiplatelet activity of 88.91±7.98% was recorded for naringin, 48.43±8.84% for naringenin, 53.83±7.87% for esculetin, 54.65±6.91% for fraxetin, and 25.75±4.12% for coumarin. Naringin showed significantly greater percentage occupation of GPIIb/IIIa receptors than did naringenin (14.82±0.81% vs. 3.90±0.55%), and esculetin returned significantly higher values than fraxetin and coumarin (12.47±0.97 vs. 7.53±0.49 and 7.90±0.69 respectively). All drugs show important antiplatelet activity. Naringin was the best antiplatelet compound, showing the greatest antiplatelet activity and the highest percentage binding of GPIIb/IIIa receptors. However, any of the compounds used could be used in the prevention of cardiovascular disease.

  4. Association between Pregnancy and Active Injection Drug Use and Sex Work among Women Injection Drug Users in Saint Petersburg, Russia.

    PubMed

    Girchenko, P; Ompad, D C; Bikmukhametov, D; Gensburg, L

    2015-06-01

    Widespread use of unsafe sexual practices among women injecting drugs both practicing and not practicing sex work leads to high levels of unplanned pregnancies in this population. The goal of this study was to investigate the association between pregnancy and active drug use and sex work. Data were collected using a convenience sample of 500 women in Saint Petersburg, Russia, in 2013. All women had recent experience of drug use, of which 200 were pregnant at the time of the study. The study consisted of a structured interview followed by a rapid HIV test. Pregnancy was protective against both active drug use and sex work. For HIV-positive women, these associations were stronger than for HIV-negative women: drug use prevalence ratio (PR) was 0.59 vs 0.85; for sex work, the PRs were 0.36 vs 0.64. Higher levels of education were associated with a lower prevalence ratio for active drug use and sex work in all models. Having children was not associated with active drug use or sex work. Pregnancy might be an optimal time for conducting interventions aimed at cessation of drug use and sex work among women injecting drugs.

  5. Medicinal chemistry of drugs with active metabolites following conjugation.

    PubMed

    Kalász, Huba; Petroianu, Georg; Hosztafi, Sándor; Darvas, Ferenc; Csermely, Tamás; Adeghate, Ernest; Siddiq, Afshan; Tekes, Kornélia

    2013-10-01

    Authorities of Drug Administration in the United States of America approved about 5000 drugs for use in the therapy or management of several diseases. About two hundred of these drugs have active metabolites and the knowledge of their medicinal chemistry is important both in medical practice and pharmaceutical research. This review gives a detailed description of the medicinal chemistry of drugs with active metabolites generated after conjugation. This review focused on glucuronide-, acetyl-, sulphate- and phosphate-conjugation of drugs, converting the drug into an active metabolite. This conversion essentially changed the lipophilicity of the drug.

  6. Macro-Level Social Forces and Micro-Level Consequences: Poverty, Alternate Occupations, and Drug Dealing

    PubMed Central

    DUNLAP, ELOISE; JOHNSON, BRUCE D.; KOTARBA, JOSEPH A.; FACKLER, JENNIFER L.

    2010-01-01

    This article is an empirical examination of the ways in which macro-level social forces have had micro-level consequences in the New Orleans drug market. The article illustrates a clear connection between poverty and entrance into the drug market, as mitigated by race, lack of societal opportunity, lack of social capital, distressed families, and closed neighborhoods. Specifically, the research illustrates the mechanisms by which macro-level social forces intersect to legitimize drug dealing as a viable alternative method of acquiring money and social capital. These intersecting macro-level social forces, such as poverty, race, family structure, and neighborhood characteristics, ultimately constrain the life chances of those living in the inner city irrespective of personal traits, individual motivations, or private achievements. PMID:20509085

  7. [Level of evidence for therapeutic drug monitoring of everolimus].

    PubMed

    Goirand, Françoise; Royer, Bernard; Hulin, Anne; Saint-Marcoux, Franck

    2011-01-01

    Everolimus has proven efficacy for prevention of rejection in adult de novo renal and cardiac transplant recipient in combination with ciclosporine and corticosteroids. Therapeutic drug monitoring (TDM) with target trough concentration (C0) value from 3 to 8 µg/L has been proposed. Through a systematic review of the literature, this work explored a level of recommendation for this TDM. Everolimus exhibits both wide interindividual pharmacokinetic variability and poor relationship between dose and exposure. A good relationship has been reported between C0 values and global exposure to the drug (i.e. AUC). Although C0 > 3 µg/L has been associated with a decreased incidence of rejection, the upper limit of 8 µg/L has never been formally validated. No clinical trial testing other exposure indices or comparing efficacy and/or toxicity of everolimus therapy with and without TDM has been published so far. Consequently the level of recommendation for everolimus monitoring is "recommended".

  8. Nitroheterocyclic drugs with broad spectrum activity.

    PubMed

    Raether, W; Hänel, H

    2003-06-01

    The group of biologically active nitroheterocyclic compounds includes various 5- and 2-nitroimidazoles and 5-nitrofurans, which can be used as therapeutic agents against a variety of protozoan and bacterial (anaerobic) infections of humans and animals. The current status in the the treatment of giardiasis, trichomoniasis, balantidiasis, histomoniasis, and amebiasis (including infections due to opportunistic amebas) is presented. The most relevant drugs (benznidazole, furazolidone, metronidazole, misonidazole, nifurtimox, nimorazole, nitazoxanide, ornidazole, secnidazole, and tinidazole) are characterized with regard to their chemical, chemotherapeutic, toxicological, pharmacokinetic, and pharmacological properties, including the mechanism of action and resistance in certain parasitic protozoa.

  9. Biologically active peptides: prospects for drug development.

    PubMed

    Hughes, J

    1980-08-11

    Biologically active peptides aree typified by their unbiquity of distribution, their high receptor affinity and an almost infinite diversity of structure. For these reasons, considerable effort is now being expended to elucidate the possible role of peptides in brain function. This effort has been stimulated by the discovery of a number of new endogenous peptides, such as the enkephalins, endorphins, vasoactive intestinal peptide and neurotensin. At present, there is no clearly defined role for these peptides, although they may form an important basis for the chemical coding of various brain functions, including pain, mood and memory. At present, the potential for drug development of peptide agonists remains in fairly circumscribed areas such as analgesia, pituitary hormone control, and gastrointestinal motor and secretory control. Peptide antagonists may provide a vast field for future development, although only one area, that of antifertility drugs based on LHRH antagonists, shows any promise of immediate success. Industrial research approaches to new peptide agonists and antagonists mainly rely at present on rational drug design through structural analogies. Other fruitful approaches to be considered are the screening of natural microbial and plant products and the possible application of genetic engineering techniques.

  10. Effects of YM155 on survivin levels and viability in neuroblastoma cells with acquired drug resistance

    PubMed Central

    Voges, Yvonne; Michaelis, Martin; Rothweiler, Florian; Schaller, Torsten; Schneider, Constanze; Politt, Katharina; Mernberger, Marco; Nist, Andrea; Stiewe, Thorsten; Wass, Mark N; Rödel, Franz; Cinatl, Jindrich

    2016-01-01

    Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action. PMID:27735941

  11. Birth Order and Activity Level in Children.

    ERIC Educational Resources Information Center

    Eaton, Warren O.; And Others

    1989-01-01

    Studied 7,018 children between birth and 7 years and 81 children of 5-8 years to test the hypothesis that birth order is negatively related to motor activity level. Activity level declined linearly across birth position, so that early-borns were rated as more active than later-borns. (RJC)

  12. Light activated liposomes: Functionality and prospects in ocular drug delivery.

    PubMed

    Lajunen, Tatu; Nurmi, Riikka; Kontturi, Leena; Viitala, Lauri; Yliperttula, Marjo; Murtomäki, Lasse; Urtti, Arto

    2016-12-28

    Ocular drug delivery, especially to the retina and choroid, is a major challenge in drug development. Liposome technology may be useful in ophthalmology in enabling new routes of delivery, prolongation of drug action and intracellular drug delivery, but drug release from the liposomes should be controlled. For that purpose, light activation may be an approach to release drug at specified time and site in the eye. Technical advances have been made in the field of light activated drug release, particularly indocyanine green loaded liposomes are a promising approach with safe materials and effective light triggered release of small and large molecules. This review discusses the liposomal drug delivery with light activated systems in the context of ophthalmic drug delivery challenges.

  13. Factors Influencing Cypriot Children's Physical Activity Levels

    ERIC Educational Resources Information Center

    Loucaides, Constantinos A.; Chedzoy, Sue M.

    2005-01-01

    The purpose of this paper is to present selected findings from a larger study, which set out to examine the physical activity levels of Cypriot primary school children and determinants of their activity. Twenty parents of children who obtained high and low activity scores based on pedometer counts and self-reports scores were interviewed. By…

  14. Effects of Recreational Drugs on Physical Activity

    PubMed Central

    Millis, Richard M.

    1987-01-01

    The literature relating to the effects of recreational drugs on physical work and endurance is reviewed. Interactions between muscular coordination and cognitive function make it difficult to formulate overall conclusions about the effect of these drugs on physical performance. PMID:3546707

  15. Stability analysis for drugs with multiple active ingredients.

    PubMed

    Chow, Shein-Chung; Shao, Jun

    2007-03-30

    For every drug product on the market, the United States Food and Drug Administration (FDA) requires that an expiration dating period (shelf-life) must be indicated on the immediate container label. For determination of the expiration dating period of a drug product, regulatory requirements and statistical methodology are provided in the FDA and ICH Guidelines. However, this guideline is developed for drug products with a single active ingredient. There are many drug products consisting of multiple active ingredients, especially for most traditional Chinese medicine. In this article, we propose a statistical method for determining the shelf-life of a drug product with multiple active ingredients following similar idea as suggested by the FDA and assuming that these active ingredients are linear combinations of some factors. Stability data observed from a traditional Chinese medicine were analysed to illustrate the proposed method.

  16. Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning

    PubMed Central

    Kaiser, Marcel; Mäser, Pascal; Tadoori, Leela Pavan; Ioset, Jean-Robert; Brun, Reto

    2015-01-01

    Neglected tropical diseases cause significant morbidity and mortality and are a source of poverty in endemic countries. Only a few drugs are available to treat diseases such as leishmaniasis, Chagas’ disease, human African trypanosomiasis and malaria. Since drug development is lengthy and expensive, a drug repurposing strategy offers an attractive fast-track approach to speed up the process. A set of 100 registered drugs with drug repositioning potential for neglected diseases was assembled and tested in vitro against four protozoan parasites associated with the aforementioned diseases. Several drugs and drug classes showed in vitro activity in those screening assays. The results are critically reviewed and discussed in the perspective of a follow-up drug repositioning strategy where R&D has to be addressed with limited resources. PMID:26270335

  17. Antiprotozoal Activity Profiling of Approved Drugs: A Starting Point toward Drug Repositioning.

    PubMed

    Kaiser, Marcel; Mäser, Pascal; Tadoori, Leela Pavan; Ioset, Jean-Robert; Brun, Reto

    2015-01-01

    Neglected tropical diseases cause significant morbidity and mortality and are a source of poverty in endemic countries. Only a few drugs are available to treat diseases such as leishmaniasis, Chagas' disease, human African trypanosomiasis and malaria. Since drug development is lengthy and expensive, a drug repurposing strategy offers an attractive fast-track approach to speed up the process. A set of 100 registered drugs with drug repositioning potential for neglected diseases was assembled and tested in vitro against four protozoan parasites associated with the aforementioned diseases. Several drugs and drug classes showed in vitro activity in those screening assays. The results are critically reviewed and discussed in the perspective of a follow-up drug repositioning strategy where R&D has to be addressed with limited resources.

  18. A knowledge-based information system for monitoring drug levels.

    PubMed

    Wiener, F; Groth, T; Mortimer, O; Hallquist, I; Rane, A

    1989-06-01

    The expert system shell SMR has been enhanced to include information system routines for designing data screens and providing facilities for data entry, storage, retrieval, queries and descriptive statistics. The data for inference making is abstracted from the data base record and inserted into a data array to which the knowledge base is applied to derive the appropriate advice and comments. The enhanced system has been used to develop an intelligent information system for monitoring serum drug levels which includes evaluation of temporal changes and production of specialized printed reports. The module for digoxin has been fully developed and validated. To demonstrate the extension to other drugs a module for phenytoin was constructed with only a rudimentary knowledge base. Data from the request forms together with the S-digoxin results are entered into the data base by the department secretary. The day's results are then reviewed by the clinical pharmacologist. For each case, previous results may be displayed and are taken into account by the system in the decision process. The knowledge base is applied to the data to formulate an evaluative comment on the report returned to the requestor. The report includes a semi-graphic presentation of the current and previous results and either the system's interpretation or one entered by the pharmacologist if he does not agree with it. The pharmacologist's comment is also recorded in the data base for future retrieval, analysis and possible updating of the knowledge base. The system is now undergoing testing and evaluation under routine operations in the clinical pharmacology service. It is a prototype for other applications in both laboratory and clinical medicine currently under development at Uppsala University Hospital. This system may thus provide a vehicle for a more intensive penetration of knowledge-based systems in practical medical applications.

  19. Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

    PubMed Central

    Kraft, John C.; McConnachie, Lisa A.; Koehn, Josefin; Kinman, Loren; Collins, Carol; Shen, Danny D.; Collier, Ann C.; Ho, Rodney J.Y.

    2017-01-01

    Objective: The aim of the present study was to determine whether a combination of anti-HIV drugs – tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) – in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma. Design: Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC-MS/MS assay. Results: For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). Conclusions: A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes. PMID:28099191

  20. Critical Choices: Making Drug Policy at the State Level.

    ERIC Educational Resources Information Center

    Drug Strategies, Washington, DC.

    This report focuses on state drug policies and their budgetary consequences. Included are the observations of the Governors Leadership Council, composed of former governors from both parties, convened to help guide state governments in dealing with substance abuse. The report examines the growth rate of the drug offender population in state…

  1. Physical activity level, waist circumference, and mortality

    PubMed Central

    Staiano, Amanda E.; Reeder, Bruce A.; Elliott, Susan; Joffres, Michel R.; Pahwa, Punam; Kirkland, Susan A.; Paradis, Gilles; Katzmarzyk, Peter T.

    2014-01-01

    This study predicted all-cause mortality based on physical activity level (active or inactive) and waist circumference (WC) in 8208 Canadian adults in Alberta, Manitoba, Nova Scotia, and Saskatchewan, surveyed between 1986–1995 and followed through 2004. Physically inactive adults had higher mortality risk than active adults overall (hazard ratio, 95% confidence interval = 1.20, 1.05–1.37) and within the low WC category (1.51, 1.19–1.92). Detrimental effects of physical inactivity and high WC demonstrate the need for physical activity promotion. PMID:22703160

  2. Active and passive transport of drugs in the human placenta.

    PubMed

    Włoch, Stanisław; Pałasz, Artur; Kamiński, Marcin

    2009-10-01

    The human placenta, characterized by the processes of passive transport and facilitated diffusion, contains numerous active transport proteins, usually located in the microvilli of the syncytiotrophoblast or in the endothelium of the capillaries of the villi. These proteins use either the energy from ATP hydrolysis or other mechanisms resulting, among others, from the formation of the maternofetal ion gradient, which facilitates the transfer of various endogenous substances or xenobiotics across the body membranes. The proteins either trigger the efflux of these substances from the fetal tissues via the placenta into the maternal bloodstream, or conversely they accumulate them in the fetal tissues. Both the placenta and the fetus are equipped with independent systems of enzymes of 1st and 2nd phase of substrate metabolism, such as CYP450, glucuronyltransferase or sulphatase. An active therapy with a wide range of drugs, often at high toxicity levels, either shortly before or during pregnancy, has naturally posed a question concerning the degree of impermeability of the placental barrier and how effectively it can be crossed, including any possible negative embryotoxic or teratogenic consequences. Such hazards seem to be quite real, as many drugs are substrates for ABC transporters. Also the placenta itself, including its structure, is subject to vast transformations during pregnancy which may be observed as the thinning of the barrier separating the maternal blood from the fetal one, from 20-30 microm in the first trimester of gestation down to 2-4 microm in the third trimester of gestation.

  3. A comprehensive analysis of the influence of drug binding kinetics on drug action at molecular and systems levels.

    PubMed

    Yin, Ning; Pei, Jianfeng; Lai, Luhua

    2013-06-01

    Binding kinetics is closely related to the efficacy of drugs. Several aspects of binding kinetics, such as long residence or frequent dissociation, have been proposed to affect drug properties such as efficacy, selectivity, and multi-target potency. However, a comprehensive and balanced study of binding kinetics in various scenarios is still needed. We performed a comprehensive computational analysis of the role of drug binding kinetics in various situations such as enzyme inhibition, receptor binding, multi-target drug targeting, signal transduction pathways, and metabolic networks. Molecular studies of enzyme inhibition, receptor binding, and multi-target drugs have shown that at constant binding affinity, fast associating drugs show better enzyme inhibitory effects, earlier and higher receptor occupancy peaks, and better multi-target performances, while slow dissociating drugs show prolonged receptor occupancy, as suggested by others. Different situations exemplify slightly different kinetic-efficacy relationships, and each must be considered separately. At the systems level, binding kinetics can not only change the overall effect of drugs, but can also affect signaling dynamics. For example, in the tumor necrosis factor α-induced nuclear factor-κB pathway, inhibitor addition can delay the onset of oscillations and decrease their frequencies, with these changes varying with the binding kinetics of the inhibitor. The effects of drug binding kinetics also depend on network topology and where the target is located in the network. For successful drug discovery, both molecular binding kinetics and systems level requirements need to be considered.

  4. [Participation of pineal gland in antistressor activity of adaptogenic drugs].

    PubMed

    Arushanian, É B; Beĭer, É V

    2015-01-01

    Chronic stress produces some morphological changes in rats, including thymus weight reduction, adrenal hypertrophy, and peptic ulcers in stomach. Repeated administration of phytoadaptogenic drugs (ginseng and bilobil) decreased these stress-induced disorders. The antistressor activity of drugs was attenuated upon by removal of the pineal gland. Histochemical and morphometric investigation of pineal tissues in stressed animals showed that that the pharmacological effect was accompanied by increasing functional activity of the pineal gland. It is suggested that pineal mobilization may participate in antistressor activity of phytoadaptogenic drugs.

  5. "Let's Talk about Drugs": Pilot Study of a Community-Level Drug Prevention Intervention Based on Motivational Interviewing Principles

    ERIC Educational Resources Information Center

    Newbery, Natasha; McCambridge, Jim; Strang, John

    2007-01-01

    Purpose: The feasibility of a community-level drug prevention intervention based upon the principles of motivational interviewing within a further education college was investigated in a pilot study. Design/methodology/approach: The implementation over the course of a single term of "Let's Talk about Drugs" was studied with both action…

  6. [Subliminal perception and the levels of activation].

    PubMed

    Borgeat, F; Chabot, R; Chaloult, L

    1981-06-01

    The influence of the auditory subliminal messages on the level of activation has been evaluated through a double-blind study. Twenty consenting subjects were alternately submitted to activating and deactivating subliminal messages. Activation changes were estimated through the variations in the scores at the Mood Adjective Check List. Five out of this test's six factors concerned by the content of the subliminal messages responded differently according to the nature of these messages; four factors did so to a statistically significant degree. These results tend to indicate that auditory subliminal perceptions can influence the level of activation. The authors raise several questions, especially stressing that the parameters regulating subliminal response and susceptibility remain largely undefined and in need of systematic investigation.

  7. On the biological activity of drug molecules: Busulfan and nabumetone

    NASA Astrophysics Data System (ADS)

    Novak, Igor; Kovač, Branka

    2010-10-01

    The electronic structures of drug molecules busulfan (BSU) and nabumetone (NAB) have been investigated by HeI and HeII UV photoelectron spectroscopy (UPS), quantum chemical calculations and virtual docking studies. Their biological activities are discussed in the framework of their electronic and molecular structures, reactivity and drug-enzyme binding.

  8. Carboxymefloquine, the major metabolite of the antimalarial drug mefloquine, induces drug-metabolizing enzyme and transporter expression by activation of pregnane X receptor.

    PubMed

    Piedade, Rita; Traub, Stefanie; Bitter, Andreas; Nüssler, Andreas K; Gil, José P; Schwab, Matthias; Burk, Oliver

    2015-01-01

    Malaria patients are frequently coinfected with HIV and mycobacteria causing tuberculosis, which increases the use of coadministered drugs and thereby enhances the risk of pharmacokinetic drug-drug interactions. Activation of the pregnane X receptor (PXR) by xenobiotics, which include many drugs, induces drug metabolism and transport, thereby resulting in possible attenuation or loss of the therapeutic responses to the drugs being coadministered. While several artemisinin-type antimalarial drugs have been shown to activate PXR, data on nonartemisinin-type antimalarials are still missing. Therefore, this study aimed to elucidate the potential of nonartemisinin antimalarial drugs and drug metabolites to activate PXR. We screened 16 clinically used antimalarial drugs and six major drug metabolites for binding to PXR using the two-hybrid PXR ligand binding domain assembly assay; this identified carboxymefloquine, the major and pharmacologically inactive metabolite of the antimalarial drug mefloquine, as a potential PXR ligand. Two-hybrid PXR-coactivator and -corepressor interaction assays and PXR-dependent promoter reporter gene assays confirmed carboxymefloquine to be a novel PXR agonist which specifically activated the human receptor. In the PXR-expressing intestinal LS174T cells and in primary human hepatocytes, carboxymefloquine induced the expression of drug-metabolizing enzymes and transporters on the mRNA and protein levels. The crucial role of PXR for the carboxymefloquine-dependent induction of gene expression was confirmed by small interfering RNA (siRNA)-mediated knockdown of the receptor. Thus, the clinical use of mefloquine may result in pharmacokinetic drug-drug interactions by means of its metabolite carboxymefloquine. Whether these in vitro findings are of in vivo relevance has to be addressed in future clinical drug-drug interaction studies.

  9. Locomotor activity and tissue levels following acute ...

    EPA Pesticide Factsheets

    Pyrethroids produce neurotoxicity that depends, in part, on the chemical structure. Common behavioral effects include locomotor activity changes and specific toxic syndromes (types I and II). In general these neurobehavioral effects correlate well with peak internal dose metrics. Products of cyhalothrin, a type II pyrethroid, include mixtures of isomers (e.g., λ-cyhalothrin) as well as enriched active isomers (e.g., γ-cyhalothrin). We measured acute changes in locomotor activity in adult male rats and directly correlated these changes to peak brain and plasma concentrations of λ- and γ-cyhalothrin using a within-subject design. One-hour locomotor activity studies were conducted 1.5 h after oral gavage dosing, and immediately thereafter plasma and brains were collected for analyzing tissue levels using LC/MS/MS methods. Both isomers produced dose-related decreases in activity counts, and the effective dose range for γ-cyhalothrin was lower than for λ-cyhalothrin. Doses calculated to decrease activity by 50% were 2-fold lower for the γ-isomer (1.29 mg/kg) compared to λ-cyhalothrin (2.65 mg/kg). Salivation, typical of type II pyrethroids, was also observed at lower doses of γ-cyhalothrin. Administered dose correlated well with brain and plasma concentrations, which furthermore showed good correlations with activity changes. Brain and plasma levels were tightly correlated across doses. While γ-cyhalothrin was 2-fold more potent based on administ

  10. Neck Muscle Activation Levels During Frontal Impacts

    DTIC Science & Technology

    2004-09-01

    right and left upper trapezius and sternocleidomastoid . Amplitude and frequency components of the signals were evaluated to determine the amount of...Gx acceleration levels. The trapezius produced more force than the sternocleidomastoid . Activity of both muscle groups was synchronized, by their...dynamic environment. The role of upper trapezius and sternocleidomastoid (SCM) during long-duration head and neck loading situations has been

  11. Identification of Clinically Used Drugs That Activate Pregnane X ReceptorsS⃞

    PubMed Central

    Shukla, Sunita J.; Sakamuru, Srilatha; Huang, Ruili; Moeller, Timothy A.; Shinn, Paul; VanLeer, Danielle; Auld, Douglas S.; Austin, Christopher P.

    2011-01-01

    The pregnane X receptor (PXR) binds xenobiotics and regulates the expression of several drug-metabolizing enzymes and transporters. Human PXR (hPXR) activation and CYP3A4 induction can be involved in drug-drug interactions, resulting in reduced efficacy or increased toxicity. However, there are known species-specific differences with regard to PXR activation that should be taken into account when animal PXR data are extrapolated to humans. We profiled 2816 clinically used drugs from the National Institutes of Health Chemical Genomics Center Pharmaceutical Collection for their ability to activate hPXR and rat PXR (rPXR) at the cellular level, induce human CYP3A4 at the cellular level, and bind human PXR at the protein level. From 6 to 11% of drugs were identified as active across the four assays, which included assay-specific and pan-active compounds. The lowest concordance was observed between the hPXR and rPXR assays, and many compounds active in both assays nonetheless demonstrated significant potency differences between species. Analysis based on clustering potency values demonstrated the greatest activity correlation between the hPXR activation and CYP3A4 induction assays. Structure-activity relationship analysis identified chemical scaffolds that were pan-active (e.g., dihydropyridine calcium channel blockers) and others that were uniquely active in individual assays (e.g., steroids and fatty acids). These results provide important information on PXR activation by clinically used drugs, highlight the species specificity of PXR activation by xenobiotics, and provide a means of prioritizing compounds for follow-up studies and optimization efforts. PMID:20966043

  12. Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target.

    PubMed

    Leitsch, David; Müller, Joachim; Müller, Norbert

    2016-12-01

    The antioxidative enzyme thioredoxin reductase (TrxR) has been suggested to be a drug target in several pathogens, including the protist parasite Giardia lamblia. TrxR is also believed to catalyse the reduction of nitro drugs, e.g. metronidazole and furazolidone, a reaction required to render these compounds toxic to G. lamblia and other microaerophiles/anaerobes. It was the objective of this study to assess the potential of TrxR as a drug target in G. lamblia and to find direct evidence for the role of this enzyme in the activation of metronidazole and other nitro drugs. TrxR was overexpressed approximately 10-fold in G. lamblia WB C6 cells by placing the trxR gene behind the arginine deiminase (ADI) promoter on a plasmid. Likewise, a mutant TrxR with a defective disulphide reductase catalytic site was strongly expressed in another G. lamblia WB C6 cell line. Susceptibilities to five antigiardial drugs, i.e. metronidazole, furazolidone, nitazoxanide, albendazole and auranofin were determined in both transfectant cell lines and compared to wildtype. Further, the impact of all five drugs on TrxR activity in vivo was measured. Overexpression of TrxR rendered G. lamblia WB C6 more susceptible to metronidazole and furazolidone but not to nitazoxanide, albendazole, and auranofin. Of all five drugs tested, only auranofin had an appreciably negative effect on TrxR activity in vivo, albeit to a much smaller extent than expected. Overexpression of TrxR and mutant TrxR had hardly any impact on growth of G. lamblia WB C6, although the enzyme also exerts a strong NADPH oxidase activity which is a source of oxidative stress. Our results constitute first direct evidence for the notion that TrxR is an activator of metronidazole and furazolidone but rather question that it is a relevant drug target of presently used antigiardial drugs.

  13. Polymeric drugs: Advances in the development of pharmacologically active polymers

    PubMed Central

    Li, Jing; Yu, Fei; Chen, Yi; Oupický, David

    2015-01-01

    Synthetic polymers play a critical role in pharmaceutical discovery and development. Current research and applications of pharmaceutical polymers are mainly focused on their functions as excipients and inert carriers of other pharmacologically active agents. This review article surveys recent advances in alternative pharmaceutical use of polymers as pharmacologically active agents known as polymeric drugs. Emphasis is placed on the benefits of polymeric drugs that are associated with their macromolecular character and their ability to explore biologically relevant multivalency processes. We discuss the main therapeutic uses of polymeric drugs as sequestrants, antimicrobials, antivirals, and anticancer and anti-inflammatory agents. PMID:26410809

  14. Discovery of drugs that possess activity against feline leukemia virus.

    PubMed

    Greggs, Willie M; Clouser, Christine L; Patterson, Steven E; Mansky, Louis M

    2012-04-01

    Feline leukemia virus (FeLV) is a gammaretrovirus that is a significant cause of neoplastic-related disorders affecting cats worldwide. Treatment options for FeLV are limited, associated with serious side effects, and can be cost-prohibitive. The development of drugs used to treat a related retrovirus, human immunodeficiency virus type 1 (HIV-1), has been rapid, leading to the approval of five drug classes. Although structural differences affect the susceptibility of gammaretroviruses to anti-HIV drugs, the similarities in mechanism of replication suggest that some anti-HIV-1 drugs may also inhibit FeLV. This study demonstrates the anti-FeLV activity of four drugs approved by the US FDA (Food and Drug Administration) at non-toxic concentrations. Of these, tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved to treat myelodysplastic syndromes and pancreatic cancer, respectively, but also have anti-HIV-1 activity in cell culture. Our results indicate that these drugs may be useful for FeLV treatment and should be investigated for mechanism of action and suitability for veterinary use.

  15. Basic College-Level Pharmacology: Therapeutic Drug Range Lesson Plan.

    ERIC Educational Resources Information Center

    Laipply, Richelle S.

    2000-01-01

    Investigations of scientific concepts using inquiry can be included in the traditional college lecture. This lesson uses the Learning Cycle to demonstrate therapeutic drug range, a basic concept in pharmaceutical science. Students use graphing to discover patterns as a part of data analysis and interpretation of provided investigation data.…

  16. Clinical application of asparaginase activity levels following treatment with pegaspargase.

    PubMed

    Bleyer, Archie; Asselin, Barbara L; Koontz, Susannah E; Hunger, Stephen P

    2015-06-01

    Asparaginase, an enzyme used to treat acute lymphoblastic leukemia and related forms of nonHodgkin lymphoma, depletes asparagine, which leads to lymphoblast cell death. Unlike most chemotherapeutic agents, asparaginase is a foreign protein that can result in clinical allergy and/or silent hypersensitivity with production of neutralizing antibodies that inactivate asparaginase. In North America, asparaginase activity levels can now be obtained via a commercially available assay, for therapeutic drug monitoring and investigation of potential allergic reactions. Herein, we provide recommendations and a corresponding algorithm for the clinical application of this assay after treatment with pegaspargase to evaluate suspected hypersensitivity reactions and/or silent inactivation.

  17. Pyrazinoic acid decreases the proton motive force, respiratory ATP synthesis activity, and cellular ATP levels.

    PubMed

    Lu, Ping; Haagsma, Anna C; Pham, Hoang; Maaskant, Janneke J; Mol, Selena; Lill, Holger; Bald, Dirk

    2011-11-01

    Pyrazinoic acid, the active form of the first-line antituberculosis drug pyrazinamide, decreased the proton motive force and respiratory ATP synthesis rates in subcellular mycobacterial membrane assays. Pyrazinoic acid also significantly lowered cellular ATP levels in Mycobacterium bovis BCG. These results indicate that the predominant mechanism of killing by this drug may operate by depletion of cellular ATP reserves.

  18. Quantification of Low-Level Drug Effects Using Real-Time, in vitro Measurement of Oxygen Consumption Rate.

    PubMed

    Neal, Adam; Rountree, Austin M; Philips, Craig W; Kavanagh, Terrance J; Williams, Dominic P; Newham, Peter; Khalil, Gamal; Cook, Daniel L; Sweet, Ian R

    2015-12-01

    There is a general need to detect toxic effects of drugs during preclinical screening. We propose that increased sensitivity of xenobiotics toxicity combined with improved in vitro physiological recapitulation will more accurately assess potentially toxic perturbations of cellular biochemistry that are near in vivo pharmacological exposure levels. Importantly, measurement of such cytopathologies avoids activating mechanisms mediating toxicity at suprapharmacologic levels not relevant to in vivo effects. We present a sensitive method to measure changes in oxygen consumption rate (OCR), a well-established parameter reflecting a potential hazard, in response to exposure to pharmacologic levels of drugs using a flow culture system and state of the art oxygen sensing system. We tested metformin and acetaminophen on rat liver slices to illustrate the method. The features of the method include continuous and very stable measurement of OCR over the course of 48 h in liver slices in a continuous flow chamber with the ability to resolve changes as small as 0.3%/h. Kinetic modeling of metformin inhibition of OCR over a wide range of concentrations revealed both a slow and fast mechanism, where the fast mechanism activated only at concentrations above 0.6 mM. For both drugs, small amounts of inhibition were reversible, but higher decrements were irreversible. Overall the study highlights the advantages of measuring low-level toxicity so as to avoid the common extrapolations made about drug toxicity based on effects of drugs tested at suprapharmacologic levels.

  19. Characterization of increased drug metabolism activity in dimethyl sulfoxide (DMSO)-treated Huh7 hepatoma cells

    PubMed Central

    Choi, S.; Sainz, B.; Corcoran, P.; Uprichard, S.; Jeong, H.

    2010-01-01

    1. The objective of this study was to characterize Huh7 cells' baseline capacity to metabolize drugs and to investigate whether the drug metabolism was enhanced upon treatment with dimethyl sulfoxide (DMSO). 2. The messenger RNA (mRNA) levels of major Phase I and Phase II enzymes were determined by quantitative real-time-polymerase chain reaction (RT-PCR), and activities of major drug-metabolizing enzymes were examined using probe drugs by analysing relevant metabolite production rates. 3. The expression levels of drug-metabolizing enzymes in control Huh7 cells were generally very low, but DMSO treatment dramatically increased the mRNA levels of most drug-metabolizing enzymes as well as other liver-specific proteins. Importantly, functionality assays confirmed concomitant increases in drug-metabolizing enzyme activity. Additionally, treatment of the Huh7 cells with 3-methylcholanthrene induced cytochrome P450 (CYP) 1A1 expression. 4. The results indicate that DMSO treatment of Huh7 cells profoundly enhances their differentiation state, thus improving the usefulness of this common cell line as an in vitro hepatocyte model. PMID:19280519

  20. Characterization of increased drug metabolism activity in dimethyl sulfoxide (DMSO)-treated Huh7 hepatoma cells.

    PubMed

    Choi, S; Sainz, B; Corcoran, P; Uprichard, S; Jeong, H

    2009-03-01

    The objective of this study was to characterize Huh7 cells' baseline capacity to metabolize drugs and to investigate whether the drug metabolism was enhanced upon treatment with dimethyl sulfoxide (DMSO). The messenger RNA (mRNA) levels of major Phase I and Phase II enzymes were determined by quantitative real-time-polymerase chain reaction (RT-PCR), and activities of major drug-metabolizing enzymes were examined using probe drugs by analysing relevant metabolite production rates. The expression levels of drug-metabolizing enzymes in control Huh7 cells were generally very low, but DMSO treatment dramatically increased the mRNA levels of most drug-metabolizing enzymes as well as other liver-specific proteins. Importantly, functionality assays confirmed concomitant increases in drug-metabolizing enzyme activity. Additionally, treatment of the Huh7 cells with 3-methylcholanthrene induced cytochrome P450 (CYP) 1A1 expression. The results indicate that DMSO treatment of Huh7 cells profoundly enhances their differentiation state, thus improving the usefulness of this common cell line as an in vitro hepatocyte model.

  1. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... DRUGS (Eff. 12-12-2011) Quality Assurance § 212.20 What activities must I perform to ensure drug...

  2. [Activity of NTDs Drug-discovery Research Consortium].

    PubMed

    Namatame, Ichiji

    2016-01-01

    Neglected tropical diseases (NTDs) are an extremely important issue facing global health care. To improve "access to health" where people are unable to access adequate medical care due to poverty and weak healthcare systems, we have established two consortiums: the NTD drug discovery research consortium, and the pediatric praziquantel consortium. The NTD drug discovery research consortium, which involves six institutions from industry, government, and academia, as well as an international non-profit organization, is committed to developing anti-protozoan active compounds for three NTDs (Leishmaniasis, Chagas disease, and African sleeping sickness). Each participating institute will contribute their efforts to accomplish the following: selection of drug targets based on information technology, and drug discovery by three different approaches (in silico drug discovery, "fragment evolution" which is a unique drug designing method of Astellas Pharma, and phenotypic screening with Astellas' compound library). The consortium has established a brand new database (Integrated Neglected Tropical Disease Database; iNTRODB), and has selected target proteins for the in silico and fragment evolution drug discovery approaches. Thus far, we have identified a number of promising compounds that inhibit the target protein, and we are currently trying to improve the anti-protozoan activity of these compounds. The pediatric praziquantel consortium was founded in July 2012 to develop and register a new praziquantel pediatric formulation for the treatment of schistosomiasis. Astellas Pharma has been a core member in this consortium since its establishment, and has provided expertise and technology in the area of pediatric formulation development and clinical development.

  3. The Use of Central Nervous System Active Drugs During Pregnancy

    PubMed Central

    Källén, Bengt; Borg, Natalia; Reis, Margareta

    2013-01-01

    CNS-active drugs are used relatively often during pregnancy. Use during early pregnancy may increase the risk of a congenital malformation; use during the later part of pregnancy may be associated with preterm birth, intrauterine growth disturbances and neonatal morbidity. There is also a possibility that drug exposure can affect brain development with long-term neuropsychological harm as a result. This paper summarizes the literature on such drugs used during pregnancy: opioids, anticonvulsants, drugs used for Parkinson’s disease, neuroleptics, sedatives and hypnotics, antidepressants, psychostimulants, and some other CNS-active drugs. In addition to an overview of the literature, data from the Swedish Medical Birth Register (1996–2011) are presented. The exposure data are either based on midwife interviews towards the end of the first trimester or on linkage with a prescribed drug register. An association between malformations and maternal use of anticonvulsants and notably valproic acid is well known from the literature and also demonstrated in the present study. Some other associations between drug exposure and outcome were found. PMID:24275849

  4. Drug Trafficking Organizations and Local Economic Activity in Mexico

    PubMed Central

    González, Felipe

    2015-01-01

    Little is known about the relationship between illegal firms and local economic activity. In this paper I study changes in satellite night lights across Mexican municipalities after the arrival of large drug trafficking organizations in the period 2000–2010. After accounting for state trends and differences in political regimes, results indicate no significant change in night lights after the arrival of these illegal firms. Estimated coefficients are precise, robust, and similar across different drug trafficking organizations. PMID:26348041

  5. Drug Trafficking Organizations and Local Economic Activity in Mexico.

    PubMed

    González, Felipe

    2015-01-01

    Little is known about the relationship between illegal firms and local economic activity. In this paper I study changes in satellite night lights across Mexican municipalities after the arrival of large drug trafficking organizations in the period 2000-2010. After accounting for state trends and differences in political regimes, results indicate no significant change in night lights after the arrival of these illegal firms. Estimated coefficients are precise, robust, and similar across different drug trafficking organizations.

  6. Microglia-inhibiting activity of Parkinson's disease drug amantadine.

    PubMed

    Kim, Jong-Heon; Lee, Ho-Won; Hwang, Jaegyu; Kim, Jaehong; Lee, Min-Jeong; Han, Hyung-Soo; Lee, Won-Ha; Suk, Kyoungho

    2012-09-01

    Amantadine is currently used as an antiviral and an antiparkinsonian drug. Although the drug is known to bind a viral proton channel protein, the mechanism of action in Parkinson's disease (PD) remains to be determined. This study investigated whether the drug has an inhibitory effect on microglial activation and neuroinflammation, which have been implicated in the progression of neurodegenerative processes. Using cultured microglial cells, it was demonstrated that the drug inhibited inflammatory activation of microglia and a signaling pathway that governs the microglial activation. The drug reduced the expression and production of proinflammatory mediators in bacterial lipopolysaccharide-stimulated microglia cells. The microglia-inhibiting activity of amantadine was also demonstrated in a microglia/neuron coculture and animal models of neuroinflammation and Parkinson's disease. Collectively, our results suggest that amantadine may act on microglia in the central nervous system to inhibit their inflammatory activation, thereby attenuating neuroinflammation. These results provide a molecular basis of the glia-targeted mechanism of action for amantadine.

  7. Drug predictive cues activate aversion-sensitive striatal neurons that encode drug seeking.

    PubMed

    Wheeler, Daniel S; Robble, Mykel A; Hebron, Emily M; Dupont, Matthew J; Ebben, Amanda L; Wheeler, Robert A

    2015-05-06

    Drug-associated cues have profound effects on an addict's emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, self-administration sessions were preceded by a taste cue that signaled delayed drug availability. Assessments of hedonic responses indicated that this delay cue became aversive during training. Both the self-administration behavior and the immediate cue were subsequently extinguished in the absence of cocaine. After extinction of self-administration behavior, the presentation of the aversive delay cue reinstated drug seeking. In vivo electrophysiology and voltammetry recordings in the nucleus accumbens measured the neural responses to both the delay and immediate drug cues after extinction. Interestingly, the presentation of the delay cue simultaneously decreased dopamine signaling and increased excitatory encoding of the immediate cue. Most importantly, the delay cue selectively enhanced the baseline activity of neurons that would later encode drug seeking. Together these observations reveal how cocaine cues can modulate not only affective state, but also the neurochemical and downstream neurophysiological environment of striatal circuits in a manner that promotes drug seeking.

  8. Drug Predictive Cues Activate Aversion-Sensitive Striatal Neurons That Encode Drug Seeking

    PubMed Central

    Wheeler, Daniel S.; Robble, Mykel A.; Hebron, Emily M.; Dupont, Matthew J.; Ebben, Amanda L.

    2015-01-01

    Drug-associated cues have profound effects on an addict's emotional state and drug-seeking behavior. Although this influence must involve the motivational neural system that initiates and encodes the drug-seeking act, surprisingly little is known about the nature of such physiological events and their motivational consequences. Three experiments investigated the effect of a cocaine-predictive stimulus on dopamine signaling, neuronal activity, and reinstatement of cocaine seeking. In all experiments, rats were divided into two groups (paired and unpaired), and trained to self-administer cocaine in the presence of a tone that signaled the immediate availability of the drug. For rats in the paired group, self-administration sessions were preceded by a taste cue that signaled delayed drug availability. Assessments of hedonic responses indicated that this delay cue became aversive during training. Both the self-administration behavior and the immediate cue were subsequently extinguished in the absence of cocaine. After extinction of self-administration behavior, the presentation of the aversive delay cue reinstated drug seeking. In vivo electrophysiology and voltammetry recordings in the nucleus accumbens measured the neural responses to both the delay and immediate drug cues after extinction. Interestingly, the presentation of the delay cue simultaneously decreased dopamine signaling and increased excitatory encoding of the immediate cue. Most importantly, the delay cue selectively enhanced the baseline activity of neurons that would later encode drug seeking. Together these observations reveal how cocaine cues can modulate not only affective state, but also the neurochemical and downstream neurophysiological environment of striatal circuits in a manner that promotes drug seeking. PMID:25948270

  9. The impact of physician-level drug budgets on prescribing behavior.

    PubMed

    Fischer, Katharina Elisabeth; Koch, Taika; Kostev, Karel; Stargardt, Tom

    2017-02-13

    To contain pharmaceutical spending, drug budgets have been introduced across health systems. Apart from analyzing whether drug budgets fulfill their overall goal of reducing spending, changes in the cost and quality of prescribing and the enforcement mechanisms put in place need evaluation to assess the effectiveness of drug budgets at the physician level. In this study, we aim to analyze the cost and quality of prescribing conditional on the level of utilization of the drug budget and in view of varying levels of enforcement in cases of overspending. We observed drug budget utilization in a panel of 440 physicians in three federal states of Germany from 2005 to 2011. At the physician level, we retrospectively calculated drug budgets, the level of drug budget utilization, and differentiated by varying levels of enforcement where physicians overspent their budgets (i.e., more than 115/125% of the drug budget). Using lagged dependent-variable regression models, we analyzed whether the level of drug budget utilization in the previous year affected current prescribing in terms of various indicators to describe the cost and quality of prescribing. We controlled for patient and physician characteristics. The mean drug budget utilization is 92.3%. The level of drug budget utilization influences selected dimensions of cost and quality of prescribing (i.e., generic share (estimate 0.000215; p = 0.0246), concentration of generic brands (estimate 0.000585; p = 0.0056) and therapeutic substances (estimate -0.000060; p < 0.0001) and the share of potentially inappropriate medicines in the elderly (estimate 0.001; p < 0.0001)), whereas the level of enforcement does not. Physicians seem to gradually adjust their prescription patterns, especially in terms of generic substitution.

  10. 76 FR 50736 - Agency Information Collection Activities; Proposed Collection; Comment Request; Extra Label Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-16

    ... HUMAN SERVICES Food and Drug Administration Agency Information Collection Activities; Proposed Collection; Comment Request; Extra Label Drug Use in Animals AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing an opportunity for...

  11. Addressing Adherence Using Genotype-Specific PBPK Modeling—Impact of Drug Holidays on Tamoxifen and Endoxifen Plasma Levels

    PubMed Central

    Dickschen, Kristin J. R.; Willmann, Stefan; Hempel, Georg; Block, Michael

    2017-01-01

    Introduction: Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes. Materials and Methods: A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes. The impact of drug holidays on steady-state kinetics was investigated assuming changing drug holiday scenarios. Results: Drug holidays in CYP2D6 extensive and intermediate metabolizers (EMs, IMs) exceeding 1 month lead to a decrease of endoxifen steady-state trough levels below the 5th percentile of the control group. Assuming drug holidays of 1, 2, or 3 months and administering a fixed-dose combination of 20 mg tamoxifen and 3 mg endoxifen EMs demonstrated re-established endoxifen steady-state trough levels after 5, 8, and 9 days. IMs receiving the same fixed-dose combination demonstrated re-established endoxifen steady-state trough levels after 7, 10, and 11 days. Discussion: The PBPK model impressively demonstrates the impact of drug holidays in different CYP2D6 genotypes on PK. Population simulation results indicate that drug holidays of more than 2 weeks cause a tremendous decrease of plasma levels despite the long half-life of tamoxifen. To improve therapeutic success, PBPK modeling allows identifying genotype-specific differences in PK following drug holidays and adequate treatment with loading doses. PMID:28382001

  12. A practical drug discovery project at the undergraduate level.

    PubMed

    Fray, M Jonathan; Macdonald, Simon J F; Baldwin, Ian R; Barton, Nick; Brown, Jack; Campbell, Ian B; Churcher, Ian; Coe, Diane M; Cooper, Anthony W J; Craven, Andrew P; Fisher, Gail; Inglis, Graham G A; Kelly, Henry A; Liddle, John; Maxwell, Aoife C; Patel, Vipulkumar K; Swanson, Stephen; Wellaway, Natalie

    2013-12-01

    In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.

  13. Indoleamides are active against drug-resistant Mycobacterium tuberculosis

    PubMed Central

    Lun, Shichun; Guo, Haidan; Onajole, Oluseye K.; Pieroni, Marco; Gunosewoyo, Hendra; Chen, Gang; Tipparaju, Suresh K.; Ammerman, Nicole C.; Kozikowski, Alan P.; Bishai, William R.

    2014-01-01

    Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3 which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent anti-mycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis. PMID:24352433

  14. Schisandra chinensis regulates drug metabolizing enzymes and drug transporters via activation of Nrf2-mediated signaling pathway

    PubMed Central

    He, Jin-Lian; Zhou, Zhi-Wei; Yin, Juan-Juan; He, Chang-Qiang; Zhou, Shu-Feng; Yu, Yang

    2015-01-01

    Drug metabolizing enzymes (DMEs) and drug transporters are regulated via epigenetic, transcriptional, posttranscriptional, and translational and posttranslational modifications. Phase I and II DMEs and drug transporters play an important role in the disposition and detoxification of a large number of endogenous and exogenous compounds. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a critical regulator of a variety of important cytoprotective genes that are involved in disposition and detoxification of xenobiotics. Schisandra chinensis (SC) is a commonly used traditional Chinese herbal medicine that has been primarily used to protect the liver because of its potent antioxidative and anti-inflammatory activities. SC can modulate some DMEs and drug transporters, but the underlying mechanisms are unclear. In this study, we aimed to explore the role of Nrf2 in the regulatory effect of SC extract (SCE) on selected DMEs and drug transporters in human hepatocellular liver carcinoma cell line (HepG2) cells. The results showed that SCE, schisandrin A, and schisandrin B significantly increased the expression of NAD(P)H: Nicotinamide Adenine Dinucleotide Phosphate-oxidase or:quinone oxidoreductase 1, heme oxygenase-1, glutamate–cysteine ligase, and glutathione S-transferase A4 at both transcriptional and posttranscriptional levels. Incubation of HepG2 cells with SCE resulted in a significant increase in the intracellular level of glutathione and total glutathione S-transferase content. SCE significantly elevated the messenger ribonucleic acid and protein levels of P-glycoprotein and multidrug resistance-associated protein 2 and 4, whereas the expression of organic anion transporting peptide 1A2 and 1B1 was significantly downregulated by SCE. Knockdown of Nrf2 by small interfering ribonucleic acid attenuated the regulatory effect of SCE on these DMEs and drug transporters. SCE significantly upregulated Nrf2 and promoted the translocation of Nrf2 from cytoplasm to

  15. The Oral Antimalarial Drug Tafenoquine Shows Activity against Trypanosoma brucei

    PubMed Central

    Carvalho, Luis; Martínez-García, Marta; Pérez-Victoria, Ignacio; Manzano, José Ignacio; Yardley, Vanessa

    2015-01-01

    The protozoan parasite Trypanosoma brucei causes human African trypanosomiasis, or sleeping sickness, a neglected tropical disease that requires new, safer, and more effective treatments. Repurposing oral drugs could reduce both the time and cost involved in sleeping sickness drug discovery. Tafenoquine (TFQ) is an oral antimalarial drug belonging to the 8-aminoquinoline family which is currently in clinical phase III. We show here that TFQ efficiently kills different T. brucei spp. in the submicromolar concentration range. Our results suggest that TFQ accumulates into acidic compartments and induces a necrotic process involving cell membrane disintegration and loss of cytoplasmic content, leading to parasite death. Cell lysis is preceded by a wide and multitarget drug action, affecting the lysosome, mitochondria, and acidocalcisomes and inducing a depolarization of the mitochondrial membrane potential, elevation of intracellular Ca2+, and production of reactive oxygen species. This is the first report of an 8-aminoquinoline demonstrating significant in vitro activity against T. brucei. PMID:26195527

  16. Chemoprotective activity of boldine: modulation of drug-metabolizing enzymes.

    PubMed

    Kubínová, R; Machala, M; Minksová, K; Neca, J; Suchý, V

    2001-03-01

    Possible chemoprotective effects of the naturally occurring alkaloid boldine, a major alkaloid of boldo (Peumus boldus Mol.) leaves and bark, including in vitro modulations of drug-metabolizing enzymes in mouse hepatoma Hepa-1 cell line and mouse hepatic microsomes, were investigated. Boldine manifested inhibition activity on hepatic microsomal CYP1A-dependent 7-ethoxyresorufin O-deethylase and CYP3A-dependent testosterone 6 beta-hydroxylase activities and stimulated glutathione S-transferase activity in Hepa-1 cells. In addition to the known antioxidant activity, boldine could decrease the metabolic activation of other xenobiotics including chemical mutagens.

  17. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients.

    PubMed

    Andes, David; Azie, Nkechi; Yang, Hongbo; Harrington, Rachel; Kelley, Caroline; Tan, Ruo-Ding; Wu, Eric Q; Franks, Billy; Kristy, Rita; Lee, Edward; Khandelwal, Nikhil; Spalding, James

    2016-06-01

    The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the

  18. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients

    PubMed Central

    Azie, Nkechi; Yang, Hongbo; Harrington, Rachel; Kelley, Caroline; Tan, Ruo-Ding; Wu, Eric Q.; Franks, Billy; Kristy, Rita; Lee, Edward; Khandelwal, Nikhil; Spalding, James

    2016-01-01

    The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the

  19. What Does It Take to Synergistically Combine Sub-Potent Natural Products into Drug-Level Potent Combinations?

    PubMed Central

    Qin, Chu; Tan, Kai Leng; Zhang, Cun Long; Tan, Chun Yan; Chen, Yu Zong; Jiang, Yu Yang

    2012-01-01

    There have been renewed interests in natural products as drug discovery sources. In particular, natural product combinations have been extensively studied, clinically tested, and widely used in traditional, folk and alternative medicines. But opinions about their therapeutic efficacies vary from placebo to synergistic effects. The important questions are whether synergistic effects can sufficiently elevate therapeutic potencies to drug levels, and by what mechanisms and at what odds such combinations can be assembled. We studied these questions by analyzing literature-reported cell-based potencies of 190 approved anticancer and antimicrobial drugs, 1378 anticancer and antimicrobial natural products, 99 natural product extracts, 124 synergistic natural product combinations, and 122 molecular interaction profiles of the 19 natural product combinations with collective potency enhanced to drug level or by >10-fold. Most of the evaluated natural products and combinations are sub-potent to drugs. Sub-potent natural products can be assembled into combinations of drug level potency at low probabilities by distinguished multi-target modes modulating primary targets, their regulators and effectors, and intracellular bioavailability of the active natural products. PMID:23209627

  20. Active Targeted Drug Delivery for Microbes Using Nano-Carriers

    PubMed Central

    Lin, Yung-Sheng; Lee, Ming-Yuan; Yang, Chih-Hui; Huang, Keng-Shiang

    2015-01-01

    Although vaccines and antibiotics could kill or inhibit microbes, many infectious diseases remain difficult to treat because of acquired resistance and adverse side effects. Nano-carriers-based technology has made significant progress for a long time and is introducing a new paradigm in drug delivery. However, it still has some challenges like lack of specificity toward targeting the infectious site. Nano-carriers utilized targeting ligands on their surface called ‘active target’ provide the promising way to solve the problems like accelerating drug delivery to infectious areas and preventing toxicity or side-effects. In this mini review, we demonstrate the recent studies using the active targeted strategy to kill or inhibit microbes. The four common nano-carriers (e.g. liposomes, nanoparticles, dendrimers and carbon nanotubes) delivering encapsulated drugs are introduced. PMID:25877093

  1. In vitro drug testing based on contractile activity of C2C12 cells in an epigenetic drug model

    PubMed Central

    Ikeda, Kazushi; Ito, Akira; Imada, Ryusuke; Sato, Masanori; Kawabe, Yoshinori; Kamihira, Masamichi

    2017-01-01

    Skeletal muscle tissue engineering holds great promise for pharmacological studies. Herein, we demonstrated an in vitro drug testing system using tissue-engineered skeletal muscle constructs. In response to epigenetic drugs, myotube differentiation of C2C12 myoblast cells was promoted in two-dimensional cell cultures, but the levels of contractile force generation of tissue-engineered skeletal muscle constructs prepared by three-dimensional cell cultures were not correlated with the levels of myotube differentiation in two-dimensional cell cultures. In contrast, sarcomere formation and contractile activity in two-dimensional cell cultures were highly correlated with contractile force generation of tissue-engineered skeletal muscle constructs. Among the epigenetic drugs tested, trichostatin A significantly improved contractile force generation of tissue-engineered skeletal muscle constructs. Follistatin expression was also enhanced by trichostatin A treatment, suggesting the importance of follistatin in sarcomere formation of muscular tissues. These observations indicate that contractility data are indispensable for in vitro drug screening. PMID:28300163

  2. DRUG EFFECTS ON THE LOCOMOTOR ACTIVITY OF LARVAL ZEBRAFISH.

    EPA Science Inventory

    As part of an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae and the effects of prototype drugs. Zebrafish larvae (6-7 days post-fertilization) were indiv...

  3. Acute Neuroactive Drug Exposures alter Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    As part of the development of a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae by assessing the acute effects of prototypic drugs that act on the central nervous system. Initially,...

  4. The Reciprocal Organization of Constructive Activity in Drug Addiction

    ERIC Educational Resources Information Center

    Akhmetzyanova, Anna I.; Nikishina, Vera B.; Klyueva, Nadezhda V.; Petrash, Ekaterina A.

    2016-01-01

    The urgency of the problem stated in the article is caused by the fact that modern scientific studies show that sustainable neuro-associative connections with the object of addiction arise at chemical addiction. The aim of this study is to examine the features of the reciprocal organization of constructive activities in drug addiction. Study of…

  5. Acute neuroactive drug exposures alter locomotor activity in larval zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA's prioritization of toxic chemicals, we are characterizing the locomotor activity of zebrafish (Danio rerio) larvae after exposure to prototypic drugs that act on the central nervous system. MPTP (1-methyl-4phenyl- 1 ,2,3,6-...

  6. Drug releasing nanoplatforms activated by alternating magnetic fields.

    PubMed

    Mertz, Damien; Sandre, Olivier; Bégin-Colin, Sylvie

    2017-02-24

    The use of an alternating magnetic field (AMF) to generate non-invasively and spatially a localized heating from a magnetic nano-mediator has become very popular these last years to develop magnetic hyperthermia (MH) as a promising therapeutic modality already used in the clinics. AMF has become highly attractive this last decade over others radiations, as AMF allows a deeper penetration in the body and a less harmful ionizing effect. In addition to pure MH which induces tumor cell death through local T elevation, this AMF-generated magneto-thermal effect can also be exploited as a relevant external stimulus to trigger a drug release from drug-loaded magnetic nanocarriers, temporally and spatially. This review article is focused especially on this concept of AMF induced drug release, possibly combined with MH. The design of such magnetically responsive drug delivery nanoplatforms requires two key and complementary components: a magnetic mediator which collects and turns the magnetic energy into local heat, and a thermoresponsive carrier ensuring thermo-induced drug release, as a consequence of magnetic stimulus. A wide panel of magnetic nanomaterials/chemistries and processes are currently developed to achieve such nanoplatforms. This review article presents a broad overview about the fundamental concepts of drug releasing nanoplatforms activated by AMF, their formulations, and their efficiency in vitro and in vivo. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader.

  7. 21 CFR 357.810 - Active ingredients for deodorant drug products for internal use.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Active ingredients for deodorant drug products for internal use. 357.810 Section 357.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... HUMAN USE Deodorant Drug Products for Internal Use § 357.810 Active ingredients for deodorant...

  8. 21 CFR 357.810 - Active ingredients for deodorant drug products for internal use.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Active ingredients for deodorant drug products for internal use. 357.810 Section 357.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... HUMAN USE Deodorant Drug Products for Internal Use § 357.810 Active ingredients for deodorant...

  9. 21 CFR 357.810 - Active ingredients for deodorant drug products for internal use.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Active ingredients for deodorant drug products for internal use. 357.810 Section 357.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... HUMAN USE Deodorant Drug Products for Internal Use § 357.810 Active ingredients for deodorant...

  10. 21 CFR 357.810 - Active ingredients for deodorant drug products for internal use.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Active ingredients for deodorant drug products for internal use. 357.810 Section 357.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... HUMAN USE Deodorant Drug Products for Internal Use § 357.810 Active ingredients for deodorant...

  11. 21 CFR 357.810 - Active ingredients for deodorant drug products for internal use.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Active ingredients for deodorant drug products for internal use. 357.810 Section 357.810 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND... HUMAN USE Deodorant Drug Products for Internal Use § 357.810 Active ingredients for deodorant...

  12. 21 CFR 201.316 - Drugs with thyroid hormone activity for human use; required warning.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 4 2011-04-01 2011-04-01 false Drugs with thyroid hormone activity for human use... AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Specific Labeling Requirements for Specific Drug Products § 201.316 Drugs with thyroid hormone activity for human use; required warning. (a)...

  13. 21 CFR 201.316 - Drugs with thyroid hormone activity for human use; required warning.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false Drugs with thyroid hormone activity for human use... AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL LABELING Specific Labeling Requirements for Specific Drug Products § 201.316 Drugs with thyroid hormone activity for human use; required warning. (a)...

  14. High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort

    PubMed Central

    Isaacs, John D; Morgan, Ann W; Wilson, Anthony G; Chinoy, Hector

    2017-01-01

    Objectives To evaluate (i) the association between random certolizumab drug levels, antidrug antibodies (ADAbs) and treatment response in patients with rheumatoid arthritis (RA); (ii) longitudinal factors associated with ADAbs and certolizumab drug levels. Methods This prospective cohort included 115 patients with RA treated with certolizumab. Serum samples were collected at 3, 6 and 12 months following treatment initiation. Drug levels and ADAbs were measured using ELISA and radioimmunoassay, respectively, at 3, 6 and 12 months. Disease Activity Score in 28 joints (DAS28) were measured at each visit and 12 months European League Against Rheumatism (EULAR) response was calculated. Patient self-reported adherence was collected longitudinally. Ordinal logistic regression and generalised estimating equation were used to test the association: (i) between drug levels, from serum sampled and treatment response; (ii) between ADAbs and drug levels; (iii) patient-centred factors and drug levels. Results ADAbs were detected in 37% (42/112 patients by 12 months). The presence of ADAbs were significantly associated with lower drug levels over 12 months (β=−0.037, 95% CI −0.055 to 0.018, p<0.0001) but not independently with 12 months EULAR response (β=0.0013 (95% CI −0.0032 to 0.00061), p=0.18). Drug level was associated with 12 months EULAR response (β=0.032 (95% CI 0.0011 to 0.063), p=0.042). In the multivariate model, ADAb level and adherence were significantly associated with drug concentrations. Conclusions This is the first study to demonstrate that higher certolizumab drug levels are associated with better 12 months EULAR response. ADAbs in certolizumab-treated patients with RA were detected at higher levels than previous studies and help determine the aetiology of a low drug level. PMID:27245864

  15. Systematic Repurposing Screening in Xenograft Models Identifies Approved Drugs with Novel Anti-Cancer Activity

    PubMed Central

    Roix, Jeffrey J.; Harrison, S. D.; Rainbolt, Elizabeth A.; Meshaw, Kathryn R.; McMurry, Avery S.; Cheung, Peter; Saha, Saurabh

    2014-01-01

    Approved drugs target approximately 400 different mechanisms of action, of which as few as 60 are currently used as anti-cancer therapies. Given that on average it takes 10–15 years for a new cancer therapeutic to be approved, and the recent success of drug repurposing for agents such as thalidomide, we hypothesized that effective, safe cancer treatments may be found by testing approved drugs in new therapeutic settings. Here, we report in-vivo testing of a broad compound collection in cancer xenograft models. Using 182 compounds that target 125 unique target mechanisms, we identified 3 drugs that displayed reproducible activity in combination with the chemotherapeutic temozolomide. Candidate drugs appear effective at dose equivalents that exceed current prescription levels, suggesting that additional pre-clinical efforts will be needed before these drugs can be tested for efficacy in clinical trials. In total, we suggest drug repurposing is a relatively resource-intensive method that can identify approved medicines with a narrow margin of anti-cancer activity. PMID:25093583

  16. Highly active ozonides selected against drug resistant malaria

    PubMed Central

    Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima

    2016-01-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  17. Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells

    PubMed Central

    Pu, Yingying; Zhao, Zhilun; Li, Yingxing; Zou, Jin; Ma, Qi; Zhao, Yanna; Ke, Yuehua; Zhu, Yun; Chen, Huiyi; Baker, Matthew A.B.; Ge, Hao; Sun, Yujie; Xie, Xiaoliang Sunney; Bai, Fan

    2016-01-01

    Summary Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a sub-group termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under β-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance. PMID:27105118

  18. Highly active ozonides selected against drug resistant malaria.

    PubMed

    Lobo, Lis; Sousa, Bruno de; Cabral, Lília; Cristiano, Maria Ls; Nogueira, Fátima

    2016-06-07

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites.

  19. Enzyme-activated intracellular drug delivery with tubule clay nanoformulation

    NASA Astrophysics Data System (ADS)

    Dzamukova, Maria R.; Naumenko, Ekaterina A.; Lvov, Yuri M.; Fakhrullin, Rawil F.

    2015-05-01

    Fabrication of stimuli-triggered drug delivery vehicle s is an important milestone in treating cancer. Here we demonstrate the selective anticancer drug delivery into human cells with biocompatible 50-nm diameter halloysite nanotube carriers. Physically-adsorbed dextrin end stoppers secure the intercellular release of brilliant green. Drug-loaded nanotubes penetrate through the cellular membranes and their uptake efficiency depends on the cells growth rate. Intercellular glycosyl hydrolases-mediated decomposition of the dextrin tube-end stoppers triggers the release of the lumen-loaded brilliant green, which allowed for preferable elimination of human lung carcinoma cells (A549) as compared with hepatoma cells (Hep3b). The enzyme-activated intracellular delivery of brilliant green using dextrin-coated halloysite nanotubes is a promising platform for anticancer treatment.

  20. Nestling activity levels during begging behaviour predicts activity level and body mass in adulthood

    PubMed Central

    Griffith, Simon C.

    2014-01-01

    Across a range of species including humans, personality traits, or differences in behaviour between individuals that are consistent over time, have been demonstrated. However, few studies have measured whether these consistent differences are evident in very young animals, and whether they persist over an individual’s entire lifespan. Here we investigated the begging behaviour of very young cross-fostered zebra finch nestlings and the relationship between that and adult activity levels. We found a link between the nestling activity behaviour head movements during begging, measured at just five and seven days after hatching, and adult activity levels, measured when individuals were between three and three and a half years old. Moreover, body mass was found to be negatively correlated with both nestling and adult activity levels, suggesting that individuals which carry less body fat as adults are less active both as adults and during begging as nestlings. Our work suggests that the personality traits identified here in both very young nestlings and adults may be linked to physiological factors such as metabolism or environmental sources of variation. Moreover, our work suggests it may be possible to predict an individual’s future adult personality at a very young age, opening up new avenues for future work to explore the relationship between personality and a number of aspects of individual life history and survival. PMID:25279258

  1. Effects of acute doses of prosocial drugs methamphetamine and alcohol on plasma oxytocin levels

    PubMed Central

    Bershad, Anya K.; Kirkpatrick, Matthew G.; Seiden, Jacob A.; de Wit, Harriet

    2015-01-01

    Many drugs, including alcohol and stimulants, demonstrably increase sociability and verbal interaction and are recreationally consumed in social settings. One drug, 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”), appears to produce its prosocial effects by increasing plasma oxytocin levels, and the oxytocin system has been implicated in responses to several other drugs of abuse. Here, we sought to investigate the effects of two other “social” drugs on plasma oxytocin levels: methamphetamine and alcohol. Based on their shared capacity to enhance sociability, we hypothesized that both methamphetamine and alcohol would increase plasma oxytocin. In Study 1, 11 healthy adult volunteers attended three sessions during which they received methamphetamine (10mg or 20mg) or placebo under double blind conditions. Subjective drug effects, cardiovascular effects, and plasma oxytocin were measured at regular intervals throughout the sessions. In Study 2, 8 healthy adult volunteers attended a single session during which they received one beverage containing placebo, and then a beverage containing alcohol (0.8 g/kg). Subjective effects, breath alcohol levels, and plasma oxytocin were measured at regular intervals. Both methamphetamine and alcohol produced their expected physiological and subjective effects, but neither drug increased plasma oxytocin levels. The neurobiological mechanisms mediating the prosocial effects of drugs such as alcohol and methamphetamine remain to be identified. PMID:25853370

  2. Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs

    PubMed Central

    Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M. A.; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E.; Casadevall, Arturo

    2015-01-01

    The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis. PMID:26711773

  3. Activation of Melanin Synthesis in Alternaria infectoria by Antifungal Drugs.

    PubMed

    Fernandes, Chantal; Prados-Rosales, Rafael; Silva, Branca M A; Nakouzi-Naranjo, Antonio; Zuzarte, Mónica; Chatterjee, Subhasish; Stark, Ruth E; Casadevall, Arturo; Gonçalves, Teresa

    2015-12-28

    The importance of Alternaria species fungi to human health ranges from their role as etiological agents of serious infections with poor prognoses in immunosuppressed individuals to their association with respiratory allergic diseases. The present work focuses on Alternaria infectoria, which was used as a model organism of the genus, and was designed to unravel melanin production in response to antifungals. After we characterized the pigment produced by A. infectoria, we studied the dynamics of 1,8-dihydroxynaphthalene (DHN)-melanin production during growth, the degree of melanization in response to antifungals, and how melanization affected susceptibility to several classes of therapeutic drugs. We demonstrate that A. infectoria increased melanin deposition in cell walls in response to nikkomycin Z, caspofungin, and itraconazole but not in response to fluconazole or amphotericin B. These results indicate that A. infectoria activates DHN-melanin synthesis in response to certain antifungal drugs, possibly as a protective mechanism against these drugs. Inhibition of DHN-melanin synthesis by pyroquilon resulted in a lower minimum effective concentration (MEC) of caspofungin and enhanced morphological changes (increased hyphal balloon size), characterized by thinner and less organized A. infectoria cell walls. In summary, A. infectoria synthesizes melanin in response to certain antifungal drugs, and its susceptibility is influenced by melanization, suggesting the therapeutic potential of drug combinations that affect melanin synthesis.

  4. Statistical methods for active pharmacovigilance, with applications to diabetes drugs.

    PubMed

    Zhuo, Lan; Farrell, Patrick J; McNair, Doug; Krewski, Daniel

    2014-01-01

    Pharmacovigilance aims to identify adverse drug reactions using postmarket surveillance data under real-world conditions of use. Unlike passive pharmacovigilance, which is based on largely voluntary (and hence incomplete) spontaneous reports of adverse drug reactions with limited information on patient characteristics, active pharmacovigilance is based on electronic health records containing detailed information about patient populations, thereby allowing consideration of modifying factors such as polypharmacy and comorbidity, as well as sociodemographic characteristics. With the present shift toward active pharmacovigilance, statistical methods capable of addressing the complexities of such data are needed. We describe four such methods here, and demonstrate their application in the analysis of a large retrospective cohort of diabetics taking anti-hyperglycemic medications that may increase the risk of adverse cardiovascular events.

  5. Dose critical in-vivo detection of anti-cancer drug levels in blood

    DOEpatents

    Miller, Holly H.; Hirschfeld, deceased, Tomas B.

    1991-01-01

    A method and apparatus are disclosed for the in vivo and in vitro detection and measurement of dose critical levels of DNA-binding anti-cancer drug levels in biological fluids. The apparatus comprises a laser based fiber optic sensor (optrode) which utilizes the secondary interactions between the drug and an intercalating fluorochrome bound to a probe DNA, which in turn is attached to the fiber tip at one end thereof. The other end of the optical fiber is attached to an illumination source, detector and recorder. The fluorescence intensity is measured as a function of the drug concentration and its binding constant to the probe DNA. Anticancer drugs which lend themselves to analysis by the use of the method and the optrode of the present invention include doxorubicin, daunorubicin, carminomycin, aclacinomycin, chlorambucil, cyclophosphamide, methotrexate, 5-uracil, arabinosyl cytosine, mitomycin, cis-platinum 11 diamine dichloride procarbazine, vinblastine vincristine and the like. The present method and device are suitable for the continuous monitoring of the levels of these and other anticancer drugs in biological fluids such as blood, serum, urine and the like. The optrode of the instant invention also enables the measurement of the levels of these drugs from a remote location and from multiple samples.

  6. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

    PubMed Central

    Funk, Juergen; Robbins, Justin B.; Crogan-Grundy, Candace; Presnell, Sharon C.; Singer, Thomas; Roth, Adrian B.

    2016-01-01

    Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level. PMID:27387377

  7. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 4 2011-04-01 2011-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION...

  8. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 4 2014-04-01 2014-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION...

  9. 21 CFR 212.20 - What activities must I perform to ensure drug quality?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 4 2013-04-01 2013-04-01 false What activities must I perform to ensure drug quality? 212.20 Section 212.20 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS: GENERAL CURRENT GOOD MANUFACTURING PRACTICE FOR POSITRON EMISSION...

  10. Abstinence-Contingent Reinforcement and Engagement in Non-drug Related Activities among Illicit Drug Abusers

    PubMed Central

    Rogers, Randall E.; Higgins, Stephen T.; Silverman, Kenneth; Thomas, Colleen S.; Badger, Gary J.; Bigelow, George; Stitzer, Maxine

    2010-01-01

    Methadone-maintained cocaine abusers (n = 78) were randomly assigned to a 52-week intervention of either (1) usual care only (UC), (2) take-home methadone doses contingent on cocaine- and opiate-negative results (THM), or (3) take-home methadone doses for cocaine- and opiate-negative results and monetary-based vouchers contingent on cocaine-negative urinalysis results (THM+V). Cocaine use was assessed by urinalysis on a thrice-weekly schedule. Frequency and enjoyability of non-drug related activities were assessed with the Pleasant Events Schedule (PES) at baseline, mid-, and end-of-treatment. The THM+V condition achieved the greatest abstinence from cocaine and opiate use, followed by the THM and UC conditions. The THM+V condition had the highest PES Frequency ratings at mid- and end-of-treatment, followed by the THM and UC conditions. There were significant differences between the THM+V and UC conditions on 10 of 12 PES subscales. Analyses revealed that abstinence mediated the effects of treatment condition on frequency ratings. There were no significant differences in Enjoyability ratings. These results suggest that when contingency-management interventions increase abstinence from drug abuse they also increase engagement in non-drug related activities in naturalistic settings. PMID:19071979

  11. Abstinence-contingent reinforcement and engagement in non-drug-related activities among illicit drug abusers.

    PubMed

    Rogers, Randall E; Higgins, Stephen T; Silverman, Kenneth; Thomas, Colleen S; Badger, Gary J; Bigelow, George; Stitzer, Maxine

    2008-12-01

    Methadone-maintained cocaine abusers (N = 78) were randomly assigned to 1 of the following 52-week interventions: (a) usual care only (UC), (b) take-home methadone doses contingent on cocaine- and opiate-negative results (THM), or (c) take-home methadone doses for cocaine- and opiate-negative results and monetary-based vouchers contingent on cocaine-negative urinalysis results (THM + V). Cocaine use was assessed by urinalysis on a thrice-weekly schedule. Frequency and enjoyability of non-drug-related activities were assessed with the Pleasant Events Schedule (PES) at baseline, midtreatment, and end of treatment. The THM + V condition achieved the greatest abstinence from cocaine and opiate use, followed by the THM and UC conditions. The THM + V condition had the highest PES frequency ratings at midtreatment and at the end of treatment, followed by the THM and UC conditions. There were significant differences between the THM + V and UC conditions on 10 of 12 PES-derived subscales. Analyses revealed that abstinence mediated the effects of treatment condition on frequency ratings. There were no significant differences in enjoyability ratings. These results suggest that when contingency-management interventions increase abstinence from drug abuse, they also increase engagement in non-drug-related activities in naturalistic settings.

  12. Prescription and consumption of solid oral drugs dispensed as unitary doses in a third level hospital

    PubMed Central

    Calderón-Guzmán, David; Juárez-Olguín, Hugo; Hernández-García, Ernestina; Medina-Andrade, Alejandro; Juarez Tapia, Belen

    2015-01-01

    Background: The knowledge about the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in Mexico is sparing. Purpose: The aim of this study was to describe the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in a third level private hospital of Mexico. A retrospective study of a 60-month period (from 2007 to 2011) was carried out to know the pattern of drugs dispensed as UD in a third level hospital. Results: Among the principal drugs consumed were analgesic, antihypertensive, antibiotic, anti-inflammatory, antiepileptic, and diuretics. The dispensation of drugs per year was as follows: 181 drugs with 85,167 UD in 2007; 199 with 90,519 UD in 2008; 193 with 101,479 UD in 2009; 195 with 100,798 UD in 2010; and 198 with 103,913 UD in 2011. Conclusion: The findings confirmed that prescription and consumption of unitary doses in the hospitalization service increased, and revealed the extensive use of analgesics as the principal prescribed drug in this kind of hospital. PMID:27013914

  13. Human Development Program: Level V Activity Guide.

    ERIC Educational Resources Information Center

    Ball, Geraldine

    The curriculum guide presents the activities component of the Human Development Program for grade 5. The Human Development Program (HDP) is an affective curricular approach developed by psychologists to help teachers instill responsibility and self-confidence in children. The activity guide presents topics and directions for 180 sequential Human…

  14. Atomic level insights into realistic molecular models of dendrimer-drug complexes through MD simulations

    NASA Astrophysics Data System (ADS)

    Jain, Vaibhav; Maiti, Prabal K.; Bharatam, Prasad V.

    2016-09-01

    Computational studies performed on dendrimer-drug complexes usually consider 1:1 stoichiometry, which is far from reality, since in experiments more number of drug molecules get encapsulated inside a dendrimer. In the present study, molecular dynamic (MD) simulations were implemented to characterize the more realistic molecular models of dendrimer-drug complexes (1:n stoichiometry) in order to understand the effect of high drug loading on the structural properties and also to unveil the atomistic level details. For this purpose, possible inclusion complexes of model drug Nateglinide (Ntg) (antidiabetic, belongs to Biopharmaceutics Classification System class II) with amine- and acetyl-terminated G4 poly(amidoamine) (G4 PAMAM(NH2) and G4 PAMAM(Ac)) dendrimers at neutral and low pH conditions are explored in this work. MD simulation analysis on dendrimer-drug complexes revealed that the drug encapsulation efficiency of G4 PAMAM(NH2) and G4 PAMAM(Ac) dendrimers at neutral pH was 6 and 5, respectively, while at low pH it was 12 and 13, respectively. Center-of-mass distance analysis showed that most of the drug molecules are located in the interior hydrophobic pockets of G4 PAMAM(NH2) at both the pH; while in the case of G4 PAMAM(Ac), most of them are distributed near to the surface at neutral pH and in the interior hydrophobic pockets at low pH. Structural properties such as radius of gyration, shape, radial density distribution, and solvent accessible surface area of dendrimer-drug complexes were also assessed and compared with that of the drug unloaded dendrimers. Further, binding energy calculations using molecular mechanics Poisson-Boltzmann surface area approach revealed that the location of drug molecules in the dendrimer is not the decisive factor for the higher and lower binding affinity of the complex, but the charged state of dendrimer and drug, intermolecular interactions, pH-induced conformational changes, and surface groups of dendrimer do play an

  15. Monthly variations of the Caspian sea level and solar activity.

    NASA Astrophysics Data System (ADS)

    Romanchuk, P. R.; Pasechnik, M. N.

    The connection between 11-year cycle of solar activity and the Caspian sea level is investigated. Seasonal changes of the Caspian sea level and annual variations of the sea level with variations of solar activity are studied. The results of the verifications of the sea level forecasts obtained with application of the rules discovered by the authors are given.

  16. AMPK Activation Prevents and Reverses Drug-Induced Mitochondrial and Hepatocyte Injury by Promoting Mitochondrial Fusion and Function

    PubMed Central

    Taniane, Caitlin; Farrell, Geoffrey; Arias, Irwin M.; Lippincott-Schwartz, Jennifer; Fu, Dong

    2016-01-01

    Mitochondrial damage is the major factor underlying drug-induced liver disease but whether conditions that thwart mitochondrial injury can prevent or reverse drug-induced liver damage is unclear. A key molecule regulating mitochondria quality control is AMP activated kinase (AMPK). When activated, AMPK causes mitochondria to elongate/fuse and proliferate, with mitochondria now producing more ATP and less reactive oxygen species. Autophagy is also triggered, a process capable of removing damaged/defective mitochondria. To explore whether AMPK activation could potentially prevent or reverse the effects of drug-induced mitochondrial and hepatocellular damage, we added an AMPK activator to collagen sandwich cultures of rat and human hepatocytes exposed to the hepatotoxic drugs, acetaminophen or diclofenac. In the absence of AMPK activation, the drugs caused hepatocytes to lose polarized morphology and have significantly decreased ATP levels and viability. At the subcellular level, mitochondria underwent fragmentation and had decreased membrane potential due to decreased expression of the mitochondrial fusion proteins Mfn1, 2 and/or Opa1. Adding AICAR, a specific AMPK activator, at the time of drug exposure prevented and reversed these effects. The mitochondria became highly fused and ATP production increased, and hepatocytes maintained polarized morphology. In exploring the mechanism responsible for this preventive and reversal effect, we found that AMPK activation prevented drug-mediated decreases in Mfn1, 2 and Opa1. AMPK activation also stimulated autophagy/mitophagy, most significantly in acetaminophen-treated cells. These results suggest that activation of AMPK prevents/reverses drug-induced mitochondrial and hepatocellular damage through regulation of mitochondrial fusion and autophagy, making it a potentially valuable approach for treatment of drug-induced liver injury. PMID:27792760

  17. Activation of latent HIV using drug-loaded nanoparticles.

    PubMed

    Kovochich, Michael; Marsden, Matthew D; Zack, Jerome A

    2011-04-05

    Antiretroviral therapy is currently only capable of controlling HIV replication rather than completely eradicating virus from patients. This is due in part to the establishment of a latent virus reservoir in resting CD4+ T cells, which persists even in the presence of HAART. It is thought that forced activation of latently infected cells could induce virus production, allowing targeting of the cell by the immune response. A variety of molecules are able to stimulate HIV from latency. However no tested purging strategy has proven capable of eliminating the infection completely or preventing viral rebound if therapy is stopped. Hence novel latency activation approaches are required. Nanoparticles can offer several advantages over more traditional drug delivery methods, including improved drug solubility, stability, and the ability to simultaneously target multiple different molecules to particular cell or tissue types. Here we describe the development of a novel lipid nanoparticle with the protein kinase C activator bryostatin-2 incorporated (LNP-Bry). These particles can target and activate primary human CD4+ T-cells and stimulate latent virus production from human T-cell lines in vitro and from latently infected cells in a humanized mouse model ex vivo. This activation was synergistically enhanced by the HDAC inhibitor sodium butyrate. Furthermore, LNP-Bry can also be loaded with the protease inhibitor nelfinavir (LNP-Bry-Nel), producing a particle capable of both activating latent virus and inhibiting viral spread. Taken together these data demonstrate the ability of nanotechnological approaches to provide improved methods for activating latent HIV and provide key proof-of-principle experiments showing how novel delivery systems may enhance future HIV therapy.

  18. Inositol Depletion Induced by Acute Treatment of the Bipolar Disorder Drug Valproate Increases Levels of Phytosphingosine.

    PubMed

    Jadhav, Shyamalagauri; Russo, Sarah; Cowart, L Ashley; Greenberg, Miriam L

    2017-03-24

    Bipolar disorder (BD) is a severe psychiatric illness affecting ∼1% of the world population. Valproate (VPA) and lithium, widely used for the treatment of BD, are not universally effective. These drugs have been shown to cause inositol depletion, but translating this observation to a specific therapeutic mechanism has been difficult, hampering the development of more effective therapies. We have shown previously in yeast that chronic VPA treatment induces the unfolded protein response due to increasing ceramide levels. To gain insight into the mechanisms activated during acute VPA treatment, we performed a genome-wide expression study in yeast treated with VPA for 30 min. We observed increased mRNA and protein levels of RSB1, which encodes an exporter of long chain bases dihydrosphingosine (DHS) and phytosphingosine (PHS), and further saw that VPA increased sensitivity of an rsb1Δ mutant to PHS, suggesting that VPA increases long chain base levels. Consistent with this, PHS levels were elevated in wild type and, to a greater extent, in rsb1Δ cells. Expression of ORM genes (negative regulators of PHS synthesis) and of fatty acid elongase genes FEN1 and SUR4 were decreased, and expression of YOR1 (exporter of PHS-1P) and DPL1 (lyase that degrades DHS-1P and PHS-1P) was increased. These effects were more pronounced in medium lacking inositol, and were mirrored by inositol starvation of an ino1Δ mutant. These findings provide a metabolic explanation as to how VPA-mediated inositol depletion causes increased synthesis of PHS and further support the therapeutic relevance of inositol depletion as a bipolar disorder treatment.

  19. Urine levels of drugs for which Triage DOA screening was positive.

    PubMed

    Moriya, Fumio

    2009-04-01

    The purpose of this study was to investigate the relationship between urine levels of target drugs of abuse for which Triage DOA gave positive results, as well as the cut-off levels for these drugs. Thirty-eight forensic urine samples positive for commonly abused drugs were involved. Of these samples, 12 were positive for barbiturates (BAR), 11 for benzodiazepines (BZO), 8 for opiates (OPI), 7 for amphetamines (AMP), and 4 for tricyclic antidepressants (TCA). In the BAR-positive urine samples, phenobarbital, amobarbital or barbital was detected at concentrations higher than cut-off levels. In the BZO-positive samples, diazepam, nordiazepam, triazolam, nitrazepam and/or midazolam was detected at concentrations lower than cut-off levels; in the triazolam-involved urine, alpha-hydroxytriazolam, a metabolite of triazolam, showed concentrations higher than cut-off level. In the AMP-positive samples, methamphetamine was detected at concentrations higher than cut-off level. Urine samples positive for OPI contained total dihydrocodeine, codeine or morphine at concentrations higher than cut-off levels. In TCA-positive samples, amitriptyline was detected at concentrations higher or lower than cut-off level, and clomipramine was detected at a concentration much lower than cut-off level. Metabolites of BZO and TCA, which are not typically analyzed by instrumental procedures, may cross-react to varying degrees with the antibodies used for Triage DOA.

  20. Entry-Level Activities in System Consultation

    ERIC Educational Resources Information Center

    Hylander, Ingrid

    2014-01-01

    System-level consultation or organizational development in schools is an area in great need of theoretical models and definitions. The three articles in this special issue provide a unique learning opportunity not only for consultation across borders but also for consultation within the same nation. In my commentary, I limit my remarks to a few…

  1. Magnesium Modulates Doxorubicin Activity through Drug Lysosomal Sequestration and Trafficking.

    PubMed

    Trapani, Valentina; Luongo, Francesca; Arduini, Daniela; Wolf, Federica I

    2016-03-21

    Magnesium is directly involved in the control of cell growth and survival, but its role in cancer biology and therapy is multifaceted; in particular, it is highly controversial whether magnesium levels can affect therapy outcomes. Here we investigated whether magnesium availability can modulate cellular responses to the widely used chemotherapeutic doxorubicin. We used an in vitro model consisting of mammary epithelial HC11 cells and found that high magnesium availability was correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations and in acutely magnesium-supplemented cells. This decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation in the face of a similar drug uptake rate. We observed that high-magnesium conditions caused a decrease in intracellular drug retention by altering drug lysosomal sequestration and trafficking. In our model, magnesium supplementation correspondingly modulated expression of the TRPM7 channel, which is known to control cytoskeletal organization and dynamics and may be involved in the proposed mechanism. Our findings suggest that magnesium supplementation in hypomagnesemic cancer patients may hinder response to therapy.

  2. Prenatal drug exposure to illicit drugs alters working memory-related brain activity and underlying network properties in adolescence.

    PubMed

    Schweitzer, Julie B; Riggins, Tracy; Liang, Xia; Gallen, Courtney; Kurup, Pradeep K; Ross, Thomas J; Black, Maureen M; Nair, Prasanna; Salmeron, Betty Jo

    2015-01-01

    The persistence of effects of prenatal drug exposure (PDE) on brain functioning during adolescence is poorly understood. We explored neural activation to a visuospatial working memory (VSWM) versus a control task using functional magnetic resonance imaging (fMRI) in adolescents with PDE and a community comparison group (CC) of non-exposed adolescents. We applied graph theory metrics to resting state data using a network of nodes derived from the VSWM task activation map to further explore connectivity underlying WM functioning. Participants (ages 12-15 years) included 47 adolescents (27 PDE and 20 CC). All analyses controlled for potentially confounding differences in birth characteristics and postnatal environment. Significant group by task differences in brain activation emerged in the left middle frontal gyrus (BA 6) with the CC group, but not the PDE group, activating this region during VSWM. The PDE group deactivated the culmen, whereas the CC group activated it during the VSWM task. The CC group demonstrated a significant relation between reaction time and culmen activation, not present in the PDE group. The network analysis underlying VSWM performance showed that PDE group had lower global efficiency than the CC group and a trend level reduction in local efficiency. The network node corresponding to the BA 6 group by task interaction showed reduced nodal efficiency and fewer direct connections to other nodes in the network. These results suggest that adolescence reveals altered neural functioning related to response planning that may reflect less efficient network functioning in youth with PDE.

  3. Impurities in Drug Products and Active Pharmaceutical Ingredients.

    PubMed

    Kątny, M; Frankowski, M

    2016-09-29

    Analytical methods should be selective and fast. In modern times, scientists strive to meet the criteria of green chemistry, so they choose analytical procedures that are as short as possible and use the least toxic solvents. It is quite obvious that the products intended for human consumption should be characterized as completely as possible. The safety of a drug is dependent mainly on the impurities that it contains. High pressure liquid chromatography and ultra-high pressure liquid chromatography have been proposed as the main techniques for forced degradation and impurity profiling. The aim of this article was to characterize the relevant classification of drug impurities and to review the methods of impurities determination for atorvastatin (ATV) and duloxetine (DLX) (both in active pharmaceutical ingredients and in different dosage forms). These drugs have an impact on two systems of the human body: cardiac and nervous. Simple characteristics of ATV and DLX, their properties and specificity of action on the human body, are also included in this review. The analyzed pharmaceuticals-ATV (brand name Lipiron) and DLX (brand name Cymbalta)-were selected for this study based on annual rankings prepared by Information Medical Statistics.

  4. Pancreatic Cancer-Associated Cathepsin E as a Drug Activator

    PubMed Central

    Abd-Elgaliel, Wael R.; Cruz-Monserrate, Zobeida; Wang, Huamin; Logsdon, Craig D.; Tung, Ching-Hsuan

    2013-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is challenging to treat, and better means to detect and/or treat pancreatic cancer are urgently needed to save lives. Cathepsin E (Cath E) is a proteolytic enzyme highly expressed in PDAC. In this study, a novel approach using Cath E activation of a Cath E-specific prodrug was demonstrated. Specific activation of the prodrug is expected to kill pancreatic cancer cells without harming normal pancreatic cells. A novel 5-aminolevulinic acid (5-ALA) prodrug was custom-designed to be activated selectively by endogenous Cath E within the PDAC cells. The 5-ALA prodrug was incubated with Cath E-positive and -negative tumor cells and illuminated with various doses of light. In addition, mice genetically engineered to develop PDAC were injected intravenously with the 5-ALA prodrug, and the pancreas was treated with light irradiation. One day after treatment, PDAC tissue was assessed for apoptosis. The 5-ALA prodrug was activated within the Cath E-positive tumor but not in the normal pancreatic tissue. When used in combination with light treatment, it allowed delivery of selective photodynamic therapy (PDT) to the cancerous tissues, with minimal harm to the adjacent normal tissues. With this novel Cath E activation approach, it is possible to detect pancreatic cancer cells accurately and specifically impair their viability, while sparing normal cells. This treatment could result in fewer side effects than the non-specific treatments currently in use. Cath E is a specific and effective drug activator for PDAC treatment. PMID:23422726

  5. In-vitro antifungal activities of sulfa drugs against clinical isolates of Aspergillus and Cryptococcus species.

    PubMed

    Hanafy, Ahmed; Uno, Jun; Mitani, Hiroki; Kang, Yingqian; Mikami, Yuzuru

    2007-01-01

    In vitro susceptibilities of ten clinical isolates, including five strains of Cryptococcus neoformans var. grubii and five strains of Aspergillus fumigatus, were determined against nine sulfa drugs using a microdilution method. Among the five tested media, minimum inhibitory concentration (MIC) values were observed only in YNB medium: no detectable level MIC value of less than 125 microg/ml was observed in the four remaining media against Cryptococcus species. Of the nine sulfa drugs, of which sulfaphenazole showed the highest antifungal activity, the MIC values for A. fumigatus and C. neoformans var. grubii were, respectively, 64 microg/ml and 4-8 microg/ml, suggesting high susceptibility of C. neoformans to sulfa drugs.

  6. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library

    PubMed Central

    Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G.; Zhang, Ying

    2016-01-01

    Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10–20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

  7. Activation of Latent HIV Using Drug-loaded Nanoparticles

    NASA Astrophysics Data System (ADS)

    Kovochich, Michael

    Antiretroviral therapy is currently only capable of controlling human immunodeficiency virus (HIV) replication, rather than completely eradicating virus from patients. This is due in part to the establishment of a latent virus reservoir in resting CD4+ T-cells, which persists even in the presence of highly active antiretroviral therapy (HAART). It is thought that forced activation of latently infected cells could induce virus production, allowing targeting of the cell by the immune response. A variety of molecules are able to stimulate HIV from latency. However, no tested purging strategy has proven capable of eliminating the infection completely or preventing viral rebound if therapy is stopped. Hence, novel latency activation approaches are required. Nanoparticles can offer several advantages over more traditional drug delivery methods, including improved drug solubility, stability, and the ability to simultaneously target multiple different molecules to particular cell or tissue types. Here we describe the development of a novel lipid nanoparticle with the protein kinase C activator bryostatin-2 incorporated (LNP-Bry). These particles can target, activate primary human CD4+ T-cells, and stimulate latent virus production from human T-cell lines in vitro and from latently infected cells in a humanized mouse model ex vivo. This activation was synergistically enhanced by the histone deacetylase inhibitor (HDACi) sodium butyrate. Furthermore, LNP-Bry can also be loaded with the protease inhibitor nelfinavir (LNP-Bry-Nel), producing a particle capable of both activating latent virus and inhibiting viral spread. LNP-Bry was further tested for its in vivo biodistribution in both wild type mice (C57 black 6), as well as humanized mice (SCID-hu Thy/Liv, and bone marrow-liver-thymus [BLT]). LNP-Bry accumulated in the spleen and induced the early activation marker CD69 in wild type mice. Taken together, these data demonstrate the ability of nanotechnological approaches to

  8. An enzymatic deconjugation method for the analysis of small molecule active drugs on antibody-drug conjugates

    PubMed Central

    Li, Yi; Gu, Christine; Gruenhagen, Jason; Yehl, Peter; Chetwyn, Nik P.; Medley, Colin D.

    2016-01-01

    ABSTRACT Antibody-drug conjugates (ADCs) are complex therapeutic agents that use the specific targeting properties of antibodies and the highly potent cytotoxicity of small molecule drugs to selectively eliminate tumor cells while limiting the toxicity to normal healthy tissues. Two critical quality attributes of ADCs are the purity and stability of the active small molecule drug linked to the ADC, but these are difficult to assess once the drug is conjugated to the antibody. In this study, we report a enzyme deconjugation approach to cleave small molecule drugs from ADCs, which allows the drugs to be subsequently characterized by reversed-phase high performance liquid chromatography. The model ADC we used in this study utilizes a valine-citrulline linker that is designed to be sensitive to endoproteases after internalization by tumor cells. We screened several proteases to determine the most effective enzyme. Among the 3 cysteine proteases evaluated, papain had the best efficiency in cleaving the small molecule drug from the model ADC. The deconjugation conditions were further optimized to achieve complete cleavage of the small molecule drug. This papain deconjugation approach demonstrated excellent specificity and precision. The purity and stability of the active drug on an ADC drug product was evaluated and the major degradation products of the active drug were identified. The papain deconjugation method was also applied to several other ADCs, with the results suggesting it could be applied generally to ADCs containing a valine-citrulline linker. Our results indicate that the papain deconjugation method is a powerful tool for characterizing the active small molecule drug conjugated to an ADC, and may be useful in ensuring the product quality, efficacy and the safety of ADCs. PMID:26891281

  9. Effects of antidepressant drugs on synaptic protein levels and dendritic outgrowth in hippocampal neuronal cultures.

    PubMed

    Seo, Mi Kyoung; Lee, Chan Hong; Cho, Hye Yeon; Lee, Jung Goo; Lee, Bong Ju; Kim, Ji Eun; Seol, Wongi; Kim, Young Hoon; Park, Sung Woo

    2014-04-01

    The alteration of hippocampal plasticity has been proposed to play a critical role in both the pathophysiology and treatment of depression. In this study, the ability of different classes of antidepressant drugs (escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine) to mediate the expression of synaptic proteins and dendritic outgrowth in rat hippocampal neurons was investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. Postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP) levels were evaluated using Western blot analyses. Additionally, dendritic outgrowth was examined to determine whether antidepressant drugs affect the dendritic morphology of hippocampal neurons in B27-deprived cultures. Escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine significantly prevented B27 deprivation-induced decreases in levels of PSD-95, BDNF, and SYP. Moreover, the independent application of fluoxetine, paroxetine, and sertraline significantly increased levels of BDNF under normal conditions. All antidepressant drugs significantly increased the total outgrowth of hippocampal dendrites under B27 deprivation. Specific inhibitors of calcium/calmodulin kinase II (CaMKII), KN-93, protein kinase A (PKA), H-89, or phosphatidylinositol 3-kinase (PI3K), LY294002, significantly decreased the effects of antidepressant drugs on dendritic outgrowth, whereas this effect was observed only with tianeptine for the PI3K inhibitor. Taken together, these results suggest that certain antidepressant drugs can enhance synaptic protein levels and encourage dendritic outgrowth in hippocampal neurons. Furthermore, effects on dendritic outgrowth likely require CaMKII, PKA, or PI3K signaling pathways. The observed effects may be may be due to chronic treatment with antidepressant drugs.

  10. Active scaffolds for on-demand drug and cell delivery

    PubMed Central

    Zhao, Xuanhe; Kim, Jaeyun; Cezar, Christine A.; Huebsch, Nathaniel; Lee, Kangwon; Bouhadir, Kamal; Mooney, David J.

    2011-01-01

    Porous biomaterials have been widely used as scaffolds in tissue engineering and cell-based therapies. The release of biological agents from conventional porous scaffolds is typically governed by molecular diffusion, material degradation, and cell migration, which do not allow for dynamic external regulation. We present a new active porous scaffold that can be remotely controlled by a magnetic field to deliver various biological agents on demand. The active porous scaffold, in the form of a macroporous ferrogel, gives a large deformation and volume change of over 70% under a moderate magnetic field. The deformation and volume variation allows a new mechanism to trigger and enhance the release of various drugs including mitoxantrone, plasmid DNA, and a chemokine from the scaffold. The porous scaffold can also act as a depot of various cells, whose release can be controlled by external magnetic fields. PMID:21149682

  11. Polymeric drugs based on random copolymers with antimitotic activity.

    PubMed

    López-Donaire, M L; Parra-Cáceres, J; Fernández-Gutiérrez, M; Vázquez-Lasa, B; Román, J San

    2010-09-13

    Polymeric drugs based on random copolymers with antimitotic activity were obtained by free radical copolymerization of oleyl 2-acetamido-2-deoxy-α-d-glucopyranoside methacrylate (OAGMA) and 2-ethyl-(2-pyrrolidone) methacrylate (EPM) at low and high conversion and analyzed in terms of microstructure, physicochemical, and biological properties. Reactivity ratios of monomers were found to be r(OAGMA) = 1.34 and r(EPM) = 0.98, indicating the obtaining of statistical copolymers with random sequence distribution of the comonomeric units in the macromolecular chains. The glass transition temperature of the copolymers presents a negative deviation from the predicted values according to the Fox equation, suggesting a higher flexibility of the alternating diad. Copolymeric systems with OAGMA contents between 10-50 mol % presented thermosensitive behavior in a heating process showing cloud point temperatures (CPT) in the range 45-28 °C with increasing OAGMA content and hysteresis in one heating-and-cooling cycle. In vitro glycolipid release studies revealed the stability of the ester group in culture medium. The polymeric drugs with 30 and 50 mol % OAGMA presented antimitotic activity on a human glioblastoma line, but they were less toxic on normal human fibroblast cultures.

  12. Photocatalytic degradation and drug activity reduction of Chloramphenicol.

    PubMed

    Chatzitakis, A; Berberidou, C; Paspaltsis, I; Kyriakou, G; Sklaviadis, T; Poulios, I

    2008-01-01

    The photocatalytic degradation of Chloramphenicol, an antibiotic drug, has been investigated in aqueous heterogeneous solutions containing n-type oxide semiconductors as photocatalysts. The disappearance of the organic molecule follows approximately a pseudo-first-order kinetics according to the Langmuir-Hinshelwood model. It was observed that, with TiO(2) P-25 as photocatalyst, quantitative degradation of the organic molecule occurs after 4h of illumination. During this time, the dechlorination of the substrate is complete, while the organic nitrogen was recovered in the form of nitrate and ammonium ions. The effect of temperature on the degradation rate of Chloramphenicol shows similar apparent activation energies for both TiO(2) P-25 and ZnO photocatalysts. The initial apparent photonic efficiency (zeta(0)) of the photo-oxidation and the mineralization under various experimental conditions have been calculated, while the Kirby-Bauer disc diffusion method showed a 100% reduction of the drug activity after 90 min of photocatalytic treatment.

  13. Recent New Drug Approvals, Part 2: Drugs Undergoing Active Clinical Studies in Children

    PubMed Central

    Chhim, Rebecca F.; Shelton, Chasity M.; Christensen, Michael L.

    2013-01-01

    The objective of this 2-part review is to provide information about drugs that have been recently approved by the US Food and Drug Administration. Part 1 reviewed recently approved drugs with pediatric indications. Part 2 reviews drugs recently approved only in adults and have published or ongoing studies in children. PMID:23616733

  14. Physical activity levels in the treatment of juvenile fibromyalgia.

    PubMed

    Sherry, David D

    2013-01-01

    Physical activity is paramount in the treatment of juvenile fibromyalgia, although some interventions use indirect methods to increase activity levels rather than address physical dysfunction head-on. New research explores the effects of a psychotherapeutic approach on levels of physical activity in adolescents with fibromyalgia.

  15. Use of Lot Quality Assurance Sampling to Ascertain Levels of Drug Resistant Tuberculosis in Western Kenya

    PubMed Central

    Cohen, Ted; Zignol, Matteo; Nyakan, Edwin; Hedt-Gauthier, Bethany L.; Gardner, Adrian; Kamle, Lydia; Injera, Wilfred; Carter, E. Jane

    2016-01-01

    Objective To classify the prevalence of multi-drug resistant tuberculosis (MDR-TB) in two different geographic settings in western Kenya using the Lot Quality Assurance Sampling (LQAS) methodology. Design The prevalence of drug resistance was classified among treatment-naïve smear positive TB patients in two settings, one rural and one urban. These regions were classified as having high or low prevalence of MDR-TB according to a static, two-way LQAS sampling plan selected to classify high resistance regions at greater than 5% resistance and low resistance regions at less than 1% resistance. Results This study classified both the urban and rural settings as having low levels of TB drug resistance. Out of the 105 patients screened in each setting, two patients were diagnosed with MDR-TB in the urban setting and one patient was diagnosed with MDR-TB in the rural setting. An additional 27 patients were diagnosed with a variety of mono- and poly- resistant strains. Conclusion Further drug resistance surveillance using LQAS may help identify the levels and geographical distribution of drug resistance in Kenya and may have applications in other countries in the African Region facing similar resource constraints. PMID:27167381

  16. Patterns of Substance Use and Correlates of Lifetime and Active Injection Drug Use Among Women in Malaysia

    PubMed Central

    Wickersham, Jeffrey A.; Loeliger, Kelsey B.; Marcus, Ruthanne; Pillai, Veena; Kamarulzaman, Adeeba; Altice, Frederick L.

    2016-01-01

    Background While drug use is associated with HIV risk in Southeast Asia, little is known about substance use behaviors among women, including drug injection. Objectives To describe patterns of substance use among women using alcohol and drugs in Malaysia and identify correlates of lifetime and active drug injection, a risk factor for HIV transmission. Methods A survey of 103 women who used drugs in the last 12 months assessed drug use history and frequency, including drug injection and drug use during pregnancy, self-reported HIV-status, childhood and adulthood physical and sexual abuse, and access to and utilization of harm reduction services, including needle-syringe exchange programs (NSEP) and opioid agonist maintenance therapy (OAT). Principal component analyses (PCA) were conducted to assess drug use grouping. Results Amphetamine-type substances (ATS; 82.5%), alcohol (75.7%) and heroin (71.8%) were the most commonly used drugs across the lifetime. Drug injection was reported by 32.0% (n=33) of participants with 21.4% (n=22) having injected in the last 30 days. PCA identified two groups of drug users: opioids/benzodiazepines and club drugs. Lifetime drug injection was significantly associated with lower education, homelessness, prior criminal justice involvement, opioid use, polysubstance use, childhood physical and sexual abuse, and being HIV-infected, but not with prior OAT. Conclusion Women who use drugs in Malaysia report high levels of polysubstance use and injection-related risk behaviors, including sharing of injection equipment and being injected by others. Low OAT utilization suggests the need for improved access to OAT services and other harm reduction measures that prioritize women. PMID:26636885

  17. [Level of evidence for therapeutic drug monitoring for etoposide after oral administration].

    PubMed

    Schieveen, Pauline Gerritsen-van; Hulin, Anne; Muret, Patrice; Royer, Bernard

    2010-01-01

    Oral etoposide displays high inter- and intra-variability. Convincing relationships were observed between hematological toxicities and exposure of which total etoposide area under the curve seems the more relevant in routine practice. Linear pharmacokinetics, limited sampling strategies and reduction of variability during concentration-controlled studies argue in favor of therapeutic drug monitoring. For these reasons, such practice can be considered as recommended or potentially useful. Further studies using Bayesian approach are nevertheless needed to definitely state regarding the level of evidence therapeutic drug monitoring of oral etoposide.

  18. Low-level laser as a device for increase of drug concentration in the kidney

    NASA Astrophysics Data System (ADS)

    Koultchavenia, Ekaterina V.

    2001-01-01

    In the West Siberia every tenth tuberculous patient has an extra pulmonary lesion. Urogenital tuberculosis cases are in the first place in occurrence among extra pulmonary forms. Complicated and widespread lesions of kidney are prevailing. The high concentration of anti-tuberculous drugs in the lesion locus is one of the most important component in the success treatment of tuberculosis, including nephrotyberculosis. We put the aim to increase the isoniazid concentration in tuberculous kidney by low-level laser therapy. It was proved that the laser therapy at the expense of improving of the blood microcirculation ensures to increase drug concentration in the lesion locus in 9 times.

  19. [Level of evidence for therapeutic drug monitoring of MPA in hematopoietic stem cell transplantation].

    PubMed

    Gerritsen-van Schieveen, Pauline; Royer, Bernard

    2011-01-01

    Mycophenolic acid (MPA) is more and more used to prevent GVHD (Graft Versus Host Disease) during hematopoietic stem cell transplantation with reduce-intensity conditioning. If several facts argue in favor of therapeutic drug monitoring, the used pharmacokinetic parameter is to be defined. Especially, the choice between total or ultrafilterable MPA is still under debate even if therapeutic drug monitoring seems to be more practicable with total MPA. The role of other factors implied in GVHD occurrence are also to be assessed in studies which aim at assessing therapeutic drug monitoring of MPA in such situation. For theses reasons, the level evidence of MPA as GVHD prophylaxis during hematopoietic stem cell transplantation with reduce-intensity conditioning is potentially useful.

  20. Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi In Vitro.

    PubMed

    Feng, Jie; Zhang, Shuo; Shi, Wanliang; Zhang, Ying

    2017-03-22

    Lyme disease is a most common vector-borne disease in the US. Although the majority of Lyme patients can be cured with the standard two- to four-week antibiotic treatment, at least 10%-20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs, sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phase B. burgdorferi enriched in persisters; however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four-drug combinations dapsone + minocycline + cefuroxime + azithromycin and dapsone + minocycline + cefuroxime + rifampin showed the best activity against stationary phase B. burgdorferi in these sulfa drug combinations. However, these four-sulfa-drug-containing combinations still had considerably less activity against B. burgdorferi stationary phase cells than the Daptomycin + cefuroxime

  1. Immunomodulatory Drugs Regulate HMGB1 Release from Activated Human Monocytes

    PubMed Central

    Schierbeck, Hanna; Wähämaa, Heidi; Andersson, Ulf; Harris, Helena Erlandsson

    2010-01-01

    Several HMGB1-specific antagonists have provided beneficial results in multiple models of inflammatory disease–preclinical trials including arthritis. Since no HMGB1-specific targeted therapy has yet reached the clinic, we have performed in vitro studies to investigate whether any of a selection of well-established antirheumatic drugs inhibit HMGB1 release as part of its mode of action. Freshly purified peripheral blood monocytes from healthy donors were stimulated in cultures with LPS and IFNγ to cause HMGB1 and TNF release detected in ELISPOT assays. Effects on the secretion were assessed in cultures supplemented with dexamethasone, cortisone, chloroquine, gold sodium thiomalate, methotrexate, colchicine, etanercept or anakinra. Pharmacologically relevant doses of dexamethasone, gold sodium thiomalate and chloroquine inhibited the extracellular release of HMGB1 in a dose-dependent mode. Immunostaining demonstrated that dexamethasone caused intracellular HMGB1 retention. No effects on HMGB1 secretion were observed in cultures with activated monocytes by any of the other studied agents. TNF production in LPS/IFNγ-activated monocytes was readily downregulated by dexamethasone and, to some extent, by chloroquine and etanercept. We conclude that dexamethasone, gold sodium thiomalate and chloroquine share a capacity to inhibit HMGB1 release from activated monocytes. PMID:20386869

  2. 78 FR 70069 - Agency Information Collection Activities; Proposed New Collection; Comments Requested: Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-22

    ... Information Collection Activities; Proposed New Collection; Comments Requested: Drug Endangered Children... information technology, e.g., permitting electronic submission of responses. Overview of This Information... Form/Collection: Drug Endangered Children Tracking System User Survey. (3) Agency form number, if...

  3. 75 FR 49946 - National Drug Intelligence Center: Agency Information Collection Activities: Proposed Extension...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-16

    ... National Drug Intelligence Center: Agency Information Collection Activities: Proposed Extension With Change... Response System. The United States Department of Justice (DOJ), National Drug Intelligence Center (NDIC... Intelligence Center, Fifth Floor, 319 Washington Street, Johnstown, PA 15901. Written comments and...

  4. Incidence of amikacin ototoxicity: a sigmoid function of total drug exposure independent of plasma levels.

    PubMed

    Beaubien, A R; Desjardins, S; Ormsby, E; Bayne, A; Carrier, K; Cauchy, M J; Henri, R; Hodgen, M; Salley, J; St Pierre, A

    1989-01-01

    A sigmoid curve was found to closely describe the relationship between the incidence of amikacin ototoxicity (greater than or equal to 15 dB hearing loss at a given frequency) and either (1) total dose, or (2) the area under the curve (AUC) describing plasma drug concentration v time over the total period of amikacin administration (total AUC) in continuously infused guinea pigs. Total dose or total AUC estimates of the drug exposure required to produce ototoxicity in 50% of the animals (ED50s) were not significantly different over an eight-fold range of dosing rates or plasma concentrations. A theoretical explanation for this result is that ototoxicity occurs only when a critical amount of drug is accumulated at the ototoxic site by an essentially unidirectional process with a rate that is slow and linearly related to the extracellular drug concentration. The sigmoid relationships for pooled data were parallel in slope for all hearing frequencies from 2 to 32 kHz, and the ED50s showed a strong negative linear relationship to the log of the hearing frequency over this range. The magnitude of ototoxicity expressed as the number of octaves (frequency ratios of 2) for which hearing loss damage was continuous from 32 kHz downward, was correlated to both total dose (r = .605) and total AUC (r = 0.703). No relationship between ototoxicity and plasma level or dosing rate was found. The extreme steepness of the dose-effect curve for the incidence of ototoxicity greatly amplified the variability between individuals and offers an explanation for the unpredictability of aminoglycoside ototoxicity in human patients. The results indicate that either total dose or total AUC (in cases of highly unpredictable blood levels), and not peak or trough serum levels, should be used as an index of ototoxic risk and that the safety limits of drug exposure should be set conservatively.

  5. Effects of cytostatic drugs on plasma level and renal excretion of beta-acetyldigoxin.

    PubMed

    Kuhlmann, J; Zilly, W; Wilke, J

    1981-10-01

    Mucosal defects decrease digoxin absorption in patients with malabsorption syndromes. Since the intestinal mucosa can be damaged by cytostatic drugs, we investigated their effects on digoxin plasma levels and urinary digoxin excretion. In six patients with malignant lymphoma who received 0.8 mg beta-acetyldigoxin before and 24 hr after treatment with a combination of cyclophosphamide, oncovin, procarbazine, and prednisone (COPP) or cyclophosphamide, oncovin, and prednisone (COP), plasma digoxin concentrations were measured 0 to 8 hr after the dose and areas under the plasma concentration-time curves were calculated. In 15 patients on 0.3 mg of beta-acetyldigoxin daily, plasma glycoside concentrations and renal excretion were measured daily before and after COPP, COP, cyclophosphamide, oncovin, cytosine-arabinosine, and prednisone (COAP), or adriamycin, bleomycin, and prednisone (ABP) treatment schemes. The diminished steady-state glycoside plasma concentrations and daily renal glycoside excretion during the 24 to 168 hr after the cytostatic drug established reversible impairment of digoxin absorption. The delayed time to peak after a single dose of digoxin during cytostatic drug therapy shows that extent and rate of digoxin absorption are reduced. To maintain adequate control of digoxin therapy in patients treated with cytostatic drugs, plasma levels should be monitored.

  6. Physical activity levels of children during school playtime.

    PubMed

    Ridgers, Nicola D; Stratton, Gareth; Fairclough, Stuart J

    2006-01-01

    School represents a suitable setting for intervention programmes aiming to promote physical activity to benefit health. During the school day, physical education and school playtime offer children regular opportunities to engage in physical activity. However, there is growing concern that, internationally, curricular time allocated to physical education is not meeting statutory guidelines. The effectiveness of the playground environment to promote physical activity has been considered as a complementary setting to physical education. Physical activity guidelines state that children should engage in at least 1 hour of moderate intensity physical activity a day. Currently no empirically tested guidelines exist for physical activity levels during playtime. However, studies cited in this article indicate that playtime can contribute between 5-40% of recommended daily physical activity levels when no interventions have been utilised. The limited school-based investigations that have been reported in the literature suggest that boys engage in more physical activity during playtime than girls. Studies that have implemented intervention strategies in order to promote physical activity levels indicate that playtime can substantially contribute towards daily optimal physical activity guidelines. Energy expenditure and physical activity levels have increased during playtime following the implementation of playtime-based interventions. In order to advance knowledge of children's physical activity during playtime, a number of key issues for consideration in future research are detailed. Research on children's use of playtime to be physically active and the extent of the contribution of playtime to daily physical activity guidelines is warranted.

  7. Application of space-time scan statistics to describe geographic and temporal clustering of visible drug activity.

    PubMed

    Linton, Sabriya L; Jennings, Jacky M; Latkin, Carl A; Gomez, Marisela B; Mehta, Shruti H

    2014-10-01

    Knowledge of the geographic and temporal clustering of drug activity can inform where health and social services are needed and can provide insight on the potential impact of local policies on drug activity. This ecologic study assessed the spatial and temporal distribution of drug activity in Baltimore, Maryland, prior to and following the implementation of a large urban redevelopment project in East Baltimore, which began in 2003. Drug activity was measured by narcotic calls for service at the neighborhood level. A space-time scan statistic approach was used to identify statistically significant clusters of narcotic calls for service across space and time, using a discrete Poisson model. After adjusting for economic deprivation and housing vacancy, clusters of narcotic calls for service were identified among neighborhoods located in Southeast, Northeast, Northwest, and West Baltimore from 2001 to 2010. Clusters of narcotic calls for service were identified among neighborhoods located in East Baltimore from 2001 to 2003, indicating a decrease in narcotic calls thereafter. A large proportion of clusters occurred among neighborhoods located in North and Northeast Baltimore after 2003, which indicated a potential spike during this time frame. These findings suggest potential displacement of drug activity coinciding with the initiation of urban redevelopment in East Baltimore. Space-time scan statistics should be used in future research to describe the potential implications of local policies on drug activity.

  8. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase.

    PubMed

    Aldred, Katie J; Blower, Tim R; Kerns, Robert J; Berger, James M; Osheroff, Neil

    2016-02-16

    Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrA(A90) and GyrA(D94). M. tuberculosis gyrase lacks a conserved serine that anchors a water-metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrA(A90)) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone-gyrase interactions. Clinically relevant mutations at GyrA(A90) and GyrA(D94) cause quinolone resistance by disrupting the bridge-enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone-enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrA(A90V) and GyrA(D94G). 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug-enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis.

  9. Tuberculosis screening and compliance with return for skin test reading among active drug users.

    PubMed Central

    Malotte, C K; Rhodes, F; Mais, K E

    1998-01-01

    OBJECTIVES: This study assessed the independent and combined effects of different levels of monetary incentives and a theory-based educational intervention on return for tuberculosis (TB) skin test reading in a sample of active injection drug and crack cocaine users. Prevalence of TB infection in this sample was also determined. METHODS: Active or recent drug users (n = 1004), recruited via street outreach techniques, were skin tested for TB. They were randomly assigned to 1 of 2 levels of monetary incentive ($5 and $10) provided at return for skin test reading, alone or in combination with a brief motivational education session. RESULTS: More than 90% of those who received $10 returned for skin test reading, in comparison with 85% of those who received $5 and 33% of those who received no monetary incentive. The education session had no impact on return for skin test reading. The prevalence of a positive tuberculin test was 18.3%. CONCLUSIONS: Monetary incentives dramatically increase the return rate for TB skin test reading among drug users who are at high risk of TB infection. PMID:9585747

  10. Using Chemoinformatics, Bioinformatics, and Bioassay to Predict and Explain the Antibacterial Activity of Nonantibiotic Food and Drug Administration Drugs.

    PubMed

    Kahlous, Nour Aldin; Bawarish, Muhammad Al Mohdi; Sarhan, Muhammad Arabi; Küpper, Manfred; Hasaba, Ali; Rajab, Mazen

    2017-03-27

    Discovering of new and effective antibiotics is a major issue facing scientists today. Luckily, the development of computer science offers new methods to overcome this issue. In this study, a set of computer software was used to predict the antibacterial activity of nonantibiotic Food and Drug Administration (FDA)-approved drugs, and to explain their action by possible binding to well-known bacterial protein targets, along with testing their antibacterial activity against Gram-positive and Gram-negative bacteria. A three-dimensional virtual screening method that relies on chemical and shape similarity was applied using rapid overlay of chemical structures (ROCS) software to select candidate compounds from the FDA-approved drugs database that share similarity with 17 known antibiotics. Then, to check their antibacterial activity, disk diffusion test was applied on Staphylococcus aureus and Escherichia coli. Finally, a protein docking method was applied using HYBRID software to predict the binding of the active candidate to the target receptor of its similar antibiotic. Of the 1,991 drugs that were screened, 34 had been selected and among them 10 drugs showed antibacterial activity, whereby drotaverine and metoclopramide activities were without precedent reports. Furthermore, the docking process predicted that diclofenac, drotaverine, (S)-flurbiprofen, (S)-ibuprofen, and indomethacin could bind to the protein target of their similar antibiotics. Nevertheless, their antibacterial activities are weak compared with those of their similar antibiotics, which can be potentiated further by performing chemical modifications on their structure.

  11. Activity of Sulfa Drugs and Their Combinations against Stationary Phase B. burgdorferi In Vitro

    PubMed Central

    Feng, Jie; Zhang, Shuo; Shi, Wanliang; Zhang, Ying

    2017-01-01

    Lyme disease is a most common vector-borne disease in the US. Although the majority of Lyme patients can be cured with the standard two- to four-week antibiotic treatment, at least 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs, sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phase B. burgdorferi enriched in persisters; however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four-drug combinations dapsone + minocycline + cefuroxime + azithromycin and dapsone + minocycline + cefuroxime + rifampin showed the best activity against stationary phase B. burgdorferi in these sulfa drug combinations. However, these four-sulfa-drug–containing combinations still had considerably less activity against B. burgdorferi stationary phase cells than the Daptomycin

  12. Quantitative structure-activity relationship models for predicting drug-induced liver injury based on FDA-approved drug labeling annotation and using a large collection of drugs.

    PubMed

    Chen, Minjun; Hong, Huixiao; Fang, Hong; Kelly, Reagan; Zhou, Guangxu; Borlak, Jürgen; Tong, Weida

    2013-11-01

    Drug-induced liver injury (DILI) is one of the leading causes of the termination of drug development programs. Consequently, identifying the risk of DILI in humans for drug candidates during the early stages of the development process would greatly reduce the drug attrition rate in the pharmaceutical industry but would require the implementation of new research and development strategies. In this regard, several in silico models have been proposed as alternative means in prioritizing drug candidates. Because the accuracy and utility of a predictive model rests largely on how to annotate the potential of a drug to cause DILI in a reliable and consistent way, the Food and Drug Administration-approved drug labeling was given prominence. Out of 387 drugs annotated, 197 drugs were used to develop a quantitative structure-activity relationship (QSAR) model and the model was subsequently challenged by the left of drugs serving as an external validation set with an overall prediction accuracy of 68.9%. The performance of the model was further assessed by the use of 2 additional independent validation sets, and the 3 validation data sets have a total of 483 unique drugs. We observed that the QSAR model's performance varied for drugs with different therapeutic uses; however, it achieved a better estimated accuracy (73.6%) as well as negative predictive value (77.0%) when focusing only on these therapeutic categories with high prediction confidence. Thus, the model's applicability domain was defined. Taken collectively, the developed QSAR model has the potential utility to prioritize compound's risk for DILI in humans, particularly for the high-confidence therapeutic subgroups like analgesics, antibacterial agents, and antihistamines.

  13. Towards a new paradigm: Activity level balanced sustainability reporting.

    PubMed

    Samudhram, Ananda; Siew, Eu-Gene; Sinnakkannu, Jothee; Yeow, Paul H P

    2016-11-01

    Technoeconomic paradigms based economic growth theories suggest that waves of technological innovations drove the economic growth of advanced economies. Widespread economic degradation and pollution is an unintended consequence of such growth. Tackling environmental and social issues at firm levels would help us to overcome such issues at macro-levels. Consequently, the Triple Bottom Line (TBL) reporting approach promotes firm level economic, environmental and social performances. Incorporating Zink's (2014) 3-pillar presentation model, this paper indicates that economic, social and environmental performances tend to be reported at firm level. All three pillars are not covered evenly at the activity levels. Thus, a loophole is identified whereby excellent environmental performance at activity levels could potentially leave poor social performance undisclosed. A refinement of the TBL paradigm, whereby all three pillars are covered at the activity level, is suggested, to enhance sustainability reporting.

  14. Solar Activity, Different Geomagnetic Activity Levels and Acute Myocardial Infarction

    NASA Astrophysics Data System (ADS)

    Dimitrova, Svetla; Jordanova, Malina; Stoilova, Irina; Taseva, Tatiana; Maslarov, Dimitar

    Results on revealing a possible relationship between solar activity (SA) and geomagnetic activity (GMA) and acute myocardial infarction (AMI) morbidity are presented. Studies were based on medical data covering the period from 1.12.1995 to 31.12.2004 and concerned daily distribution of patients with AMI diagnose (in total 1192 cases) from Sofia region on the day of admission at the hospital. Analysis of variance (ANOVA) was applied to check the significance of GMA intensity effect and the type of geomagnetic storms, those caused by Magnetic Clouds (MC) and by High Speed Solar Wind Streams (HSSWS), on AMI morbidity. Relevant correlation coefficients were calculated. Results revealed statistically significant positive correlation between considered GMA indices and AMI. ANOVA revealed that AMI number was signifi- cantly increased from the day before (-1st) till the day after (+1st) geomagnetic storms with different intensities. Geomagnetic storms caused by MC were related to significant increase of AMI number in comparison with the storms caused by HSSWS. There was a trend for such different effects even on -1st and +1st day.

  15. Fluvoxamine, a new antidepressant drug, fails to show antiserotonin activity.

    PubMed

    Maj, J; Rogóz, Z; Skuza, G

    1982-07-09

    Fluvoxamine, (E)-5-methoxy-4'-(trifluoromethyl)valerophenone O-2(2-aminoethyl)oxime, a new antidepressant drug inhibiting serotonin (5-HT) uptake, was studied in rats and mice in order to check whether it has any central anti-5-HT activity, as do some tricyclic antidepressants, e.g. amitriptyline and doxepin. Fluvoxamine did not influence either the 5-hydroxytryptophan-induced head twitch response in mice or the tryptamine convulsions in rats. In the hind limb flexor reflex of the spinal rat the stimulation induced by fenfluramine was inhibited, that induced by LSD was not changed. Fluvoxamine also antagonized the hyperthermia (at ambient temperature of 28 degrees C), induced in rats by fenfluramine or p-chloroamphetamine. The hyperthermia caused by m-chlorophenylpiperazine was not inhibited. Fluvoxamine did not antagonize the 5-HT pressor effect in pithed rats. It has no effect on the immobility time in the behavioural despair test in rats. The results indicate that fluvoxamine fails to show anti-5-HT activity.

  16. Effect of three anorectic drugs on brain GABA levels and synthesis in the Zucker rat.

    PubMed

    Orosco, M; Bremond, J; Jacquot, C; Cohen, Y

    1983-01-01

    1. Genetically obese Zucker rats and their lean littermates were submitted to a subchronic treatment with fenfluramine, mazindol and amphetamine. GABA levels and synthesis index were measured in different brain areas. 2. GABA levels, similar in obese and lean controls, were not changed after the three treatments. 3. A higher synthesis index of GABA was found in lean rats, in the striatum after mazindol and in the hypothalamus after amphetamine. 4. The three drugs increased the synthesis index of GABA in the remainder of the brain of both obese and lean rats.

  17. Model of complex chiral drug metabolic systems and numerical simulation of the remaining chirality toward analysis of dynamical pharmacological activity.

    PubMed

    Ogino, Yoshiyuki; Asahi, Toru

    2015-05-21

    In this study, systems of complicated pathways involved in chiral drug metabolism were investigated. The development of chiral drugs resulted in significant improvement in the remedies available for the treatment of various severe sicknesses. Enantiopure drugs undergo various biological transformations that involve chiral inversion and thus result in the generation of multiple enantiomeric metabolites. Identification of the specific active substances determining a given drug׳s efficacy among such a mixture of different metabolites remains a challenge. To comprehend this complexity, we constructed a mathematical model representing the complicated metabolic pathways simultaneously involving chiral inversion. Moreover, this model is applied to the metabolism of thalidomide, which has recently been revived as a potentially effective prescription drug for a number of intractable diseases. The numerical simulation results indicate that retained chirality in the metabolites reflects the original chirality of the unmetabolized drug, and a higher level of enantiomeric purity is preserved during spontaneous degradation. In addition, chirality remaining after equilibration is directly related to the rate constant not only for chiral inversion but also for generation and degradation. Furthermore, the retention of chirality is quantitatively predictable using this combination of kinetic parameters. Our simulation results well explain the behavior of thalidomide in the practical biological experimental data. Therefore, this model promises a comprehensive understanding of dynamic metabolic systems involving chiral drugs that express multiple enantiospecific drug efficacies.

  18. Ferromagnetic interaction model of activity level in workplace communication

    NASA Astrophysics Data System (ADS)

    Akitomi, Tomoaki; Ara, Koji; Watanabe, Jun-ichiro; Yano, Kazuo

    2013-03-01

    The nature of human-human interaction, specifically, how people synchronize with each other in multiple-participant conversations, is described by a ferromagnetic interaction model of people’s activity levels. We found two microscopic human interaction characteristics from a real-environment face-to-face conversation. The first characteristic is that people quite regularly synchronize their activity level with that of the other participants in a conversation. The second characteristic is that the degree of synchronization increases as the number of participants increases. Based on these microscopic ferromagnetic characteristics, a “conversation activity level” was modeled according to the Ising model. The results of a simulation of activity level based on this model well reproduce macroscopic experimental measurements of activity level. This model will give a new insight into how people interact with each other in a conversation.

  19. ToxDB: pathway-level interpretation of drug-treatment data

    PubMed Central

    Hardt, C.; Beber, M.E.; Rasche, A.; Kamburov, A.; Hebels, D.G.; Kleinjans, J.C.; Herwig, R.

    2016-01-01

    Motivation: Extensive drug treatment gene expression data have been generated in order to identify biomarkers that are predictive for toxicity or to classify compounds. However, such patterns are often highly variable across compounds and lack robustness. We and others have previously shown that supervised expression patterns based on pathway concepts rather than unsupervised patterns are more robust and can be used to assess toxicity for entire classes of drugs more reliably. Results: We have developed a database, ToxDB, for the analysis of the functional consequences of drug treatment at the pathway level. We have collected 2694 pathway concepts and computed numerical response scores of these pathways for 437 drugs and chemicals and 7464 different experimental conditions. ToxDB provides functionalities for exploring these pathway responses by offering tools for visualization and differential analysis allowing for comparisons of different treatment parameters and for linking this data with toxicity annotation and chemical information. Database URL: http://toxdb.molgen.mpg.de PMID:27074805

  20. Harms and benefits associated with psychoactive drugs: findings of an international survey of active drug users

    PubMed Central

    Morgan, Celia JA; Noronha, Louise A; Muetzelfeldt, Mark; Fielding, Amanda

    2013-01-01

    There have been several recent efforts in the UK and the Netherlands to describe the harms of psychoactive substances based on ratings of either experts or drug users. This study aimed to assess the perceived benefits as well as harms of widely used recreational drugs, both licit and illicit, in an international sample of drug users. The survey was hosted at https://www.internationaldrugsurvey.org/ and was available in three languages. Residents reported their experience of 15 commonly used drugs or drug classes; regular users then rated their harms and benefits. In all, 5791 individuals from over 40 countries completed the survey, although the majority were from English speaking countries. Rankings of drugs differed across 10 categories of perceived benefits. Skunk and herbal cannabis were ranked consistently beneficial, whilst alcohol and tobacco fell below many classified drugs. There was no correlation at all between users’ harm ranking of drugs and their classification in schedules of the USA or ABC system in the UK. Prescription analgesics, alcohol and tobacco were ranked within the top 10 most harmful drugs. These findings suggest that neither the UK nor US classification systems act to inform users of the harms of psychoactive substances. It is hoped the results might inform health professionals and educators of what are considered to be both the harms and benefits of psychoactive substances to young people. PMID:23438502

  1. Drug-DNA interactions at single molecule level: A view with optical tweezers

    NASA Astrophysics Data System (ADS)

    Paramanathan, Thayaparan

    Studies of small molecule--DNA interactions are essential for developing new drugs for challenging diseases like cancer and HIV. The main idea behind developing these molecules is to target and inhibit the reproduction of the tumor cells and infected cells. We mechanically manipulate single DNA molecule using optical tweezers to investigate two molecules that have complex and multiple binding modes. Mononuclear ruthenium complexes have been extensively studied as a test for rational drug design. Potential drug candidates should have high affinity to DNA and slow dissociation kinetics. To achieve this, motifs of the ruthenium complexes are altered. Our collaborators designed a dumb-bell shaped binuclear ruthenium complex that can only intercalate DNA by threading through its bases. Studying the binding properties of this complex in bulk studies took hours. By mechanically manipulating a single DNA molecule held with optical tweezers, we lower the barrier to thread and make it fast compared to the bulk experiments. Stretching single DNA molecules with different concentration of drug molecules and holding it at a constant force allows the binding to reach equilibrium. By this we can obtain the equilibrium fractional ligand binding and length of DNA at saturated binding. Fitting these results yields quantitative measurements of the binding thermodynamics and kinetics of this complex process. The second complex discussed in this study is Actinomycin D (ActD), a well studied anti-cancer agent that is used as a prototype for developing new generations of drugs. However, the biophysical basis of its activity is still unclear. Because ActD is known to intercalate double stranded DNA (dsDNA), it was assumed to block replication by stabilizing dsDNA in front of the replication fork. However, recent studies have shown that ActD binds with even higher affinity to imperfect duplexes and some sequences of single stranded DNA (ssDNA). We directly measure the on and off rates by

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

    PubMed

    Poulin, Patrick

    2015-07-01

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

  3. [Pharmacological influences on the brain level and transport of GABA. II) Effect of various psychoactive drugs on brain level and uptake of GABA].

    PubMed

    Gabana, M A; Varotto, M; Saladini, M; Zanchin, G; Battistin, L

    1981-04-30

    The effects of some psychoactive drugs on the level and uptake of GABA in the mouse brain was studied using well standardized procedures, mainely the silica-gel cromatography for determining the GABA content and the brain slices for measuring GABA uptake. It was found that levomepromazine, sulpiride, haloperidol and amytryptiline were without effects on the cerebral level of GABA; it was also found that these drugs do not influence the rates of uptake of GABA by mouse brain slices. Such results do indicate that the psychoactive drugs studied are without effects on the level and uptake of GABA in the brain.

  4. Activation of Antibiotic Production in Bacillus spp. by Cumulative Drug Resistance Mutations.

    PubMed

    Tojo, Shigeo; Tanaka, Yukinori; Ochi, Kozo

    2015-12-01

    Bacillus subtilis strains produce a wide range of antibiotics, including ribosomal and nonribosomal peptide antibiotics, as well as bacilysocin and neotrehalosadiamine. Mutations in B. subtilis strain 168 that conferred resistance to drugs such as streptomycin and rifampin resulted in overproduction of the dipeptide antibiotic bacilysin. Cumulative drug resistance mutations, such as mutations in the mthA and rpsL genes, which confer low- and high-level resistance, respectively, to streptomycin, and mutations in rpoB, which confer resistance to rifampin, resulted in cells that overproduced bacilysin. Transcriptional analysis demonstrated that the enhanced transcription of biosynthesis genes was responsible for the overproduction of bacilysin. This approach was effective also in activating the cryptic genes of Bacillus amyloliquefaciens, leading to actual production of antibiotic(s).

  5. Activation of Antibiotic Production in Bacillus spp. by Cumulative Drug Resistance Mutations

    PubMed Central

    Tojo, Shigeo; Tanaka, Yukinori

    2015-01-01

    Bacillus subtilis strains produce a wide range of antibiotics, including ribosomal and nonribosomal peptide antibiotics, as well as bacilysocin and neotrehalosadiamine. Mutations in B. subtilis strain 168 that conferred resistance to drugs such as streptomycin and rifampin resulted in overproduction of the dipeptide antibiotic bacilysin. Cumulative drug resistance mutations, such as mutations in the mthA and rpsL genes, which confer low- and high-level resistance, respectively, to streptomycin, and mutations in rpoB, which confer resistance to rifampin, resulted in cells that overproduced bacilysin. Transcriptional analysis demonstrated that the enhanced transcription of biosynthesis genes was responsible for the overproduction of bacilysin. This approach was effective also in activating the cryptic genes of Bacillus amyloliquefaciens, leading to actual production of antibiotic(s). PMID:26369962

  6. Erythrocyte aldose reductase activity and sorbitol levels in diabetic retinopathy

    PubMed Central

    Satyanarayana, A.; Balakrishna, N.; Ayyagari, Radha; Padma, M.; Viswanath, K.; Petrash, J. Mark

    2008-01-01

    Purpose Activation of polyol pathway due to increased aldose reductase (ALR2) activity has been implicated in the development of diabetic complications including diabetic retinopathy (DR), a leading cause of blindness. However, the relationship between hyperglycemia-induced activation of polyol pathway in retina and DR is still uncertain. We investigated the relationship between ALR2 levels and human DR by measuring ALR2 activity and its product, sorbitol, in erythrocytes. Methods We enrolled 362 type 2 diabetic subjects (T2D) with and without DR and 66 normal subjects in this clinical case-control study. Clinical evaluation of DR in T2D patients was done by fundus examination. ALR2 activity and sorbitol levels along with glucose and glycosylated hemoglobin (HbA1C) levels in erythrocytes were determined. Results T2D patients with DR showed significantly higher specific activity of ALR2 as compared to T2D patients without DR. Elevated levels of sorbitol in T2D patients with DR, as compared to T2D patients without DR, corroborated the increased ALR2 activity in erythrocytes of DR patients. However, the increased ALR2 activity was not significantly associated with diabetes duration, age, and HbA1C in both the DR group and total T2D subjects. Conclusions Levels of ALR2 activity as well as sorbitol in erythrocytes may have value as a quantitative trait to be included among other markers to establish a risk profile for development of DR. PMID:18385795

  7. The Brazilian Military: Its Role in Counter-Drug Activities

    DTIC Science & Technology

    1992-06-01

    Peru and Bolivia, the three primary cocaine producing countries in the region. The DPF is also responsible for attacking the drug trade in Brazil’s...limited to similar initiatives in the Andean nations (Bolivia, C61ombia and Peru ) and the United States. In these countries drug trafficking was considered...Brazilian officials recognized the drug problem in the neighboring countries of Bolivia, Colombia and Peru , but generally dismissed the fact that Brazil was

  8. Using the level of Service Inventory-Revised to improve assessment and treatment in drug court.

    PubMed

    Guastaferro, Wendy P

    2012-08-01

    More than 2,000 drug courts in the United States provide supervision and substance-abuse treatment to thousands of offenders. Yet the treatment continuum from assessment to aftercare is underexplored. The effectiveness of the Level of Service Inventory-Revised (LSI-R) as a risk assessment tool is well established. However, fewer studies have considered its use in guiding treatment strategies. In using the LSI-R, the drug court program relied on the structured interview protocol (not the risk classification scores) to identify criminogenic needs that then helped determine placement in a high- or low-needs treatment track. To evaluate the effectiveness of these treatment placement decisions, this research used the LSI-R scores to examine individual and group differences (N = 182). Significant and substantive differences at the individual and group levels were found thus providing empirical support for using the LSI-R as a link between assessment and treatment. Implications for developing standards and practice protocols for drug courts are discussed.

  9. [Potential of pharmacological modulation of level and activity incretins on diabetes mellitus type 2].

    PubMed

    Spasov, A A; Chepljaeva, N I

    2015-01-01

    This review summarizes data on the main approaches used for the search of biologically active compounds modulating the level and physiological activity of incretins. Currently two groups of drugs are used in clinical practice: they either replenish the deficit of incretins (glucagon-like peptide-1 receptor agonists) or inhibit the degradation processes (dipeptidyl peptidase 4 inhibitors). In addition, new groups of substances are actively searched. These include non-peptide agonists of glucagon-like peptide-1 receptors, agonists/antagonists of glucose-dependent insulinotropic peptide, the hybrid polypeptides based on glucagon-like peptide-1 and glucagon.

  10. THE ACTION OF DRUGS ON FUNCTION AND PHOSPHORYLASE ACTIVITY.

    DTIC Science & Technology

    ACETYLCHOLINE, *METABOLISM, AMINES, AUTONOMIC NERVOUS SYSTEM, CARBOHYDRATES, DRUGS, EPINEPHRINE, ERGOT ALKALOIDS, GLUCOSE, GLYCOGEN, HEART, INHIBITION, LIVER, MUSCLES, RATS, RESERPINE, STIMULATION(PHYSIOLOGY)

  11. CFU-GM assay for evaluation of drug myelotoxic activity.

    PubMed

    Pessina, Augusto; Bonomi, Arianna

    2007-11-01

    To study hematotoxicity of compounds on the myeloid cell compartment, the authors describe a standard procedure developed as a workable good laboratory practices-compliant protocol to determine the in vitro myelotoxic effect of drugs and chemicals. Specific protocols are presented to prepare human and murine myeloid progenitors (CFU-GM) for testing in a validated CFU-GM assay. Details are given for performing a screening test when toxicity data are not available and for passing on to an accurate inhibitory concentration-determination phase. To quantify the potential hematotoxicity of xenobiotics from their direct adverse effects on CFU-GM, the unit describes how to manage the results by means of an algorithm able to predict the acute xenobiotic exposure levels that cause maximum tolerated decreases (MTD) in absolute neutrophil count (ANC). A protocol describes a miniaturized application of the procedure in 96-well plates for high-throughput screening of compounds or for testing compounds that are available in very small quantities.

  12. Effect of Antiepileptic drugs on plasma lipoprotein (a) and other lipid levels in childhood.

    PubMed

    Aynaci, F M; Orhan, F; Orem, A; Yildirmis, S; Gedik, Y

    2001-05-01

    Antiepileptic drugs may alter plasma lipid status in epileptic patients. We conducted a study to assess the effect of phenobarbital, carbamazepine, and valproate on plasma levels of lipoprotein (a), total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, apolipoprotein A, and apolipoprotein B in 22 epileptic children. The children were separated as group 1, seven children, mean age 1.6+/-0.2 years, treated with phenobarbital, 5 mg/kg/day, twice daily; group 2, seven children, mean age 9.8+/-1.2 years, treated with carbamazepine, 20 mg/kg/day, twice daily; and group 3, eight children, mean age 6.8+/-0.6 years, treated with valproate, 20 mg/kg/day, twice daily. Plasma lipoprotein (a) and other lipid levels were studied before (pretreatment) and at 3 and 6 months of treatment. Friedman two-way analysis of variance and Wilcoxon's signed-rank test were used for statistical analysis, and the results were expressed as the mean and standard error of the mean. The mean age of children in group 1 was significantly low, compared with groups 2 and, 3 (P < .001). The mean pretreatment lipid levels between the groups were not significant. The increase in lipoprotein (a) at 3 and 6 months and high-density lipoprotein cholesterol at 6 months was statistically significant in group 1 (P < .025). We suggest a careful monitoring of plasma levels of lipoprotein (a) and other lipids in epileptic children treated with antiepileptic drugs.

  13. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase

    PubMed Central

    Aldred, Katie J.; Kerns, Robert J.; Berger, James M.; Osheroff, Neil

    2016-01-01

    Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrAA90 and GyrAD94. M. tuberculosis gyrase lacks a conserved serine that anchors a water–metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrAA90) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone–gyrase interactions. Clinically relevant mutations at GyrAA90 and GyrAD94 cause quinolone resistance by disrupting the bridge–enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone–enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrAA90V and GyrAD94G. 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug–enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis. PMID:26792518

  14. Drug use and criminal activity among rural probationers with DUI histories.

    PubMed

    Webster, J Matthew; Oser, Carrie B; Mateyoke-Scrivner, Allison; Cline, Virginia Depp; Havens, Jennifer R; Leukefeld, Carl G

    2009-12-01

    The present study examined whether ever being arrested for driving under the influence (DUI) was associated with higher levels of substance use and criminal activity in a sample of 800 probationers. Lifetime and 30-day histories of substance use and criminal activity were compared across three groups of probationers from rural Kentucky: those with a single DUI arrest, those with two or more DUI arrests, and those with no DUI arrests. A larger percentage of probationers with a DUI arrest reported lifetime and 30-day substance use than non-DUI offenders in almost all drug and alcohol categories. Higher prevalence of criminal activity was limited primarily to the multiple DUI arrest group. Findings add to the literature on rural substance abusers and indicate that DUI may be used as a marker to help identify opportunities for targeted substance abuse interventions.

  15. Physical Activity Levels in Portuguese High School Physical Education

    ERIC Educational Resources Information Center

    Marmeleira, Jose Francisco Filipe; Aldeias, Nuno Micael Carrasqueira; da Graca, Pedro Miguel dos Santos Medeira

    2012-01-01

    The main aim of this study was to evaluate the physical activity (PA) levels of high school Portuguese students during physical education (PE) and investigate the association of PA levels with students' goal orientation and intrinsic motivation. Forty-six students from three high schools participated. Heart rate telemetry and pedometry were used…

  16. Children's Physical Activity Levels during Indoor Recess Dance Videos

    ERIC Educational Resources Information Center

    Erwin, Heather; Koufoudakis, Ryann; Beighle, Aaron

    2013-01-01

    Background: Children's physical activity (PA) levels remain low, and schools are being asked to assume a leadership role in PA promotion. Research suggests outdoor recess contributes to children's overall PA levels. However, similar research is not available for indoor recess, which occurs frequently due to a variety of factors. The purpose of…

  17. Movement Activity Levels on Traditional and Contemporary Playground Structures.

    ERIC Educational Resources Information Center

    Gabbard, Carl P.; LeBlanc, Elizabeth

    This study investigated playground activity levels of children in grades K-4 and compared levels of use of traditional and creative playground apparatus. The traditional playground area consisted of climbing bars, slides, ladders, chin bars, swings, see saws, and a merry-go-round. The creative playground contained tire hurdles, tire walk, tire…

  18. Taste clusters of music and drugs: evidence from three analytic levels.

    PubMed

    Vuolo, Mike; Uggen, Christopher; Lageson, Sarah

    2014-09-01

    This article examines taste clusters of musical preferences and substance use among adolescents and young adults. Three analytic levels are considered: fixed effects analyses of aggregate listening patterns and substance use in US radio markets, logistic regressions of individual genre preferences and drug use from a nationally representative survey of US youth, and arrest and seizure data from a large American concert venue. A consistent picture emerges from all three levels: rock music is positively associated with substance use, with some substance-specific variability across rock sub-genres. Hip hop music is also associated with higher use, while pop and religious music are associated with lower use. These results are robust to fixed effects models that account for changes over time in radio markets, a comprehensive battery of controls in the individual-level survey, and concert data establishing the co-occurrence of substance use and music listening in the same place and time. The results affirm a rich tradition of qualitative and experimental studies, demonstrating how symbolic boundaries are simultaneously drawn around music and drugs.

  19. The Role of Various Curriculum Models on Physical Activity Levels

    ERIC Educational Resources Information Center

    Culpepper, Dean O.; Tarr, Susan J.; Killion, Lorraine E.

    2011-01-01

    Researchers have suggested that physical education curricula can be highly effective in increasing physical activity levels at school (Sallis & Owen, 1999). The purpose of this study was to investigate the impact of various curriculum models on physical activity. Total steps were measured on 1,111 subjects and three curriculum models were studied…

  20. African American Preschool Children's Physical Activity Levels in Head Start

    ERIC Educational Resources Information Center

    Shen, Bo; Reinhart-Lee, Tamara; Janisse, Heather; Brogan, Kathryn; Danford, Cynthia; Jen, K-L. C.

    2012-01-01

    The purpose of this study was to describe the physical activity levels of urban inner city preschoolers while attending Head Start, the federally funded preschool program for children from low-income families. Participants were 158 African American children. Their physical activity during Head Start days was measured using programmed RT-3…

  1. Seasonality in Children's Pedometer-Measured Physical Activity Levels

    ERIC Educational Resources Information Center

    Beighle, Aaron; Alderman, Brandon; Morgan, Charles F.; Le Masurier, Guy

    2008-01-01

    Seasonality appears to have an impact on children's physical activity levels, but equivocal findings demand more study in this area. With the increased use of pedometers in both research and practice, collecting descriptive data in various seasons to examine the impact of seasonality on pedometer-measured physical activity among children is…

  2. Active Ageing Level of Older Persons: Regional Comparison in Thailand

    PubMed Central

    Haque, Md. Nuruzzaman

    2016-01-01

    Active ageing level and its discrepancy in different regions (Bangkok, Central, North, Northeast, and South) of Thailand have been examined for prioritizing the policy agenda to be implemented. Attempt has been made to test preliminary active ageing models for Thai older persons and hence active ageing index (AAI, ranges from 0 to 1) has been estimated. Using nationally representative data and confirmatory factor analysis approach, this study justified active ageing models for female and male older persons in Thailand. Results revealed that active ageing level of Thai older persons is not high (mean AAIs for female and male older persons are 0.64 and 0.61, resp., and those are significantly different (p < 0.001)). Mean AAI in Central region is lower than North, Northeast, and South regions but there is no significant difference in the latter three regions of Thailand. Special emphasis should be given to Central region and policy should be undertaken for increasing active ageing level. Implementation of an Integrated Active Ageing Package (IAAP), containing policies for older persons to improve their health and economic security, to promote participation in social groups and longer working lives, and to arrange learning programs, would be helpful for increasing older persons' active ageing level in Thailand. PMID:27375903

  3. Mechanisms of cell death pathway activation following drug-induced inhibition of mitochondrial complex I

    PubMed Central

    Imaizumi, Naoki; Kwang Lee, Kang; Zhang, Carmen; Boelsterli, Urs A.

    2015-01-01

    Respiratory complex I inhibition by drugs and other chemicals has been implicated as a frequent mode of mitochondria-mediated cell injury. However, the exact mechanisms leading to the activation of cell death pathways are incompletely understood. This study was designed to explore the relative contributions to cell injury of three distinct consequences of complex I inhibition, i.e., impairment of ATP biosynthesis, increased formation of superoxide and, hence, peroxynitrite, and inhibition of the mitochondrial protein deacetylase, Sirt3, due to imbalance of the NADH/NAD+ ratio. We used the antiviral drug efavirenz (EFV) to model drug-induced complex I inhibition. Exposure of cultured mouse hepatocytes to EFV resulted in a rapid onset of cell injury, featuring a no-effect level at 30 µM EFV and submaximal effects at 50 µM EFV. EFV caused a concentration-dependent decrease in cellular ATP levels. Furthermore, EFV resulted in increased formation of peroxynitrite and oxidation of mitochondrial protein thiols, including cyclophilin D (CypD). This was prevented by the superoxide scavenger, Fe-TCP, or the peroxynitrite decomposition catalyst, Fe-TMPyP. Both ferroporphyrins completely protected from EFV-induced cell injury, suggesting that peroxynitrite contributed to the cell injury. Finally, EFV increased the NADH/NAD+ ratio, inhibited Sirt3 activity, and led to hyperacetylated lysine residues, including those in CypD. However, hepatocytes isolated from Sirt3-null mice were protected against 40 µM EFV as compared to their wild-type controls. In conclusion, these data are compatible with the concept that chemical inhibition of complex I activates multiple pathways leading to cell injury; among these, peroxynitrite formation may be the most critical. PMID:25625582

  4. Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo.

    PubMed

    Brain, E G; Yu, L J; Gustafsson, K; Drewes, P; Waxman, D J

    1998-06-01

    The anti-cancer prodrug ifosfamide (IF) is metabolized by liver P450 enzymes by two alternative pathways. IF is activated to 4-hydroxy IF (4-OH-IF), which ultimately yields the alkylating mustard isophosphoramide, whereas IF N-dechlororethylation inactivates the drug and produces the neurotoxic metabolite chloroacetaldehyde (CA). Both reactions are catalysed by multiple liver P450 enzymes in vitro in isolated rat liver microsomes. The present pharmacokinetic study investigates the potential for modulation of these alternative pathways of IF metabolism in vivo using the adult male Fischer 344 rat model. Rats were treated with IF alone or in conjunction with various P450 inducers and inhibitors in an effort to improve the balance between drug activation and drug inactivation. Plasma concentrations, areas under the curve (AUC) and half-lives were calculated for 4-OH-IF and CA, allowing estimations of the extent of IF activation and deactivation/toxification. Induction of liver P450 2B enzymes by 4-day high-dose phenobarbital (PB) pretreatment significantly decreased the fraction of IF undergoing 4-hydroxylation (AUC(4-OH-IF)/AUC(4-OH-IF)+AUC(CA)), from 37% to 22% of total metabolism (P < 0.05), consistent with in vitro findings that the PB-inducible P450 enzyme 2B1 plays a major role in IF N-dechloroethylation. Pretreatment with the P450 3A inducer dexamethasone proportionally decreased the AUC for both IF metabolites, without any net impact on the fraction of IF undergoing metabolic activation. By contrast, the P450 2B1 inhibitor metyrapone preferentially increased the AUC for the 4-hydroxylation pathway in 3-day low-dose PB-induced rats, thereby increasing the total fraction of IF metabolized via the activation pathway from 36% to 54% (P < 0.05), whereas the P450 inhibitors orphenadrine and troleandomycin had no significant affect on AUC values. These findings demonstrate specific roles for P450 2B and 3A enzymes in catalysing these pathways of IF metabolism in vivo

  5. Do Drug Treatment Facilities Increase Clients’ Exposure to Potential Neighborhood-Level Triggers for Relapse? A Small-Area Assessment of a Large, Public Treatment System

    PubMed Central

    2006-01-01

    Research on drug treatment facility locations has focused narrowly on the issue of geographic proximity to clients. We argue that neighborhood conditions should also enter into the facility location decision and illustrate a formal assessment of neighborhood conditions at facilities in a large, metropolitan area, taking into account conditions clients already face at home. We discuss choice and construction of small-area measures relevant to the drug treatment context, including drug activity, disadvantage, and violence as well as statistical comparisons of clients’ home and treatment locations with respect to these measures. Analysis of 22,707 clients discharged from 494 community-based outpatient and residential treatment facilities that received public funds during 1998–2000 in Los Angeles County revealed no significant mean differences between home and treatment neighborhoods. However, up to 20% of clients are exposed to markedly higher levels of disadvantage, violence, or drug activity where they attend treatment than where they live, suggesting that it is not uncommon for treatment locations to increase clients’ exposure to potential environmental triggers for relapse. Whereas on average both home and treatment locations exhibit higher levels of these measures than the household locations of the general population, substantial variability in public treatment clients’ home neighborhoods calls into question the notion that they hail exclusively from poor, high drug activity areas. Shortcomings of measures available for neighborhood assessment of treatment locations and implications of the findings for other areas of treatment research are also discussed. PMID:16736365

  6. Comparative antipneumococcal activities of sulopenem and other drugs.

    PubMed

    Kosowska-Shick, Klaudia; Ednie, Lois M; McGhee, Pamela; Appelbaum, Peter C

    2009-06-01

    For 297 penicillin-susceptible, -intermediate, and -resistant pneumococcal strains, the sulopenem MIC(50)s were 0.008, 0.06, and 0.25, respectively, and the sulopenem MIC(90)s were 0.016, 0.25, and 0.5 microg/ml, respectively. The MIC(50)s of amoxicillin for the corresponding strains were 0.03, 0.25, and 2.0 microg/ml, respectively, and the MIC(90)s were 0.03, 1.0, and 8.0 microg/ml, respectively. The combination of amoxicillin and clavulanate gave MICs similar to those obtained with amoxicillin alone. The sulopenem MICs were similar to those of imipenem and meropenem. The MICs of ss-lactams increased with those of penicillin G, and among the quinolones tested, moxifloxacin had the lowest MICs. Additionally, 45 strains of drug-resistant type 19A pneumococci were tested by agar dilution and gave sulopenem MIC(50)s and MIC(90)s of 1.0 and 2.0 microg/ml, respectively. Both sulopenem and amoxicillin (with and without clavulanate) were bactericidal against all 12 strains tested at 2x MIC after 24 h. Thirty-one strains from 10 countries with various penicillin, amoxicillin, and carbapenems MICs, including those with the highest sulopenem MICs, were selected for sequencing analysis of the pbp1a, pbp2x, and pbp2b regions encoding the transpeptidase active site and MurM. We did not find any correlations between specific penicillin-binding protein-MurM patterns and changes in the MICs.

  7. Drugs.

    ERIC Educational Resources Information Center

    Hurst, Hunter, Ed.; And Others

    1984-01-01

    This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

  8. Effect of three anorectic drugs on central catecholamine levels and synthesis in the Zucker rat.

    PubMed

    Orosco, M; Bremond, J; Jacquot, C; Cohen, Y

    1983-01-01

    1. Genetically obese Zucker rats and their lean littermates were treated during 5 days with fenfluramine, mazindol or amphetamine. Norepinephrine and dopamine levels were assayed in the hypothalamus, striatum, medulla-oblongata pons and remainder of the brain, and the amine synthesis was estimated, when possible. 2. Fenfluramine acted especially on norepinephrine in the obese rat hypothalamus. 3. Mazindol was active on norepinephrine and dopamine levels only in obese animals. 4. Amphetamine acted on norepinephrine levels only in obese rats and on dopamine levels in both obese and lean rats.

  9. Addressing metabolic activation as an integral component of drug design.

    PubMed

    Doss, George A; Baillie, Thomas A

    2006-01-01

    Formation of reactive intermediates by metabolism of xenobiotics represents a potential liability in drug discovery and development. Although it is difficult, if not impossible, to predict toxicities of drug candidates accurately, it is prudent to try to minimize bioactivation liabilities as early as possible in the stage of drug discovery and lead optimization. Measurement of covalent binding to liver microsomal proteins in the presence and the absence of NADPH, as well as the use of trapping agents such as glutathione or cyanide ions to provide structural information on reactive intermediates, have been used routinely to screen drug candidates. These in vitro experiments are often supplemented with in vivo covalent binding data in rats. The resulting data are not only used to eliminate potentially risky compounds, but, more importantly, they provide invaluable information to direct the Medicinal Chemistry group efforts to design analogs with less propensity to undergo bioactivation. Select case histories are presented in which this approach was successfully applied at Merck.

  10. QSAR study on the antibacterial activity of some sulfa drugs: building blockers of Mannich bases.

    PubMed

    Mandloi, Dheeraj; Joshi, Sheela; Khadikar, Padmakar V; Khosla, Navita

    2005-01-17

    Sulfa drugs are building blockers of several types of Mannich bases. Consequently, the antibacterial activities of sulfa drugs are reported in this paper, which will help in explaining and understanding antibacterial activities of Mannich bases. Reported QSAR is carried out using distance-based topological indices and discussed critically on the basis of statistical parameters.

  11. Young Adult Follow-Up of Hyperactive Children: Antisocial Activities and Drug Use

    ERIC Educational Resources Information Center

    Barkley, Russell A.; Fischer, Mariellen; Smallish, Lori; Fletcher, Kenneth

    2004-01-01

    Background: Hyperactive/ADHD children are believed to be a greater risk for adolescent and young adult antisocial activity and drug use/abuse, particularly that subset having comorbid conduct problems/disorder. Method: We report on the lifetime antisocial activities and illegal drug use self-reported at young adult follow-up (mean age 20-21 years;…

  12. Anti-TNF levels and anti-drug antibodies, immunosuppressants and clinical outcomes in inflammatory bowel disease.

    PubMed

    Ha, Christina; Mathur, Jagrati; Kornbluth, Asher

    2015-04-01

    The anti-tumor necrosis factor-α (TNF) antibodies have revolutionized the management of ulcerative colitis and Crohn's disease. The development of assays to allow for the measurements of serum drug levels and anti-drug antibodies have provided a more objective means of therapeutic decision making, particularly among patients losing response to treatment. Additionally, more evidence is emerging that indicates the relationship between drug levels and response to therapy including clinical response, mucosal healing and sustained remission. The use of combination therapies of the anti-TNF agents and the thiopurine immunosuppressants may also decrease immunogenicity to the anti-TNF agents and potentiate response to therapy. With more evidence emerging evidence of the importance of therapeutic drug levels and anti-drug antibodies, clinicians may be able to better optimize the current arsenal of inflammatory bowel disease therapeutics to achieve greater rates of durable remission and improved quality of life.

  13. 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains

    PubMed Central

    2016-01-01

    2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug–drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment. PMID:26985307

  14. Combatting synthetic designer opioids: active vaccination ablates lethal doses of fentanyl class drugs

    PubMed Central

    Bremer, Paul T.; Kimishima, Atsushi; Schlosburg, Joel E.; Zhou, Bin; Collins, Karen C.; Janda, Kim D.

    2016-01-01

    Fentanyl is an addictive prescription opioid that is over 80 times more potent than morphine. The synthetic nature of fentanyl has enabled the creation of dangerous ‘designer drug’ analogues that escape toxicology screening, yet display comparable potency to the parent drug. Alarmingly, a large number of fatalities have been linked to overdose of fentanyl derivatives. Herein, we report an effective immunotherapy for reducing the psychoactive effects of fentanyl class drugs. A single conjugate vaccine was created that elicited high levels of antibodies with cross-reactivity for a wide panel of fentanyl analogues. Moreover, vaccinated mice gained significant protection from lethal fentanyl doses. Lastly, a surface plasmon resonance (SPR)-based technique was established enabling drug specificity profiling of antibodies derived directly from serum. Our newly developed fentanyl vaccine and analytical methods may assist in the battle against synthetic opioid abuse. Fentanyl is an effective synthetic opioid that is used legally as a schedule II prescription pain reliever. However, fentanyl presents a significant abuse liability due to the euphoric feeling it induces via activation of μ-opioid receptors (MOR) in the brain; the same pharmacological target as the illegal schedule I opioid, heroin.[1] Excessive activation of MOR results in respiratory depression which can be fatal.[2] Fentanyl exceeds the potency of heroin by >10-fold, and morphine by >80-fold posing a significant risk of overdose when it is consumed from unregulated sources.[3] Furthermore, the ease of fentanyl synthesis enables illegal production and the creation of designer drug analogues.[4] The fact that the pharmacology of these analogues has yet to be properly characterized makes them particularly dangerous, especially when certain modifications, even methyl additions, can increase potency, notably at the 3-position (Figure 1).[5] PMID:26879590

  15. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    PubMed Central

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-01-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations. PMID:27312339

  16. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    NASA Astrophysics Data System (ADS)

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-06-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

  17. Enhancement of biological activities of nanostructured hydrophobic drug species

    NASA Astrophysics Data System (ADS)

    Han, Qiusen; Yang, Rong; Li, Jingying; Liang, Wei; Zhang, Ying; Dong, Mingdong; Besenbacher, Flemming; Wang, Chen

    2012-03-01

    We report a study of nanoribbons of quercetin, a phase I clinical trial anticancer drug, and their inhibitory effects on cancer cell proliferation. Novel quercetin nanoribbons have been prepared by atmospheric pressure physical vapor deposition (PVD). The nanostructures have been characterized by optical microscopy, scanning electron microscopy, transmission electron microscopy, and Raman spectroscopy, etc. Significantly enhanced solubility in PBS solution and increased drug release rate have been observed for quercetin nanoribbons in comparison to those of quercetin powder. The observed increase of inhibitory effects of quercetin nanoribbons on 4T1 cancel cell growth is correlated with an improvement in their solubility and drug release behavior.We report a study of nanoribbons of quercetin, a phase I clinical trial anticancer drug, and their inhibitory effects on cancer cell proliferation. Novel quercetin nanoribbons have been prepared by atmospheric pressure physical vapor deposition (PVD). The nanostructures have been characterized by optical microscopy, scanning electron microscopy, transmission electron microscopy, and Raman spectroscopy, etc. Significantly enhanced solubility in PBS solution and increased drug release rate have been observed for quercetin nanoribbons in comparison to those of quercetin powder. The observed increase of inhibitory effects of quercetin nanoribbons on 4T1 cancel cell growth is correlated with an improvement in their solubility and drug release behavior. Electronic supplementary information (ESI) available. See DOI: 10.1039/c2nr12013e

  18. Active transmembrane drug transport in microgravity: a validation study using an ABC transporter model.

    PubMed

    Vaquer, Sergi; Cuyàs, Elisabet; Rabadán, Arnau; González, Albert; Fenollosa, Felip; de la Torre, Rafael

    2014-01-01

    Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette) transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay (®) (Solvo Biotechnology, Hungary) was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2) trans-membrane estradiol-17-β-glucuronide (E17βG) transport activity, when activated by adenosine-tri-phosphate (ATP) during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology opens new and

  19. Active transmembrane drug transport in microgravity: a validation study using an ABC transporter model

    PubMed Central

    Vaquer, Sergi; Cuyàs, Elisabet; Rabadán, Arnau; González, Albert; Fenollosa, Felip; de la Torre, Rafael

    2014-01-01

    Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette) transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay ® (Solvo Biotechnology, Hungary) was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2) trans-membrane estradiol-17-β-glucuronide (E17βG) transport activity, when activated by adenosine-tri-phosphate (ATP) during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology opens new and

  20. Regulation of Human Hepatic Drug Transporter Activity and Expression by Diesel Exhaust Particle Extract

    PubMed Central

    Le Vee, Marc; Jouan, Elodie; Stieger, Bruno; Lecureur, Valérie; Fardel, Olivier

    2015-01-01

    Diesel exhaust particles (DEPs) are common environmental air pollutants primarily affecting the lung. DEPs or chemicals adsorbed on DEPs also exert extra-pulmonary effects, including alteration of hepatic drug detoxifying enzyme expression. The present study was designed to determine whether organic DEP extract (DEPe) may target hepatic drug transporters that contribute in a major way to drug detoxification. Using primary human hepatocytes and transporter-overexpressing cells, DEPe was first shown to strongly inhibit activities of the sinusoidal solute carrier (SLC) uptake transporters organic anion-transporting polypeptides (OATP) 1B1, 1B3 and 2B1 and of the canalicular ATP-binding cassette (ABC) efflux pump multidrug resistance-associated protein 2, with IC50 values ranging from approximately 1 to 20 μg/mL and relevant to environmental exposure situations. By contrast, 25 μg/mL DEPe failed to alter activities of the SLC transporter organic cation transporter (OCT) 1 and of the ABC efflux pumps P-glycoprotein and bile salt export pump (BSEP), whereas it only moderately inhibited those of sodium taurocholate co-transporting polypeptide and of breast cancer resistance protein (BCRP). Treatment by 25 μg/mL DEPe was next demonstrated to induce expression of BCRP at both mRNA and protein level in cultured human hepatic cells, whereas it concomitantly repressed mRNA expression of various transporters, including OATP1B3, OATP2B1, OCT1 and BSEP. Such changes in transporter expression were found to be highly correlated to those caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a reference activator of the aryl hydrocarbon receptor (AhR) pathway. This suggests that DEPe, which is enriched in known ligands of AhR like polycyclic aromatic hydrocarbons, alters drug transporter expression via activation of the AhR cascade. Taken together, these data established human hepatic transporters as targets of organic chemicals containing in DEPs, which may contribute to their

  1. Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs.

    PubMed

    Corradini, Irene; Donzelli, Andrea; Antonucci, Flavia; Welzl, Hans; Loos, Maarten; Martucci, Roberta; De Astis, Silvia; Pattini, Linda; Inverardi, Francesca; Wolfer, David; Caleo, Matteo; Bozzi, Yuri; Verderio, Claudia; Frassoni, Carolina; Braida, Daniela; Clerici, Mario; Lipp, Hans-Peter; Sala, Mariaelvina; Matteoli, Michela

    2014-02-01

    Synaptosomal-associated protein of 25 kDa (SNAP-25) is a protein that participates in the regulation of synaptic vesicle exocytosis through the formation of the soluble NSF attachment protein receptor complex and modulates voltage-gated calcium channels activity. The Snap25 gene has been associated with schizophrenia, attention deficit hyperactivity disorder, and bipolar disorder, and lower levels of SNAP-25 have been described in patients with schizophrenia. We used SNAP-25 heterozygous (SNAP-25(+/-)) mice to investigate at which extent the reduction of the protein levels affects neuronal network function and mouse behavior. As interactions of genotype with the specific laboratory conditions may impact behavioral results, the study was performed through a multilaboratory study in which behavioral tests were replicated in at least 2 of 3 distinct European laboratories. Reductions of SNAP-25 levels were associated with a moderate hyperactivity, which disappeared in the adult animals, and with impaired associative learning and memory. Electroencephalographic recordings revealed the occurrence of frequent spikes, suggesting a diffuse network hyperexcitability. Consistently, SNAP-25(+/-) mice displayed higher susceptibility to kainate-induced seizures, paralleled by degeneration of hilar neurons. Notably, both EEG profile and cognitive defects were improved by antiepileptic drugs. These results indicate that reduction of SNAP-25 expression is associated to generation of epileptiform discharges and cognitive dysfunctions, which can be effectively treated by antiepileptic drugs.

  2. Activating mutations and senescence secretome: new insights into HER2 activation, drug sensitivity and metastatic progression.

    PubMed

    Acharyya, Swarnali

    2013-04-23

    HER2 amplification and overexpression is observed in approximately 20% of breast cancers and is strongly associated with poor prognosis and therapeutic responsiveness to HER2 targeted agents. A recent study by Bose and colleagues suggests that another subset of breast cancer patients without HER2 amplification but with activating HER2 mutation might also benefit from existing HER2-targeted agents and the authors functionally characterize these somatic mutations in experimental models. In a second study on HER2-driven breast cancer, Angelini and colleagues investigate how the constitutively active, truncated carboxy-terminal fragment of HER2, p95HER2, promotes metastatic progression through non-cellautonomous secretion of factors from senescent cells. These new findings advance our understanding of HER2 biology in the context of HER2 activation as well as offer new insights into our understanding of drug sensitivity and metastatic progression.

  3. Best approaches to drug-resistance surveillance at the country level.

    PubMed

    Cabibbe, A M; Cirillo, D M

    2016-12-01

    In 2014, the World Health Organization (WHO) recommendation to include the endorsed rapid molecular technologies (Xpert MTB/RIF, line probe assays) into surveillance systems and surveys allowed the testing of more tuberculosis (TB) patients for drug resistance at country level than ever before. The whole genome sequencing (WGS) approach is emerging as a more powerful tool for epidemiological and drug-resistant routine surveillances, promising a rapid and simultaneous screening of all the clinically-relevant mutations for the determination of resistance to the first-, second-line, and new anti-TB drugs. In addition, WGS can support the conventional contact tracing for epidemiological studies with high discriminatory power by tracking the circulating strains and their relatedness. These features make WGS, moreso than the conventional molecular tools, an ideal tool to monitor transmission and drug resistance trends in countries, providing deep and wide information in a standardized way. WGS technologies have already been adopted in many supranational and reference laboratories at the centralized level, and several research groups are working to reduce the complexity and costs of these platforms, from sample preparation to the downstream analysis and interpretation of sequencing reads, with the final aim to expand the use of WGS to all laboratory levels. The landscape of the platforms available for next-generation sequencing (NGS) is rapidly enriching. It includes high-throughput instruments that can be used for centralized surveillance studies on a large scale, and "benchtop" sequencers that conversely can reach more peripheral settings for rapid and non-extensive surveys. Traditionally, WGS is performed on genomic DNA samples extracted from clinical isolates to ensure the required high DNA quality and quantity for the following library preparation and sequencing reaction steps. Nevertheless, the researchers are trying to apply the WGS to early primary cultures and in

  4. Chronic lamotrigine treatment increases rat hippocampal GABA shunt activity and elevates cerebral taurine levels.

    PubMed

    Hassel, B; Taubøll, E; Gjerstad, L

    2001-02-01

    The mechanism of action of the antiepileptic drug lamotrigine has previously been investigated only in acute experiments and is thought to involve inhibition of voltage-dependent sodium channels. However, lamotrigine is effective against more forms of epilepsies than other antiepileptic drugs that also inhibit sodium channels. We investigated whether chronic lamotrigine treatment may affect cerebral amino acid levels. Rats received lamotrigine, 10 mg/kg/day, for 90 days. The hippocampal level of GABA increased 25%, and the activities of glutamate decarboxylase and succinic semialdehyde/GABA transaminase increased 12 and 21% (p< 0.05), respectively, indicating increased GABA turnover. The uptake of GABA and glutamate into proteoliposomes remained unaltered. The level of taurine increased 27% in the hippocampus and 16% in the frontal and parietal cortices. The activities of hexokinase and alpha-ketoglutarate dehydrogenase, remained at control values. Serum lamotrigine was 41.7+/-1.5 microM (mean+/-S.E.M.), which is within the range seen in epileptic patients. Acute experiments with 5, 20 or 100 mg lamotrigine/kg, caused no changes in brain amino acid levels. The results suggest that chronic lamotrigine treatment increases GABAergic activity in the hippocampus. The cerebral increase in taurine, which has neuromodulatory properties, may contribute to the antiepileptic effect of lamotrigine.

  5. Relationship between electronic properties and drug activity of seven quinoxaline compounds: A DFT study

    NASA Astrophysics Data System (ADS)

    Behzadi, Hadi; Roonasi, Payman; Assle taghipour, Khatoon; van der Spoel, David; Manzetti, Sergio

    2015-07-01

    The quantum chemical calculations at the DFT/B3LYP level of theory were carried out on seven quinoxaline compounds, which have been synthesized as anti-Mycobacterium tuberculosis agents. Three conformers were optimized for each compound and the lowest energy structure was found and used in further calculations. The electronic properties including EHOMO, ELUMO and related parameters as well as electron density around oxygen and nitrogen atoms were calculated for each compound. The relationship between the calculated electronic parameters and biological activity of the studied compounds were investigated. Six similar quinoxaline derivatives with possible more drug activity were suggested based on the calculated electronic descriptors. A mechanism was proposed and discussed based on the calculated electronic parameters and bond dissociation energies.

  6. Physical Activity Levels of Adolescents With Type 1 Diabetes.

    PubMed

    de Lima, Valderi Abreu; Mascarenhas, Luis Paulo Gomes; Decimo, Juliana Pereira; de Souza, William Cordeiro; Monteiro, Anna Louise Stellfeld; Lahard, Ian; França, Suzana Nesi; Leite, Neiva

    2017-01-04

    The aim of this study was to evaluate the level of physical activity and cardiorespiratory fitness in teenagers with type 1 diabetes mellitus (T1D) in comparison with healthy scholar participants. Total of 154 teenagers (T1D=45 and CON=109). Height, weight, cardiorespiratory fitness (VO2max), and the level of physical activity by the Bouchard's Physical Activity Record were measured, and glycated hemoglobin (HbA1c) in T1D. The VO2 max was lower in the T1D (38.38 ± 7.54) in comparison with the CON (42.44 ± 4.65; p<0.05). The VO2max had correlation with the amount of time of moderate-to-vigorous physical activity (r = 0.63; p = 0.0001) and an inverse correlation with sedentary activities (r = -0.46; p = 0.006). In the T1D the levels of HbA1c had an inverse correlation with the amount of time of moderate-to-vigorous physical activity (r = -0.34; p = 0.041) and correlation with the BMI z-score (r = 0.43; p = 0.017). Only 37,8% of the participants in the T1D reached the adequate amount of daily moderate-to-vigorous intensity physical activity, in the CON 81,7% reached the WHO's recommendation.

  7. Ultrasonic-Activated Micellar Drug Delivery for Cancer Treatment

    PubMed Central

    Husseini, Ghaleb A.; Pitt, William G.

    2008-01-01

    The use of nanoparticles and ultrasound in medicine continues to evolve. Great strides have been made in the areas of producing micelles, nanoemulsions and solid nanoparticles that can be used in drug delivery. An effective nanocarrier allows for the delivery of a high concentration of potent medications to targeted tissue while minimizing the side effect of the agent to the rest of the body. Polymeric micelles have been shown to encapsulate therapeutic agents and maintain their structural integrity at lower concentrations. Ultrasound is currently being used in drug delivery as well as diagnostics, and has many advantages that elevate its importance in drug delivery. The technique is non-invasive, thus no surgery is needed; the ultrasonic waves can be easily controlled by advanced electronic technology so that they can be focused on the desired target volume. Additionally, the physics of ultrasound are widely used and well understood; thus ultrasonic application can be tailored towards a particular drug delivery system. In this article, we review the recent progress made in research that utilizes both polymeric micelles and ultrasonic power in drug delivery. PMID:18506804

  8. Extraction of Children's Friendship Relation from Activity Level

    NASA Astrophysics Data System (ADS)

    Kono, Aki; Shintani, Kimio; Katsuki, Takuya; Kihara, Shin'ya; Ueda, Mari; Kaneda, Shigeo; Haga, Hirohide

    Children learn to fit into society through living in a group, and it's greatly influenced by their friend relations. Although preschool teachers need to observe them to assist in the growth of children's social progress and support the development each child's personality, only experienced teachers can watch over children while providing high-quality guidance. To resolve the problem, this paper proposes a mathematical and objective method that assists teachers with observation. It uses numerical data of activity level recorded by pedometers, and we make tree diagram called dendrogram based on hierarchical clustering with recorded activity level. Also, we calculate children's ``breadth'' and ``depth'' of friend relations by using more than one dendrogram. When we record children's activity level in a certain kindergarten for two months and evaluated the proposed method, the results usually coincide with remarks of teachers about the children.

  9. Dopamine D4 receptor stimulation prevents nigrostriatal dopamine pathway activation by morphine: relevance for drug addiction.

    PubMed

    Rivera, Alicia; Gago, Belén; Suárez-Boomgaard, Diana; Yoshitake, Takashi; Roales-Buján, Ruth; Valderrama-Carvajal, Alejandra; Bilbao, Ainhoa; Medina-Luque, José; Díaz-Cabiale, Zaida; Craenenbroeck, Kathleen Van; Borroto-Escuela, Dasiel O; Kehr, Jan; Rodríguez de Fonseca, Fernando; Santín, Luis; de la Calle, Adelaida; Fuxe, Kjell

    2016-05-22

    Morphine is one of the most effective drugs used for pain management, but it is also highly addictive. Morphine elicits acute and long-term adaptive changes at cellular and molecular level in the brain, which play a critical role in the development of tolerance, dependence and addiction. Previous studies indicated that the dopamine D4 receptor (D4 R) activation counteracts morphine-induced adaptive changes of the μ opioid receptor (MOR) signaling in the striosomes of the caudate putamen (CPu), as well as the induction of several Fos family transcription factors. Thus, it has been suggested that D4 R could play an important role avoiding some of the addictive effects of morphine. Here, using different drugs administration paradigms, it is determined that the D4 R agonist PD168,077 prevents morphine-induced activation of the nigrostriatal dopamine pathway and morphological changes of substantia nigra pars compacta (SNc) dopamine neurons, leading to a restoration of dopamine levels and metabolism in the CPu. Results from receptor autoradiography indicate that D4 R activation modulates MOR function in the substantia nigra pars reticulata (SNr) and the striosomes of the CPu, suggesting that these regions are critically involved in the modulation of SNc dopamine neuronal function through a functional D4 R/MOR interaction. In addition, D4 R activation counteracts the rewarding effects of morphine, as well as the development of hyperlocomotion and physical dependence without any effect on its analgesic properties. These results provide a novel role of D4 R agonist as a pharmacological strategy to prevent the adverse effects of morphine in the treatment of pain.

  10. Activity level and risk of overweight in male health professionals.

    PubMed Central

    Ching, P L; Willett, W C; Rimm, E B; Colditz, G A; Gortmaker, S L; Stampfer, M J

    1996-01-01

    OBJECTIVES. This study undertook to examine relationships between nonsedentary activity level, time spent watching television (TV)/videocassette recorder (VCR), and risk of overweight among men. METHODS. Men participating in the Health Professionals Follow-Up Study were mailed surveys. Cross-sectional analyses examined the prevalence and odds of being overweight, prospective analyses determined cumulative incidence rates and relative risks of becoming overweight over 2 years of follow-up. RESULTS. Cross-sectionally, odds of being overweight were 50% (95% confidence interval [CI] = 45%; 55%) lower for men in the highest quintile of nonsedentary activity level when compared with men in the lowest quintile. Among men watching 41 or more hours of TV/VCR per week, the odds of being overweight were 406 (95% CI = 2.67, 6.17) times greater than those for men watching no more than 1 hour per week. Prospectively, higher levels is of nonsedentary activity and lower levels of TV/VCR viewing were independently associated with lower relative risks for becoming overweight between survey years. CONCLUSIONS. Both a lack of nonsedentary activity and time spent watching TV/VCR contribute to the development of overweight in men. Sedentary and nonsedentary activities represent separate domains, each with independent risks for overweight. PMID:8561237

  11. Peripheral mechanisms II: the pharmacology of peripherally active antitussive drugs.

    PubMed

    Spina, D; McFadzean, I; Bertram, F K R; Page, C P

    2009-01-01

    Cough is an indispensable defensive reflex. Although generally beneficial, it is also a common symptom of diseases such as asthma, chronic obstructive pulmonary disease, upper respiratory tract infections, idiopathic pulmonary fibrosis and lung cancer. Cough remains a major unmet medical need and although the centrally acting opioids have remained the antitussive of choice for decades, they have many unwanted side effects. However, new research into the behaviour of airway sensory nerves has provided greater insight into the mechanisms of cough and new avenues for the discovery of novel non-opioid antitussive drugs. In this review, the pathophysiological mechanisms of cough and the development of novel antitussive drugs are reviewed.

  12. Play equipment, physical activity opportunities, and children's activity levels at childcare.

    PubMed

    Gubbels, Jessica S; Van Kann, Dave H H; Jansen, Maria W J

    2012-01-01

    This study investigated the association between physical activity facilities at childcare (e.g., play equipment) and physical activity of 2- and 3-year olds. Observations of physical activity intensity were performed among 175 children at 9 childcare centers in The Netherlands, using the OSRAC-P. The physical activity facilities were assessed for indoors and outdoors separately, using the EPAO instrument. Regular (single-level) multivariate and multilevel linear regression analyses examined the association of the facilities and child characteristics (age and sex) with children's activity levels. Various physical activity facilities were available in all childcare centers (e.g., balls). Riding toys and a small playing area were associated with lower indoor physical activity levels. Outdoor physical activity levels were positively associated with the availability of portable jumping equipment and the presence of a structured track on the playground. Portable slides, fixed swinging equipment, and sandboxes were negatively associated with outdoor activity levels. In addition, the 3-year old children were more active outdoors than the 2-year olds. In conclusion, not all physical activity facilities at childcare were indeed positively associated with children's activity levels. The current findings provide concrete leads for childcare providers regarding which factors they can improve in the physical environment to facilitate children's physical activity.

  13. Antineoplastic Drugs

    NASA Astrophysics Data System (ADS)

    Sadée, Wolfgang; El Sayed, Yousry Mahmoud

    The limited scope of therapeutic drug-level monitoring in cancer chemotherapy results from the often complex biochemical mechanisms that contribute to antineoplastic activity and obscure the relationships among drug serum levels and therapeutic benefits. Moreover, new agents for cancer chemotherapy are being introduced at a more rapid rate than for the treatment of other diseases, although the successful application of therapeutic drug-level monitoring may require several years of intensive study of the significance of serum drug levels. However, drug level monitoring can be of considerable value during phase I clinical trials of new antineoplastic agents in order to assess drug metabolism, bioavailability, and intersubject variability; these are important parameters in the interpretation of clinical studies, but have no immediate benefit to the patient. High performance liquid chromatography (HPLC) probably represents the most versatile and easily adaptable analytical technique for drug metabolite screening (1). HPLC may therefore now be the method of choice during phase I clinical trials of antineoplastic drugs. For example, within a single week we developed an HPLC assay—using a C18 reverse-phase column, UV detection, and direct serum injection after protein precipitation—for the new radiosensitizer, misonidazole (2).

  14. Daily ambulatory activity levels in idiopathic Parkinson disease.

    PubMed

    Skidmore, Frank M; Mackman, Chad A; Pav, Breckon; Shulman, Lisa M; Garvan, Cyndi; Macko, Richard F; Heilman, Kenneth M

    2008-01-01

    Patients with Parkinson disease (PD) may have decreased physical activity due to motor deficits. We recently validated the reliability of step activity monitors (SAMs) to accurately count steps in PD, and we wished to use them to evaluate the impact of disease severity on home activity levels in PD. Twenty-six subjects with PD (Hoehn and Yahr disease stage 2-4) were recruited to participate in a study of activity levels over 48 hours. Ability to achieve 95% device accuracy was an entry requirement. A Unified Parkinson Disease Rating Scale (UPDRS) evaluation was performed on all subjects, subjects were monitored for 48 hours, and total number of steps per day and maximum steps taken per hour were calculated. Out of 26 subjects, 25 met entry requirements. We calculated the number of steps taken per day, as well as maximal activity levels, and correlated these with UPDRS total score, the activity of daily living subscale, and the UPDRS motor function subscale off and on medication (all p < 0.01). Transition from Hoehn and Yahr stage 2 to stage 3 was associated with a decline in functional mobility (p < 0.005). A microprocessor-linked SAM accurately counted steps in subjects with PD. The number of steps taken correlated highly with disease severity. SAMs may be useful outcome measures in PD.

  15. Routine activities and sexual assault: an analysis of individual- and school-level factors.

    PubMed

    Cass, Amy I

    2007-01-01

    The efficacy of routine activities theory is examined to explain sexual assault on the college campus. Although many research studies have utilized routine activities theory to predict sexual assault using individual-level factors, little is known about the effect of school-level factors on a student's risk of sexual assault. Based on interviews from 3,036 randomly selected students and surveys from 11 randomly selected colleges in the United States, a hierarchical linear model was created to predict student victimizations by school characteristics. For the individual, results reveal that being female, drug use, and marital status are statistically significant for predicting the probability of a sexual assault. At the institutional level, however, none of the variables are significant in predicting sexual assault among college coeds. Policy implications for prevention measures on college campuses are discussed.

  16. A Survey of Physical Activity Levels of Certified Athletic Trainers

    PubMed Central

    Cuppett, Marchell; Latin, Richard W.

    2002-01-01

    Objective: To determine the self-reported physical activities of certified athletic trainers (ATCs), both at work and at leisure. Design and Setting: We used the Baecke Questionnaire of Habitual Physical Activity and also asked for demographic information, including employment setting, years of experience, education level, and position. Subjects: The questionnaire was sent to 1200 randomly selected ATCs in the Mid-America Athletic Trainers' Association; the return rate was 53%. Measurements: We used means, standard deviations, and ranges to describe the age, total fitness index, work, and leisure and sport indexes of men and women subjects. Independent t tests were used to compare the mean total activity index between men and women within this study and with previous studies. We examined differences in activity indexes by employment setting, position, and age with one-way analysis of variance and Fisher pairwise comparison tests. Two-way χ2 analysis was used to determine the relationship between activity level and employment setting and position. Statistical significance was set at P = .05 for all analyses. Results: Certified athletic trainers who work in a clinical setting had the highest mean total activity score at 9.1 points. Clinic ATCs scored significantly higher than high school ATCs and college ATCs. When compared by position, there were no significant differences among the mean total activity indexes; however, the mean work index of program directors was significantly lower than all other positions and the mean work index of high school and clinic ATCs was significantly higher than all other employment settings. Conclusions: Female ATCs scored significantly higher in total activity levels on the Baecke Questionnaire than their male counterparts. This is in contrast to the general population, investigated by other authors, in which men scored significantly higher than women on the same scale. Additionally, we compared the total activity levels by age

  17. Detection of anti-drug antibodies using a bridging ELISA compared with radioimmunoassay in adalimumab-treated rheumatoid arthritis patients with random drug levels

    PubMed Central

    Jani, Meghna; Isaacs, John D.; Morgan, Ann W.; Wilson, Anthony G.; Plant, Darren; Hyrich, Kimme L.; Chinoy, Hector

    2016-01-01

    Objective. To determine the concordance between RIA and bridging ELISA at detecting anti-drug antibodies (ADAbs) in the context of random adalimumab levels and investigate the additional clinical utility of detecting ADAbs in RA patients who test ADAb positive by RIA and negative by ELISA. Methods. ADAb levels were determined using RIA and bridging ELISA in 63 adalimumab-treated RA patients (159 samples). Immunogenicity concordance was determined using receiver operating characteristic curves. To determine the additional clinical value provided by a positive RIA in the presence of negative ELISA, association between treatment response (ΔDAS28), adalimumab drug levels and ADAbs was evaluated longitudinally using generalized estimating equation. Results. Of the 60 RIA+ samples (n = 31 patients), 19 (n = 10 patients) were also ELISA+, corresponding to 31.7% of samples. Area under the curve for detecting ADAbs using ELISA (compared with RIA) using receiver operating characteristic curves was 0.65 (95% CI: 0.59, 0.71); this increased to 0.91 (95% CI: 0.81, 0.99) if ADAbs were ⩾100 AU/ml using RIA. In RIA+/ELISA− patients, adalimumab levels were associated with ΔDAS28 over 12 months [regression coefficient: 0.098 (95% CI: 0.043, 0.15), P < 0.0001] and while ADAbs were significantly associated with drug level, they were not directly associated with ΔDAS28 over 12 months [β coefficient: 0.00083 (95% CI: −0.0038 to 0.0054), P = 0.72]. Conclusion. ADAbs were detected using ELISA more frequently when present in high titres as measured by RIA. In RIA+/ELISA− patients, only drug levels were significantly associated with treatment response. Although ADAbs were not independently associated with treatment response, they may be helpful in determining the aetiology of low drug levels. PMID:27565176

  18. Systems-level modeling of mycobacterial metabolism for the identification of new (multi-)drug targets.

    PubMed

    Rienksma, Rienk A; Suarez-Diez, Maria; Spina, Lucie; Schaap, Peter J; Martins dos Santos, Vitor A P

    2014-12-01

    Systems-level metabolic network reconstructions and the derived constraint-based (CB) mathematical models are efficient tools to explore bacterial metabolism. Approximately one-fourth of the Mycobacterium tuberculosis (Mtb) genome contains genes that encode proteins directly involved in its metabolism. These represent potential drug targets that can be systematically probed with CB models through the prediction of genes essential (or the combination thereof) for the pathogen to grow. However, gene essentiality depends on the growth conditions and, so far, no in vitro model precisely mimics the host at the different stages of mycobacterial infection, limiting model predictions. These limitations can be circumvented by combining expression data from in vivo samples with a validated CB model, creating an accurate description of pathogen metabolism in the host. To this end, we present here a thoroughly curated and extended genome-scale CB metabolic model of Mtb quantitatively validated using 13C measurements. We describe some of the efforts made in integrating CB models and high-throughput data to generate condition specific models, and we will discuss challenges ahead. This knowledge and the framework herein presented will enable to identify potential new drug targets, and will foster the development of optimal therapeutic strategies.

  19. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity.

    PubMed

    Johansen, Lisa M; DeWald, Lisa Evans; Shoemaker, Charles J; Hoffstrom, Benjamin G; Lear-Rooney, Calli M; Stossel, Andrea; Nelson, Elizabeth; Delos, Sue E; Simmons, James A; Grenier, Jill M; Pierce, Laura T; Pajouhesh, Hassan; Lehár, Joseph; Hensley, Lisa E; Glass, Pamela J; White, Judith M; Olinger, Gene G

    2015-06-03

    Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration-approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections.

  20. Alteration of serum inflammatory cytokines in active pulmonary tuberculosis following anti-tuberculosis drug therapy.

    PubMed

    Chowdhury, Imran Hussain; Ahmed, Albin Mostaque; Choudhuri, Subhadip; Sen, Aditi; Hazra, Avijit; Pal, Nishith Kumar; Bhattacharya, Basudev; Bahar, Bojlul

    2014-11-01

    Active pulmonary tuberculosis (APTB) is associated with a failure of the host immune system to control the invading Mycobacterium tuberculosis (Mtb). The objective of this study was to quantify and assess the role of serum inflammatory cytokines in active pulmonary tuberculosis patients following anti-tuberculosis drug (ATD) therapy. Blood samples were collected from APTB patients and normal healthy subjects (NHS) (total n=204) at baseline and 2, 4 and 6 months post-therapy and the abundance of serum inflammatory cytokines were measured by cytokine specific ELISA. Compared to NHS, APTB patients at baseline had higher levels of serum pro-inflammatory cytokines IL-12p40 (P<0.001), IFN-γ (P<0.001), TNF-α (P<0.01), IL-1β (P<0.001) and IL-6 (P<0.001) and anti-inflammatory cytokines IL-10 (P<0.001) and TGF-β1 (P<0.001) while there was no change in the level of IL-4. In APTB patients, the serum levels of IFN-γ, TNF-α, IL-6 and TGF-β1 directly relate to the bacterial load while the TNF-α, IL-1β, IL-6 and TGF-β1 relate to radiological severity. At baseline, the IL-6 level in NHS and APTB patients differed most and following ATD therapy, this level rapidly decreased and stabilized by 4-month in APTB patients. It is concluded that a subtle reduction in the serum level of IL-6 of the APTB patients following ATD therapy might play a vital role in immune-protection of the host against Mtb infection and hence the serum IL-6 level can be a useful marker to diagnose the effectiveness of therapy in the patients.

  1. Predicting tumor responses to mitomycin C on the basis of DT-diaphorase activity or drug metabolism by tumor homogenates: implications for enzyme-directed bioreductive drug development.

    PubMed

    Phillips, R M; Burger, A M; Loadman, P M; Jarrett, C M; Swaine, D J; Fiebig, H H

    2000-11-15

    Mitomycin C (MMC) is a clinically used anticancer drug that is reduced to cytotoxic metabolites by cellular reductases via a process known as bioreductive drug activation. The identification of key enzymes responsible for drug activation has been investigated extensively with the ultimate aim of tailoring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable interest has been centered upon the enzyme DT-diaphorase (DTD) although conflicting reports of good and poor correlations between enzyme activity and response in vitro and in vivo have been published. The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts. DTD levels were measured in 45 human tumor xenografts that had been characterized previously in terms of their sensitivity to MMC in vitro and in vivo (the in vivo response profile to MMC was taken from work published previously). A poor correlation between DTD activity and antitumor activity in vitro as well as in vivo was obtained. This study also assessed the predictive value of an alternative approach based upon the ability of tumor homogenates to metabolize MMC. This approach is based on the premise that the overall rate of MMC metabolism may provide a better indicator of response than single enzyme measurements. MMC metabolism was evaluated in tumor homogenates (clarified by centrifugation at 1000 x g for 1 min) by measuring the disappearance of the parent compound by HPLC. In responsive [T/C <10% (T/C defined as the relative size of treated and control tumors)] and resistant (T/C >50%) tumors, the mean half life of MMC was 75+/-48.3 and 280+/-129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005). In conclusion, these results unequivocally demonstrate that response to

  2. Effect of Culture Time on the Basal Expression Levels of Drug Transporters in Sandwich-Cultured Primary Rat HepatocytesS⃞

    PubMed Central

    Houghton, Jessica S.; Uyeda, Craig; Grillo, Mark P.; Jin, Lixia

    2011-01-01

    Sandwich-cultured rat hepatocytes are used in drug discovery for pharmacological and toxicological assessment of drug candidates, yet their utility as a functional model for drug transporters has not been fully characterized. To evaluate the system as an in vitro model for drug transport, expression changes of hepatic transporters relative to whole liver and freshly isolated hepatocytes (day 0) were examined by real-time quantitative reverse transcription-polymerase chain reaction for 4 consecutive days of culture. No significant differences in transporter expression levels were observed between freshly isolated hepatocytes and whole liver. Two distinct mRNA profiles were detected over time showing 1) a more than 5-fold decline in levels of uptake transporters such as Na+-taurocholate cotransporting polypeptide (Ntcp), organic anion transporter (Oat) 2, organic anion-transporting polypeptide (Oatp) 1a1, Oatp1a4, and Oatp1b2 and 2) a greater than 5-fold increase of efflux transporters P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and multidrug resistance-related proteins (Mrp) 1, 2, 3, and 4. In addition, protein levels and functional activities for selected transporters were also determined. Protein levels for Mrp2, Bcrp, P-gp, Ntcp, and Oatp1a4 corresponded to changes in mRNA. Functional activities of Oatps and Oct1 exhibited a 3- and 4-fold decrease on day 2 and day 4, respectively, relative to that on day 0, whereas a more than 10-fold reduction in Oat2 activity was observed. These results indicate that the cell culture conditions used herein did not provide an optimal environment for expression of all hepatic transporters. Significant time-dependent alterations in basal gene expression patterns of transporters were detected compared with those in liver or freshly isolated hepatocytes. Further work and new strategies are required to improve the validity of this model as an in vitro tool for in vivo drug transport or biliary clearance prediction

  3. Cascading Activation across Levels of Representation in Children's Lexical Processing

    ERIC Educational Resources Information Center

    Huang, Yi Ting; Snedeker, Jesse

    2011-01-01

    Recent work in adult psycholinguistics has demonstrated that activation of semantic representations begins long before phonological processing is complete. This incremental propagation of information across multiple levels of analysis is a hallmark of adult language processing but how does this ability develop? In two experiments, we elicit…

  4. Pedometer-Assessed Physical Activity Levels of Rural Appalachian Youth

    ERIC Educational Resources Information Center

    Oh, Hyun-Ju; Rana, Sharon

    2014-01-01

    The purposes of this investigation were to examine whether pedometer-assessed physical activity (PA) in Appalachian Ohio students differed by body mass index (BMI), school level (middle school vs. high school), and gender during school days and nonschool days and whether students met the recommended PA guidelines. Participants (N = 149) were…

  5. Cardiovascular effects of variations in habitual levels of physical activity

    NASA Technical Reports Server (NTRS)

    Blomqvist, C. G.; Mitchell, J. H.

    1975-01-01

    Mechanisms involved in human cardiovascular adaption to stress, particularly adaption to different levels of physical activity are determined along with quantitative noninvasive methods for evaluation of cardiovascular function during stess in normal subjects and in individuals with latent or manifest cardiovascular disease. Results are summarized.

  6. 34 CFR 300.814 - Other State-level activities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 2 2010-07-01 2010-07-01 false Other State-level activities. 300.814 Section 300.814 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION...

  7. Genetic Influences on Mechanically-Assessed Activity Level in Children

    ERIC Educational Resources Information Center

    Wood, Alexis C.; Saudino, Kimberly J.; Rogers, Hannah; Asherson, Philip; Kuntsi, Jonna

    2007-01-01

    Background: Activity level is an important component of children's temperament, as well as being part of the core symptom domain of hyperactivity-impulsivity within attention deficit hyperactivity disorder (ADHD). Yet it is poorly understood, due partly to limitations on parent and teacher ratings, which are typically used as measurements of these…

  8. Anterior cingulate activity and level of cognitive conflict: explicit comparisons.

    PubMed

    Mitchell, Rachel L C

    2006-12-01

    The role of anterior cingulate cortex (ACC) in attention is a matter of debate. One hypothesis suggests that its role is to monitor response-level conflict, but explicit evidence is somewhat lacking. In this study, the activation of ACC was compared in (a) color and number standard Stroop tasks in which response preparation and interference shared modality (response-level conflict) and (b) color and number matching Stroop tasks in which response preparation and interference did not share modality (non-response-level conflict). In the congruent conditions, there was no effect of task type. In the interference conditions, anterior cingulate activity in the matching tasks was less than that in the standard tasks. These results support the hypothesis that ACC specifically mediates generalized modality-independent selection processes invoked by response competition.

  9. Neighborhood-level LGBT hate crimes and current illicit drug use among sexual minority youth

    PubMed Central

    Duncan, Dustin T.; Hatzenbuehler, Mark L.; Johnson, Renee M.

    2014-01-01

    Objective To investigate whether past-30 day illicit drug use among sexual minority youth was more common in neighborhoods with a greater prevalence of hate crimes targeting lesbian, gay, bisexual, and transgender (LGBT, or sexual minority) individuals. Methods We used a population-based survey of public school youth in Boston, Massachusetts, consisting of 1292 9th–12th grade students from the 2008 Boston Youth Survey Geospatial Dataset (sexual minority n = 108). Data on LGBT hate crimes involving assaults or assaults and battery between 2005 and 2008 were obtained from the Boston Police Department and linked to youths’ residential address. Youth reported past-30 day use of marijuana and other illicit drugs. Wilcoxon–Mann–Whitney tests and corresponding p-values were computed to assess differences in substance use by neighborhood-level LGBT assault hate crime rate among sexual minority youth (n = 103). Results The LGBT assault hate crime rate in the neighborhoods of sexual minority youth who reported current marijuana use was 23.7 per 100,000, compared to 12.9 per 100,000 for sexual minority youth who reported no marijuana use (p = 0.04). No associations between LGBT assault hate crimes and marijuana use among heterosexual youth (p > 0.05) or between sexual minority marijuana use and overall neighborhood-level violent and property crimes (p > 0.05) were detected, providing evidence for result specificity. Conclusions We found a significantly greater prevalence of marijuana use among sexual minority youth in neighborhoods with a higher prevalence of LGBT assault hate crimes. These results suggest that neighborhood context (i.e., LGBT hate crimes) may contribute to sexual orientation disparities in marijuana use. PMID:24326203

  10. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network

    PubMed Central

    Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda; Rathod, Pradipsinh K.; Rosenthal, Philip J.

    2015-01-01

    Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs. PMID:26259943

  11. Research on drug-receptor interactions and prediction of drug activity via oriented immobilized receptor capillary electrophoresis.

    PubMed

    Liu, Chunye; Zhang, Xuejiao; Jing, Hui; Miao, Yanqing; Zhao, Lingzhi; Han, Yan; Cui, Cuixia

    2015-10-01

    Oriented covalent immobilized β2 -adrenergic receptor (β2 -AR) CE (OIRCE) was developed to determine the interactions between a set of natural extracts of Radix Paeoniae Rubra (NERPR) and β2 -AR, and to predict the activity of NERPR. The inner capillary surface is chemically bonded with stable β2 -AR coating via microwave-assisted technical synthesis. The modified capillaries were characterized via infrared spectroscopy and fluorescence microscopy. Furthermore, the bonding amounts of β2 -AR were first obtained via fluorescence spectroscopy method. In determining the amount of bonded β2 -AR, the regression equation A  =  576 707C + 35.449 and the correlation coefficient 0.9995 were obtained. This result revealed an excellent linear relationship in the range of 2 × 10(-4)  mg/mL to 1 × 10(-3)  mg/mL. The normalized capacity factor (KRCE ) was obtained using OIRCE in evaluating drug-receptor interactions. Related theories and equations were used to calculate KRCE values from apparent migration times of a solute and EOF. The order of KRCE and the binding constant (Kb ) values between drugs and β2 -AR was well consistent. The results confirmed that the OIRCE and KRCE values can be effectually used to investigate drug-receptor interactions, and OIRCE has the potential to predict drug activity and to select leading compounds from natural chemicals.

  12. Spasmolytic activity of a herbal drug isolated from Tephrosia purpurea in guinea pigs.

    PubMed

    Soni, Kapil K; Khare, M L; Saxena, R C

    2004-04-01

    We investigated the spasmolytic activity of herbal drugs isolated from Tephrosia purpurea on guinea pigs for the treatment of asthma in India. For this investigation, the herbal drug was extracted with 70% ethanol in soxhlet apparatus. After purification and isolution, the drug was used in experimental animals to observe prophylactic activity. For anaphylactic activity, horse serum 0.5 ml along with triple antigen (0.5 ml) was induced in guinea pigs. To observe prophylactic activity, male guinea pigs weighing about 250-450 gms were killed by cervical dislocation and the trachea was isolated. Each trachea was cut in to six segments. Each segment consists of three cartilage rings. Each end of tracheal muscles was attached to the bronchospasm transducers for isometric recording of the tension charges on a polygraph. The results of experiments clearly showed the spasmolytic activity of the drug. The preliminary phytochemical investigation, however shows the presence of glycoside saponins.

  13. Randomized Controlled Evaluation of the "Too Good for Drugs" Prevention Program: Impact on Adolescents at Different Risk Levels for Drug Use

    ERIC Educational Resources Information Center

    Hall, Bruce W.; Bacon, Tina P.; Ferron, John M.

    2013-01-01

    Sixth graders participating in the "Too Good for Drugs" (TGFD) prevention program in comparison to 6th graders not participating show different results by student risk level. Sixth graders from 20 middle schools were randomly assigned to receive the intervention and those from 20 paired middle schools assigned to serve as controls (N =…

  14. Decreased Level of Klotho Contributes to Drug Resistance in Lung Cancer Cells: Involving in Klotho-Mediated Cell Autophagy.

    PubMed

    Chen, TianJun; Ren, Hui; Thakur, Asmitanand; Yang, Tian; Li, Yang; Zhang, Shuo; Wang, Ting; Chen, MingWei

    2016-12-01

    Klotho is originally discovered as an anti-aging gene and recently identified as a tumor suppressor in various human cancers. Drug resistance is a major obstacle to affect the treatment of chemotherapy. In the present study, we explore the role of klotho on drug resistance in human lung cancers and investigate the mechanism of klotho on drug resistance in lung cancer cells. First, we detected a panel of six human lung cancer cell lines, including H460, SK-MES-1, cisplatin (DDP)-resistant A549/DDP, its parental subline A549, docetaxel (DTX)-resistant SPC-A-1/DTX, and SPC-A-1 by western blotting analysis. The results showed that klotho level was significantly decreased in chemotherapeutic drug-resistant lung cancer cells. Next, klotho was overexpressed in drug-resistant cancer cell lines and the results showed that overexpression of klotho significantly inhibited cell proliferation of A549/DDP and SPC-A-1/DTX. Conversely, knockdown of the expression of klotho significantly promoted cell growth of lung cancer cells. Furthermore, overexpression of klotho had synergistic effects with cisplatin to inhibit the proliferation of drug-resistant lung cancer cells in a dose- and time-dependent manner. The molecular mechanism was explored by western blotting analysis and the results revealed that the levels of beclin 1 and LC3-II were obviously increased, suggesting cell autophagy enhanced in drug-resistant cancer cells. Importantly, overexpression of klotho would inhibit cell autophagy in A549/DDP cells. All the results demonstrated that the levels of klotho were significantly decreased, which was accompanied by the increased cell autophagy in drug-resistant lung cancer cells. Overexpression of klotho would inhibit cell autophagy in drug-resistant lung cancers, which may probably contribute to reverse drug resistance in lung cancer cells.

  15. Drug Delivery to Extravascular Tissue by Ultrasound-activated Microbubbles

    NASA Astrophysics Data System (ADS)

    Kooiman, Klazina; Harteveld, Miranda; de Jong, Nico; van Wamel, Annemieke

    2007-05-01

    Drugs will be delivered to tissue more efficiently if the vascular endothelial permeability is increased. Although recent studies have established that the permeability of single-cell membranes is increased by ultrasound in combination with contrast agents, it is not known whether this combination can also increase the permeability of an endothelial layer. To investigate endothelial layer permeability, we treated monolayers of human umbilical vein endothelial cells with ultrasound and the contrast agent BR14. Endothelial layer permeability was assessed by measuring the transendothelial electrical resistance (TEER) and the transendothelial transport of fluorescein. Ultrasound in combination with BR14 significantly decreased TEER to 68.0 ± 3.1% of initial values and temporally increased endothelial permeability for fluorescein by 38.1 ± 16.4 %. After treatment, no cell loss or damage was observed. In conclusion, ultrasound in combination with BR14 increased the endothelial layer permeability. This feature may be used for future ultrasound-guided drug delivery systems.

  16. Chemotherapy drug response in ovarian cancer cells strictly depends on a cathepsin D-Bax activation loop

    PubMed Central

    Castino, Roberta; Peracchio, Claudia; Salini, Alessandra; Nicotra, Giuseppina; Trincheri, Nicol F; Démoz, Marina; Valente, Guido; Isidoro, Ciro

    2009-01-01

    The ovarian cancer cell lines A2780 (wild-type p53) and NIHOVCAR3 (mutated p53) showed, respectively, sensitivity and resistance towards several chemotherapy drugs. We hypothesized that the two cell lines differ in their ability to activate the intrinsic death pathway and have, therefore, dissected the lysosome-mitochondrion signalling pathway by pharmacological inhibition or genetic manipulation of key regulators and executioners. Biochemical and morphological confocal fluorescence studies showed that: (1) In A2780 cells bcl-2 is expressed at an undetectable level, whereas Bax is expressed at a rather high level; by contrast, bcl-2 is highly expressed and Bax is expressed at extremely low levels in NIHOVCAR3 cells; (2) Chemotherapy treatment reduced the expression of bcl-2 in NIHOVCAR3 cells, yet these cells resisted to drug toxicity; (3) Cathepsin D (CD), not cathepsin B or L, mediates the activation of the mitochondrial intrinsic death pathway in A2780 cells; (4) Lysosome leakage and cytosolic relocation of CD occurs in the chemosensitive A2780 cells, not in the chemoresistant NIHOVCAR3 cells; (5) Bax is essential for the permeabilization of both lysosomes and mitochondria in A2780 cells exposed to chemotherapy drugs; (6) CD activity is mandatory for the oligomerization of Bax on both mitochondrial and lysosomal membranes; (7) Bax activation did not occur in the resistant NIHOVCAR3 cells despite their high content in CD. The present data are consistent with a model in which on treatment with a cytotoxic drug the activation of a CD-Bax loop leads to the generalized permeabilization of lysosomes and eventually of mitochondria, thus reaching the point of no return, and culminates with the activation of the caspase cascade. Our data also imply that dysfunctional permeabilization of lysosomes contributes to the development of chemoresistance. PMID:18657225

  17. Effects of Curricular Activity on Students' Situational Motivation and Physical Activity Levels

    ERIC Educational Resources Information Center

    Gao, Zan; Hannon, James C.; Newton, Maria; Huang, Chaoqun

    2011-01-01

    The purpose of this study was to examine (a) the effects of three curricular activities on students' situational motivation (intrinsic motivation [IM], identified regulation [IR], external regulation, and amotivation [AM]) and physical activity (PA) levels, and (b) the predictive strength of situational motivation to PA levels. Four hundred twelve…

  18. Lesture Less And Listen More...A Laboratory, Activity Oriented Unit On Drug Abuse

    ERIC Educational Resources Information Center

    Spaulding, Jerry; Munch, Theodore W.

    1973-01-01

    Describes a drug unit which uses videotape interviews to: (1) motivate adolescents to develop positive attitudes toward drug abuse; (2) increase student participation in classroom activities; (3) use appropriate science exercises to further understandings; and (4) permit students to work on things of personal interest. (Author/CJ)

  19. Increased Interleukin-17 and decreased BAFF serum levels in drug-free acute schizophrenia.

    PubMed

    El Kissi, Yousri; Samoud, Samar; Mtiraoui, Ahlem; Letaief, Leila; Hannachi, Neila; Ayachi, Mouna; Ali, Bechir Ben Hadj; Boukadida, Jalel

    2015-01-30

    Hypotheses regarding an immune-cytokine basis of schizophrenia have been postulated with controversial findings and a lack of data related to many cytokines. The aim of this study was to assess serum levels of Interferon-γ (IFN-γ), Interleukin-4 (IL-4), Transforming Growth Factor-β (TGF-β), Interleukin-17 (IL-17) and B-cell Activating Factor (BAFF) in schizophrenic patients and to determine correlations between cytokine levels and clinical parameters. Serum cytokine levels were measured with ELISA techniques in 60 neuroleptic-free patients on acute phase of the disease (BPRS≥40) and 28 healthy controls matched for age and sex. Current symptoms were assessed with Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS). No significant difference was found between patients and controls regarding IFN-γ serum levels. IL-4 was not detected in both groups. Patients exhibited significantly higher IL-17 and lower BAFF serum levels. IL-17 and BAFF levels were negatively correlated in schizophrenic patients. SANS global score was negatively correlated with IL-17 and positively correlated with IFN-γ serum levels. These results argue against the involvement of Th1 or Th2 population cells in schizophrenia. IL-17 and BAFF could be valuable markers for schizophrenia.

  20. EGFR inhibition evokes innate drug resistance in lung cancer cells by preventing Akt activity and thus inactivating Ets-1 function.

    PubMed

    Phuchareon, Janyaporn; McCormick, Frank; Eisele, David W; Tetsu, Osamu

    2015-07-21

    Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.

  1. Cancer in Utah Mormon women by church activity level.

    PubMed

    Gardner, J W; Lyon, J L

    1982-08-01

    In light of low cancer rates by the Mormon Church, this study classifies female Mormon cancer patients in Utah according to measures of adherence to Church doctrines. The distribution by Church activity level is compared for each site to a group of other cancer sites felt to represent the overall activity level distribution of Utah Mormon women. Mormon women classified as having the strongest adherence to Church doctrines had lung cancer rates during 1966-1970 much lower than did women with the weakest adherence. The relationship was not as strong, however, as that seen in Mormon men when classified by lay priesthood office. Cancer of the uterine cervix also showed lower rates in the more active groups, but this finding was not statistically significant. Cancers of the breast and ovary did not show consistent associations with Church activity level, nor did most of the gastrointestinal cancers. These data suggest that some of the differences in cancer incidence between Mormons and non-Mormons may not be explained by adherence to specific Church doctrines.

  2. Determinants affecting physical activity levels in animal models

    NASA Technical Reports Server (NTRS)

    Tou, Janet C L.; Wade, Charles E.

    2002-01-01

    Weight control is dependent on energy balance. Reduced energy expenditure (EE) associated with decreased physical activity is suggested to be a major underlying cause in the increasing prevalence of weight gain and obesity. Therefore, a better understanding of the biological determinants involved in the regulation of physical activity is essential. To facilitate interpretation in humans, it is helpful to consider the evidence from animal studies. This review focuses on animal studies examining the biological determinants influencing activity and potential implications to human. It appears that physical activity is influenced by a number of parameters. However, regardless of the parameter involved, body weight appears to play an underlying role in the regulation of activity. Furthermore, the regulation of activity associated with body weight appears to occur only after the animal achieves a critical weight. This suggests that activity levels are a consequence rather than a contributor to weight control. However, the existence of an inverse weight-activity relationship remains inconclusive. Confounding the results are the multifactorial nature of physical activity and the lack of appropriate measuring devices. Furthermore, many determinants of body weight are closely interlocked, making it difficult to determine whether a single, combination, or interaction of factors is important for the regulation of activity. For example, diet-induced obesity, aging, lesions to the ventral medial hypothalamus, and genetics all produce hypoactivity. Providing a better understanding of the biological determinants involved in the regulation of activity has important implications for the development of strategies for the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population.

  3. Determinants Affecting Physical Activity Levels In Animal Models

    NASA Technical Reports Server (NTRS)

    Tou, Janet C. L.; Wade, Charles E.; Dalton, Bonnie P. (Technical Monitor)

    2001-01-01

    Weight control is dependent on energy balance. Reduced energy expenditure (EE) associated with decreased physical activity is suggested to be a major underlying cause in the increasing prevalence of weight gain and obesity. Therefore, a better understanding of the biological determinants involved in the regulation of physical activity is essential. To facilitate interpretation in humans, it is helpful to consider the evidence from animal studies. This review focuses on animal studies examining the biological determinants influencing activity and potential implications to human. It appears that physical activity is influenced by a number of parameters. However, regardless of the parameter involved, body weight appears to play all underlying role in the regulation of activity. Furthermore, the regulation of activity associated with body weight appears to occur only after the animal achieves a critical weight. This suggests that activity levels are a consequence rather than a contributor to weight control. However, the existence of an inverse weight-activity relationship remains inconclusive. Confounding the results are the multi-factorial nature of physical activity and the lack of appropriate measuring devices. Furthermore, many determinants of body weight are closely interlocked making it difficult to determine whether a single, combination or interaction of factors is important for the regulation of activity. For example, diet-induced obesity, aging, lesions to tile ventral medial hypothalamus and genetics all produce hypoactivity. Providing a better understanding of the biological determinants involved in the regulation of activity has important implications for the development of strategies for the prevention of weight gain leading to obesity and subsequent morbidity and mortality in the human population.

  4. DrugCentral: online drug compendium

    PubMed Central

    Ursu, Oleg; Holmes, Jayme; Knockel, Jeffrey; Bologa, Cristian G.; Yang, Jeremy J.; Mathias, Stephen L.; Nelson, Stuart J.; Oprea, Tudor I.

    2017-01-01

    DrugCentral (http://drugcentral.org) is an open-access online drug compendium. DrugCentral integrates structure, bioactivity, regulatory, pharmacologic actions and indications for active pharmaceutical ingredients approved by FDA and other regulatory agencies. Monitoring of regulatory agencies for new drugs approvals ensures the resource is up-to-date. DrugCentral integrates content for active ingredients with pharmaceutical formulations, indexing drugs and drug label annotations, complementing similar resources available online. Its complementarity with other online resources is facilitated by cross referencing to external resources. At the molecular level, DrugCentral bridges drug-target interactions with pharmacological action and indications. The integration with FDA drug labels enables text mining applications for drug adverse events and clinical trial information. Chemical structure overlap between DrugCentral and five online drug resources, and the overlap between DrugCentral FDA-approved drugs and their presence in four different chemical collections, are discussed. DrugCentral can be accessed via the web application or downloaded in relational database format. PMID:27789690

  5. Food and drug cues activate similar brain regions: a meta-analysis of functional MRI studies.

    PubMed

    Tang, D W; Fellows, L K; Small, D M; Dagher, A

    2012-06-06

    In healthy individuals, food cues can trigger hunger and feeding behavior. Likewise, smoking cues can trigger craving and relapse in smokers. Brain imaging studies report that structures involved in appetitive behaviors and reward, notably the insula, striatum, amygdala and orbital frontal cortex, tend to be activated by both visual food and smoking cues. Here, by carrying out a meta-analysis of human neuro-imaging studies, we investigate the neural network activated by: 1) food versus neutral cues (14 studies, 142 foci) 2) smoking versus neutral cues (15 studies, 176 foci) 3) smoking versus neutral cues when correlated with craving scores (7 studies, 108 foci). PubMed was used to identify cue-reactivity imaging studies that compared brain response to visual food or smoking cues to neutral cues. Fourteen articles were identified for the food meta-analysis and fifteen articles were identified for the smoking meta-analysis. Six articles were identified for the smoking cue correlated with craving analysis. Meta-analyses were carried out using activation likelihood estimation. Food cues were associated with increased blood oxygen level dependent (BOLD) response in the left amygdala, bilateral insula, bilateral orbital frontal cortex, and striatum. Smoking cues were associated with increased BOLD signal in the same areas, with the exception of the insula. However, the smoking meta-analysis of brain maps correlating cue-reactivity with subjective craving did identify the insula, suggesting that insula activation is only found when craving levels are high. The brain areas identified here are involved in learning, memory and motivation, and their cue-induced activity is an index of the incentive salience of the cues. Using meta-analytic techniques to combine a series of studies, we found that food and smoking cues activate comparable brain networks. There is significant overlap in brain regions responding to conditioned cues associated with natural and drug rewards.

  6. Low level laser therapy reduces inflammation in activated Achilles tendinitis

    NASA Astrophysics Data System (ADS)

    Bjordal, Jan M.; Iversen, Vegard; Lopes-Martins, Rodrigo Alvaro B.

    2006-02-01

    Objective: Low level laser therapy (LLLT) has been forwarded as therapy for osteoarthritis and tendinopathy. Results in animal and cell studies suggest that LLLT may act through a biological mechanism of inflammatory modulation. The current study was designed to investigate if LLLT has an anti-inflammatory effect on activated tendinitis of the Achilles tendon. Methods: Seven patients with bilateral Achilles tendonitis (14 tendons) who had aggravated symptoms by pain-inducing activity immediately prior to the study. LLLT (1.8 Joules for each of three points along the Achilles tendon with 904nm infrared laser) and placebo LLLT were administered to either Achilles tendons in a random order to which patients and therapist were blinded. Inflammation was examined by 1) mini-invasive microdialysis for measuring the concentration of inflammatory marker PGE II in the peritendinous tissue, 2) ultrasound with Doppler measurement of peri- and intratendinous blood flow, 3) pressure pain algometry and 4) single hop test. Results: PGE 2- levels were significantly reduced at 75, 90 and 105 minutes after active LLLT compared both to pre-treatment levels (p=0.026) and to placebo LLLT (p=0.009). Changes in pressure pain threshold (PPT) were significantly different (P=0.012) between groups. PPT increased by a mean value of 0.19 kg/cm2 [95%CI:0.04 to 0.34] after treatment in the active LLLT group, while pressure pain threshold was reduced by -0.20 kg/cm2 [95%CI:-0.45 to 0.05] after placebo LLLT. Conclusion: LLLT can be used to reduce inflammatory musculskeletal pain as it reduces inflammation and increases pressure pain threshold levels in activity-induced pain episodes of Achilles tendinopathy.

  7. Pharmaceutical penetration of new drug and pharmaceutical market structure in Taiwan: hospital-level prescription of thiazolidinediones for diabetes.

    PubMed

    Tsai, Yi-Wen; Wen, Yu-Wen; Huang, Weng-Foung; Kuo, Ken N; Chen, Pei-Fen; Shih, Hsin-Wei; Lee, Yue-Chune

    2010-06-01

    This study used Taiwan's National Health Insurance claim database (years 2000-2005) to examine how thiazolidinediones (TZD), a new class of drugs for diabetes, penetrated into Taiwan's hospitals, and its association with the concentration of all diabetes drugs at the hospital level. We collected 72 monthly summaries of diabetes prescriptions from all hospitals in Taiwan. Hospital-level pharmaceutical concentration was measured by penetration of TZD, defined as monthly market share of TZD in each hospital. Concentration of diabetes drugs was measured by Herfindahl-Hirschman indices. We found a negative association (coefficient = -0.3610) between TZD penetration and concentration of diabetes drug but a positive association between penetration of TZD and the volume of prescribed diabetes drugs (coefficient = 0.4088). In conclusion, hospital characteristics and volume of services determined the concentration of pharmaceuticals at the institution level, reflecting the heterogeneous competition between pharmaceutical companies within each hospital. Institution-level pharmaceutical concentration influences the adoption and penetration of new drugs.

  8. Iran’s Activities on Prevention, Treatment and Harm Reduction of Drug Abuse

    PubMed Central

    Saberi Zafarghandi, Mohammad Bagher; Jadidi, Mohsen; Khalili, Narjes

    2015-01-01

    Context: In the present review study, authors investigated Iran’s activities regarding prevention, abuse and harm reduction of drugs nationwide. The issue appears to be important in order to show the trend of activities in the country. Evidence Acquisition: In this report, authors gathered data from different Farsi/English peer review journals issued both in printed and online versions. These journals have been indexed in PubMed, ISI, ISC, SID, Magiran, UN, etc. These are among the most referred and cited databases. Results: Summarizing the data led to three distinguished sections: 1) drug supply reduction activities; 2) drug demand reduction activities; 3) harm reduction activities. Conclusions: As the results showed, the trend of activities was encouraging and some additional activities could be included to future programs relying on early-onset preventions. PMID:26870709

  9. Erectile Dysfunction Drugs Changed the Protein Expressions and Activities of Drug-Metabolising Enzymes in the Liver of Male Rats

    PubMed Central

    Hassan, Mostafa

    2016-01-01

    Erectile dysfunction (ED) is a major health problem and is mainly associated with the persistent inability of men to maintain sufficient erection for satisfactory sexual performance. Millions of men are using sildenafil, vardenafil, and/or tadalafil for ED treatment. Cytochrome P450s (CYPs) play a central role in the metabolism of a wide range of xenobiotics as well as endogenous compounds. Susceptibility of individuals to the adverse effects of different drugs is mainly dependent on the expression of CYPs proteins. Therefore, changes in activities of phase I drug-metabolising enzymes [arylhydrocarbon hydroxylase (AHH), dimethylnitrosamine N-demethylase (DMN-dI), 7-ethoxycoumarin-O-deethylase (ECOD), and ethoxyresorufin-O-deethylase ((EROD)] and the protein expression of different CYPs isozymes (CYP1A2, CYP2E1, CYP2B1/2, CYP3A4, CYP2C23, and CYP2C6) were determined after treatment of male rats with either low or high doses of sildenafil (Viagra), tadalafil (Cialis), and/or vardenafil (Levitra) for 3 weeks. The present study showed that low doses of tadalafil and vardenafil increased DMN-dI activity by 32 and 23%, respectively. On the other hand, high doses of tadalafil, vardenafil, and sildenafil decreased such activity by 50, 56, and 52%, respectively. In addition, low doses of tadalafil and vardenafil induced the protein expression of CYP2E1. On the other hand, high doses of either tadalafil or sildenafil were more potent inhibitors to CYP2E1 expression than vardenafil. Moreover, low doses of both vardenafil and sildenafil markedly increased AHH activity by 162 and 247%, respectively, whereas high doses of tadalafil, vardenafil, and sildenafil inhibited such activity by 36, 49, and 57% and inhibited the EROD activity by 39, 49, and 33%, respectively. Low and high doses of tadalafil, vardenafil, and sildenafil inhibited the activity of NADPH-cytochrome c reductase as well as its protein expression. In addition, such drugs inhibited the expression of CYP B1/2 along

  10. Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients.

    PubMed

    Arima, Hidetoshi; Motoyama, Keiichi; Higashi, Taishi

    2017-01-01

    Cyclodextrins (CyDs) are extensively used in various fields, and especially have been widely utilized as pharmaceutical excipients and drug carriers in the pharmaceutical field. Owing to the multi-functional and biocompatible characteristics, CyDs can improve the undesirable properties of drug molecules. This review outlines the current application of CyDs in pharmaceutical formulations, focusing on their use as CyD-based drug carriers for several kinds of drugs. Additionally, CyDs have great potential as active pharmaceutical ingredients against various diseases with few side effects.

  11. Cytostatic drugs are without significant effect on digitoxin plasma level and renal excretion.

    PubMed

    Kuhlmann, J; Wilke, J; Rietbrock, N

    1982-11-01

    In three patients with malignant lymphoma who received 0.5 mg digitoxin before and 24 hr after combination therapy with cyclophosphamide, Oncovin, procarbazine, and prednisone (COPP) or cyclophosphamide, Oncovin, and prednisone (COP), plasma glycoside concentrations and renal excretion were measured 0 to 168 hr after digitoxin and the areas under plasma concentration-time curves *(AUCs) were calculated. In 10 patients receiving 0.1 mg digitoxin, daily plasma glycoside concentration and daily renal excretion were measured before and after COPP, COP, or cyclophosphamide, Oncovin, cytosine-arabinoside, and prednisone (COAP) treatment schemes. In contrast to previous reports on digoxin, cytostatic drug therapy does not lead to a reduction in steady-state digitoxin plasma levels and daily renal excretion. During cytostatic therapy attainment of peak digitoxin level was delayed after a single dose, showing that the rate of digitoxin absorption was reduced, but that the AUCs and renal excretion of digitoxin (parameters of the extent of digitoxin absorption) were not diminished. Since the absorption rate is not clinically relevant in patients on long-term glycoside therapy, our results indicate that digitoxin is preferable to digoxin in such patients.

  12. Microgravity: a Teacher's Guide with Activities, Secondary Level

    NASA Technical Reports Server (NTRS)

    Vogt, Gregory L. (Editor); Wargo, Michael J. (Editor)

    1992-01-01

    This NASA Educational Publication is a teacher's guide that focuses on microgravity for the secondary level student. The introduction answers the question 'What is microgravity?', as well as describing gravity and creating microgravity. Following the introduction is a microgravity primer which covers such topics as the fluid state, combustion science, materials science, biotechnology, as well as microgravity and space flight. Seven different activities are described in the activities section and are written by authors prominent in the field. The concluding sections of the book include a glossary, microgravity references, and NASA educational resources.

  13. Effect of Learning Activity on Students' Motivation, Physical Activity Levels and Effort/Persistence

    ERIC Educational Resources Information Center

    Gao, Zan; Lee, Amelia M.; Xiang, Ping; Kosma, Maria

    2011-01-01

    The type of learning activity offered in physical education may influence students' motivational beliefs, physical activity participation and effort/persistence in class. However, most empirical studies have focused on the individual level rather than on the learner-content interactions. Accordingly, the potential effects of learning activities on…

  14. Opiate-induced Changes in Brain Adenosine Levels and Narcotic Drug Responses

    PubMed Central

    Wu, Manhong; Sahbaie, Peyman; Zheng, Ming; Lobato, Robert; Boison, Detlev; Clark, J. David; Peltz, Gary

    2012-01-01

    We have very little information about the metabolomic changes that mediate neurobehavioral responses, including addiction. It was possible that opioid-induced metabolomic changes in brain could mediate some of the pharmacodynamic effects of opioids. To investigate this, opiate-induced brain metabolomic responses were profiled using a semi-targeted method in C57BL/6 and 129Sv1 mice, which exhibit extreme differences in their tendency to become opiate dependent. Escalating morphine doses (10–40 mg/kg) administered over a 4-day period selectively induced a two-fold decrease (p<0.00005) in adenosine abundance in the brainstem of C57BL/6 mice, which exhibited symptoms of narcotic drug dependence; but did not decrease adenosine abundance in 129Sv1 mice, which do not exhibit symptoms of dependence. Based on this finding, the effect of adenosine on dependence was investigated in genetically engineered mice with alterations in adenosine tone in the brain and in pharmacologic experiments. Morphine withdrawal behaviors were significantly diminished (P<0.0004) in genetically engineered mice with reduced adenosine tone in the brainstem, and by treatment with an adenosine receptor1 (A1) agonist (2-chloro-N6-cyclopentyladenosine, 0.5 mg/kg) or an A2a receptor (A2a) antagonist (SCH 58261 1 mg/kg). These results indicate that adenosine homeostasis plays a crucial role in narcotic drug responses. Opiate-induced changes in brain adenosine levels may explain many important neurobehavioral features associated with opiate addiction and withdrawal. PMID:23098802

  15. High levels of pre-treatment HIV drug resistance and treatment failure in Nigerian children

    PubMed Central

    Boerma, Ragna S; Boender, T Sonia; Sigaloff, Kim C.E.; Rinke de Wit, Tobias F; van Hensbroek, Michael Boele; Ndembi, Nicaise; Adeyemo, Titilope; Temiye, Edamisan O; Osibogun, Akin; Ondoa, Pascale; Calis, Job C; Akanmu, Alani Sulaimon

    2016-01-01

    Introduction Pre-treatment HIV drug resistance (PDR) is an increasing problem in sub-Saharan Africa. Children are an especially vulnerable population to develop PDR given that paediatric second-line treatment options are limited. Although monitoring of PDR is important, data on the paediatric prevalence in sub-Saharan Africa and its consequences for treatment outcomes are scarce. We designed a prospective paediatric cohort study to document the prevalence of PDR and its effect on subsequent treatment failure in Nigeria, the country with the second highest number of HIV-infected children in the world. Methods HIV-1-infected children ≤12 years, who had not been exposed to drugs for the prevention of mother-to-child transmission (PMTCT), were enrolled between 2012 and 2013, and followed up for 24 months in Lagos, Nigeria. Pre-antiretroviral treatment (ART) population-based pol genotypic testing and six-monthly viral load (VL) testing were performed. Logistic regression analysis was used to assess the effect of PDR (World Health Organization (WHO) list for transmitted drug resistance) on subsequent treatment failure (two consecutive VL measurements >1000 cps/ml or death). Results Of the total 82 PMTCT-naïve children, 13 (15.9%) had PDR. All 13 children harboured non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations, of whom seven also had nucleoside reverse transcriptase inhibitor resistance. After 24 months, 33% had experienced treatment failure. Treatment failure was associated with PDR and a higher log VL before treatment initiation (adjusted odds ratio (aOR) 7.53 (95%CI 1.61–35.15) and 2.85 (95%CI 1.04–7.78), respectively). Discussion PDR was present in one out of six Nigerian children. These high numbers corroborate with recent findings in other African countries. The presence of PDR was relevant as it was the strongest predictor of first-line treatment failure. Conclusions Our findings stress the importance of implementing fully active regimens

  16. Scopolamine-induced convulsions in fasted mice after food intake: effects of glucose intake, antimuscarinic activity and anticonvulsant drugs.

    PubMed

    Enginar, Nurhan; Nurten, Asiye; Celik, Pinar Yamantürk; Açikmeşe, Bariş

    2005-09-01

    The present study was performed to further evaluate the contribution of antimuscarinic activity and hypoglycaemia to the development of scopolamine-induced convulsions in fasted mice after food intake. The effects of anticonvulsant drugs on convulsions were also evaluated. Antimuscarinic drugs atropine (3 mg/kg) and biperiden (10 mg/kg) were given intraperitoneally (i.p) to animals fasted for 48 h. Like scopolamine, both drugs induced convulsions after animals were allowed to eat ad libitum. Another group of animals was given glucose (5%) in drinking water during fasting. These animals, although they had normoglycaemic blood levels after fasting, also developed convulsions after treated with scopolamine i.p. (3 mg/kg), atropine (3 mg/kg) or biperiden (10 mg/kg) and allowed to eat ad libitum. Among the drugs studied, only valproate (340 mg/kg), gabapentin (50 mg/kg) and diazepam (2.5 and 5 mg/kg) markedly reduced the incidence of scopolamine-induced convulsions. The present results indicate that antimuscarinic activity, but not hypoglycaemia, underlies these convulsions which do not respond to most of the conventional anticonvulsant drugs.

  17. 78 FR 3900 - Generic Drug User Fee-Active Pharmaceutical Ingredient and Finished Dosage Form Facility Fee...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-01-17

    ... HUMAN SERVICES Food and Drug Administration Generic Drug User Fee--Active Pharmaceutical Ingredient and... drug active pharmaceutical ingredient (API) and finished dosage form (FDF) facilities user fees for... applications in the backlog as of October 1, 2012, on finished dosage form (FDF) and active...

  18. Let's Get AHEAD (Health-Education-Alcohol & Drug). Activities K-6.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Div. of Program Development.

    This book of activities for use with elementary school students lists 10 salient points in each of three areas: health education, alcohol education, and drug education. Suggested activities are then described for students in kindergarten through third grade and for students in fourth through six grades. Activities are suggested in 10 categories:…

  19. Let's Get AHEAD (Health-Education-Alcohol & Drug). Activities 7-12.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Div. of Program Development.

    This book of activities for use with secondary school students lists 10 salient points in each of three areas: health education, alcohol education, and drug education. Suggested activities are then described for students in grades 7 and 8 and for students in grades 9 through 12. Activities are suggested in 10 categories: (1) human growth and…

  20. Adapting Judicial Supervision to the Risk Level of Drug Offenders: Discharge and 6-month Outcomes from a Prospective Matching Study

    PubMed Central

    Marlowe, Douglas B.; Festinger, David S.; Dugosh, Karen L.; Lee, Patricia A.; Benasutti, Kathleen M.

    2007-01-01

    This article reports recent findings from a program of experimental research examining the effects of adapting judicial supervision to the risk level of drug-abusing offenders. Prior studies revealed that high-risk participants with (1) antisocial personality disorder or (2) a history of drug abuse treatment performed significantly better in drug court when they were scheduled to attend frequent, bi-weekly judicial status hearings in court. Low-risk participants performed equivalently regardless of the schedule of court hearings. The current study prospectively matched misdemeanor drug court clients to the optimal schedule of court hearings based upon an assessment of their risk status, and compared outcomes to those of clients randomly assigned to the standard schedule of court hearings. Results confirmed that high-risk participants graduated at a higher rate, provided more drug-negative urine specimens at 6 months post-admission, and reported significantly less drug use and alcohol intoxication at 6 months post-admission when they were matched to bi-weekly hearings as compared to the usual schedule of hearings. These findings yield practical information for enhancing the efficacy and cost-efficiency of drug court services. Directions for future research on adaptive programming for drug offenders are discussed. PMID:17071020

  1. Adapting judicial supervision to the risk level of drug offenders: discharge and 6-month outcomes from a prospective matching study.

    PubMed

    Marlowe, Douglas B; Festinger, David S; Dugosh, Karen L; Lee, Patricia A; Benasutti, Kathleen M

    2007-05-01

    This article reports recent findings from a program of experimental research examining the effects of adapting judicial supervision to the risk level of drug-abusing offenders. Prior studies revealed that high-risk participants with (1) antisocial personality disorder or (2) a history of drug abuse treatment performed significantly better in drug court when they were scheduled to attend frequent, bi-weekly judicial status hearings in court. Low-risk participants performed equivalently regardless of the schedule of court hearings. The current study prospectively matched misdemeanor drug court clients to the optimal schedule of court hearings based upon an assessment of their risk status, and compared outcomes to those of clients randomly assigned to the standard schedule of court hearings. Results confirmed that high-risk participants graduated at a higher rate, provided more drug-negative urine specimens at 6 months post-admission, and reported significantly less drug use and alcohol intoxication at 6 months post-admission when they were matched to bi-weekly hearings as compared to the usual schedule of hearings. These findings yield practical information for enhancing the efficacy and cost-efficiency of drug court services. Directions for future research on adaptive programming for drug offenders are discussed.

  2. Cadmium effect on microsomal drug-metabolizing enzyme activity in rat livers with respect to differences in age and sex

    SciTech Connect

    Ando, M.

    1982-04-01

    The effect of cadmium on the hepatic microsomal drug-metabolizing enzyme system was investigated. Cadmium chloride caused the conversion of cytochrome P-450 to P-420 in rat liver microsomes. The destruction of cytochrome P-450 by cadmium caused the reduction of microsomal drug-metabolizing enzyme activity and prolonged the pentobarbital sleeping time. There is a sex-related difference in the ability of cadmium to inhibit the hepatic drug metabolism in rats: male rats are more sensitive to cadmium than females. The effective period when cadmium prolonged their sleep depended upon the age of rats; older rats were more sensitive to cadmium than younger ones. The maximum increase of sleeping time depended upon the dose level of cadium, and the rate constant of the equations seems to depend upon the age of the animals.

  3. Chemotherapy pro-drug activation by biocatalytic virus-like nanoparticles containing cytochrome P450.

    PubMed

    Sánchez-Sánchez, Lorena; Cadena-Nava, Rubén D; Palomares, Laura A; Ruiz-Garcia, Jaime; Koay, Melissa S T; Cornelissen, Jeroen J M T; Vazquez-Duhalt, Rafael

    2014-06-10

    This work shows, for the first time, the encapsulation of a highly relevant protein in the biomedical field into virus-like particles (VLPs). A bacterial CYP variant was effectively encapsulated in VLPs constituted of coat protein from cowpea chlorotic mottle virus (CCMV). The catalytic VLPs are able to transform the chemotherapeutic pro-drug, tamoxifen, and the emerging pro-drug resveratrol. The chemical nature of the products was identified, confirming similar active products than those obtained with human CYP. The enzymatic VLPs remain stable after the catalytic reaction. The potential use of these biocatalytic nanoparticles as targeted CYP carriers for the activation of chemotherapy drugs is discussed.

  4. Effect of selected anti-malarial drugs on the blood chemistry and brain serotonin levels in male rabbits.

    PubMed

    Eigbibhalu, Ukpo Grace; Albert Taiwo, Ebuehi Osaretin; Douglass, Idiakheua Akhabue; Abimbola, Efunogbon Aderonke

    2013-01-01

    The effects of oral administration of sulfadoxine - pyrimethamine (SP), artesunate (A) and sulfadoxine - pyrimethamine - artesunate (SPA) on blood chemistry and brain serotonin in rabbits were investigated. Forty rabbits were divided into four groups of ten animals each. The group that served as the control received 2ml of distilled water while the other groups were received 1.25/25mg base/kg body weight of SP, 3.3mg/kg body weight of A and 1.25/25mg base/kg body weight of SP plus 3.3mg/kg body weight of A respectively by oral route daily for 3 days in a week for four weeks. At the end of each week of drug administration, three rabbits from each group were anaesthetized, blood was taken from the jugular veins using sterile needle and serum was extracted. The rabbits were sacrificed by decapitation; the liver and brain tissues were excised and homogenized. Total blood protein, cholesterol, triglyceride, albumin, creatinine and urea concentrations, creatine kinase, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, ALP activities were assayed using CX5 synchron autoanalyzer. The brain and liver serotonin levels were determined using high performance liquid chromatography (HPLC). There were no significant differences (P < 0.05) in the concentrations of serum albumin, urea, creatinine, cholesterol and triglyceride of rabbits administered SP, A and SPA for 4 weeks, except in serum total protein. No significant differences existed in the activities of AST, ALT and ALP, except in creatine kinase which was elevated in the control. The brain serotonin levels of rabbits administered SP, A and SPA were significantly higher as compared to the control throughout the duration of the study Data of the study indicate that oral administration of SP, A or SPA in rabbits do not affect blood chemistry, but affected brain serotonin levels and could alter some neural functions.

  5. Secular trends in storm-level geomagnetic activity

    USGS Publications Warehouse

    Love, J.J.

    2011-01-01

    Analysis is made of K-index data from groups of ground-based geomagnetic observatories in Germany, Britain, and Australia, 1868.0-2009.0, solar cycles 11-23. Methods include nonparametric measures of trends and statistical significance used by the hydrological and climatological research communities. Among the three observatory groups, German K data systematically record the highest disturbance levels, followed by the British and, then, the Australian data. Signals consistently seen in K data from all three observatory groups can be reasonably interpreted as physically meaninginful: (1) geomagnetic activity has generally increased over the past 141 years. However, the detailed secular evolution of geomagnetic activity is not well characterized by either a linear trend nor, even, a monotonic trend. Therefore, simple, phenomenological extrapolations of past trends in solar and geomagnetic activity levels are unlikely to be useful for making quantitative predictions of future trends lasting longer than a solar cycle or so. (2) The well-known tendency for magnetic storms to occur during the declining phase of a sunspot-solar cycles is clearly seen for cycles 14-23; it is not, however, clearly seen for cycles 11-13. Therefore, in addition to an increase in geomagnetic activity, the nature of solar-terrestrial interaction has also apparently changed over the past 141 years. ?? Author(s) 2011.

  6. Associations between personality traits, physical activity level, and muscle strength.

    PubMed

    Tolea, Magdalena I; Terracciano, Antonio; Simonsick, Eleanor M; Metter, E Jeffrey; Costa, Paul T; Ferrucci, Luigi

    2012-06-01

    Associations among personality as measured by the Five Factor Model, physical activity, and muscle strength were assessed using data from the Baltimore Longitudinal Study of Aging (N = 1220, age: mean = 58, SD = 16). General linear modeling with adjustment for age, sex, race, and body mass index, and bootstrapping for mediation were used. We found neuroticism and most of its facets to negatively correlate with strength. The extraversion domain and its facets of warmth, activity, and positive-emotions were positively correlated with strength, independent of covariates. Mediation analysis results suggest that these associations are partly explained by physical activity level. Findings extend the evidence of an association between personality and physical function to its strength component and indicate health behavior as an important pathway.

  7. Age, gender, and level of activity as moderators of personal incentives to physical activity in Israel.

    PubMed

    Raviv, Shulamith; Netz, Yael

    2007-05-01

    The authors conducted an exploratory study with Israeli adults examining their personal incentives for physical activity (e.g., appearance, weight management). The participants formed a sample of 379 physically active Israelis, aged 20-89 years, divided into 3 age groups and 3 levels of activity. The authors found a similar profile for men and women for most incentives, with men scoring more highly than did women on only competition and fitness. Participants in the highest level of activity attributed greater importance to all incentives than did those in the other levels, and older adults attributed less importance to all incentives except for health benefits. The findings are relevant for planning activities intended to encourage adults to engage in more physical activity.

  8. Enhanced Histone Deacetylase Activity in Malignant Melanoma Provokes RAD51 and FANCD2-Triggered Drug Resistance.

    PubMed

    Krumm, Andrea; Barckhausen, Christina; Kücük, Pelin; Tomaszowski, Karl-Heinz; Loquai, Carmen; Fahrer, Jörg; Krämer, Oliver Holger; Kaina, Bernd; Roos, Wynand Paul

    2016-05-15

    DNA-damaging anticancer drugs remain a part of metastatic melanoma therapy. Epigenetic reprogramming caused by increased histone deacetylase (HDAC) activity arising during tumor formation may contribute to resistance of melanomas to the alkylating drugs temozolomide, dacarbazine, and fotemustine. Here, we report on the impact of class I HDACs on the response of malignant melanoma cells treated with alkylating agents. The data show that malignant melanomas in situ contain a high level of HDAC1/2 and malignant melanoma cells overexpress HDAC1/2/3 compared with noncancer cells. Furthermore, pharmacologic inhibition of class I HDACs sensitizes malignant melanoma cells to apoptosis following exposure to alkylating agents, while not affecting primary melanocytes. Inhibition of HDAC1/2/3 caused sensitization of melanoma cells to temozolomide in vitro and in melanoma xenografts in vivo HDAC1/2/3 inhibition resulted in suppression of DNA double-strand break (DSB) repair by homologous recombination because of downregulation of RAD51 and FANCD2. This sensitized cells to the cytotoxic DNA lesion O(6)-methylguanine and caused a synthetic lethal interaction with the PARP-1 inhibitor olaparib. Furthermore, knockdown experiments identified HDAC2 as being responsible for the regulation of RAD51. The influence of class I HDACs on DSB repair by homologous recombination and the possible clinical implication on malignant melanoma therapy with temozolomide and other alkylating drugs suggests a combination approach where class I HDAC inhibitors such as valproic acid or MS-275 (entinostat) appear to counteract HDAC- and RAD51/FANCD2-mediated melanoma cell resistance. Cancer Res; 76(10); 3067-77. ©2016 AACR.

  9. KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction

    PubMed Central

    Padula, Audrey E; Griffin, William C; Lopez, Marcelo F; Nimitvilai, Sudarat; Cannady, Reginald; McGuier, Natalie S; Chesler, Elissa J; Miles, Michael F; Williams, Robert W; Randall, Patrick K; Woodward, John J; Becker, Howard C; Mulholland, Patrick J

    2015-01-01

    Small-conductance Ca2+-activated K+ (KCa2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode KCa2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the KCa2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of KCa2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. KCa2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction. PMID:25662840

  10. KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction.

    PubMed

    Padula, Audrey E; Griffin, William C; Lopez, Marcelo F; Nimitvilai, Sudarat; Cannady, Reginald; McGuier, Natalie S; Chesler, Elissa J; Miles, Michael F; Williams, Robert W; Randall, Patrick K; Woodward, John J; Becker, Howard C; Mulholland, Patrick J

    2015-07-01

    Small-conductance Ca(2+)-activated K(+) (KCa2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode KCa2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the KCa2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of KCa2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. KCa2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.

  11. Effect of membrane filtration of antimalarial drug solutions on in vitro activity against Plasmodium falciparum*

    PubMed Central

    Baird, J. K.; Lambros, C.

    1984-01-01

    Antimalarial activities of chloroquine, mefloquine, amodiaquine, and quinine in vitro against Plasmodium falciparum were diminished as a consequence of membrane filtration. Filtered drug solutions gave ID50 values up to 25-fold greater than those of non-filtered (ethanol-sterilized) drug solutions. Loss of activity by filtration was overcome by increasing the drug concentration prior to filtration. Water solutions filtered through Millex-GS filter units consistently showed an absorbance maximum at 277 nm, accompanied by a lesser peak at 225 nm. Water filtrates from Nucleopore and Millex-GV filters showed no absorbance at 277 nm and only slight absorbance was evident for the Gelman filter unit. Activity losses were attributed to extractable contaminating moieties in the membrane filters and/or drug binding to the membrane filters. PMID:6380786

  12. Psychoactive-drug response is affected by acute low-level microwave irradiation

    SciTech Connect

    Lai, H.; Horita, A.; Chou, C.K.; Guy, A.W.

    1983-01-01

    The effects of various psychoactive drugs were studied in rats exposed for 45 min in a circularly polarized, pulsed microwave field (2450 MHz; SAR 0.6 W/kg; 2-microseconds pulses, 500 pps). Apomorphine-induced hypothermia and stereotypy were enhanced by irradiation. Amphetamine-induced hyperthermia was attenuated while stereotypy was unaffected. Morphine-induced catalepsy and lethality were enhanced by irradiation at certain dosages of the drug. Since these drugs have different modes of action on central neural mechanisms and the effects of microwaves depend on the particular drug studied, these results show the complex nature of the effect of microwave irradiation on brain functions.

  13. Teratogenic potential of almokalant, dofetilide, and d-sotalol: drugs with potassium channel blocking activity.

    PubMed

    Webster, W S; Brown-Woodman, P D; Snow, M D; Danielsson, B R

    1996-03-01

    Drugs with class III antiarrhythmic activity are potential human teratogens because of their ability to cause bradycardia in the embryo during the organogenic period. Three drugs with class III antiarrhythmic activity, almokalant, dofetilide and d-sotalol, were compared in vitro using rat embryo culture. Each of these drugs caused a concentration-dependent bradycardia in 11- or 13-day rat embryos. For each drug the effective concentration was considerably greater than the human therapeutic plasma concentration. The reproductive outcome was also compared in vivo in Sprague-Dawley rats by oral administration of almokalant or dofetilide on single days during the organogenic period. Both drugs caused increased resorptions and the same stage-dependent malformations. Dosing on gestational day (GD) 11 was associated with right-sided oblique cleft lip and short tail, while dosing on day 13 caused digital hypoplasia and/or amputation. Susceptibility to these drugs started on GD 9 when the embryonic heart starts beating and ended on GD 15. The malformations were preceded by hemorrhage; which is consistent with the proposed pathogenesis that the drug-induced bradycardia caused embryonic hypoxia/ischemia. This study indicates that the induction of malformations/embryonic death by class III antiarrhythmic drugs which inhibit Ikr is a class effect secondary to a common pharmacological action on the embryonic heart.

  14. System-level effects of integrating a promising treatment into juvenile drug courts.

    PubMed

    McCart, Michael R; Henggeler, Scott W; Chapman, Jason E; Cunningham, Phillippe B

    2012-09-01

    This study examined the system-level effects of implementing a promising treatment for adolescent substance abuse in juvenile drug courts (JDCs). Six JDCs were randomized to receive training in the experimental intervention (contingency management-family engagement [CM-FAM]) or to continue their usual services (US). Participants were 104 families served by the courts, 51 therapists, and 74 JDC stakeholders (e.g., judges, prosecutors, defense attorneys). Assessments included repeated measurements of CM-FAM implementation by therapists and therapist and stakeholder perceptions of incentive-based interventions and organizational characteristics. Results revealed greater use of CM and family engagement techniques among CM-FAM relative to US therapists. In addition, therapists and stakeholders in the CM-FAM condition reported more favorable attitudes toward the use of incentives and greater improvement on several domains of organizational functioning relative to US counterparts. Taken together, these findings suggest that JDC professionals are amenable to the adoption and implementation of a treatment model that holds promise for improving youth outcomes.

  15. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells

    PubMed Central

    Neviani, Paolo; Harb, Jason G.; Oaks, Joshua J.; Santhanam, Ramasamy; Walker, Christopher J.; Ellis, Justin J.; Ferenchak, Gregory; Dorrance, Adrienne M.; Paisie, Carolyn A.; Eiring, Anna M.; Ma, Yihui; Mao, Hsiaoyin C.; Zhang, Bin; Wunderlich, Mark; May, Philippa C.; Sun, Chaode; Saddoughi, Sahar A.; Bielawski, Jacek; Blum, William; Klisovic, Rebecca B.; Solt, Janelle A.; Byrd, John C.; Volinia, Stefano; Cortes, Jorge; Huettner, Claudia S.; Koschmieder, Steffen; Holyoake, Tessa L.; Devine, Steven; Caligiuri, Michael A.; Croce, Carlo M.; Garzon, Ramiro; Ogretmen, Besim; Arlinghaus, Ralph B.; Chen, Ching-Shih; Bittman, Robert; Hokland, Peter; Roy, Denis-Claude; Milojkovic, Dragana; Apperley, Jane; Goldman, John M.; Reid, Alistair; Mulloy, James C.; Bhatia, Ravi; Marcucci, Guido; Perrotti, Danilo

    2013-01-01

    The success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML) depends on the requirement for BCR-ABL1 kinase activity in CML progenitors. However, CML quiescent HSCs are TKI resistant and represent a BCR-ABL1 kinase–independent disease reservoir. Here we have shown that persistence of leukemic HSCs in BM requires inhibition of the tumor suppressor protein phosphatase 2A (PP2A) and expression — but not activity — of the BCR-ABL1 oncogene. Examination of HSCs from CML patients and healthy individuals revealed that PP2A activity was suppressed in CML compared with normal HSCs. TKI-resistant CML quiescent HSCs showed increased levels of BCR-ABL1, but very low kinase activity. BCR-ABL1 expression, but not kinase function, was required for recruitment of JAK2, activation of a JAK2/β-catenin survival/self-renewal pathway, and inhibition of PP2A. PP2A-activating drugs (PADs) markedly reduced survival and self-renewal of CML quiescent HSCs, but not normal quiescent HSCs, through BCR-ABL1 kinase–independent and PP2A-mediated inhibition of JAK2 and β-catenin. This led to suppression of human leukemic, but not normal, HSC/progenitor survival in BM xenografts and interference with long-term maintenance of BCR-ABL1–positive HSCs in serial transplantation assays. Targeting the JAK2/PP2A/β-catenin network in quiescent HSCs with PADs (e.g., FTY720) has the potential to treat TKI-refractory CML and relieve lifelong patient dependence on TKIs. PMID:23999433

  16. Electrocortical activity distinguishes between uphill and level walking in humans.

    PubMed

    Bradford, J Cortney; Lukos, Jamie R; Ferris, Daniel P

    2016-02-01

    The objective of this study was to determine if electrocortical activity is different between walking on an incline compared with level surface. Subjects walked on a treadmill at 0% and 15% grades for 30 min while we recorded electroencephalography (EEG). We used independent component (IC) analysis to parse EEG signals into maximally independent sources and then computed dipole estimations for each IC. We clustered cortical source ICs and analyzed event-related spectral perturbations synchronized to gait events. Theta power fluctuated across the gait cycle for both conditions, but was greater during incline walking in the anterior cingulate, sensorimotor and posterior parietal clusters. We found greater gamma power during level walking in the left sensorimotor and anterior cingulate clusters. We also found distinct alpha and beta fluctuations, depending on the phase of the gait cycle for the left and right sensorimotor cortices, indicating cortical lateralization for both walking conditions. We validated the results by isolating movement artifact. We found that the frequency activation patterns of the artifact were different than the actual EEG data, providing evidence that the differences between walking conditions were cortically driven rather than a residual artifact of the experiment. These findings suggest that the locomotor pattern adjustments necessary to walk on an incline compared with level surface may require supraspinal input, especially from the left sensorimotor cortex, anterior cingulate, and posterior parietal areas. These results are a promising step toward the use of EEG as a feed-forward control signal for ambulatory brain-computer interface technologies.

  17. Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates.

    PubMed

    Dey, Diganta; Ray, Ratnamala; Hazra, Banasri

    2014-07-01

    Multi-drug resistant Mycobacterium tuberculosis and other bacterial pathogens represent a major threat to human health. In view of the critical need to augment the current drug regime, we have investigated therapeutic potential of five quinonoids, viz. emodin, diospyrin, plumbagin, menadione and thymoquinone, derived from natural products. The antimicrobial activity of quinonoids was evaluated against a broad panel of multi-drug and extensively drug-resistant tuberculosis (M/XDR-TB) strains, rapid growing mycobacteria and other bacterial isolates, some of which were producers of β-lactamase, Extended-spectrum β-lactamase (ESBL), AmpC β-lactamase, metallo-beta-lactamase (MBL) enzymes, as well as their drug-sensitive ATCC counterparts. All the tested quinones exhibited antimycobacterial and broad spectrum antibacterial activity, particularly against M. tuberculosis (lowest MIC 0.25 µg/mL) and Gram-positive bacteria (lowest MIC <4 µg/mL) of clinical origin. The order of antitubercular activity of the tested quinonoids was plumbagin > emodin ~ menadione ~ thymoquinone > diospyrin, whereas their antibacterial efficacy was plumbagin > menadione ~ thymoquinone > diospyrin > emodin. Furthermore, this is the first evaluation performed on these quinonoids against a broad panel of drug-resistant and drug-sensitive clinical isolates, to the best of our knowledge.

  18. Lack of effect of antipsychotic and antidepressant drugs on glutamate receptor mRNA levels in rat brains.

    PubMed

    Oretti, R G; Spurlock, G; Buckland, P R; McGuffin, P

    1994-08-15

    By employing multiprobe oligonucleotide solution hybridisation (MOSH) we have measured the levels of mRNA encoding the NMDA receptor subtypes (R1, R2A, R2B and R2C) and the non-NMDA glutamate receptor subtypes (GluR1, 2, 3, and 4) within rat brain following, 1-32 days of antipsychotic or antidepressant drug administration. The results suggest that the drugs studied do not significantly alter rat glutamatergic system mRNA levels when compared to controls.

  19. Cortisol and ACTH levels in drug-naive adolescents with first-episode early onset schizophrenia.

    PubMed

    Şimşek, Şeref; Gençoğlan, Salih; Yüksel, Tuğba; Aktaş, Hüseyin

    2017-03-01

    The aim of this study was to investigate serum levels of cortisol and adrenocorticotropic hormone in adolescents with first-episode early onset schizophrenia. A total of 23 adolescent patients, who did not receive prior therapy and who were diagnosed with psychosis according to DSM-IV, were included. Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version, Positive and Negative Symptom Scale, and Clinical Global Impression Scale were conducted with the participants. No significant differences were found between the patients and the control subjects in serum cortisol and adrenocorticotropic hormone levels (P > .05). Our study's findings do not support the hypothesis of increased hypothalamic-pituitary-adrenal axis activity in first-episode early onset schizophrenia.

  20. Effects of concurrent drug therapy and of feeding on plasma chloramphenicol levels after oral administration of chloramphenicol in dogs.

    PubMed

    Watson, A D

    1977-01-01

    On separate occasions, five fasted adult greyhounds were dosed orally with 50 mg chloramphenicol/kg, both alone and in conjunction with other drugs. The same five dogs were later given 50 mg chloramphenicol/kg when fed ad lib. Chloramphenicol levels in plasma were determined at intervals after dosing. The intial plasma chloramphenicol levels were higher when the drug was administered concurrently with calcium lactate tablets (50 mg/kg) or a proprietary enteric mixture containing kaolin, pectin, aluminium hydroxide and belladonna extract. Lower plasma levels resulted when the antibiotic was given with dry extract of belladonna (20 mg/dog) or intravenous chlorpromazine (2 mg/kg). There was no significant effect with coated ferrous gluconate tablets (30 mg/kg). Feeding ad lib increased the initial chloramphenicol levels, but produced lower levels subsequently.

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

    PubMed

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

    2015-07-09

    In order to recycle and dispose of all people's expired drugs, the government should design a subsidy policy to stimulate users to return their expired drugs, and drug-stores should take the responsibility of recycling expired drugs, in other words, to be recycling stations. For this purpose it is necessary for the government to select the right recycling stations and treatment stations to optimize the expired drug recycling logistics network and minimize the total costs of recycling and disposal. This paper establishes a tri-level programming model to study how the government can optimize an expired drug recycling logistics network and the appropriate subsidy policies. Furthermore, a Hybrid Genetic Simulated Annealing Algorithm (HGSAA) is proposed to search for the optimal solution of the model. An experiment is discussed to illustrate the good quality of the recycling logistics network and government subsides obtained by the HGSAA. The HGSAA is proven to have the ability to converge on the global optimal solution, and to act as an effective algorithm for solving the optimization problem of expired drug recycling logistics network and government subsidies.

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

    PubMed Central

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

    2015-01-01

    In order to recycle and dispose of all people’s expired drugs, the government should design a subsidy policy to stimulate users to return their expired drugs, and drug-stores should take the responsibility of recycling expired drugs, in other words, to be recycling stations. For this purpose it is necessary for the government to select the right recycling stations and treatment stations to optimize the expired drug recycling logistics network and minimize the total costs of recycling and disposal. This paper establishes a tri-level programming model to study how the government can optimize an expired drug recycling logistics network and the appropriate subsidy policies. Furthermore, a Hybrid Genetic Simulated Annealing Algorithm (HGSAA) is proposed to search for the optimal solution of the model. An experiment is discussed to illustrate the good quality of the recycling logistics network and government subsides obtained by the HGSAA. The HGSAA is proven to have the ability to converge on the global optimal solution, and to act as an effective algorithm for solving the optimization problem of expired drug recycling logistics network and government subsidies. PMID:26184252

  3. Molecular Mechanisms of Antiseizure Drug Activity at GABAA Receptors

    PubMed Central

    Greenfield, L. John

    2013-01-01

    The GABAA receptor (GABAAR) is a major target of antiseizure drugs (ASDs). A variety of agents that act at GABAARs s are used to terminate or prevent seizures. Many act at distinct receptor sites determined by the subunit composition of the holoreceptor. For the benzodiazepines, barbiturates, and loreclezole, actions at the GABAAR are the primary or only known mechanism of antiseizure action. For topiramate, felbamate, retigabine, losigamone and stiripentol, GABAAR modulation is one of several possible antiseizure mechanisms. Allopregnanolone, a progesterone metabolite that enhances GABAAR function, led to the development of ganaxolone. Other agents modulate GABAergic “tone” by regulating the synthesis, transport or breakdown of GABA. GABAAR efficacy is also affected by the transmembrane chloride gradient, which changes during development and in chronic epilepsy. This may provide an additional target for “GABAergic” ASDs. GABAAR subunit changes occur both acutely during status epilepticus and in chronic epilepsy, which alter both intrinsic GABAAR function and the response to GABAAR-acting ASDs. Manipulation of subunit expression patterns or novel ASDs targeting the altered receptors may provide a novel approach for seizure prevention. PMID:23683707

  4. The Relationship between Housing Status and HIV Risk among Active Drug Users: A Qualitative Analysis

    PubMed Central

    Dickson-Gomez, Julia; Hilario, Helena; Convey, Mark; Corbett, A. Michelle; Weeks, Margaret; Martinez, Maria

    2009-01-01

    This paper examines the relationship between housing status and HIV risk using longitudinal, qualitative data collected in 2004-2005, from a purposeful sample of 65 active drug users in a variety of housed and homeless situations in Hartford, Connecticut. These data were supplemented with observations and in-depth interviews regarding drug use behavior collected in 2001-2005 to evaluate a peer-led HIV prevention intervention. Data reveal differences in social context within and among different housing statuses that affect HIV risky or protective behaviors including the ability to carry drug paraphernalia and HIV prevention materials, the amount of drugs in the immediate environment, access to subsidized and supportive housing, and relationships with others with whom drug users live. Policy implications of the findings, limitations to the data and future research are discussed. PMID:19142817

  5. Detecting Drug Interactions From Adverse-Event Reports: Interaction Between Paroxetine and Pravastatin Increases Blood Glucose Levels

    PubMed Central

    Tatonetti, NP; Denny, JC; Murphy, SN; Fernald, GH; Krishnan, G; Castro, V; Yue, P; Tsau, PS; Kohane, I; Roden, DM; Altman, RB

    2011-01-01

    The lipid-lowering agent pravastatin and the antidepressant paroxetine are among the most widely prescribed drugs in the world. Unexpected interactions between them could have important public health implications. We mined the US Food and Drug Administration’s (FDA’s) Adverse Event Reporting System (AERS) for side-effect profiles involving glucose homeostasis and found a surprisingly strong signal for comedication with pravastatin and paroxetine. We retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received comedication with these two drugs, using data in electronic medical record (EMR) systems of three geographically distinct sites. We assessed the mean random blood glucose levels before and after treatment with the drugs. We found that pravastatin and paroxetine, when administered together, had a synergistic effect on blood glucose. The average increase was 19 mg/dl (1.0 mmol/l) overall, and in those with diabetes it was 48 mg/dl (2.7 mmol/l). In contrast, neither drug administered singly was associated with such changes in glucose levels. An increase in glucose levels is not a general effect of combined therapy with selective serotonin reuptake inhibitors (SSRIs) and statins. PMID:21613990

  6. Considerations about the structure—activity relationships of 8-aminoquinoline antimalarial drugs

    PubMed Central

    McChesney, James D.

    1981-01-01

    A discussion of the structure-activity relationships (SAR) of 8-aminoquinoline antimalarial drugs is presented. Consideration is given to the potential role of metabolic transformations in the in vivo activation of 8-aminoquinolines. It is emphasized that the mechanism of action of 8-aminoquinoline agents has not yet been established and thus any analysis of SAR must be speculative. PMID:6976853

  7. Guardians to Counter Adolescent Drug Use?: Limitations of a Routine Activities Approach

    ERIC Educational Resources Information Center

    Bratt, Christopher

    2008-01-01

    Based on suggestions made by routine activities theory and data from two surveys, the present study discusses the use of adult guardians as a means to counter drug use among adolescents who seek out unsupervised routine activities with peers. Two surveys with 13- to 15-year-olds were conducted 4 years apart in a Norwegian town (Ns = 1,455 and…

  8. Guanfacine effects on stress, drug craving and prefrontal activation in cocaine dependent individuals: preliminary findings

    PubMed Central

    Fox, Helen C.; Seo, Dongju; Tuit, Keri; Hansen, Julie; Kimmerling, Anne; Morgan, Peter T.; Sinha, Rajita

    2013-01-01

    Cocaine dependence is associated with increased stress and drug cue-induced craving and physiological arousal but decreased prefrontal activity to emotional and cognitive challenge. As these changes are associated with relapse risk, we investigated the effects of α2 receptor agonist guanfacine on these processes. Twenty-nine early abstinent treatment-seeking cocaine dependent individuals were randomly assigned to either daily placebo or guanfacine (up to 3 mg) for four weeks. In a laboratory experiment, all patients were exposed to three 10-min guided imagery conditions (stress/stress, drug cue/drug cue, stress/drug cue), one per day, consecutively in a random, counterbalanced order. Subjective craving, anxiety and arousal as well as cardiovascular output were assessed repeatedly. Brain response to stress, drug cue and relaxing imagery was also assessed during a functional magnetic resonance (fMRI) imaging session. In the current study, guanfacine was found to be safe and well-tolerated. Lower basal heart rate and blood pressure was observed in the guanfacine versus placebo group. Guanfacine lowered stress and cue-induced nicotine craving and cue-induced cocaine craving, anxiety and arousal. The guanfacine group also showed increased medial and lateral prefrontal activity following stress and drug cue exposure compared with placebo. Data suggest further exploration of guanfacine is warranted in terms of its potential for reducing stress-induced and cue-induced drug craving and arousal. PMID:22234929

  9. Regulatory mechanisms of cAMP levels as a multiple target for antiplatelet activity and less bleeding risk.

    PubMed

    Fuentes, Eduardo; Palomo, Iván

    2014-08-01

    Platelet activation is a critical component of atherothrombosis. The multiple pathways of platelet activation limit the effect of specific receptor/pathway inhibitors, resulting in limited clinical efficacy. Recent research has confirmed that combination therapy results in enhanced antithrombotic efficacy without increasing bleeding risk. In this way, the best-known inhibitor and turn off signaling in platelet activation is cAMP. In this article we discuss the mechanisms of regulation of intraplatelet cAMP levels, a) platelet-dependent pathway: Gi/Gs protein-coupled receptors, phosphodiesterase inhibition and activation of PPARs and b) platelet-independent pathway: inhibition of adenosine uptake by erythrocytes. With respect to the association between intraplatelet cAMP levels and bleeding risk it is possible to establish that compounds/drugs with pleitropic effect for increased intraplatelet cAMP level could have an antithrombotic activity with less risk of bleeding.

  10. Mediating role of activity level in the depressive realism effect.

    PubMed

    Blanco, Fernando; Matute, Helena; A Vadillo, Miguel

    2012-01-01

    Several classic studies have concluded that the accuracy of identifying uncontrollable situations depends heavily on depressive mood. Nondepressed participants tend to exhibit an optimistic illusion of control, whereas depressed participants tend to better detect a lack of control. Recently, we suggested that the different activity levels (measured as the probability of responding during a contingency learning task) exhibited by depressed and nondepressed individuals is partly responsible for this effect. The two studies presented in this paper provide further support for this mediational hypothesis, in which mood is the distal cause of the illusion of control operating through activity level, the proximal cause. In Study 1, the probability of responding, P(R), was found to be a mediator variable between the depressive symptoms and the judgments of control. In Study 2, we intervened directly on the mediator variable: The P(R) for both depressed and nondepressed participants was manipulated through instructions. Our results confirm that P(R) manipulation produced differences in the participants' perceptions of uncontrollability. Importantly, the intervention on the mediator variable cancelled the effect of the distal cause; the participants' judgments of control were no longer mood dependent when the P(R) was manipulated. This result supports the hypothesis that the so-called depressive realism effect is actually mediated by the probability of responding.

  11. Identification of Levothyroxine Antichagasic Activity through Computer-Aided Drug Repurposing

    PubMed Central

    Bellera, Carolina L.; Balcazar, Darío E.; Alberca, Lucas; Labriola, Carlos A.; Carrillo, Carolina

    2014-01-01

    Cruzipain (Cz) is the major cysteine protease of the protozoan Trypanosoma cruzi, etiological agent of Chagas disease. A conformation-independent classifier capable of identifying Cz inhibitors was derived from a 163-compound dataset and later applied in a virtual screening campaign on the DrugBank database, which compiles FDA-approved and investigational drugs. 54 approved drugs were selected as candidates, 3 of which were acquired and tested on Cz and T. cruzi epimastigotes proliferation. Among them, levothyroxine, traditionally used in hormone replacement therapy in patients with hypothyroidism, showed dose-dependent inhibition of Cz and antiproliferative activity on the parasite. PMID:24592161

  12. Laser-activated nano-biomaterials for tissue repair and controlled drug release

    SciTech Connect

    Matteini, P; Ratto, F; Rossi, F; Pini, R

    2014-07-31

    We present recent achievements of minimally invasive welding of biological tissue and controlled drug release based on laser-activated nano-biomaterials. In particular, we consider new advancements in the biomedical application of near-IR absorbing gold nano-chromophores as an original solution for the photothermal repair of surgical incisions and as nanotriggers of controlled drug release from hybrid biopolymer scaffolds. (laser biophotonics)

  13. Activity profile of high-level Australian lacrosse players.

    PubMed

    Polley, Chris S; Cormack, Stuart J; Gabbett, Tim J; Polglaze, Ted

    2015-01-01

    Despite lacrosse being one of the fastest growing team sports in the world, there is a paucity of information detailing the activity profile of high-level players. Microtechnology systems (global positioning systems and accelerometers) provide the opportunity to obtain detailed information on the activity profile in lacrosse. Therefore, this study aimed to analyze the activity profile of lacrosse match-play using microtechnology. Activity profile variables assessed relative to minutes of playing time included relative distance (meter per minute), distance spent standing (0-0.1 m·min), walking (0.2-1.7 m·min), jogging (1.8-3.2 m·min), running (3.3-5.6 m·min), sprinting (≥5.7 m·min), number of high, moderate, low accelerations and decelerations, and player load (PL per minute), calculated as the square root of the sum of the squared instantaneous rate of change in acceleration in 3 vectors (medio-lateral, anterior-posterior, and vertical). Activity was recorded from 14 lacrosse players over 4 matches during a national tournament. Players were separated into positions of attack, midfield, or defense. Differences (effect size [ES] ± 90% confidence interval) between positions and periods of play were considered likely positive when there was ≥75% likelihood of the difference exceeding an ES threshold of 0.2. Midfielders had likely covered higher (mean ± SD) meters per minute (100 ± 11) compared with attackers (87 ± 14; ES = 0.89 ± 1.04) and defenders (79 ± 14; ES = 1.54 ± 0.94) and more moderate and high accelerations and decelerations. Almost all variables across positions were reduced in quarter 4 compared with quarter 1. Coaches should accommodate for positional differences when preparing lacrosse players for competition.

  14. Anti-viral drug treatment along with immune activator IL-2: a control-based mathematical approach for HIV infection

    NASA Astrophysics Data System (ADS)

    Nath Chatterjee, Amar; Roy, Priti Kumar

    2012-02-01

    Recent development in antiretroviral treatment against HIV can help AIDS patients to fight against HIV. But the question that whether the disease is to be partially or totally eradicated from HIV infected individuals still remains unsolved. Usually, the most effective treatment for the disease is HAART which can only control the disease progression. But as the immune system becomes weak, the patients can not fight against other diseases. Immune cells are activated and proliferated by IL-2 after the identification of antigen. IL-2 production is impaired in HIV positive patients and intermitted administration of immune activator IL-2 together with HAART which is a more effective treatment to fight against the disease. Thus, its expediency is essential and is yet to be explored. In this article we anticipated a mathematical model of the effect of IL-2 together with RTIs therapy in HIV positive patients. Our analytical as well as numerical study shows that the optimal schedule of treatment for best result is to be obtained by systematic drug therapy. But at the last stage of treatment, the infection level raises again due to minimisation of drug dosage. Thus we study the perfect adherence of the drugs and found out if RTIs are taken with sufficient interval then for fixed interval of IL-2 therapy, certain amount of drug dosages may be able to sustain the immune system at pre-infection stage and the infected CD4+T cells are going towards extinction.

  15. Plantar pressures during level walking compared with other ambulatory activities.

    PubMed

    Lundeen, S; Lundquist, K; Cornwall, M W; McPoil, T G

    1994-06-01

    This study was designed to determine the magnitude of plantar pressures during level walking in comparison to other activities. These activities included climbing up stairs, going down stairs, a simple pivot while walking, and a crossover pivot while walking in normal individuals. Twelve volunteers, six men and six women, mean age 28 years, served as subjects. Data were collected on the dominant foot with an EMED-SF pressure sensor platform as each subject walked barefoot and did each of the five activities. Maximum plantar pressure (MPP) and pressure-time integral (PTI) was found in the metatarsal and heel regions. The results of repeated-measures analysis of variance tests showed that the five experimental conditions were statistically different for both MPP and PTI in the metatarsal and heel regions. Post hoc analysis indicated that MPP and PTI were decreased during the going down stairs condition in the heel and increased during the crossover pivot while walking and pivot while walking conditions for the metatarsal region.

  16. Active and Passive Immunization Protects against Lethal, Extreme Drug Resistant-Acinetobacter baumannii Infection

    PubMed Central

    Luo, Guanpingshen; Lin, Lin; Ibrahim, Ashraf S.; Baquir, Beverlie; Pantapalangkoor, Paul; Bonomo, Robert A.; Doi, Yohei; Adams, Mark D.; Russo, Thomas A.; Spellberg, Brad

    2012-01-01

    Extreme-drug-resistant (XDR) Acinetobacter baumannii is a rapidly emerging pathogen causing infections with unacceptably high mortality rates due to inadequate available treatment. New methods to prevent and treat such infections are a critical unmet medical need. To conduct a rational vaccine discovery program, OmpA was identified as the primary target of humoral immune response after intravenous infection by A. baumannii in mice. OmpA was >99% conserved at the amino acid level across clinical isolates harvested between 1951 and 2009 from cerebrospinal fluid, blood, lung, and wound infections, including carbapenem-resistant isolates, and was ≥89% conserved among other sequenced strains, but had minimal homology to the human proteome. Vaccination of diabetic mice with recombinant OmpA (rOmpA) with aluminum hydroxide adjuvant markedly improved survival and reduced tissue bacterial burden in mice infected intravenously. Vaccination induced high titers of anti-OmpA antibodies, the levels of which correlated with survival in mice. Passive transfer with immune sera recapitulated protection. Immune sera did not enhance complement-mediated killing but did enhance opsonophagocytic killing of A. baumannii. These results define active and passive immunization strategies to prevent and treat highly lethal, XDR A. baumannii infections. PMID:22253723

  17. Impurities contained in antifungal drug ketoconazole are potent activators of human aryl hydrocarbon receptor.

    PubMed

    Grycová, Aneta; Dořičáková, Aneta; Dvořák, Zdeněk

    2015-12-03

    Antifungal drug ketoconazole is a mixture of (+)/(-) cis-enantiomers, which also contains several impurities. Ketoconazole was identified as an activator of aryl hydrocarbon receptor AhR by three independent research teams. In the current paper we demonstrate that impurities contained in ketoconazole preparations are strong activators of human AhR and inducers of CYP1A1. Impurity IMP-C had similar potency (EC50), but 10-15 times higher efficacy (magnitude of induction) towards AhR, comparing to (+)-ketoconazole, as revealed by gene reporter assay in AZ-AHR stably transfected cells. Impurities IMP-B and IMP-C, and in lesser extent IMP-E, induced a formation of AhR-DNA complex, as demonstrated by electromobility shift assay EMSA. Impurities IMP-C and IMP-E dose-dependently induced CYP1A1 mRNA after 24 h, and their effects were comparable to those by (+)-ketoconazole. The level of CYP1A1 protein in HepG2 cells was strongly increased by IMP-C after 48h. In conclusion, our data further elucidated molecular effects of ketoconazole towards AhR signaling pathway, with possible implications in ketoconazole role in skin chemoprevention and/or damage, involving AhR.

  18. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library.

    PubMed

    Feng, Jie; Wang, Ting; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

    2014-07-01

    Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients.

  19. Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library

    PubMed Central

    Feng, Jie; Wang, Ting; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

    2014-01-01

    Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA)-approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients. PMID:26038747

  20. The Effect of Gender and Level of Vision on the Physical Activity Level of Children and Adolescents with Visual Impairment

    ERIC Educational Resources Information Center

    Aslan, Ummuhan Bas; Calik, Bilge Basakci; Kitis, Ali

    2012-01-01

    This study was planned in order to determine physical activity levels of visually impaired children and adolescents and to investigate the effect of gender and level of vision on physical activity level in visually impaired children and adolescents. A total of 30 visually impaired children and adolescents (16 low vision and 14 blind) aged between…

  1. Infrared spectroscopic studies to understand the effect of drugs at molecular level

    NASA Astrophysics Data System (ADS)

    Singh, Bhawana; Gautam, Rekha; Chandrasekar, Bhagawat; Rakshit, Srabanti; Kumar B. N., Vinay; Boopathy, Sivaraman; Nandi, Dipankar; Somasundaram, Kumaravel; Umapathy, Siva

    2012-06-01

    In the recent past, there have been enormous efforts to understand effect of drugs on human body. Prior to understand the effect of drugs on human body most of the experiments are carried out on cells or model organisms. Here we present our study on the effect of chemotherapeutic drugs on cancer cells and the acetaminophen (APAP) induced hepatotoxicity in mouse model. Histone deacetylase inhibitors (HDIs) have attracted attention as potential drug molecules for the treatment of cancer. These are the chemotherapeutic drugs which have indirect mechanistic action against cancer cells via acting against histone deacetylases (HDAC). It has been known that different HDAC enzymes are over-expressed in various types of cancers for example; HDAC1 is over expressed in prostate, gastric and breast carcinomas. Therefore, in order to optimise chemotherapy, it is important to determine the efficacy of various classes of HDAC inhibitor drugs against variety of over-expressed HDAC enzymes. In the present study, FTIR microspectroscopy has been employed to predict the acetylation and propionylation brought in by HDIs. The liver plays an important role in cellular metabolism and is highly susceptible to drug toxicity. APAP which is an analgesic and antipyretic drug is extensively used for therapeutic purposes and has become the most common cause of acute liver failure (ALF). In the current study, we have focused to understand APAP induced hepatotoxicity using FTIR microspectroscopy. In the IR spectrum the bands corresponding to glycogen, ester group and were found to be suitable markers to predict liver injury at early time point (0.5hr) due to APAP both in tissue and serum in comparison to standard biochemical assays. Our studies show the potential of FTIR spectroscopy as a rapid, sensitive and non invasive detection technique for future clinical diagnosis.

  2. A quantitative reverse-transcriptase PCR assay for the assessment of drug activities against intracellular Theileria annulata schizonts

    PubMed Central

    Hostettler, Isabel; Müller, Joachim; Stephens, Chad E.; Haynes, Richard; Hemphill, Andrew

    2014-01-01

    Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leucocytes thereby causing fatal immunoproliferative diseases. Buparvaquone, a hydroxynaphthoquinone related to parvaquone, is the only drug available against Theileria. The drug is only effective at the onset of infection and emerging resistance underlines the need for identifying alternative compounds. Current drug assays employ monitoring of proliferation of infected cells, with apoptosis of the infected host cell as a read-out, but it is often unclear whether active compounds directly impair the viability of the parasite or primarily induce host cell death. We here report on the development of a quantitative reverse transcriptase real time PCR method based on two Theileria genes, tasp and tap104, which are both expressed in schizonts. Upon in vitro treatment of T. annulata infected bovine monocytes with buparvaquone, TaSP and Tap104 mRNA expression levels significantly decreased in relation to host cell actin already within 4 h of drug exposure, while significant differences in host cell proliferation were detectable only after 48–72 h. TEM revealed marked alterations of the schizont ultrastructure already after 2 h of buparvaquone treatment, while the host cell remained unaffected. Expression of TaSP and Tap104 proteins showed a marked decrease only after 24 h. Therefore, the analysis of expression levels of mRNA coding for TaSP and Tap104 allows to directly measuring impairment of parasite viability. We subsequently applied this method using a series of compounds affecting different targets in other apicomplexan parasites, and show that monitoring of TaSP- and Tap104 mRNA levels constitutes a suitable tool for anti-theilerial drug development. PMID:25516828

  3. A quantitative reverse-transcriptase PCR assay for the assessment of drug activities against intracellular Theileria annulata schizonts.

    PubMed

    Hostettler, Isabel; Müller, Joachim; Stephens, Chad E; Haynes, Richard; Hemphill, Andrew

    2014-12-01

    Intracellular schizonts of the apicomplexans Theileria annulata and Theileria parva immortalize bovine leucocytes thereby causing fatal immunoproliferative diseases. Buparvaquone, a hydroxynaphthoquinone related to parvaquone, is the only drug available against Theileria. The drug is only effective at the onset of infection and emerging resistance underlines the need for identifying alternative compounds. Current drug assays employ monitoring of proliferation of infected cells, with apoptosis of the infected host cell as a read-out, but it is often unclear whether active compounds directly impair the viability of the parasite or primarily induce host cell death. We here report on the development of a quantitative reverse transcriptase real time PCR method based on two Theileria genes, tasp and tap104, which are both expressed in schizonts. Upon in vitro treatment of T. annulata infected bovine monocytes with buparvaquone, TaSP and Tap104 mRNA expression levels significantly decreased in relation to host cell actin already within 4 h of drug exposure, while significant differences in host cell proliferation were detectable only after 48-72 h. TEM revealed marked alterations of the schizont ultrastructure already after 2 h of buparvaquone treatment, while the host cell remained unaffected. Expression of TaSP and Tap104 proteins showed a marked decrease only after 24 h. Therefore, the analysis of expression levels of mRNA coding for TaSP and Tap104 allows to directly measuring impairment of parasite viability. We subsequently applied this method using a series of compounds affecting different targets in other apicomplexan parasites, and show that monitoring of TaSP- and Tap104 mRNA levels constitutes a suitable tool for anti-theilerial drug development.

  4. Effects of Chronic Active Cannabis Use on Visuomotor Integration, in Relation to Brain Activation and Cortisol Levels

    PubMed Central

    King, G.R.; Ernst, T.; Deng, W.; Stenger, A.; Gonzales, R.M.K; Nakama, H.; Chang, L.

    2012-01-01

    Cannabis is the most abused illegal substance in the United States. Alterations in brain function and motor behavior have been reported in chronic cannabis users, but the results have been variable. The current study aimed to determine whether chronic active cannabis use in humans may alter psychomotor function, brain activation, and hypothalamic-pituitary-axis (HPA) function in men and women. 30 cannabis users (16 men and 14 women, 18 to 45 years old) and 30 non-drug user controls (16 men and 14 women, 19 to 44 years old) were evaluated with neuropsychological tests designed to assess motor behavior and functional MRI (fMRI), using a 3 Tesla scanner, during a visually paced finger-sequencing task, cued by a flashing checkerboard (at 2 or 4 Hz). Salivary cortisol was measured to assess HPA function. Male, but not female, cannabis users had significantly slower performance on psychomotor speed tests. As a group, cannabis users had greater activation in BA 6 than controls, while controls had greater activation in the visual area BA 17 than cannabis users. Cannabis users also had higher salivary cortisol levels than controls (p = 0.002). Chronic active cannabis use is associated with slower and less efficient psychomotor function, especially in the male users, as indicated by a shift from regions involved with automated visually guided responses to more executive or attentional control areas. These brain activities may be attenuated by the higher cortisol levels in the cannabis users which in turn may lead to less efficient visual-motor function. PMID:22159107

  5. Solubility Enhancement of a Poorly Water Soluble Drug by Forming Solid Dispersions using Mechanochemical Activation

    PubMed Central

    Rojas-Oviedo, I.; Retchkiman-Corona, B.; Quirino-Barreda, C. T.; Cárdenas, J.; Schabes-Retchkiman, P. S.

    2012-01-01

    Mechanochemical activation is a practical cogrinding operation used to obtain a solid dispersion of a poorly water soluble drug through changes in the solid state molecular aggregation of drug-carrier mixtures and the formation of noncovalent interactions (hydrogen bonds) between two crystalline solids such as a soluble carrier, lactose, and a poorly soluble drug, indomethacin, in order to improve its solubility and dissolution rate. Samples of indomethacin and a physical mixture with a weight ratio of 1:1 of indomethacin and lactose were ground using a high speed vibrating ball mill. Particle size was determined by electron microscopy, the reduction of crystallinity was determined by calorimetry and transmission electron microscopy, infrared spectroscopy was used to find evidence of any interactions between the drug and the carrier and the determination of apparent solubility allowed for the corroboration of changes in solubility. Before grinding, scanning electron microscopy showed the drug and lactose to have an average particle size of around 50 and 30 μm, respectively. After high speed grinding, indomethacin and the mixture had a reduced average particle size of around 5 and 2 μm, respectively, showing a morphological change. The ground mixture produced a solid dispersion that had a loss of crystallinity that reached 81% after 30 min of grinding while the drug solubility of indomethacin within the solid dispersion increased by 2.76 fold as compared to the pure drug. Drug activation due to hydrogen bonds between the carboxylic group of the drug and the hydroxyl group of lactose as well as the decrease in crystallinity of the solid dispersion and the reduction of the particle size led to a better water solubility of indomethacin. PMID:23798775

  6. AMP-activated protein kinase: a target for drugs both ancient and modern.

    PubMed

    Hardie, D Grahame; Ross, Fiona A; Hawley, Simon A

    2012-10-26

    The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is activated, by a mechanism requiring the tumor suppressor LKB1, by metabolic stresses that increase cellular ADP:ATP and/or AMP:ATP ratios. Once activated, it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and cell-cycle progress. These effects suggest that AMPK activators might be useful for treatment and/or prevention of type 2 diabetes and cancer. Indeed, AMPK is activated by the drugs metformin and salicylate, the latter being the major breakdown product of aspirin. Metformin is widely used to treat diabetes, while there is epidemiological evidence that both metformin and aspirin provide protection against cancer. We review the mechanisms of AMPK activation by these and other drugs, and by natural products derived from traditional herbal medicines.

  7. Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole.

    PubMed Central

    Iuliano, L.; Colavita, A. R.; Camastra, C.; Bello, V.; Quintarelli, C.; Alessandroni, M.; Piovella, F.; Violi, F.

    1996-01-01

    1. The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Natural and synthetic antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Synthetic antioxidants are currently being tested, by they are not necessarily safe for human use. 2. We have previously reported that dipyridamole, currently used in clinical practice, is a potent scavenger of free radicals. Thus, we tested whether dipyridamole could affect LDL oxidation at chemical and cellular level. 3. Chemically induced LDL oxidation was made by Cu(II), Cu(II) plus hydrogen peroxide or peroxyl radicals generated by thermolysis of 2,2'-azo-bis(2-amidino propane). Dipyridamole, (1-10 microM), inhibited LDL oxidation as monitored by diene formation, evolution of hydroperoxides and thiobarbituric acid reactive substances, apoprotein modification and by the fluorescence of cis-parinaric acid. 4. The physiological relevance of the antioxidant activity was validated by experiments at the cellular level where dipyridamole inhibited endothelial cell-mediated LDL oxidation, their degradation by monocytes, and cytotoxicity. 5. In comparison with ascorbic acid, alpha-tocopherol and probucol, dipyridamole was the more efficient antioxidant with the following order of activity: dipyridamole > probucol > ascorbic acid > alpha-tocopherol. The present study shows that dipyridamole inhibits oxidation of LDL at pharmacologically relevant concentrations. The inhibition of LDL oxidation is unequivocally confirmed by use of three different methods of chemical oxidation, by several methods of oxidation monitoring, and the pharmacological relevance is demonstrated by the superiority of dipyridamole over the naturally occurring antioxidants, ascorbic acid and alpha-tocopherol and the synthetic antioxidant probucol. Images Figure 6 PMID:8968553

  8. Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery.

    PubMed

    Bond, Richard A; Ijzerman, Ad P

    2006-02-01

    The concept of constitutively active G-protein-coupled receptors is now firmly rooted in receptor pharmacology. Many independent research groups have contributed to its acceptance since its introduction by Costa and Herz in 1989. This concept necessitated a revised ligand classification, and a new category of inverse agonists was introduced alongside existing agonist and antagonist ligands. Initially, it was hoped that new therapeutic modalities would become available. However, the drug industry has not adopted inverse agonism as a design criterion and instead accepted that some compounds emerge as (neutral) antagonists in compound screening, whereas other compounds possess inverse agonistic activity. In this article, we summarize aspects of the impact of constitutive activity on the drug-discovery process: for example, its use in orphan receptor assays, its link with pharmacogenetics and genomics, and its relevance for currently marketed drugs.

  9. From multiply active natural product to candidate drug? Antibacterial (and other) minor groove binders for DNA.

    PubMed

    Suckling, Colin

    2012-05-01

    Natural products that bind to DNA in the minor groove are valuable templates for drug design. Examples include distamycin, netropsin, duocarmycin and anthramycin. Anticancer and anti-infective drugs feature strongly amongst their derivatives. The structures and activities of chemotypes with various therapeutic actions are discussed in the context of the broader field of therapeutically active minor groove binders. The evolution of a series of exceptionally potent and nontoxic antibacterial compounds is discussed using the general design principle of introducing additional hydrophobicity into the distamycin template to increase the strength of binding to DNA. As well as potent antibacterial compounds, antifungal and antiparasitic compounds with exceptional cellular activity against trypanosomes have been identified. Possible mechanisms of action including gene regulation and topoisomerase inhibition are discussed with the need in mind to understand selective toxicity in the series to support future drug discovery.

  10. Activity of various drugs alone or in combination against Mycobacterium fortuitum.

    PubMed

    Santos, A; Cremades, R; Rodríguez, J C; Garcia-Pachon, E; Ruiz, M; Royo, G

    2010-02-01

    Interest in Mycobacterium fortuitum has increased since it was recognized as an emergent pathogen. The objective of this study was to screen a large number of drug combinations in order to evaluate the activity of classical and new potentially useful antibiotics against M. fortuitum. Twenty M. fortuitum clinical isolates were studied with 51 combinations of two drugs and 47 combinations of three drugs belonging to different families: fluoroquinolones, linezolid, macrolides, rifamycins, aminoglycosides, and carbapenems. Activity was determined in Mueller Hinton broth by seeing whether the cultures were negative after 4 days of incubation with the combination of antibiotics. The most active drugs were moxifloxacin and gatifloxacin, which were active against 15 of the 20 strains studied, followed by amikacin (14 of the 20). The combinations of gatifloxacin with rifampicin or rifabutin, moxifloxacin with rifampicin or amikacin, and ciprofloxacin with amikacin were the most useful against M. fortuitum, as they showed activity in 18 of the 20 strains studied. Linezolid, imipenem, and ertapenem showed poor activity in this experimental model when they were used on their own. Larger studies, both in vitro and in vivo, should be done to confirm the true usefulness of the new fluoroquinolones, alone or in combination, in the treatment of M. fortuitum.

  11. Idaho Senior Center Activities, Activity Participation Level, and Managers' Perceptions of Activity Success.

    ERIC Educational Resources Information Center

    Girvan, James T.; Harris, Frances

    A survey completed by managers of 77 senior centers in Idaho revealed that meals, blood pressure screening, and games and trips were the most successful activities offered. Alzheimer's support groups, library books for loan, and exercise classes were the least successful. Possible reasons for the success or failure of these activities were…

  12. Fitting Transporter Activities to Cellular Drug Concentrations and Fluxes: Why the Bumblebee Can Fly

    PubMed Central

    Mendes, Pedro; Oliver, Stephen G.; Kell, Douglas B.

    2015-01-01

    A recent paper in this journal argued that reported expression levels, kcat and Km for drug transporters could be used to estimate the likelihood that drug fluxes through Caco-2 cells could be accounted for solely by protein transporters. It was in fact concluded that if five such transporters contributed ‘randomly’ they could account for the flux of the most permeable drug tested (verapamil) 35% of the time. However, the values of permeability cited for verapamil were unusually high; this and other drugs have much lower permeabilities. Even for the claimed permeabilities, we found that a single ‘random’ transporter could account for the flux 42% of the time, and that two transporters can achieve 10 · 10−6 cm·s−1 90% of the time. Parameter optimisation methods show that even a single transporter can account for Caco-2 drug uptake of the most permeable drug. Overall, the proposal that ‘phospholipid bilayer diffusion (of drugs) is negligible’ is not disproved by the calculations of ‘likely’ transporter-based fluxes. PMID:26538313

  13. Activation of Bicyclic Nitro-drugs by a Novel Nitroreductase (NTR2) in Leishmania

    PubMed Central

    Patterson, Stephen; Read, Kevin D.

    2016-01-01

    Drug discovery pipelines for the “neglected diseases” are now heavily populated with nitroheterocyclic compounds. Recently, the bicyclic nitro-compounds (R)-PA-824, DNDI-VL-2098 and delamanid have been identified as potential candidates for the treatment of visceral leishmaniasis. Using a combination of quantitative proteomics and whole genome sequencing of susceptible and drug-resistant parasites we identified a putative NAD(P)H oxidase as the activating nitroreductase (NTR2). Whole genome sequencing revealed that deletion of a single cytosine in the gene for NTR2 that is likely to result in the expression of a non-functional truncated protein. Susceptibility of leishmania was restored by reintroduction of the wild-type gene into the resistant line, which was accompanied by the ability to metabolise these compounds. Overexpression of NTR2 in wild-type parasites rendered cells hyper-sensitive to bicyclic nitro-compounds, but only marginally to the monocyclic nitro-drugs, nifurtimox and fexinidazole sulfone, known to be activated by a mitochondrial oxygen-insensitive nitroreductase (NTR1). Conversely, a double knockout NTR2 null cell line was completely resistant to bicyclic nitro-compounds and only marginally resistant to nifurtimox. Sensitivity was fully restored on expression of NTR2 in the null background. Thus, NTR2 is necessary and sufficient for activation of these bicyclic nitro-drugs. Recombinant NTR2 was capable of reducing bicyclic nitro-compounds in the same rank order as drug sensitivity in vitro. These findings may aid the future development of better, novel anti-leishmanial drugs. Moreover, the discovery of anti-leishmanial nitro-drugs with independent modes of activation and independent mechanisms of resistance alleviates many of the concerns over the continued development of these compound series. PMID:27812217

  14. Alarming Levels of Drug-Resistant Tuberculosis in HIV-Infected Patients in Metropolitan Mumbai, India

    PubMed Central

    Isaakidis, Petros; Das, Mrinalini; Kumar, Ajay M V; Peskett, Christopher; Khetarpal, Minni; Bamne, Arun; Adsul, Balkrishna; Manglani, Mamta; Sachdeva, Kuldeep Singh; Parmar, Malik; Kanchar, Avinash; Rewari, B.B.; Deshpande, Alaka; Rodrigues, Camilla; Shetty, Anjali; Rebello, Lorraine; Saranchuk, Peter

    2014-01-01

    Background Drug-resistant tuberculosis (DR-TB) is a looming threat to tuberculosis control in India. However, no countrywide prevalence data are available. The burden of DR-TB in HIV-co-infected patients is likewise unknown. Undiagnosed and untreated DR-TB among HIV-infected patients is a major cause of mortality and morbidity. We aimed to assess the prevalence of DR-TB (defined as resistance to any anti-TB drug) in patients attending public antiretroviral treatment (ART) centers in greater metropolitan Mumbai, India. Methods A cross-sectional survey was conducted among adults and children ART-center attendees. Smear microscopy, culture and drug-susceptibility-testing (DST) against all first and second-line TB-drugs using phenotypic liquid culture (MGIT) were conducted on all presumptive tuberculosis patients. Analyses were performed to determine DR-TB prevalence and resistance patterns separately for new and previously treated, culture-positive TB-cases. Results Between March 2013 and January 2014, ART-center attendees were screened during 14135 visits, of whom 1724 had presumptive TB. Of 1724 attendees, 72 (4%) were smear-positive and 202 (12%) had a positive culture for Mycobacterium tuberculosis. Overall DR-TB was diagnosed in 68 (34%, 95% CI: 27%–40%) TB-patients. The proportions of DR-TB were 25% (29/114) and 44% (39/88) among new and previously treated cases respectively. The patterns of DR-TB were: 21% mono-resistant, 12% poly-resistant, 38% multidrug-resistant (MDR-TB), 21% pre-extensively-drug-resistant (MDR-TB plus resistance to either a fluoroquinolone or second-line injectable), 6% extensively drug-resistant (XDR-TB) and 2% extremely drug-resistant TB (XDR-TB plus resistance to any group-IV/V drug). Only previous history of TB was significantly associated with the diagnosis of DR-TB in multivariate models. Conclusion The burden of DR-TB among HIV-infected patients attending public ART-centers in Mumbai was alarmingly high, likely representing ongoing

  15. Intentional Medication Non-Adherence Due to Interactive Toxicity Beliefs among HIV Positive Active Drug Users

    PubMed Central

    Kalichman, Seth C.; Kalichman, Moira O.; Cherry, Charsey; Hoyt, Ginger; Washington, Christopher; Grebler, Tamar; Merely, Cindy; Welles, Brandi

    2015-01-01

    Drug use poses significant challenges to medical management of HIV infection. While most research has focused on the influence of intoxication on unintentional adherence to HIV treatment, drug use may also lead to intentional non-adherence, particularly when individuals believe that mixing medications with drugs is harmful. This study examined whether interactive toxicity beliefs predict non-adherence to antiretroviral therapy (ART) over a prospective period of adherence monitoring. Men and women living with HIV who screened positive for drug use and were being treated with ART (N=530) completed computerized self-interviews, three prospective unannounced pill counts to measure ART adherence, provided urine specimens for drug screening, and HIV viral load results from medical records. Results showed that 189 (35%) participants indicated that they intentionally miss their ART when they are using drugs. These participants also reported common beliefs regarding the perceived hazards of mixing HIV medications with alcohol and other drugs. Multivariable models that controlled for demographic and health characteristics, as well as frequency of alcohol use, showed that intentional non-adherence predicted poorer ART adherence over the prospective month and also predicted poorer treatment outcomes as indexed by unsuppressed HIV viral load. These findings extend previous research to show that interactive toxicity beliefs and intentional non-adherence play a significant role in medication non-adherence for a substantial number of people living with HIV and should be actively addressed in HIV clinical care. PMID:26226250

  16. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library

    PubMed Central

    Feng, Jie; Weitner, Megan; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Zhang, Ying

    2015-01-01

    Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and

  17. Inhibition of the enzymatic activity of heme oxygenases by azole-based antifungal drugs.

    PubMed

    Kinobe, Robert T; Dercho, Ryan A; Vlahakis, Jason Z; Brien, James F; Szarek, Walter A; Nakatsu, Kanji

    2006-10-01

    Ketoconazole (KTZ) and other azole antifungal agents are known to have a variety of actions beyond the inhibition of sterol synthesis in fungi. These drugs share structural features with a series of novel heme oxygenase (HO) inhibitors designed in our laboratory. Accordingly, we hypothesized that therapeutically used azole-based antifungal drugs are effective HO inhibitors. Using gas chromatography to quantify carbon monoxide formation in vitro and in vivo, we have shown that azole-containing antifungal drugs are potent HO inhibitors. Terconazole, sulconazole, and KTZ were the most potent drugs with IC(50) values of 0.41 +/- 0.01, 1.1 +/- 0.4, and 0.3 +/- 0.1 microM for rat spleen microsomal HO activity, respectively. Kinetic characterization revealed that KTZ was a noncompetitive HO inhibitor. In the presence of KTZ (2.5 and 10 microM), K(m) values for both rat spleen and brain microsomal HO were not altered; however, a significant decrease in the catalytic capacity (V(max)) was observed (P < 0.005). KTZ was also found to weakly inhibit nitric-oxide synthase with an IC(50) of 177 +/- 2 microM but had no effect on the enzymatic activity of NADPH cytochrome P450 reductase. Because these drugs were effective within the concentration range observed in humans, it is possible that inhibition of HO may play a role in some of the pharmacological actions of these antimycotic drugs.

  18. Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice.

    PubMed

    Szopa, Aleksandra; Poleszak, Ewa; Wyska, Elżbieta; Serefko, Anna; Wośko, Sylwia; Wlaź, Aleksandra; Pieróg, Mateusz; Wróbel, Andrzej; Wlaź, Piotr

    2016-02-01

    Caffeine is the most widely used behaviorally active drug in the world which exerts its activity on central nervous system through adenosine receptors. Worrying data indicate that excessive caffeine intake applies to patients suffering from mental disorders, including depression. The main goal of the present study was to evaluate the influence of caffeine on animals' behavior in forced swim test (FST) as well as the effect of caffeine (5 mg/kg) on the activity of six typical antidepressants, such as imipramine (15 mg/kg), desipramine (10 mg/kg), fluoxetine (5 mg/kg), paroxetine (0.5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). Locomotor activity was estimated to verify and exclude false-positive/negative results. In order to assess the influence of caffeine on the levels of antidepressant drugs studied, their concentrations were determined in murine serum and brains using high-performance liquid chromatography. The results showed that caffeine at a dose of 10, 20, and 50 mg/kg exhibited antidepressant activity in the FST, and it was not related to changes in locomotor activity in the animals. Caffeine at a dose of 5 mg/kg potentiated the activity of all antidepressants, and the observed effects were not due to the increase in locomotor activity in the animals. The interactions between caffeine and desipramine, fluoxetine, escitalopram, and reboxetine were exclusively of pharmacodynamic character, because caffeine did not cause any changes in the concentrations of these drugs neither in blood serum nor in brain tissue. As a result of joint administration of caffeine and paroxetine, an increase in the antidepressant drug concentrations in serum was observed. No such change was noticed in the brain tissue. A decrease in the antidepressant drug concentrations in brain was observed in the case of imipramine administered together with caffeine. Therefore, it can be assumed that the interactions caffeine-paroxetine and caffeine-imipramine occur at least in

  19. Closure Plan for Active Low Level Burial Grounds

    SciTech Connect

    SKELLY, W.A.

    2000-11-16

    This plan has been prepared in response to direction from the U.S. Department of Energy. The purpose of the plan is to define approaches that will be implemented to ensure protection of the public and the environment when active Low-Level Burial Grounds (LLBGs) at the Hanford Site are closed. Performance assessments for active burial grounds in the 200 East and West 200 Areas provide current estimates of potential environmental contamination and doses to the ''maximum exposed individual'' from burial ground operation and closure and compare dose estimates to performance objective dose limits for the facilities. This is an Operational Closure Plan. The intent of the guidance in DOE Order 435.1 is that this plan will be a living document, like the facility performance assessments, and will be revised periodically through the operational life of the LLBGs to reflect updated information on waste inventory. management practices, facility transition planning, schedule dates, assessments of post-closure performance, and environmental consequences. Out year dates identified in this plan are tentative. A Final Closure Plan will be prepared in the future when the timing and extent of closure-related activities for LLBGs can be established with greater certainty. After current operations at the LLBGs are concluded, this plan proposes transitioning of these facilities to the Environmental Restoration Program. This action will enable the Environmental Restoration Program to design and implement consistent and coordinated final remedial actions for active and inactive LLBGs. Active and inactive burial grounds in the 200 West and 200 East Areas are commingled. This plan describes approaches that will be implemented during Interim Closure, Final Closure, and Institutional Control Periods to prepare LLBGs for surface barriers, and the construction of barriers, as well as the scope of inspection, monitoring and maintenance practices that will be performed during and after closure

  20. Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection.

    PubMed

    Wei, Shuang; Daniel, Benjamin J; Brumlik, Michael J; Burow, Matthew E; Zou, Weiping; Khan, Imtiaz A; Wadsworth, Scott; Siekierka, John; Curiel, Tyler J

    2007-12-01

    We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation, also inhibited replication of the medically important intracellular parasite Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful for treating T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with either of the approved anti-Toxoplasma drugs sulfadiazine and pyrimethamine resulted in improved survival among mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of antiparasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities for more-selective agents.

  1. Levels of physical activity and predictors of mortality in COPD*

    PubMed Central

    Nyssen, Samantha Maria; dos Santos, Júlia Gianjoppe; Barusso, Marina Sallum; de Oliveira, Antônio Delfino; Lorenzo, Valéria Amorim Pires Di; Jamami, Mauricio

    2013-01-01

    OBJECTIVE: To compare the Body mass index, airway Obstruction, Dyspnea, and Exercise capacity (BODE) index scores and its individual components between COPD patients with and without severe physical inactivity, as well as to correlate the number of steps/day with scores of physical activity questionnaires, age, and the BODE index (including its components). METHODS: We included 30 patients, who were evaluated for body composition, pulmonary function (FEV1), perception of dyspnea (modified Medical Research Council scale), and exercise capacity (six-minute walk distance [6MWD]). The patients also completed the International Physical Activity Questionnaire (IPAQ), short version, and the modified Baecke questionnaire (mBQ). The level of physical activity was assessed by the number of steps/day (as determined by pedometer), using the cut-off of 4,580 steps/day to form two groups: no severe physical inactivity (SPI−) and severe physical inactivity (SPI+). We used the Mann-Whitney test or t-test, as well as Pearson's or Spearman's correlation tests, in the statistical analysis. RESULTS: In comparison with the SPI− group, the SPI+ group showed more advanced age, higher mBQ scores (leisure domain), lower 6MWD (in m and % of predicted), and lower IPAQ scores (metabolic equivalent-walk/week domain and total). The IPAQ scores showed weak correlations with steps/day (r = 0.399), age (r = −0.459), and 6MWD-in m (r = 0.446) and in % of predicted (r = 0.422). CONCLUSIONS: In our sample, the cut-off of 4,580 steps/day was not sensitive enough to identify differences between the groups when compared with the predictors of mortality. The IPAQ, short version score correlated with steps/day. PMID:24473759

  2. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    NASA Astrophysics Data System (ADS)

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F.; Daemen, Luke; Saeki, Margarida J.; Bordallo, Heloisa N.

    2016-03-01

    The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells.

  3. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    SciTech Connect

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F.; Daemen, Luke; Saeki, Margarida J.; Bordallo, Heloisa N.

    2016-03-02

    Here, the most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. In conclusion, from these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells.

  4. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    DOE PAGES

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; ...

    2016-03-02

    Here, the most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigatemore » the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. In conclusion, from these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells.« less

  5. Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells

    PubMed Central

    Martins, Murillo L.; Ignazzi, Rosanna; Eckert, Juergen; Watts, Benjamin; Kaneno, Ramon; Zambuzzi, Willian F.; Daemen, Luke; Saeki, Margarida J.; Bordallo, Heloisa N.

    2016-01-01

    The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells. PMID:26932808

  6. Macrophage Folate Receptor-Targeted Antiretroviral Therapy Facilitates Drug Entry, Retention, Antiretroviral Activities and Biodistribution for Reduction of Human Immunodeficiency Virus Infections

    PubMed Central

    Puligujja, Pavan; McMillan, JoEllyn; Kendrick, Lindsey; Li, Tianyuzi; Balkundi, Shantanu; Smith, Nathan; Veerubhotla, Ram S.; Edagwa, Benson J.; Kabanov, Alexander V.; Bronich, Tatiana; Gendelman, Howard E.; Liu, Xin-Ming

    2013-01-01

    Macrophages serve as vehicles for the carriage and delivery of polymer-coated nanoformulated antiretroviral therapy (nanoART). Although superior to native drug, high drug concentrations are required for viral inhibition. Herein, folate-modified atazanavir/ritonavir (ATV/r)-encased polymers facilitated macrophage receptor targeting for optimizing drug dosing. Folate coating of nanoART ATV/r significantly enhanced cell uptake, retention and antiretroviral activities without altering cell viability. Enhanced retentions of folate-coated nanoART within recycling endosomes provided a stable subcellular drug depot. Importantly, five-fold enhanced plasma and tissue drug levels followed folate-coated formulation injection in mice. Folate polymer encased ATV/r improves nanoART pharmacokinetics bringing the technology one step closer to human use. PMID:23680933

  7. Spatiotemporally synchronized cancer combination therapy using photo-activated nanoparticle drug delivery systems (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hasan, Tayyaba

    2016-03-01

    This talk will introduce a new nanotechnology platform for cancer combination therapy that utilizes near infrared light activation not only for photodynamic damage but also as an extrinsic mechanism to initiate release of complimentary drugs to suppress dynamic bursts in molecular signaling networks that promote tumor cell survival and treatment escape. The goal is to achieve co-delivery with concomitant activity of photodynamic, molecular inhibitor and chemotherapeutic agents, selectively within the tumor. This approach overcomes challenges in achieving synergistic interactions using sequential drug delivery. Conventional drug delivery is compromised by the differential pharmacokinetics of individual agents and potentially antagonistic effects—such as vascular shutdown by one agent that limits delivery of the second. Here, photodynamic damage—which efficiently kills drug-resistant cells via damage of common proteins involved in drug-resistance (such as anti-apoptosis factors and drug-efflux transporters)—is synchronized spatially and temporally with the photo-initiated release of complimentary agents—to enable full interaction amongst the individual therapies. This spatiotemporal synchronization offers new prospects for exploiting time-sensitive synergistic interactions. Specific implementations of these concepts will be presented in preclinical models of cancer. Strategies to enable molecular-targeting of cancer cells via site-specific attachment of targeting moieties to the outer lipid shell of these nanovehicles will also be discussed. If successful in humans, this new paradigm for synchronized, tumor-focused combination therapy will ultimately supersede the present use of chronic drug injection by increasing efficacy per cycle whilst reducing systemic exposure to toxic drugs.

  8. Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model.

    PubMed

    Knapp, Richard J; Goldenberg, Rachel; Shuck, Caroline; Cecil, Alicia; Watkins, Jeff; Miller, Cortland; Crites, Glenda; Malatynska, Ewa

    2002-04-05

    The present study tests the activity of nootropic drugs in a behavioral test linked to depression. This test measures the reduction of submissive behavior in a competition test as the relative success of two food-restricted rats to gain access to a feeder. Nootropic drugs tested include piracetam (2-oxo-1-pyrrolidineacetamide), aniracetam (1-(4-methoxybenzoyl)-2-pyrrolidinone), the Ampakine, Ampalex, 1-(quinoxalin-6-ylcarbonyl)piperidine, and analogs were compared to the antidepressants, fluoxetine ((+/-)-N-methyl-gamma-(4-[trifluoromethyl]phenoxy)-benzenepropanamine) and desimpramine (5H-dibenz[b,f]azepine-5-propanamine, 10,11-dihydro-N-methyl-, monohydrochloride), while the anxiolytic diazepam (7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one) served as a control. Drugs were given intraperitoneally for 3 weeks. The antidepressant and nootropic drugs reduced submissive behavior over time. The effect was dose dependent as measured for fluoxetine and Ampakines. The reduction of submissive behavior by Ampakines gradually faded after cessation of treatment and had a more rapid onset of activity (during the 1st week of treatment) than fluoxetine (after 2 weeks). The results suggest that Ampakines may have antidepressant activity. The potential of depression treatment with memory-enhancing drugs is hypothesized and the link between cognition and depression is discussed.

  9. Randomized controlled evaluation of the Too Good for Drugs prevention program: impact on adolescents at different risk levels for drug use.

    PubMed

    Hall, Bruce W; Bacon, Tina P; Ferron, John M

    2013-01-01

    Sixth graders participating in the Too Good for Drugs (TGFD) prevention program in comparison to 6th graders not participating show different results by student risk level. Sixth graders from 20 middle schools were randomly assigned to receive the intervention and those from 20 paired middle schools assigned to serve as controls (N = 10,762). Participants were identified as low, moderate, or high risk for drug usage based on their rates of behaviors reported prior to the start of the study. Student behavior outcomes (smoking, alcohol consumption, binge drinking, and marijuana usage) as well as risk and protective (R&P) outcomes were surveyed at three points in time (before, after, and 6 months following treatment). Results show the TGFD to have a suppressive effect on reported drug use behavior and a strengthening effect on R&P outcomes among high risk students following treatment and 6 months later. Some effects were also found for low and moderate risk students. A favorable treatment effect was found on mathematics achievement.

  10. The antipsychotic drug loxapine is an opener of the sodium-activated potassium channel slack (Slo2.2).

    PubMed

    Biton, B; Sethuramanujam, S; Picchione, Kelly E; Bhattacharjee, A; Khessibi, N; Chesney, F; Lanneau, C; Curet, O; Avenet, P

    2012-03-01

    Sodium-activated potassium (K(Na)) channels have been suggested to set the resting potential, to modulate slow after-hyperpolarizations, and to control bursting behavior or spike frequency adaptation (Trends Neurosci 28:422-428, 2005). One of the genes that encodes K(Na) channels is called Slack (Kcnt1, Slo2.2). Studies found that Slack channels were highly expressed in nociceptive dorsal root ganglion neurons and modulated their firing frequency (J Neurosci 30:14165-14172, 2010). Therefore, Slack channel openers are of significant interest as putative analgesic drugs. We screened the library of pharmacologically active compounds with recombinant human Slack channels expressed in Chinese hamster ovary cells, by using rubidium efflux measurements with atomic absorption spectrometry. Riluzole at 500 μM was used as a reference agonist. The antipsychotic drug loxapine and the anthelmintic drug niclosamide were both found to activate Slack channels, which was confirmed by using manual patch-clamp analyses (EC(50) = 4.4 μM and EC(50) = 2.9 μM, respectively). Psychotropic drugs structurally related to loxapine were also evaluated in patch-clamp experiments, but none was found to be as active as loxapine. Loxapine properties were confirmed at the single-channel level with recombinant rat Slack channels. In dorsal root ganglion neurons, loxapine was found to behave as an opener of native K(Na) channels and to increase the rheobase of action potential. This study identifies new K(Na) channel pharmacological tools, which will be useful for further Slack channel investigations.

  11. Herbal modulation of drug bioavailability: enhancement of rifampicin levels in plasma by herbal products and a flavonoid glycoside derived from Cuminum cyminum.

    PubMed

    Sachin, B S; Sharma, S C; Sethi, S; Tasduq, S A; Tikoo, M K; Tikoo, A K; Satti, N K; Gupta, B D; Suri, K A; Johri, R K; Qazi, G N

    2007-02-01

    The bioavailability of rifampicin (RIF) in a fixed dose combination (FDC) used for the treatment of tuberculosis remains an area of clinical concern and several pharmaceutical alternatives are being explored to overcome this problem. The present study presents a pharmacological approach in which the bioavailability of a drug may be modulated by utilizing the herb-drug synergism. The pharmacokinetic interaction of some herbal products and a pure molecule isolated from Cuminum cyminum with RIF is shown in this paper. An aqueous extract derived from cumin seeds produced a significant enhancement of RIF levels in rat plasma. This activity was found to be due to a flavonoid glycoside, 3',5-dihydroxyflavone 7-O-beta-D-galacturonide 4'-O-beta-D-glucopyranoside (CC-I). CC-I enhanced the Cmax by 35% and AUC by 53% of RIF. The altered bioavailability profile of RIF could be attributed to a permeation enhancing effect of this glycoside.

  12. Fluorescent TEM-1 β-lactamase with wild-type activity as a rapid drug sensor for in vitro drug screening

    PubMed Central

    Cheong, Wing-Lam; Tsang, Ming-San; So, Pui-Kin; Chung, Wai-Hong; Leung, Yun-Chung; Chan, Pak-Ho

    2014-01-01

    We report the development of a novel fluorescent drug sensor from the bacterial drug target TEM-1 β-lactamase through the combined strategy of Val216→Cys216 mutation and fluorophore labelling for in vitro drug screening. The Val216 residue in TEM-1 is replaced with a cysteine residue, and the environment-sensitive fluorophore fluorescein-5-maleimide is specifically attached to the Cys216 residue in the V216C mutant for sensing drug binding at the active site. The labelled V216C mutant has wild-type catalytic activity and gives stronger fluorescence when β-lactam antibiotics bind to the active site. The labelled V216C mutant can differentiate between potent and impotent β-lactam antibiotics and can distinguish active-site binders from non-binders (including aggregates formed by small molecules in aqueous solution) by giving characteristic time-course fluorescence profiles. Mass spectrometric, molecular modelling and trypsin digestion results indicate that drug binding at the active site is likely to cause the fluorescein label to stay away from the active site and experience weaker fluorescence quenching by the residues around the active site, thus making the labelled V216C mutant to give stronger fluorescence in the drug-bound state. Given the ancestor's role of TEM-1 in the TEM family, the fluorescent TEM-1 drug sensor represents a good model to demonstrate the general combined strategy of Val216→Cys216 mutation and fluorophore labelling for fabricating tailor-made fluorescent drug sensors from other clinically significant TEM-type β-lactamase variants for in vitro drug screening. PMID:25074398

  13. Drug Transporter Expression and Activity in Human Hepatoma HuH-7 Cells

    PubMed Central

    Jouan, Elodie; Le Vée, Marc; Denizot, Claire; Parmentier, Yannick; Fardel, Olivier

    2016-01-01

    Human hepatoma cells may represent a valuable alternative to the use of human hepatocytes for studying hepatic drug transporters, which is now a regulatory issue during drug development. In the present work, we have characterized hepatic drug transporter expression, activity and regulation in human hepatoma HuH-7 cells, in order to determine the potential relevance of these cells for drug transport assays. HuH-7 cells displayed notable multidrug resistance-associated protein (MRP) activity, presumed to reflect expression of various hepatic MRPs, including MRP2. By contrast, they failed to display functional activities of the uptake transporters sodium taurocholate co-transporting polypeptide (NTCP), organic anion-transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1), and of the canalicular transporters P-glycoprotein and breast cancer resistance protein (BCRP). Concomitantly, mRNA expressions of various sinusoidal and canalicular hepatic drug transporters were not detected (NTCP, OATP1B1, organic anion transporter 2 (OAT2), OCT1 and bile salt export pump) or were found to be lower (OATP1B3, OATP2B1, multidrug and toxin extrusion protein 1, BCRP and MRP3) in hepatoma HuH-7 cells than those found in human hepatocytes, whereas other transporters such as OAT7, MRP4 and MRP5 were up-regulated. HuH-7 cells additionally exhibited farnesoid X receptor (FXR)- and nuclear factor erythroid 2-related factor 2 (Nrf2)-related up-regulation of some transporters. Such data indicate that HuH-7 cells, although expressing rather poorly some main hepatic drug transporters, may be useful for investigating interactions of drugs with MRPs, notably MRP2, and for studying FXR- or Nrf2-mediated gene regulation. PMID:28036031

  14. Evaluation of trypanocidal activity of combinations of anti-sleeping sickness drugs with cysteine protease inhibitors.

    PubMed

    Steverding, Dietmar

    2015-01-01

    Chemotherapy of human African trypanosomiasis (HAT) is unsatisfactory because only a few drugs, with serious side effects and poor efficacy, are available. As drug combination regimes often achieve greater therapeutic efficacy than monotherapies, here the trypanocidal activity of the cysteine protease inhibitor K11777 in combination with current anti-HAT drugs using bloodstream forms of Trypanosoma brucei was investigated. Isobolographic analysis was used to determine the interaction between cysteine protease inhibitors (K11777, CA-074Me and CAA0225) and anti-HAT drugs (suramin, pentamidine, melarsoprol and eflornithine). Bloodstream forms of T. brucei were incubated in culture medium containing cysteine protease inhibitors or anti-HAT drugs alone or in combination at a 1:1 fixed-dose ratio. After 48 h incubation, live cells were counted, the 50% growth inhibition values determined and combination indices calculated. The general cytotoxicity of drug combinations was evaluated with human leukaemia HL-60 cells. Combinations of K11777 with suramin, pentamidine and melarsoprol showed antagonistic effects while with eflornithine a synergistic effect was observed. Whereas eflornithine antagonises with CA-074Me, an inhibitor inactivating the targeted TbCATL only under reducing conditions, it synergises with CAA0255, an inhibitor structurally related to CA-074Me which inactivates TbCATL independently of thiols. These findings indicate an essential role of thiols for the synergistic interaction between K11777 and eflornithine. Encouragingly, the K11777/eflornithine combination displayed higher trypanocidal than cytotoxic activity. The results of this study suggest that the combination of the cysteine protease inhibitor K11777 and eflornithine display promising synergistic trypanocidal activity that warrants further investigation of the drug combination as possible alternative treatment of HAT.

  15. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs.

    PubMed

    File, S E

    1980-06-01

    The social interaction test in rats provides a method for detecting anxiolytic activity that does not use food or water deprivation, or electric shock, and therefore obviates difficulties of interpretation that might arise from drug-induced changes in motivation. Since social interaction is measured under more than one test condition any overall increase or decrease in social behaviour can be detected independently from the drug x test condition interaction that characterizes an anxiolytic drug. The Geller-Seifter conflict test was designed with two schedules of reinforcement for the same reasons. Any candidate test for anxiolytic action that examines drug effects under only one experimental condition is open to misinterpretation and may also prove unreliable if the critical experimental factors ( e.g. the level of food deprivation or the shock intensity) are changed. The testing procedure in the social interaction test is relatively time consuming in terms of observer-hours, but no lengthy pretraining of the animals is required. There is no way of fully automating the scoring and therefore it is important that the observers do not know the experimental group of the rats that they are scoring, and that tape recordings are made so that the scores can be checked. It has not so far been fruitful to analyze drug effects on every individual social behaviour, but this method does allow changes in individual behaviours to be detected. By entering the data directly into a computer we are now able to store the frequency and duration of each behaviour as well as the sequence of behaviours. It will then be possible to determine whether a detailed analysis of drug effects on the patterning of social behaviours will prove a useful addition to the social interaction test

  16. Hyaluronic acid conjugates as vectors for the active targeting of drugs, genes and nanocomposites in cancer treatment.

    PubMed

    Arpicco, Silvia; Milla, Paola; Stella, Barbara; Dosio, Franco

    2014-03-17

    Hyaluronic acid (HA) is a naturally-occurring glycosaminoglycan and a major component of the extracellular matrix. Low levels of the hyaluronic acid receptor CD44 are found on the surface of epithelial, hematopoietic, and neuronal cells; it is overexpressed in many cancer cells, and in particular in tumor-initiating cells. HA has recently attracted considerable interest in the field of developing drug delivery systems, having been used, as such or encapsulated in different types of nanoassembly, as ligand to prepare nano-platforms for actively targeting drugs, genes, and diagnostic agents. This review describes recent progress made with the several chemical strategies adopted to synthesize conjugates and prepare novel delivery systems with improved behaviors.

  17. Melanogenesis Inhibitory Activity of Two Generic Drugs: Cinnarizine and Trazodone in Mouse B16 Melanoma Cells

    PubMed Central

    Chang, Te-Sheng; Lin, Victor Chia-Hsiang

    2011-01-01

    More than 200 generic drugs were screened to identify the inhibitory activity on melanogenesis in mouse B16 melanoma cells. Cinnarizine and trazodone were identified as melanogenesis inhibitors. The inhibitory effects of the two drugs on cell survival, melanogenesis, and tyrosinase activity were investigated. The results showed that both cinnarizine and trazodone inhibited melanogenesis in B16 cells by a dose-dependent manner at the non-cytotoxic concentrations. Based on the results of the present study, seeking new melanogenesis inhibitors from generic drugs is an alternative approach to developing new depigmenting agents in cosmeceuticals. Moreover, cinnarizine and trazodone were proven to be good candidates as skin-whitening agents for treatment of skin hyperpigmentation. PMID:22272104

  18. Melanogenesis inhibitory activity of two generic drugs: cinnarizine and trazodone in mouse B16 melanoma cells.

    PubMed

    Chang, Te-Sheng; Lin, Victor Chia-Hsiang

    2011-01-01

    More than 200 generic drugs were screened to identify the inhibitory activity on melanogenesis in mouse B16 melanoma cells. Cinnarizine and trazodone were identified as melanogenesis inhibitors. The inhibitory effects of the two drugs on cell survival, melanogenesis, and tyrosinase activity were investigated. The results showed that both cinnarizine and trazodone inhibited melanogenesis in B16 cells by a dose-dependent manner at the non-cytotoxic concentrations. Based on the results of the present study, seeking new melanogenesis inhibitors from generic drugs is an alternative approach to developing new depigmenting agents in cosmeceuticals. Moreover, cinnarizine and trazodone were proven to be good candidates as skin-whitening agents for treatment of skin hyperpigmentation.

  19. [The original nootropic and neuroprotective drug noopept potentiates the anticonvulsant activity of valproate in mice].

    PubMed

    Kravchenko, E V; Ponteleeva, I V; Trofimov, S S; Lapa, V I; Ostrovskaia, R U; Voronina, T A

    2009-01-01

    The influence of the original dipeptide drug noopept, known to possess nootrope, neuroprotector, and anxiolytic properties, on the anticonvulsant activity of the antiepileptic drug valproate has been studied on the model of corazole-induced convulsions in mice. Neither a single administration of noopept (0.5 mg/kg, i.p.) nor its repeated introduction in 10 or 35 days enhanced the convulsant effect of corazole, which is evidence that noopept alone does not possess anticonvulsant properties. Prolonged (five weeks) preliminary administration of noopept enhanced the anticonvulsant activity of valproate. This result justifies the joint chronic administration of noopept in combination with valproate in order to potentiate the anticonvulsant effect of the latter drug. In addition, the administration of noopept favorably influences the cognitive functions and suppresses the development of neurodegenerative processes.

  20. Assertive/Leveling Communication and Empathy in Adolescent Drug Abuse Prevention.

    ERIC Educational Resources Information Center

    Englander-Golden, Paula; And Others

    This paper reports feedback from 349 fifth through eighth graders who participated in Say It Straight (SIS), a school-based drug abuse prevention program which combines assertiveness training with role playing and guided imagery. The feedback presented concerns students' feelings about sending and receiving messages using the following…

  1. Associations between Socio-Motivational Factors, Physical Education Activity Levels and Physical Activity Behavior among Youth

    ERIC Educational Resources Information Center

    Ning, Weihong; Gao, Zan; Lodewyk, Ken

    2012-01-01

    This study examined the relationships between established socio-motivational factors and children's physical activity levels daily and during physical education classes. A total of 307 middle school students (149 boys, 158 girls) from a suburban public school in the Southern United States participated in this study. Participants completed…

  2. Effects of a Classroom-Based Physical Activity Program on Children's Physical Activity Levels

    ERIC Educational Resources Information Center

    Goh, Tan Leng; Hannon, James; Webster, Collin Andrew; Podlog, Leslie William; Brusseau, Timothy; Newton, Maria

    2014-01-01

    High levels of physical inactivity are evident among many American children. To address this problem, providing physical activity (PA) during the school day within the CSPAP framework, is one strategy to increase children's PA. Thus, the purpose of this study was to examine the effects of a classroom-based PA program on children's PA. Two hundred…

  3. Measurement of anti-TNF agents and anti-drug antibodies serum levels in patients with inflammatory bowel disease.

    PubMed

    Guerra, Iván; Chaparro, María; Bermejo, Fernando; Gisbert, Javier P

    2014-01-01

    Despite its undoubted benefit in patients with inflammatory bowel disease, anti-TNF therapy has some limitations including the lack of primary response and the loss of response to treatment in some patients. An empirical approach to these problems is frequently used based on clinical outcome. The measurement of anti-TNF drug serum levels and anti-drug antibodies (ADAb) levels has been proposed for improving the management of anti-TNF drugs. Although their role in routine clinical practice has not been clearly defined, current data support their relationship with clinical outcomes and suggest their clinical utility primarily in patients with loss of response to anti-TNF agents. The presence of pre-existing ADAb before starting the anti-TNF therapy has recently been described. Transient ADAb, non-neutralizing ADAb and some cut-offs points have been proposed, extending the knowledge about this topic. A standardized and widely available test with cut-off points for each anti-TNF agent and the definition of the most appropriate actions to be taken given the serum concentration of the drugs and ADAb are needed before recommending their routine use.

  4. Ion Channel Blockers as Antimicrobial Agents, Efflux Inhibitors, and Enhancers of Macrophage Killing Activity against Drug Resistant Mycobacterium tuberculosis

    PubMed Central

    Perdigão, João; Couto, Isabel; Portugal, Isabel; Martins, Marta; Amaral, Leonard; Anes, Elsa; Viveiros, Miguel

    2016-01-01

    Given the ability of M. tuberculosis to survive as an intracellular pathogen and its propensity to develop resistance to the existing antituberculosis drugs, its treatment requires new approaches. Here the antimycobacterial properties of verapamil, thioridazine, chlorpromazine, flupenthixol and haloperidol were investigated against a panel of drug resistant M. tuberculosis strains, both in vitro and on human-infected macrophages. These compounds are efflux inhibitors that share among them the characteristic of being ion channel blockers. In vitro, all compounds exhibited synergistic inhibitory activities when combined with isoniazid and rifampicin, and were able to inhibit active efflux, demonstrating their role as efflux inhibitors. Gene expression analysis showed that M. tuberculosis efflux genes were overexpressed in response to antibiotic exposure, in vitro and within macrophages, irrespective of their resistance pattern. These compounds displayed a rapid and high killing activity against M. tuberculosis, associated with a decrease in intracellular ATP levels demonstrating that the bactericidal action of the ion channel blockers against M. tuberculosis clinical strains is associated with their interference with energy metabolism. The compounds led to a decrease in the intracellular mycobacterial load by increasing phagosome acidification and activating lysosomal hydrolases. The results presented in this study enable us to propose the following mechanism of action for these compounds: a) in the bacteria, the compounds generate a cascade of events involving the inhibition of the respiratory chain complexes and energy production for efflux activity. Indirectly, this reduce the resistance level to antituberculosis drugs potentiating their activity; b) on the host cell, the treatment with the ion channel blockers increases phagosome acidification and induces the expression of phagosomal hydrolases, leading to bacterial growth restriction irrespective of their

  5. Evaluation and appraisal of drug information services in a rural secondary level care hospital, Anantapur, AP

    PubMed Central

    Bhavsar, Rohit; Zachariah, Seeba; Thomas, Dixon; Kannan, Shanmugha M.

    2012-01-01

    Background: Drug Information Center (DIC) is an information center which provides drug information (DI) to healthcare professionals. The aim was to evaluate the performance of DIC for improving the quality and quantity of information services provided to the healthcare professionals. The service was provided free of cost to the customers. Materials and Methods: This descriptive study was conducted for the period of 6 months from February to August 2011 excluding May due to vacation. Customers were asked: how did they find the service provided to them? Was it good, satisfactory, or need improvement? There were written feedback forms to be filled by the customers, including customer satisfaction questions. The official publication of the DIC, RIPER PDIC Bulletin was screened for its types of articles/number of drug news published. The bulletin is circulated for free to the healthcare professionals electronically. Results and Discussion: A total of 232 queries were obtained during the study period of 6 months. Average number of queried received to the DIC was 39 per month. Most preferred mode of queries was personal access (89%). Majority of queries were received from nurses, i.e., 162 (70%) queries and 81% of all queries were drug oriented for improving knowledge. There were only 19% of the queries for individual patients; doctors asked most of those queries. Only 3% queries answered were rated as need improvement by the healthcare professionals. Rest were considered as either Good (56%) or satisfactory (49%). Range of drug news published in each bulletin was 3–4 and most of the other articles include expert opinion to improve practice or training. Conclusion: The DI services were satisfactorily used for academic interests. Nurses used the service for the highest compared to other health care professionals. Future studies should plan to establish the usefulness of DI to improve healthcare practice. PMID:23248563

  6. Influence of plasticizer level on the drug release from sustained release film coated and hot-melt extruded dosage forms.

    PubMed

    Zhu, Yucun; Mehta, Ketan A; McGinity, James W

    2006-01-01

    In the current study, the influence of plasticizer level on drug release was investigated for solid dosage forms prepared by hot-melt extrusion and film coating. The properties of two highly water-soluble compounds, diltiazem hydrochloride (DTZ) and chlorpheniramine maleate (CPM), and a poorly water-soluble drug, indomethacin (IDM), were investigated in the melt extrudates containing either Eudragit RSPO or Eudragit RD 100 and triethyl citrate (TEC) as the plasticizer. In addition, pellets containing DTZ were film coated with Eudragit RS 30D and varying levels of TEC using a fluidized bed coating unit. Differential scanning calorimetry (DSC) demonstrated that both CPM and IDM exhibited a plasticization effect on the acrylic polymers, whereas no plasticizing effect by DTZ on Eudragit RSPO was observed. Thermogravimetric analysis (TGA) was used to investigate the thermal stability of the DTZ, Eudragit RSPO and TEC at 140 degrees C, the maximum temperature used in the hot-melt extrusion process. The chemical stability of DTZ and IDM in the extrudate following hot-melt processing was determined by high pressure liquid chromatography (HPLC). Drug release rates of both DTZ and CPM from hot-melt extrudates increased with an increase in the TEC level in the formulations, while the release rate of DTZ from the Eudragit RS 30D-coated pellets decreased with an increase in TEC in the coating dispersion. This phenomenon was due to the formation of a reservoir polymeric structure as a result of the thermal stress and shear stress involved in the hot-melt extrusion process regardless of the TEC level. In contrast, coalescence of the polymer particles in the film coating process was enhanced with higher levels of TEC, as demonstrated by scanning electron microscopy (SEM). The addition of TEC (0% to 8%) in the IDM hot-melt extrudate formulation had no influence on the drug release rate as the drug release rate was controlled by drug diffusion through the inside of the polymeric

  7. Moderate Levels of Pre-Treatment HIV-1 Antiretroviral Drug Resistance Detected in the First South African National Survey

    PubMed Central

    Steegen, Kim; Carmona, Sergio; Bronze, Michelle; Papathanasopoulos, Maria A.; van Zyl, Gert; Goedhals, Dominique; MacLeod, William; Sanne, Ian; Stevens, Wendy S.

    2016-01-01

    Background In order to assess the level of transmitted and/or pre-treatment antiretroviral drug resistance to HIV-1, the World Health Organization (WHO) recommends that regular surveys are conducted. This study’s objective was to assess the frequency of HIV-1 antiretroviral drug resistance in patients initiating antiretroviral treatment (ART) in the public sector throughout South Africa. Methods A prospective cross-sectional survey was conducted using probability proportional to size sampling. This method ensured that samples from each province were proportionally collected, based on the number of patients receiving ART in each region. Samples were collected between March 2013 and October 2014. Pol sequences were obtained using RT-PCR and Sanger sequencing and submitted to the Stanford Calibrated Population Resistance tool v6.0. Results A total of 277 sequences were available for analysis. Most participants were female (58.8%) and the median age was 34 years (IQR: 29–42). The median baseline CD4-count was 149 cells/mm3 (IQR: 62–249) and, based on self-reporting, participants had been diagnosed as HIV-positive approximately 44 days prior to sample collection (IQR: 23–179). Subtyping revealed that 98.2% were infected with HIV-1 subtype C. Overall, 25 out of 277 patients presented with ≥1 surveillance drug resistance mutation (SDRM, 9.0%, 95% CI: 6.1–13.0%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations were the most numerous mutations detected (n = 23). Only two patients presented with a protease inhibitor (PI) mutation. In four patients ≥4 SDRMs were detected, which might indicate that these patients were not truly ART-naïve or were infected with a multi-resistant virus. Conclusions These results show that the level of antiretroviral drug resistance in ART-naïve South Africans has reached moderate levels, as per the WHO classification. Therefore, regular surveys of pre-treatment drug resistance levels in all regions of South Africa

  8. Basophil activation after nonsteroidal anti-inflammatory drugs stimulation in patients with immediate hypersensitivity reactions to these drugs.

    PubMed

    Ariza, Adriana; Fernandez, Tahia D; Doña, Inmaculada; Aranda, Ana; Blanca-Lopez, Natalia; Melendez, Lidia; Canto, Gabriela; Blanca, Miguel; Torres, Maria J; Mayorga, Cristobalina

    2014-05-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in allergic reactions of which two main types exist: IgE-mediated and crossintolerance. The diagnosis of crossintolerance reactions is often based on the drug provocation test. The potential value of the basophil activation test (BAT) was evaluated using different basophil markers in the diagnosis of patients with crossintolerance to NSAIDs and cutaneous symptoms. We studied 46 patients with crossintolerance to NSAIDs and 45 tolerant controls. BAT was performed with acetyl salicylic acid, paracetamol, diclofenac, dipyrone, naproxen, and ibuprofen at four different concentrations using CD193 and CD203c as basophil markers and CD63 as activation marker. We compared BAT results using CD193⁺ or CD193⁺ CD203c⁺ for basophil selection and found a significant increase in the stimulation index when using CD193⁺ CD203c⁺ in both patients and controls (P = 0.004 and P = 0.017, respectively). Selection of living cells only produced an increase in basophil stimulation in patients for both CD193⁺ and CD193⁺ CD203c⁺ (P < 0.001 for both), whereas in controls there was no change with CD193⁺ and a decrease with CD193⁺ CD203c⁺ (P = 0.001). We found that CD193⁺ CD203c⁺ increased the percentage of positive cases in patients and controls when compared with CD193⁺. When excluding dead cells, there was an increase of 21.7% in patients and 10% in controls. These results indicate that using CD193⁺ CD203⁺, excluding dead cells, is the best approach for BAT although this test is not recommended for the diagnosis of patients with crossintolerance to NSAIDs owing to its low sensitivity and specificity.

  9. The anticancer drug tirapazamine has antimicrobial activity against Escherichia coli, Staphylococcus aureus and Clostridium difficile.

    PubMed

    Shah, Zarna; Mahbuba, Raya; Turcotte, Bernard

    2013-10-01

    Rapidly increasing bacterial resistance to existing therapies creates an urgent need for the development of new antibacterials. Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4 dioxide) is a prodrug undergoing clinical trials for various types of cancers. In this study, we showed that TPZ has antibacterial activity, particularly at low oxygen levels. With Escherichia coli, TPZ was bactericidal under both aerobic and anaerobic conditions. Escherichia coli mutants deficient in homologous recombination were hypersusceptible to TPZ, suggesting that drug toxicity may be due to DNA damage. Moreover, E. coli strains deleted for genes encoding putative reductases were resistant to TPZ, implying that these enzymes are responsible for conversion of the prodrug to a toxic compound. Fluoroquinolone-resistant E. coli strains were as susceptible to TPZ as a wild-type strain. Methicillin-resistant Staphylococcus aureus strains were also susceptible to TPZ (MIC = 0.5 μg mL(-1) ), as were pathogenic strains of Clostridium difficile (MIC = 7.5 ng mL(-1) ). TPZ may merit additional study as a broad-spectrum antibacterial, particularly for anaerobes.

  10. Activation pathway of Src kinase reveals intermediate states as targets for drug design

    NASA Astrophysics Data System (ADS)

    Shukla, Diwakar; Meng, Yilin; Roux, Benoît; Pande, Vijay S.

    2014-03-01

    Unregulated activation of Src kinases leads to aberrant signalling, uncontrolled growth and differentiation of cancerous cells. Reaching a complete mechanistic understanding of large-scale conformational transformations underlying the activation of kinases could greatly help in the development of therapeutic drugs for the treatment of these pathologies. In principle, the nature of conformational transition could be modelled in silico via atomistic molecular dynamics simulations, although this is very challenging because of the long activation timescales. Here we employ a computational paradigm that couples transition pathway techniques and Markov state model-based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key structural intermediates. Furthermore, the presence of a novel allosteric site in an intermediate state of c-src that could be potentially used for drug design is predicted.

  11. Changes in antibacterial activity of triclosan and sulfa drugs due to photochemical transformations.

    PubMed

    Wammer, Kristine H; Lapara, Timothy M; McNeill, Kristopher; Arnold, William A; Swackhamer, Deborah L

    2006-06-01

    Sulfa drugs and triclosan represent two classes of antibacterials that have been found in natural waters and for which photodegradation is anticipated to be a significant loss process. Parent antibacterial compounds and the products of photolysis reactions were compared for three sulfa drugs and triclosan to determine the extent to which photolysis affects their antibacterial potency on Escherichia coli DH5alpha. Sulfathiazole (median effective concentration [EC50] = 20.0 microM), sulfamethoxazole (EC50 = 12.3 microM), and sulfachloropyridazine (EC50 = 6.9 microM) inhibited bacterial growth but did not affect respiratory activity. Photolysis products of these sulfa drugs did not retain any measurable ability to inhibit growth. Triclosan inhibited both the growth (EC50 = 0.24 microM) and respiratory activity of E. coli DH5alpha. Triclosan photolysis products also exhibited no measurable effect on growth or respiratory activity. These experiments indicate that the products of triclosan and sulfa drug photolysis are unlikely to possess antibacterial activity in natural waters. The rapid screening method used for these two classes of compounds will be useful for helping to identify photolabile antibacterial compounds, for which photoproducts could require further investigation.

  12. Polyvinylpyrrolidone induced artefactual prolongation of activated partial thromboplastin times in intravenous drug users with renal failure.

    PubMed

    Kristoffersen, A H; Bjånes, T K; Jordal, S; Leh, S; Leh, F; Svarstad, E

    2016-05-01

    Essentials Prolonged activated partial thromboplastin times (APTT) were found in drug users with renal failure. An oral methadone solution containing polyvinylpyrrolidone (PVP) had been injected intravenously. Spiking normal plasma with increasing concentrations of PVP resulted in artifically prolonged APTT. APTT prolongation may indicate PVP deposits as underlying cause in patients with renal failure.

  13. Drugs that Target Dopamine Receptors: Changes in Locomotor Activity in Larval Zebrafish

    EPA Science Inventory

    As part of an effort at the US Environmental Protection Agency to develop a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae. This includes assessing the acute effects of drugs known...

  14. The Effects of Acute Exposure to Neuroactive Drugs on the Locomotor Activity of Larval Zebrafish

    EPA Science Inventory

    In an effort to develop a rapid in vivo screen for EPA’s prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish (Danio rerio) larvae using prototypic drugs that act on the central nervous system. Initially, we chose to define the beh...

  15. In Vitro Bactericidal Activity of the Antiprotozoal Drug Miltefosine against Streptococcus pneumoniae and Other Pathogenic Streptococci▿

    PubMed Central

    Llull, Daniel; Rivas, Luis; García, Ernesto

    2007-01-01

    Miltefosine (hexadecylphosphocholine), the first oral drug against visceral leishmaniasis, triggered pneumococcal autolysis at concentrations higher than 2.5 μM. Bactericidal activity was also observed in cultures of other streptococci, although these failed to undergo lysis. The autolysis elicited by miltefosine can be attributed to triggering of the pneumococcal autolysin LytA. PMID:17353242

  16. U.S. Food and Drug Administration perspective of the inclusion of effects of low-level exposures in safety and risk assessment.

    PubMed Central

    Gaylor, D W; Bolger, P M; Schwetz, B A

    1998-01-01

    A brief overview is provided of some of the general safety and risk assessment procedures used by the different centers of the U.S. Food and Drug Administration (U.S. FDA) to evaluate low-level exposures. The U.S. FDA protects public health by regulating a wide variety of consumer products including foods, human and animal drugs, biologics, and medical devices under the federal Food, Drug, and Cosmetic Act. The diverse legal and regulatory standards in the act allow for the consideration of benefits for some products (e.g., drugs) but preclude them from others (e.g., food additives). When not precluded by statutory mandates (e.g., Delaney prohibition), the U.S. FDA considers both physiologic adaptive responses and beneficial effects. For the basic safety assessment paradigm as presently used, for example in the premarket approval of food additives, the emphasis is on the identification of adverse effects and no observed adverse effect level(s) (NOAEL). Generally, the NOAEL is divided by safety factors to establish an acceptable exposure level. This safety assessment paradigm does not preclude the consideration of effects whether they are biologically adaptive or beneficial at lower dose levels. The flexibility to consider issues such as mechanisms of action and adaptive and beneficial responses depends on the product under consideration. For carcinogenic contaminants and radiation from medical devices, the U.S. FDA considers the potential cancer risk at low exposure levels. This generally involves downward extrapolation from the observed dose-response range. The consideration of adverse effects of other toxicologic end points (e.g., reproductive, immunologic, neurologic, developmental) associated with low exposure levels is also becoming more of a reality (e.g., endocrine disrupters). The evaluation of the biologic effects of low-level exposures to toxic substances must include whether the effect is adverse or a normal physiologic adaptive response and also

  17. Mapping lifecycle management activities for blockbuster drugs in Japan based on drug approvals and patent term extensions.

    PubMed

    Yamanaka, Takayuki; Kano, Shingo

    2016-02-01

    Drug lifecycle management (LCM), which entails acquiring drug approvals and patent protections, contributes to maximizing drug discovery investment returns. In a previous survey, a comparative analysis between Japan and the USA indicated that a unique patent term extension system has an important role in Japanese drug LCM. Therefore, in this survey, we focused on drug approvals and patent term extensions, and found that the LCM for blockbuster drugs in Japan can be categorized into three types (drug approval-oriented LCM, patent term extension-oriented LCM, and inactive-type LCM), of which the first two have been implemented recently. Here, we suggest a strategy for selecting a suitable LCM approach among these three types based on the prospects for drug improvements.

  18. Potentiation of antiproliferative drug activity by lonidamine in hepatocellular carcinoma cells.

    PubMed

    Ricotti, L; Tesei, A; De Paola, F; Milandri, C; Amadori, D; Frassineti, G L; Ulivi, P; Zoli, W

    2003-10-01

    The ability of lonidamine (LND), a derivative of indazole-carboxylic acid, to modulate the cytotoxic activity of anticancer drugs was investigated in two human hepatocarcinoma (HCC) cell lines. The cytotoxicity of drugs used singly, in association or in sequence was evaluated using the Sulforhodamine B (SRB) assay. LND did not appreciably potentiate the effect of antitumor drugs when given before or simultaneously, in either cell line. Conversely, a synergistic interaction was observed in both cell lines when LND was given after conventional drugs. LND produced a moderate decrease in S-phase cell fraction and did not induce apoptosis. Conversely, paclitaxel (TAX) induced an important block in G2 and an increase in apoptosis. Following a 48-h TAX wash out, a progressive passage of cells from G2 to M phase was observed with a corresponding increase in apoptotic cells. Post-treatment with LND increased the cytotoxicity of some antitumor drugs, especially TAX, in hepatocarcinoma cells, possibly by preventing, as an energolytic drug, cell damage repair or by producing an additional effect on microtubule stabilization.

  19. Magnetic field activated lipid–polymer hybrid nanoparticles for stimuli-responsive drug release

    PubMed Central

    Kong, Seong Deok; Sartor, Marta; Hu, Che-Ming Jack; Zhang, Weizhou; Zhang, Liangfang; Jin, Sungho

    2014-01-01

    Stimuli-responsive nanoparticles (SRNPs) offer the potential of enhancing the therapeutic efficacy and minimizing the side-effects of chemotherapeutics by controllably releasing the encapsulated drug at the target site. Currently controlled drug release through external activation remains a major challenge during the delivery of therapeutic agents. Here we report a lipid–polymer hybrid nanoparticle system containing magnetic beads for stimuli-responsive drug release using a remote radio frequency (RF) magnetic field. These hybrid nanoparticles show long-term stability in terms of particle size and polydispersity index in phosphate-buffered saline (PBS). Controllable loading of camptothecin (CPT) and Fe3O4 in the hybrid nanoparticles was demonstrated. RF-controlled drug release from these nanoparticles was observed. In addition, cellular uptake of the SRNPs into MT2 mouse breast cancer cells was examined. Using CPT as a model anticancer drug the nanoparticles showed a significant reduction in MT2 mouse breast cancer cell growth in vitro in the presence of a remote RF field. The ease of preparation, stability, and controllable drug release are the strengths of the platform and provide the opportunity to improve cancer chemotherapy. PMID:23149252

  20. Drug ligand-induced activation of translocator protein (TSPO) stimulates steroid production by aged brown Norway rat Leydig cells.

    PubMed

    Chung, J Y; Chen, H; Midzak, A; Burnett, A L; Papadopoulos, V; Zirkin, B R

    2013-06-01

    Translocator protein (TSPO; 18 kDA) is a high-affinity cholesterol-binding protein that is integrally involved in cholesterol transfer from intracellular stores into mitochondria, the rate-determining step in steroid formation. Previous studies have shown that TSPO drug ligands are able to activate steroid production by MA-10 mouse Leydig tumor cells and by mitochondria isolated from steroidogenic cells. We hypothesized herein that the direct, pharmacological activation of TSPO might induce aged Leydig cells, which are characterized by reduced T production, to produce significantly higher levels of T both in vitro and in vivo. To test this, we first examined the in vitro effects of the TSPO selective and structurally distinct drug ligands N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and benzodiazepine 4'-chlorodiazepam (Ro5-4864) on steroidogenesis by Leydig cells isolated from aged (21-24 months old) and young adult (3-6 months old) Brown Norway rats. The ligands stimulated Leydig cell T production significantly, and equivalently, in cells of both ages, an effect that was significantly inhibited by the specific TSPO inhibitor 5-androsten-3,17,19-triol (19-Atriol). Additionally, we examined the in vivo effects of administering FGIN-1-27 to young and aged rats. In both cases, serum T levels increased significantly, consistent with the in vitro results. Indeed, serum T levels in aged rats administered FGIN-1-27 were equivalent to T levels in the serum of control young rats. Taken together, these results indicate that although there are reduced amounts of TSPO in aged Leydig cells, its direct activation is able to increase T production. We suggest that this approach might serve as a therapeutic means to increase steroid levels in vivo in cases of primary hypogonadism.

  1. Some recent approaches of biologically active substituted pyridazine and phthalazine drugs.

    PubMed

    Asif, M

    2012-01-01

    Nitrogen atom containing heterocyclic compounds, pyridazines, pyridazinones and phthalazines are important structural feature of many biologically active compounds and show diverse pharmacological properties. Pyridazines and phthalazines hold considerable interest relative to the preparation of organic intermediates and physiologically active compounds. On the basis of literature, pyridazines, pyridazinone and phthalazines further focus our attention because of their easy fictionalization at various ring positions, which makes them attractive synthetic compounds for designing and development of the novel pyridazines and phthalazines drugs in future.

  2. Computer-guided drug repurposing: identification of trypanocidal activity of clofazimine, benidipine and saquinavir.

    PubMed

    Bellera, Carolina L; Balcazar, Darío E; Vanrell, M Cristina; Casassa, A Florencia; Palestro, Pablo H; Gavernet, Luciana; Labriola, Carlos A; Gálvez, Jorge; Bruno-Blanch, Luis E; Romano, Patricia S; Carrillo, Carolina; Talevi, Alan

    2015-03-26

    In spite of remarkable advances in the knowledge on Trypanosoma cruzi biology, no medications to treat Chagas disease have been approved in the last 40 years and almost 8 million people remain infected. Since the public sector and non-profit organizations play a significant role in the research efforts on Chagas disease, it is important to implement research strategies that promote translation of basic research into the clinical practice. Recent international public-private initiatives address the potential of drug repositioning (i.e. finding second or further medical uses for known-medications) which can substantially improve the success at clinical trials and the innovation in the pharmaceutical field. In this work, we present the computer-aided identification of approved drugs clofazimine, benidipine and saquinavir as potential trypanocidal compounds and test their effects at biochemical as much as cellular level on different parasite stages. According to the obtained results, we discuss biopharmaceutical, toxicological and physiopathological criteria applied to decide to move clofazimine and benidipine into preclinical phase, in an acute model of infection. The article illustrates the potential of computer-guided drug repositioning to integrate and optimize drug discovery and preclinical development; it also proposes rational rules to select which among repositioned candidates should advance to investigational drug status and offers a new insight on clofazimine and benidipine as candidate treatments for Chagas disease. One Sentence Summary: We present the computer-guided drug repositioning of three approved drugs as potential new treatments for Chagas disease, integrating computer-aided drug screening and biochemical, cellular and preclinical tests.

  3. Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity

    NASA Astrophysics Data System (ADS)

    Fan, Rangrang; Li, Xiaoling; Deng, Jiaojiao; Gao, Xiang; Zhou, Liangxue; Zheng, Yu; Tong, Aiping; Zhang, Xiaoning; You, Chao; Guo, Gang

    2016-06-01

    One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer.

  4. Dual Drug Loaded Biodegradable Nanofibrous Microsphere for Improving Anti-Colon Cancer Activity

    PubMed Central

    Fan, Rangrang; Li, Xiaoling; Deng, Jiaojiao; Gao, Xiang; Zhou, Liangxue; Zheng, Yu; Tong, Aiping; Zhang, Xiaoning; You, Chao; Guo, Gang

    2016-01-01

    One of the approaches being explored to increase antitumor activity of chemotherapeutics is to inject drug-loaded microspheres locally to specific anatomic sites, providing for a slow, long term release of a chemotherapeutic while minimizing systemic exposure. However, the used clinically drug carriers available at present have limitations, such as their low stability, renal clearance and residual surfactant. Here, we report docetaxel (DOC) and curcumin (CUR) loaded nanofibrous microspheres (DOC + CUR/nanofibrous microspheres), self-assembled from biodegradable PLA-PEO-PPO-PEO-PLA polymers as an injectable drug carrier without adding surfactant during the emulsification process. The obtained nanofibrous microspheres are composed entirely of nanofibers and have an open hole on the shell without the assistance of a template. It was shown that these DOC + CUR/nanofibrous microspheres could release curcumin and docetaxel slowly in vitro. The slow, sustained release of curcumin and docetaxel in vivo may help maintain local concentrations of active drug. The mechanism by which DOC + CUR/nanofibrous microspheres inhibit colorectal peritoneal carcinomatosis might involve increased induction of apoptosis in tumor cells and inhibition of tumor angiogenesis. In vitro and in vivo evaluations demonstrated efficacious synergistic antitumor effects against CT26 of curcumin and docetaxel combined nanofibrous microspheres. In conclusion, the dual drug loaded nanofibrous microspheres were considered potentially useful for treating abdominal metastases of colorectal cancer. PMID:27324595

  5. Migration and invasion of drug-resistant lung adenocarcinoma cells are dependent on mitochondrial activity

    PubMed Central

    Jeon, Ji Hoon; Kim, Dong Keon; Shin, Youngmi; Kim, Hee Yeon; Song, Bomin; Lee, Eun Young; Kim, Jong Kwang; You, Hye Jin; Cheong, Heesun; Shin, Dong Hoon; Kim, Seong-Tae; Cheong, Jae-Ho; Kim, Soo Youl; Jang, Hyonchol

    2016-01-01

    A small proportion of cancer cells have stem-cell-like properties, are resistant to standard therapy and are associated with a poor prognosis. The metabolism of such drug-resistant cells differs from that of nearby non-resistant cells. In this study, the metabolism of drug-resistant lung adenocarcinoma cells was investigated. The expression of genes associated with oxidative phosphorylation in the mitochondrial membrane was negatively correlated with the prognosis of lung adenocarcinoma. Because the mitochondrial membrane potential (MMP) reflects the functional status of mitochondria and metastasis is the principal cause of death due to cancer, the relationship between MMP and metastasis was evaluated. Cells with a higher MMP exhibited greater migration and invasion than those with a lower MMP. Cells that survived treatment with cisplatin, a standard chemotherapeutic drug for lung adenocarcinoma, exhibited increased MMP and enhanced migration and invasion compared with parental cells. Consistent with these findings, inhibition of mitochondrial activity significantly impeded the migration and invasion of cisplatin-resistant cells. RNA-sequencing analysis indicated that the expression of mitochondrial complex genes was upregulated in cisplatin-resistant cells. These results suggested that drug-resistant cells have a greater MMP and that inhibition of mitochondrial activity could be used to prevent metastasis of drug-resistant lung adenocarcinoma cells. PMID:27932791

  6. Patents of bio-active compounds based on computer-aided drug discovery techniques.

    PubMed

    Prado-Prado, Francisco; Garcia-Mera, Xerardo; Rodriguez-Borges, Jose Enrique; Concu, Riccardo; Perez-Montoto, Lazaro Guillermo; Gonzalez-Diaz, Humberto; Duardo-Sanchez, Aliuska

    2013-01-01

    In recent times, there has been an increased use of Computer-Aided Drug Discovery (CADD) techniques in Medicinal Chemistry as auxiliary tools in drug discovery. Whilst the ultimate goal of Medicinal Chemistry research is for the discovery of new drug candidates, a secondary yet important outcome that results is in the creation of new computational tools. This process is often accompanied by a lack of understanding of the legal aspects related to software and model use, that is, the copyright protection of new medicinal chemistry software and software-mediated discovered products. In the center of picture, which lies in the frontiers of legal, chemistry, and biosciences, we found computational modeling-based drug discovery patents. This article aims to review prominent cases of patents of bio-active organic compounds that involved/protect also computational techniques. We put special emphasis on patents based on Quantitative Structure-Activity Relationships (QSAR) models but we include other techniques too. An overview of relevant international issues on drug patenting is also presented.

  7. Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users

    PubMed Central

    Nestor, Liam; Hester, Robert; Garavan, Hugh

    2009-01-01

    Despite an increased understanding of the pharmacology and long-term cognitive effects of cannabis in humans, there has been no research to date examining its chronic effects upon reward processing in the brain. Motivational theories regarding long-term drug use posit contrasting predictions with respect to how drug users are likely to process non-drug incentives. The reward deficiency syndrome (RDS) of addiction posits that there are deficits in dopamine (DA) motivational circuitry for non-drug rewards, such that only drugs of abuse are capable of normalizing DA in the ventral striatum (VS). Alternatively, the opponent process theory (OPT) holds that in individuals prone to drug use, there exists some form of mesolimbic hyperactivity, in which there is a bias towards reward-centred behaviour concomitant with impulsivity. The current study examined BOLD responses during reward and loss anticipation and their outcome deliveries in 14 chronic cannabis users and 14 drug-naïve controls during a monetary incentive delay (MID) task. Despite no significant behavioural differences between the two groups, cannabis users had significantly more right VS BOLD activity during reward anticipation. Correlation analyses demonstrated that this right VS BOLD response was significantly correlated with life-time use and reported life-time cannabis joints consumed. No correlations between cannabis abstinence and BOLD responses were observed. We also observed a number of group differences following outcome deliveries, most notably hypoactivity in the left insula cortex in response to loss and loss avoidance outcome notifications in the cannabis group. These results may suggest hypersensitivity during instrumental response anticipation for non-drug rewards and a hyposensitivity to loss outcomes in chronic cannabis users; the implications of which are discussed with respect to the potentially sensitizing effects of cannabis for other rewards. PMID:19631753

  8. "New drug" designations for new therapeutic entities: new active substance, new chemical entity, new biological entity, new molecular entity.

    PubMed

    Branch, Sarah K; Agranat, Israel

    2014-11-13

    This Perspective addresses ambiguities in designations of "new drugs" intended as new therapeutic entities (NTEs). Designation of an NTE as a new drug is significant, as it may confer regulatory exclusivity, an important incentive for development of novel compounds. Such designations differ between jurisdictions according to their drug laws and drug regulations. Chemical, biological, and innovative drugs are addressed in turn. The terms new chemical entity (NCE), new molecular entity (NME), new active substance (NAS), and new biological entity (NBE) as applied in worldwide jurisdictions are clarified. Differences between them are explored through case studies showing why new drugs have different periods of exclusivity in different jurisdictions or none at all. Finally, this Perspective recommends that in future, for the purpose of new drug compilations, NME is used for a new chemical drug, NBE for a new biological drug, and the combined designation NTE should refer to either an NME or an NBE.

  9. Chemotherapy-induced activation of ADAM-17: a novel mechanism of drug resistance in colorectal cancer

    PubMed Central

    Kyula, Joan N.; Van Schaeybroeck, Sandra; Doherty, Joanne; Fenning, Catherine S.; Longley, Daniel B.; Johnston, Patrick G.

    2010-01-01

    Purpose: We have shown previously that exposure to anticancer drugs can trigger the activation of human epidermal receptor (HER) survival pathways in colorectal cancer (CRC). In this study, we examined the role of ADAMs (a desintegrin and metalloproteases) and soluble growth factors in this acute drug resistance mechanism. Experimental design: In vitro and in vivo models of CRC were assessed. ADAM-17 activity was measured using a fluorometric assay. Ligand shedding was assessed by ELISA or Western blotting. Apoptosis was assessed by flow cytometry and Western blotting. Results: Chemotherapy (5-Fluorouracil, 5-FU) treatment resulted in acute increases in TGF-α-, amphiregulin- and heregulin-ligand shedding in vitro and in vivo that correlated with significantly increased ADAM-17 activity. siRNA-mediated silencing and pharmacological inhibition confirmed that ADAM-17 was the principal ADAM involved in this pro-survival response. Furthermore, overexpression of ADAM-17 significantly decreased the effect of chemotherapy on tumour growth and apoptosis. Mechanistically, we found that ADAM-17 not only regulated phosphorylation of HERs, but also increased the activity of a number of other growth factor receptors, such as IGF-1R and VEGFR. Conclusions: Chemotherapy acutely activates ADAM-17 which results in growth factor shedding, growth factor receptor activation and drug resistance in CRC tumours. Thus, pharmacological inhibition of ADAM-17 in conjunction with chemotherapy may have therapeutic potential for the treatment of CRC. PMID:20570921

  10. Elevated levels of Insulin-like Growth Factor-1 (IGF-1) in drug-naïve patients with psychosis.

    PubMed

    Petrikis, Petros; Boumba, Vassiliki A; Tzallas, Alexandros T; Voulgari, Paraskevi V; Archimandriti, Dimitra T; Skapinakis, Petros; Mavreas, Venetsanos

    2016-12-30

    Insulin-like growth factor 1 (IGF-1) plays an important role in neurogenesis and synaptogenesis and may be implicated in schizophrenia, although data so far have been inconclusive. The aim of our study was to compare levels of IGF-1 in drug-naïve patients with a first episode of schizophrenia and related disorders with matched healthy controls. Forty drug naïve first-episode patients with schizophrenia and related disorders and forty healthy subjects matched for age, gender, body mass index (BMI) and smoking status were enrolled in the study. Serum levels of IGF-1 for each sample were measured in duplicate by the enzyme-linked immunosorbent assay (ELISA) method using human IGF-1. The median IGF-1 levels were significantly higher in drug-naive patients with psychosis compared to healthy controls (109.66ng/ml vs. 86.96ng/ml, respectively p=0.039). Multiple regression analysis revealed that differences in serum IGF-1 values were independent of glucose metabolism (fasting glucose, fasting insulin, insulin resistance) and cortisol. These results show that IGF-1 may be implicated in the pathophysiology of psychosis but confirmation is needed from other studies.

  11. The Limits of the Czar’s Ukase: Drug Policy at the Local Level

    DTIC Science & Technology

    1990-06-01

    for which post-arrest data are available, approximately seven times as many persons were sen- tenced to incarceration in state prisons and local jails...referred to treatment programs than incarcerated . No doubt the cocaine epidemic would have put a great strain on big city treatment agencies anyway, bitt... recidivism . cooperation among treat ment and correct ions agencies wil haet-buh more efl’ ctive than it was during pre- vious drug abuse epidemics. 2

  12. Differential effects of chronic lead intoxication on circadian rhythm of ambulatory activity and on regional brain norepinephrine levels in rats

    SciTech Connect

    Shafiq-ur-Rehman; Khushnood-ur-Rehman; Kabir-ud-Din; Chandra, O.

    1986-01-01

    Changes in biochemical mechanisms and amine concentrations in the brain have been manifested in the form of varying disorders and abnormalities in behavior, including motor-activity, which has been proved with a number of psychoactive drugs. It has been reported that increased level of cerebral norepinephrine (NE) has been shown to be associated with motor hyper-activity, and in lead exposed rats. No study is available which could account for the pattern of changes in spontaneous ambulatory responses in an open field situation together with the steady state regional levels of NE in the brain of chronically lead exposed rats. Therefore, it seemed to be worthwhile to study the circadian rhythm of ambulatory activity and its association with NE levels in various brain regions of rats exposed to lead.

  13. Innate Activation of MDC and NK Cells in High-risk HIV-1 Exposed, Sero-Negative (HESN) IV-Drug Users that Share Needles When Compared to Low-risk Non-sharing IV-Drug User Controls

    PubMed Central

    Tomescu, Costin; Seaton, Kelly E.; Smith, Peter; Taylor, Mack; Tomaras, Georgia D.; Metzger, David S.; Montaner, Luis J.

    2014-01-01

    Background Previous studies have described increased innate immune activation in HIV-1 exposed, sero-negative intra-venous drug users (HESN-IDU), but have not addressed the independent role of injected drugs and/or repeated injections in driving immune activation. Methods Here, we investigated innate (NK cells and dendritic cells) and adaptive (HIV-specific antibody and CD8+ T cell) immune parameters among a high-risk cohort of needle-sharing HESN-IDU subjects and compared them to low-risk non-sharing IDU subjects (NS-IDU) and non drug-user controls. Results We observed that HIV-specific antibody and CD8+ T cell responses were not detected in HESN-IDU subjects, yet innate immune cell activation was found to be significantly increased on NK cells (CD69 and CD107a upregulation) and MDCs (CD40 and CD83 upregulation) when compared to NS-IDU subjects or non drug-user controls (p<0.01, and p<0.05, respectively). HESN-IDU subjects maintained strong NK cell CD107a degranulation and cytokine (IFN-gamma, TNF-alpha and MIP-1 beta) production following target cell-incubation suggesting that constitutive innate activation does not induce functional exhaustion of innate cells in HESN-IDU subjects. NK activation in HESN-IDU subjects was independent of drug use patterns but was durable over time and correlated with plasma levels of IP-10 by Luminex analysis (rho=0.5073, p=0.0059, n=28). Conclusions Our results indicate that heightened innate immune cell activation in HESN-IDU subjects is not the result of the IV-drugs and repeated injection practice itself, but to repeated exposure to factors intrinsic to sharing needles (i.e., exposure to pathogens or heterologous cells among donor blood). PMID:25514793

  14. Effects of curricular activity on students' situational motivation and physical activity levels.

    PubMed

    Gao, Zan; Hannon, James C; Newton, Maria; Huang, Chaoqun

    2011-09-01

    The purpose of this study was to examine (a) the effects of three curricular activities on students'situational motivation (intrinsic motivation [IM], identified regulation [IR], external regulation, and amotivation [AM]) and physical activity (PA) levels, and (b) the predictive strength of situational motivation to PA levels. Four hundred twelve students in grades 7-9 participated in three activities (cardiovascular fitness, ultimate football, and Dance Dance Revolution [DDR]) in physical education. ActiGraph GT1M accelerometers were used to measure students' PA levels for three classes for each activity. Students also completed a Situational Motivation Scale (Guay, Vallerand, & Blanchard, 2000) at the end of each class. Multivariate analysis of variance revealed that students spent significantly higher percentages of time in moderate-to-vigorous PA (MVPA) in fitness and football classes than they did in DDR class. Students reported higher lM and IR toward fitness than DDR They also scored higher in IR toward fitness than football. In contrast, students displayed significantly lower AM toward fitness than football and DDR Hierarchical Linear Modeling revealed that IM was the only positive predictor for time in MVPA (p = .02), whereas AM was the negative predictor (p < .01). The findings are discussed in regard to the implications for educational practice.

  15. An automated biological assay to determine levels of the trypanocidal drug melarsoprol in biological fluids.

    PubMed

    Onyango, J D; Burri, C; Brun, R

    2000-01-05

    For the investigation of the pharmacokinetic properties of a drug, methods for sensitive and precise quantification are a prerequisite. Only few functional methods exist for the determination of the trypanocidal drug melarsoprol in biological fluids: A bioassay which requires microscopical evaluation and two HPLC methods, which require sample extraction and are difficult to automatize due to the drug's properties. We report the development of an automated biological assay, based on the fluorescent dye Alamar blue. To validate the assay for melarsoprol, 108 serum and 37 cerebrospinal fluid (CSF) samples were spiked with melarsoprol at concentrations of 17-92 ng/ml for CSF and 17 ng/ml-2.2 microg/ml for serum. The precision (repeatability) expressed as the interday average coefficient of variation was 9.9% for serum and 18.8% for CSF samples over the respective concentration range. The accuracy (measurement for the systematic error) of the test was 99.4% for serum and 96.4% for CSF. The assay's limit of quantitation with the use of the trypanosome stock STI 704 BABA was 4 ng/ml for both serum and CSF samples.

  16. Alarming levels of drug-resistant tuberculosis in Belarus: results of a survey in Minsk.

    PubMed

    Skrahina, Alena; Hurevich, Henadz; Zalutskaya, Aksana; Sahalchyk, Evgeni; Astrauko, Andrei; van Gemert, Wayne; Hoffner, Sven; Rusovich, Valiantsin; Zignol, Matteo

    2012-06-01

    Resistance to anti-tuberculosis (TB) medicines is a major public health threat in most countries of the former Soviet Union. As no representative and quality-assured information on the magnitude of this problem existed in Belarus, a survey was conducted in the capital city of Minsk. Between November 2009 and December 2010, 156 consecutively diagnosed new and 68 previously treated culture-positive TB patients residing in Minsk were enrolled in the survey. Mycobacterium tuberculosis isolates were obtained from each patient and tested for susceptibility to first- and second-line anti-TB drugs. Multidrug-resistant (MDR)-TB was found in 35.3% (95% CI 27.7-42.8) of new patients and 76.5% (95% CI 66.1-86.8) of those previously treated. Overall, nearly one in two patients enrolled had MDR-TB. Extensively drug-resistant TB was reported in 15 of the 107 MDR-TB patients (14.0%, 95% CI 7.3-20.7). Patients <35 yrs of age have shown a two times higher odds ratio of multidrug-resistant TB than those aged >35 yrs. The findings of this survey in Minsk city are alarming and represent the highest proportions of MDR-TB ever recorded in the world. This study greatly contributes to the understanding of the burden of drug-resistant TB in urban areas of Belarus.

  17. Millimeter-Wave Measurements of High Level and Low Level Activity Glass Melts

    SciTech Connect

    Woskov, Paul P.; Sundaram, S.K.; Daniel, William E., Jr.

    2006-06-01

    The primary objectives of the current research is to develop on-line sensors for characterizing molten glass in high-level and low-activity waste glass melters using millimeter-wave (MMW) technology and to use this technology to do novel research of melt dynamics. Existing and planned waste glass melters lack sophisticated diagnostics due to the hot, corrosive, and radioactive melter environments. Without process control diagnostics, the Defense Waste Processing Facility (DWPF) and the Waste Treatment Plant (WTP) under construction at Hanford operate by a feed forward process control scheme that relies on predictive models with large uncertainties. This scheme severely limits production throughput and waste loading. Also operations at DWPF have shown susceptibility to anomalies such as pouring, foaming, and combustion gas build up, which can seriously disrupt operations. Future waste chemistries will be even more challenging. The scientific goals of this project are to develop new reliable on-line monitoring capability for important glass process parameters such as temperature profiles, emissivity, density, viscosity, and other characteristics using the unique advantages of millimeter wave electromagnetic radiation that can be eventually implemented in the operating melters. Once successfully developed and implemented, significant cost savings would be realized in melter operations by increasing production through put, reduced storage volumes (through higher waste loading), and reduced risks (prevention or mitigation of anomalies).

  18. Are self-reported physical activity levels associated with perceived desirability of activity-friendly communities?

    PubMed

    Librett, John J; Yore, Michelle M; Schmid, Thomas L; Kohl, Harold W

    2007-09-01

    People living in activity-friendly communities (AFCs) are more active but the self-selection influence is unknown. From 4856 respondents we explored mediating variables with expressed desire to live in AFCs. Association with desire to live in AFCs included ages 18-24 years (odds ratio [OR]=1.9), African American (OR=1.9) or Hispanic (OR=1.5), and believing AFCs would support activity-based transportation (OR=2.4). Regular physical activity (PA) was marginally associated with desire to live in AFCs (OR=1.3). These findings suggest that PA may be a significant factor in communities of this style. Strategies for social marketing along with changes to the built environment to increase PA levels are discussed.

  19. Plasma drug activity in patients on treatment for multidrug-resistant tuberculosis.

    PubMed

    Mpagama, Stellah G; Ndusilo, Norah; Stroup, Suzanne; Kumburu, Happiness; Peloquin, Charles A; Gratz, Jean; Houpt, Eric R; Kibiki, Gibson S; Heysell, Scott K

    2014-01-01

    Little is known about plasma drug concentrations relative to quantitative susceptibility in patients with multidrug-resistant tuberculosis (MDR-TB). We previously described a TB drug activity (TDA) assay that determines the ratio of the time to detection of plasma-cocultured Mycobacterium tuberculosis versus control growth in a Bactec MGIT system. Here, we assess the activity of individual drugs in a typical MDR-TB regimen using the TDA assay. We also examined the relationship of the TDA to the drug concentration at 2 h (C2) and the MICs among adults on a MDR-TB regimen in Tanzania. These parameters were also compared to the treatment outcome of sputum culture conversion. Individually, moxifloxacin yielded superior TDA results versus ofloxacin, and only moxifloxacin and amikacin yielded TDAs equivalent to a -2-log killing. In the 25 patients enrolled on a regimen of kanamycin, levofloxacin, ethionamide, pyrazinamide, and cycloserine, the C2 values were found to be below the expected range for levofloxacin in 13 (52%) and kanamycin in 10 (40%). Three subjects with the lowest TDA result (<1.5, a finding indicative of poor killing) had significantly lower kanamycin C2/MIC ratios than subjects with a TDA of ≥1.5 (9.8 ± 8.7 versus 27.0 ± 19.1; P = 0.04). The mean TDAs were 2.52 ± 0.76 in subjects converting to negative in ≤2 months and 1.88 ± 0.57 in subjects converting to negative in >2 months (P = 0.08). In Tanzania, MDR-TB drug concentrations were frequently low, and a wide concentration/MIC range was observed that affected plasma drug activity ex vivo. An opportunity exists for pharmacokinetic optimization in current MDR-TB regimens, which may improve treatment response.

  20. Convergence of dopamine and glutamate signaling onto striatal ERK activation in response to drugs of abuse

    PubMed Central

    Cahill, Emma; Salery, Marine; Vanhoutte, Peter; Caboche, Jocelyne

    2014-01-01

    Despite their distinct targets, all addictive drugs commonly abused by humans evoke increases in dopamine (DA) concentration within the striatum. The main DA Guanine nucleotide binding protein couple receptors (GPCRs) expressed by medium-sized spiny neurons of the striatum are the D1R and D2R, which are positively and negatively coupled to cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, respectively. These two DA GPCRs are largely segregated into distinct neuronal populations, where they are co-expressed with glutamate receptors in dendritic spines. Direct and indirect interactions between DA GPCRs and glutamate receptors are the molecular basis by which DA modulates glutamate transmission and controls striatal plasticity and behavior induced by drugs of abuse. A major downstream target of striatal D1R is the extracellular signal-regulated kinase (ERK) kinase pathway. ERK activation by drugs of abuse behaves as a key integrator of D1R and glutamate NMDAR signaling. Once activated, ERK can trigger chromatin remodeling and induce gene expression that permits long-term cellular alterations and drug-induced morphological and behavioral changes. Besides the classical cAMP/PKA pathway, downstream of D1R, recent evidence implicates a cAMP-independent crosstalk mechanism by which the D1R potentiates NMDAR-mediated calcium influx and ERK activation. The mounting evidence of reciprocal modulation of DA and glutamate receptors adds further intricacy to striatal synaptic signaling and is liable to prove relevant for addictive drug-induced signaling, plasticity, and behavior. Herein, we review the evidence that built our understanding of the consequences of this synergistic signaling for the actions of drugs of abuse. PMID:24409148

  1. Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid

    PubMed Central

    Ro, Dae-Kyun; Ouellet, Mario; Paradise, Eric M; Burd, Helcio; Eng, Diana; Paddon, Chris J; Newman, Jack D; Keasling, Jay D

    2008-01-01

    yeast microarray further demonstrated that the induction of drug-resistant genes such as ABC transporters and major facilitator superfamily (MSF) genes is the primary cellular stress-response; in addition, oxidative and osmotic stress responses were observed in the engineered yeast. Conclusion The data presented here suggest that the engineered yeast producing artemisinic acid suffers oxidative and drug-associated stresses. The use of plant-derived transporters and optimizing AMO activity may improve the yield of artemisinic acid production in the engineered yeast. PMID:18983675

  2. Fixed-Dose Combination Drug Approvals, Patents and Market Exclusivities Compared to Single Active Ingredient Pharmaceuticals

    PubMed Central

    Hao, Jing; Rodriguez-Monguio, Rosa; Seoane-Vazquez, Enrique

    2015-01-01

    Introduction Fixed-dose combinations (FDC) contain two or more active ingredients. The effective patent and exclusivity life of FDC compared to single active ingredient has not been assessed. Objectives Trends in FDA approved FDC in the period 1980–2012 and time lag between approval of FDC and single active ingredients in the combination were assessed, and the effective patent and exclusivity life of FDC was compared with their single active ingredients. Materials and Methods New molecular entities (NMEs), new therapeutic biologics license applications (BLAs) and FDC data were collected from the FDA Orange Book and Drugs@FDA. Analysis included FDC containing one or more NMEs or BLAs at first FDA approval (NMEs-FDC) and only already marketed drugs (Non-NMEs-FDC). Descriptive, Kruskal-Wallis and Wilcoxon Rank Sum analyses were performed. Results During the study period, the FDA approved 28 NMEs-FDC (3.5% of NMEs) and 117 non-NMEs-FDC. FDC approvals increased from 12 in the 1980s to 59 in the 2000s. Non-NMEs-FDC entered the market at a median of 5.43 years (interquartile range 1.74, 10.31) after first FDA approval of single active ingredients in the combination. The Non-NMEs-FDC entered the market at a median of 2.33 years (-7.55, 2.39) before approval of generic single active ingredient. Non-NME-FDC added a median of 9.70 (2.75, 16.24) years to the patent and exclusivity life of the single active ingredients in the combination. Conclusion FDC approvals significantly increased over the last twenty years. Pharmaceutical companies market FDC drugs shortly before the generic versions of the single ingredients enter the market extending the patent and exclusivity life of drugs included in the combination. PMID:26469277

  3. Inhibition of Human Drug Transporter Activities by the Pyrethroid Pesticides Allethrin and Tetramethrin

    PubMed Central

    Chedik, Lisa; Bruyere, Arnaud; Le Vee, Marc; Stieger, Bruno; Denizot, Claire; Parmentier, Yannick; Potin, Sophie; Fardel, Olivier

    2017-01-01

    Pyrethroids are widely-used chemical insecticides, to which humans are commonly exposed, and known to alter functional expression of drug metabolizing enzymes. Limited data have additionally suggested that drug transporters, that constitute key-actors of the drug detoxification system, may also be targeted by pyrethroids. The present study was therefore designed to analyze the potential regulatory effects of these pesticides towards activities of main ATP-binding cassette (ABC) and solute carrier (SLC) drug transporters, using transporter-overexpressing cells. The pyrethroids allethrin and tetramethrin were found to inhibit various ABC and SLC drug transporters, including multidrug resistance-associated protein (MRP) 2, breast cancer resistance protein (BCRP), organic anion transporter polypeptide (OATP) 1B1, organic anion transporter (OAT) 3, multidrug and toxin extrusion transporter (MATE) 1, organic cation transporter (OCT) 1 and OCT2, with IC50 values however ranging from 2.6 μM (OCT1 inhibition by allethrin) to 77.6 μM (OAT3 inhibition by tetramethrin) and thus much higher than pyrethroid concentrations (in the nM range) reached in environmentally pyrethroid-exposed humans. By contrast, allethrin and tetramethrin cis-stimulated OATP2B1 activity and failed to alter activities of OATP1B3, OAT1 and MATE2-K, whereas P-glycoprotein activity was additionally moderately inhibited. Twelve other pyrethoids used at 100 μM did not block activities of the various investigated transporters, or only moderately inhibited some of them (inhibition by less than 50%). In silico analysis of structure-activity relationships next revealed that molecular parameters, including molecular weight and lipophilicity, are associated with transporter inhibition by allethrin/tetramethrin and successfully predicted transporter inhibition by the pyrethroids imiprothrin and prallethrin. Taken together, these data fully demonstrated that two pyrethoids, i.e., allethrin and tetramethrin, can

  4. Structural basis for activation of alpha-boranophosphate nucleotide analogues targeting drug-resistant reverse transcriptase.

    PubMed

    Meyer, P; Schneider, B; Sarfati, S; Deville-Bonne, D; Guerreiro, C; Boretto, J; Janin, J; Véron, M; Canard, B

    2000-07-17

    AIDS chemotherapy is limited by inadequate intracellular concentrations of the active triphosphate form of nucleoside analogues, leading to incomplete inhibition of viral replication and the appearance of drug-resistant virus. Drug activation by nucleoside diphosphate kinase and inhibition of HIV-1 reverse transcriptase were studied comparatively. We synthesized analogues with a borano (BH(3)(-)) group on the alpha-phosphate, and found that they are substrates for both enzymes. X-ray structures of complexes with nucleotide diphosphate kinase provided a structural basis for their activation. The complex with d4T triphosphate displayed an intramolecular CH.O bond contributing to catalysis, and the R(p) diastereoisomer of thymidine alpha-boranotriphosphate bound like a normal substrate. Using alpha-(R(p))-boranophosphate derivatives of the clinically relevant compounds AZT and d4T, the presence of the alpha-borano group improved both phosphorylation by nucleotide diphosphate kinase and inhibition of reverse transcription. Moreover, repair of blocked DNA chains by pyrophosphorolysis was reduced significantly in variant reverse transcriptases bearing substitutions found in drug-resistant viruses. Thus, the alpha-borano modification of analogues targeting reverse transcriptase may be of generic value in fighting viral drug resistance.

  5. Structural basis for activation of α-boranophosphate nucleotide analogues targeting drug-resistant reverse transcriptase

    PubMed Central

    Meyer, Philippe; Schneider, Benoît; Sarfati, Simon; Deville-Bonne, Dominique; Guerreiro, Catherine; Boretto, Joëlle; Janin, Joël; Véron, Michel; Canard, Bruno

    2000-01-01

    AIDS chemotherapy is limited by inadequate intracellular concentrations of the active triphosphate form of nucleoside analogues, leading to incomplete inhibition of viral replication and the appearance of drug-resistant virus. Drug activation by nucleoside diphosphate kinase and inhibition of HIV-1 reverse transcriptase were studied comparatively. We synthesized analogues with a borano (BH3–) group on the α-phosphate, and found that they are substrates for both enzymes. X-ray structures of complexes with nucleotide diphosphate kinase provided a structural basis for their activation. The complex with d4T triphosphate displayed an intramolecular CH…O bond contributing to catalysis, and the Rp diastereoisomer of thymidine α-boranotriphosphate bound like a normal substrate. Using α-(Rp)-boranophosphate derivatives of the clinically relevant compounds AZT and d4T, the presence of the α-borano group improved both phosphorylation by nucleotide diphosphate kinase and inhibition of reverse transcription. Moreover, repair of blocked DNA chains by pyrophosphorolysis was reduced significantly in variant reverse transcriptases bearing substitutions found in drug-resistant viruses. Thus, the α-borano modification of analogues targeting reverse transcriptase may be of generic value in fighting viral drug resistance. PMID:10899107

  6. Bitter melon extracts enhance the activity of chemotherapeutic agents through the modulation of multiple drug resistance

    PubMed Central

    Kwatra, Deep; Venugopal, Anand; Standing, David; Ponnurangam, Sivapriya; Dhar, Animesh; Mitra, Ashim; Anant, Shrikant

    2014-01-01

    Recently we demonstrated that extracts of bitter melon (BME) can be used as a preventive/therapeutic agent in colon cancers. Here, we determined BME effects on anticancer activity and bioavailability of doxorubicin (DOX) in colon cancer cells. BME enhanced the effect of DOX on cell proliferation and sensitized the cells towards DOX upon pretreatment. Furthermore, there was both increased drug uptake and reduced drug efflux. We also observed a reduction in the expression of Multidrug resistance conferring proteins (MDRCP) P-glycoprotein, MRP-2 and BCRP. Further BME suppressed DOX efflux in MDCK cells overexpressing the three efflux proteins individually, suggesting that BME is a potent inhibitor of MDR function. Next, we determined the effect of BME on PXR, a xenobiotic sensing nuclear receptor and a transcription factor that controls the expression of the three MDR genes. BME suppressed PXR promoter activity thereby suppressing its expression. Finally, we determined the effect of AMPK pathway on drug efflux because we have previously demonstrated that BME affects the pathway. However, inhibiting AMPK did not affect drug resistance, suggesting that BME may use different pathways for the anticancer and MDR modulating activities. Together, these results suggest that BME can enhance the bioavailability and efficacy of conventional chemotherapy. PMID:24129966

  7. Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography.

    PubMed

    Sander, Kerstin; Galante, Eva; Gendron, Thibault; Yiannaki, Elena; Patel, Niral; Kalber, Tammy L; Badar, Adam; Robson, Mathew; Johnson, Sean P; Bauer, Florian; Mairinger, Severin; Stanek, Johann; Wanek, Thomas; Kuntner, Claudia; Kottke, Tim; Weizel, Lilia; Dickens, David; Erlandsson, Kjell; Hutton, Brian F; Lythgoe, Mark F; Stark, Holger; Langer, Oliver; Koepp, Matthias; Årstad, Erik

    2015-08-13

    Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood-brain barrier is a pathological hallmark of many neurological diseases, and the resulting multiple drug resistance represents a major clinical challenge. Noninvasive imaging of transporter activity can help to clarify the underlying mechanisms of drug resistance and facilitate diagnosis, patient stratification, and treatment monitoring. We have developed a metabolically activated radiotracer for functional imaging of P-gp/BCRP activity with positron emission tomography (PET). In preclinical studies, the tracer showed excellent initial brain uptake and clean conversion to the desired metabolite, although at a sluggish rate. Blocking with P-gp/BCRP modulators led to increased levels of brain radioactivity; however, dynamic PET did not show differential clearance rates between treatment and control groups. Our results provide proof-of-concept for development of prodrug tracers for imaging of P-gp/BCRP function in vivo but also highlight some challenges associated with this strategy.

  8. Postgraduation Activities: All Degree Levels in Pennsylvania, 1980.

    ERIC Educational Resources Information Center

    Donny, William F.

    The employment of graduates of all degree levels in Pennsylvania institutions of higher education was assessed in 1980, based on data for 48,162 graduates, or 54.3 percent of the graduates at all degree levels. Attention was directed to the proportions of graduates in each degree field and level: (1) employed in their fields of preparation, (2)…

  9. Inhibition of MDR3 Activity in Human Hepatocytes by Drugs Associated with Liver Injury.

    PubMed

    He, Kan; Cai, Lining; Shi, Qin; Liu, Hao; Woolf, Thomas F

    2015-10-19

    MDR3 dysfunction is associated with liver diseases. We report here a novel MDR3 activity assay involving in situ biosynthesis in primary hepatocytes of deuterium (d9)-labeled PC and LC-MS/MS determination of transported extracellular PC-d9. Several drugs associated with DILI such as chlorpromazine, imipramine, itraconazole, haloperidol, ketoconazole, sequinavir, clotrimazole, ritonavir, and troglitazone inhibit MDR3 activity. MDR3 inhibition may play an important role in drug-induced cholestasis and vanishing bile duct syndrome. Several lines of evidence demonstrate that the reported assay is physiologically relevant and can be used to assess the potential of chemical entities and their metabolites to modulate MDR3 activity and/or PC biosynthesis in hepatocytes.

  10. Measurement of caspase-2 activation during different anti-tumor drugs induced apoptosis by FRET technique

    NASA Astrophysics Data System (ADS)

    Lin, Juqiang; Zeng, Shaoqun; Luo, Qingming; Rong, Chen; Zhang, Zhihong

    2007-11-01

    Caspase-2 is important for the engagement of the mitochondrial apoptotic pathway, in the presence of DNA-damaging agents, such as cisplatin; however, the mechanism by which caspase-2 executes apoptosis remains obscure. In this study, we carried out the measurements of the dynamics of caspase-2 activation in a single living cell by a FRET (fluorescence resonance energy transfer) probe. A FRET probe was constructed that encoded a CRS (caspase-2 recognition site) fused with a cyan fluorescent protein (CFP) and a red fluorescent protein (DsRed) (CFP-CRS-DsRed). Using this probe, we found that during TRAIL-induced apoptosis, caspase-2 was not activated, and caspase-2 activation occurred in etoposide and cisplatin treated cells. However, during cisplatin-induced apoptosis caspase-2 activation was initiated much earlier than that of etoposide. Cisplatin and etoposide is one of the most broadly used drugs in the Clinical applications of cancer chemotherapy, and TRAIL, which belongs to the TNF family proteins, can selectively induce apoptosis in many transformed cells but not in normal cells. Most of anticancer drugs can induce apoptosis mediated by the activation of caspase pathway. Thus, the perfect synergistic effect group of multi-drug can be selected by using our FRET probe.

  11. The activation of phosphoramide mustard anticancer drugs from ab initio simulations.

    NASA Astrophysics Data System (ADS)

    Allesch, Markus; Schwegler, Eric; Colvin, Mike; Gygi, Francois; Galli, Giulia

    2007-03-01

    The nitrogen mustard based DNA alkylating agents were the first nonhormonal drugs to be used effectively in the treatment of cancer and remain one of the most important drugs for the chemotherapeutic management of many common malignancies today. An understanding of the activation of these compounds is, in itself, of scientific interest, but also critical in designing improved analogs of greater selectivity and efficacy. We have investigated the activation pathways of one of the most active metabolites, phosphoramide mustard (PM), and its methylated ester (PMME). In particular, we have examined the activation barrier and reaction free energy for the intramolecular cyclization reaction using first principles molecular dynamics simulations with explicit and continuum solvation models. Structural, dynamical and electronic properties along the reaction path have been computed mainly to address the question why de-esterification is required to activate these drugs. This work was performed under the auspices of the U.S. Dept. of Energy at the University of California/Lawrence Livermore National Laboratory under contract no. W-7405-Eng-48.

  12. Altered serum levels of interleukin-3 in first-episode drug-naive and chronic medicated schizophrenia.

    PubMed

    Fu, Yin Yang; Zhang, Tong; Xiu, Mei Hong; Tang, Wei; Han, Mei; Yun, Long Tan; Chen, Da Chun; Chen, Song; Tan, Shu Ping; Soares, Jair C; Tang, Wen Jie; Zhang, Xiang Yang

    2016-10-01

    Elevated serum levels of Interleukin-3 (IL-3), a major component of the cytokines, have been observed in chronic and medicated patients with schizophrenia, but this elevation may reflect either or both medication and illness chronicity effects. Thus, we compared serum IL-3 levels in first-episode drug-naive (FEDN) to chronic medicated patients with schizophrenia and examined the association of IL-3 with their psychopathological symptoms. Serum IL-3 levels were assessed in 55 FEDN patients, 52 chronic medicated patients and 43 healthy controls. Schizophrenia symptomatology was assessed with the Positive and Negative Syndrome Scale (PANSS). Serum IL-3 levels were measured by sandwich enzyme-linked immunosorbent assay (ELISA). We found significantly lower IL-3 levels in FEDN patients than both chronic patients and healthy controls (both p<0.001), while IL-3 levels in chronic patients were markedly higher than in healthy controls. No significant association was observed between IL-3 and any clinical psychopathology in FEDN patients; however, we found a significant correlation between serum IL-3 levels and the PANSS general psychopathology subscore in chronic medicated patients (p<0.05). Decreased IL-3 levels in FEDN patients suggest that suppressed immune function may be associated with developing schizophrenia, but as the disease progresses IL-3 levels increase perhaps related to medication treatment or other factors that occur during chronic illness.

  13. The Application of Pattern Recognition to Screening Prospective Anti-Cancer Drugs: Adenocarcinoma 775 Biological Activity Test.

    DTIC Science & Technology

    A novel application of pattern recognition to the screening of potential anti-cancer drugs is presented. Structural features of 200 drugs previously tested by the National Cancer Institute for activity in the solid tumor adenocarcinoma 755 screening test are input to a master program of pattern recognition methods. The programs were 93.5% accurate in discriminating drugs with positive anti-neoplastic activity versus those with no anti-cancer activity. Extensions to a more rational approach to ’ drug design ’ are also discussed. (Author)

  14. Drugs@FDA: FDA Approved Drug Products

    MedlinePlus

    ... Cosmetics Tobacco Products Home Drug Databases Drugs@FDA Drugs@FDA: FDA Approved Drug Products Share Tweet Linkedin Pin it More sharing options Linkedin Pin it Email Print Search by Drug Name, Active Ingredient, or Application Number Enter at ...

  15. A Survey of Physical Activity Levels of Certified Athletic Trainers.

    ERIC Educational Resources Information Center

    Cuppett, Marchell; Latin, Richard W.

    2002-01-01

    Investigated the physical activities of certified athletic trainers (ATCs), both at work and at leisure. Survey data indicated that those who worked in clinical versus school settings had the highest mean total activity score. Females scored significantly higher than males. The mean total index activity of the over-36-years-old group was…

  16. Cytotoxic Activity of Salicylic Acid-Containing Drug Models with Ionic and Covalent Binding.

    PubMed

    Egorova, Ksenia S; Seitkalieva, Marina M; Posvyatenko, Alexandra V; Khrustalev, Victor N; Ananikov, Valentine P

    2015-11-12

    Three different types of drug delivery platforms based on imidazolium ionic liquids (ILs) were synthesized in high preparative yields, namely, the models involving (i) ionic binding of drug and IL; (ii) covalent binding of drug and IL; and (iii) dual binding using both ionic and covalent approaches. Seven ionic liquids containing salicylic acid (SA-ILs) in the cation or/and in the anion were prepared, and their cytotoxicity toward the human cell lines CaCo-2 (colorectal adenocarcinoma) and 3215 LS (normal fibroblasts) was evaluated. Cytotoxicity of SA-ILs was significantly higher than that of conventional imidazolium-based ILs and was comparable to the pure salicylic acid. It is important to note that the obtained SA-ILs dissolved in water more readily than salicylic acid, suggesting benefits of possible usage of traditional nonsoluble active pharmaceutical ingredients in an ionic liquid form.

  17. Observations of Interrank Conflicts at the Company Level: Drug and Alcohol Abuse.

    DTIC Science & Technology

    1975-12-01

    N L (N N Marihuana 40.3 (683) 26.7 (452) 30.0 (508) 3.0 (51) 100.0 (1694) Hashish 26.9 (455) 27.9 (473) 42.0 (712) 3.2 (54) i00.0 (1694) Cocaine 5.6...7) (5) free time Legalize soft drugs, allow 0 0 5 9 8 10 alcohol in the barracks (0) (0) (1) (2) (3) (4) Don’t open clubs until 0 0 5 0 0 2 Beatter

  18. Basophil activation test for investigation of IgE-mediated mechanisms in drug hypersensitivity.

    PubMed

    Steiner, Markus; Harrer, Andrea; Lang, Roland; Schneider, Michael; Ferreira, Tima; Hawranek, Thomas; Himly, Martin

    2011-09-16

    Hypersensitivity reactions against non-steroidal anti-inflammatory drugs (NSAIDs) like propyphenazone (PP) and diclofenac (DF) can manifest as Type I-like allergic reactions (1). In clinical practice, diagnosis of drug hypersensitivity is mainly performed by patient history, as skin testing is not reliable and oral provocation testing bears life-threatening risks for the patient (2). Hence, evidence for an underlying IgE-mediated pathomechanism is hard to obtain. Here, we present an in vitro method based on the use of human basophils derived from drug-hypersensitive patients that mimics the allergic effector reaction in vivo. As basophils of drug-allergic patients carry IgE molecules specific for the culprit drug, they become activated upon IgE receptor crosslinking and release allergic effector molecules. The activation of basophils can be monitored by the determination of the upregulation of CD63 surface expression using flow cytometry (3). In the case of low molecular weight drugs, conjugates are designed to enable IgE receptor crosslinking on basophils. As depicted in Figure 1, two representatives of NSAIDs, PP and DF, are covalently bound to human serum albumin (HSA) via a carboxyl group reacting with the primary amino group of lysine residues. DF carries an intrinsic carboxyl group and, thus, can be used directly (4), whereas a carboxyl group-containing derivative of PP had to be organochemically synthesized prior to the study (1). The coupling degree of the low molecular weight compounds on the protein carrier molecule and their spatial distribution is important to guarantee crosslinking of two IgE receptor molecules. The here described protocol applies high performance-size exclusion chromatography (HPSEC) equipped with a sequential refractive index (RI) and ultra violet (UV) detection system for determination of the coupling degree. As the described methodology may be applied for other drugs, the basophil activation test (BAT) bears the potential to be

  19. Chill activation of compatible solute transporters in Corynebacterium glutamicum at the level of transport activity.

    PubMed

    Ozcan, Nuran; Krämer, Reinhard; Morbach, Susanne

    2005-07-01

    The gram-positive soil bacterium Corynebacterium glutamicum harbors four osmoregulated secondary uptake systems for compatible solutes, BetP, EctP, LcoP, and ProP. When reconstituted in proteoliposomes, BetP was shown to sense hyperosmotic conditions via the increase in luminal K(+) and to respond by instant activation. To study further putative ways of stimulus perception and signal transduction, we have investigated the responses of EctP, LcoP, and BetP, all belonging to the betaine-carnitine-choline transporter family, to chill stress at the level of activity. When fully activated by hyperosmotic stress, they showed the expected increase of activity at increasing temperature. In the absence of osmotic stress, EctP was not activated by chill and LcoP to only a very low extent, whereas BetP was significantly stimulated at low temperature. BetP was maximally activated at 10 degrees C, reaching the same transport rate as that observed under hyperosmotic conditions at this temperature. A role of cytoplasmic K(+) in chill-dependent activation of BetP was ruled out, since (i) the cytoplasmic K(+) concentration did not change significantly at lower temperatures and (ii) a mutant BetP lacking the C-terminal 25 amino acids, which was previously shown to have lost the ability to be activated by luminal K(+), was fully competent in chill sensing. When heterologously expressed in Escherichia coli, BetP did not respond to chill stress. This may indicate that the membrane in which BetP is inserted plays an important role in chill activation and thus in signal transduction by BetP, different from the previously established K(+)-mediated process.

  20. Photothermally activated drug release from liposomes coupled to hollow gold nanoshells

    NASA Astrophysics Data System (ADS)

    Forbes, Natalie; Zasadzinski, Joseph A.

    2011-03-01

    Liposomes show great promise as intravenous drug delivery vehicles, but it is difficult to combine stability in the circulation, extended drug retention and rapid, targeted release at the site of interest. Accessorizing conventional and multicompartment liposomes with photo-activated hollow gold nanoshells (HGN) provides a convenient method to initiate drug release with spatial and temporal control. HGN efficiently absorb near infrared (NIR) light and rapidly convert the absorbed optical energy into heat. Femto- to nano-second NIR light pulses cause the HGNs to rapidly heat, creating large temperature gradients between the HGNs and surrounding fluid. The formation and collapse of unstable vapor bubbles transiently rupture liposome and other bilayer membranes to trigger contents release. Near-complete contents release occurs when the nanoshells are encapsulated within the liposome or tethered to the outer surface of the liposome, with no chemical damage to the contents. Release is achieved by focusing the laser beam at the target, eliminating the need for highly specific targeting ligands or antibodies. Although HGN heating can be intense, the overall energy input is small causing minimal heating of the surroundings. To ensure that drugs are retained within the liposomes until delivery in a physiological environment, we have made novel multicompartment carriers called vesosomes, which consist of an outer lipid bilayer shell that encloses and protects the drug-carrying liposomes. The second bilayer increases the serum half-life of ciprofloxacin from <10 minutes in liposomes to 6 hours in vesosomes and alters the release kinetics. The enhanced drug retention is due to the outer membrane preventing enzymes and proteins in the blood from breaking down the drug-carrying interior compartments.

  1. Folic acid-conjugated amphiphilic alternating copolymer as a new active tumor targeting drug delivery platform

    PubMed Central

    Li, Xia; Szewczuk, Myron R; Malardier-Jugroot, Cecile

    2016-01-01

    Targeted drug delivery using polymeric nanostructures is an emerging cancer research area, engineered for safer, more efficient, and effective use of chemotherapeutic drugs. A pH-responsive, active targeting delivery system was designed using folic acid functionalized amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA). The polymeric template is pH responsive, forming amphiphilic nanostructures at pH 7, allowing the encapsulation of hydrophobic drugs on its interior. Moreover, the structure is stable only at neutral pH and collapses in the acidic tumor microenvironment, releasing drugs on-site from its core. The delivery vehicle is investigated using human pancreatic PANC-1 cancer cells and RAW-Blue™ mouse macrophage reporter cell line, both of which have overly expression of folic acid receptors. To trace the cellular uptake by both cell lines, curcumin was selected as a dye and drug mimic owing to its fluorescence nature and hydrophobic properties. Fluorescent microscopy of FA-DABA-SMA loaded with curcumin revealed a significant internalization of the dye by human pancreatic PANC-1 cancer cells compared to those with unfunctionalized polymers (SMA). Moreover, the FA-DABA-SMA polymers exhibit rodlike association specific to the cells. Both empty SMA and FA-DABA-SMA show little toxicity to PANC-1 cells as characterized by WST-1 cell proliferation assay. These results clearly indicate that FA-DABA-SMA polymers show potential as an active tumor targeting drug delivery system with the ability to internalize hydrophobic chemotherapeutics after they specifically attach to cancer cells. PMID:28008233

  2. Prediction of cis-regulatory elements for drug-activated transcription factors in the regulation of drug-metabolising enzymes and drug transporters.

    PubMed

    Podvinec, Michael; Meyer, Urs A

    2006-06-01

    The expression of drug-metabolising enzymes is affected by many endogenous and exogenous factors, including sex, age, diet and exposure to xenobiotics and drugs. To understand fully how the organism metabolises a drug, these alterations in gene expression must be taken into account. The central process, the definition of likely regulatory elements in the genes coding for enzymes and transporters involved in drug disposition, can be vastly accelerated using existing and emerging bioinformatics methods to unravel the regulatory networks causing drug-mediated induction of genes. Here, various approaches to predict transcription factor interactions with regulatory DNA elements are reviewed.

  3. [Effects of nootropic drugs on hippocampal and cortical BDNF levels in mice with different exploratory behavior efficacy].

    PubMed

    Firstova, Iu Iu; Dolotov, O V; Kondrakhin, e A; Dubynina, E V; Grivennikov, I A; Kovalev, G I

    2009-01-01

    The influence of subchronic administration of nootropic drugs (piracetam, phenotropil, meclophenoxate, pantocalcine, semax, nooglutil) on the brain-derived neurotrophic factor (BDNF) content in hippocampal and cortical tissues in mice with different exploratory behavior--high efficacy (HE) against low efficacy (LE)--in cross-maze test has been studied. The initial BDNF concentration in hippocamp (but not in cortex) of control HE mice was higher than that in LE mice (LE, 0.091 +/- 0.005 pg/microg; HE, 0.177 +/- 0.005 pg/microg; p < 0.0005). After drug administration, changes in the BDNF level were only observed in the hippocamp of LE mice, where it reached (pg/microg) 0.115 +/- 0.004 (for piracetam); 0.119 +/- 0.006 (for phenotropil); 0.123 +/- 0.007 (for semax); and 0.122 +/- 0.009 (for meclophenoxate). In the LE mice cortex, the BDNF content increased only after piracetam and semax injections (to 0.083 +/- 0.003 and 0.093 +/- 0.008, respectively, vs. 0.071 +/- 0.003 pg/microg in the control group; p < 0.0005). No changes were observed in the cortex of HE mice. Thus, the obtained results demonstrate that clinically used drugs piracetam, phenotropil, meclophenoxate, and semax realize their nootrope effects, at least partially, via increase in hippocampal BDNF level, which is achieved only under conditions of cognitive deficiency.

  4. An elevated level of physical activity is associated with normal lipoprotein(a) levels in individuals from Maracaibo, Venezuela.

    PubMed

    Bermúdez, Valmore; Aparicio, Daniel; Rojas, Edward; Peñaranda, Lianny; Finol, Freddy; Acosta, Luis; Mengual, Edgardo; Rojas, Joselyn; Arráiz, Nailet; Toledo, Alexandra; Colmenares, Carlos; Urribarí, Jesica; Sanchez, Wireynis; Pineda, Carlos; Rodriguez, Dalia; Faria, Judith; Añez, Roberto; Cano, Raquel; Cano, Clímaco; Sorell, Luis; Velasco, Manuel

    2010-01-01

    Coronary artery disease is the main cause of death worldwide. Lipoprotein(a) [Lp(a)], is an independent risk factor for coronary artery disease in which concentrations are genetically regulated. Contradictory results have been published about physical activity influence on Lp(a) concentration. This research aimed to determine associations between different physical activity levels and Lp(a) concentration. A descriptive and cross-sectional study was made in 1340 randomly selected subjects (males = 598; females = 712) to whom a complete clinical history, the International Physical Activity Questionnaire, and Lp(a) level determination were made. Statistical analysis was carried out to assess qualitative variables relationship by chi2 and differences between means by one-way analysis of variance considering a P value <0.05 as statistically significant. Results are shown as absolute frequencies, percentages, and mean +/- standard deviation according to case. Physical activity levels were ordinal classified as follows: low activity with 24.3% (n = 318), moderate activity with 35.0% (n = 458), and high physical activity with 40.8% (n = 534). Lp(a) concentration in the studied sample was 26.28 +/- 12.64 (IC: 25.59-26.96) mg/dL. Lp(a) concentration according to low, moderate, and high physical activity levels were 29.22 +/- 13.74, 26.27 +/- 12.91, and 24.53 +/- 11.35 mg/dL, respectively, observing statistically significant differences between low and moderate level (P = 0.004) and low and high level (P < 0.001). A strong association (chi2 = 9.771; P = 0.002) was observed among a high physical activity level and a normal concentration of Lp(a) (less than 30 mg/dL). A lifestyle characterized by high physical activity is associated with normal Lp(a) levels.

  5. The association between sterilizing activity and drug distribution into tuberculosis lesions

    PubMed Central

    Prideaux, Brendan; Via, Laura E.; Zimmerman, Matthew D.; Eum, Seokyong; Sarathy, Jansy; O’Brien, Paul; Chen, Chao; Kaya, Firat; Weiner, Danielle M.; Chen, Pei-Yu; Song, Taeksun; Lee, Myungsun; Shim, TaeSun; Cho, Jeong Su; Kim, Wooshik; Cho, Sang Nae; Olivier, Kenneth N.; Barry, Clifton E.; Dartois, Véronique

    2015-01-01

    Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a MALDI mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside1. In contrast, moxifloxacin which is active in vitro against persisters, a sub-population of Mycobacterium tuberculosis that persists in specific niches under drug pressure, and achieved treatment shortening in mice2, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We also suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration contributes to treatment outcome has wide implications for TB. PMID:26343800

  6. The rheological properties of modified microcrystalline cellulose containing high levels of model drugs.

    PubMed

    Knight, Paul E; Podczeck, Fridrun; Newton, J Michael

    2009-06-01

    The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of non-Newtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets.

  7. Matrix elimination ion chromatography method for trace level azide determination in irbesartan drug.

    PubMed

    Subramanian, Narayanan Harihara; Babu, V R Sankar; Jeevan, R Ganesh; Radhakrishnan, Ganga

    2009-08-01

    Ultra-trace analysis of azide in complicated Irbesartan sample matrix is achieved by the in-line sample preparation technique. Sodium azide is the precursor of Irbesartan, which is used as an anti-hypertensive drug. Due to the toxic nature of sodium azide, reliable determination of azide in Irbesartan is necessary. Irbesartan when analyzed for sodium azide, as per the USP 31-NF26 method, gets adsorbed to the analytical column, leading to reduction in column capacity and irreproducible retention time. The retained drug has to be removed with special rinsing solution, followed by re-equilibration with the mobile phase. This process takes at least 3 to 4 h for each sample analysis. The new method developed overcomes the limitations of the USP 31-NF26 method. This method is validated for specificity, linearity, accuracy, precision, sample solution stability, and robustness as per International Conference on Harmonization guidelines. The relationship between peak response and concentration is found to be linear between 5 to 80 ng/mL of sodium azide, with the correlation coefficient (r(2)) of 0.9995. The limits of detection and quantification for sodium azide are 0.532 and 1.61 microg/gm with respect to the sample weight.

  8. 24 CFR 960.204 - Denial of admission for criminal activity or drug abuse by household members.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Denial of admission for criminal... HOUSING Admission § 960.204 Denial of admission for criminal activity or drug abuse by household members. (a) Required denial of admission—(1) Persons evicted for drug-related criminal activity. The...

  9. In vitro model systems to investigate bile salt export pump (BSEP) activity and drug interactions: A review.

    PubMed

    Cheng, Yaofeng; Woolf, Thomas F; Gan, Jinping; He, Kan

    2016-08-05

    The bile salt export pump protein (BSEP), expressed on the canalicular membranes of hepatocytes, is primarily responsible for the biliary excretion of bile salts. The inhibition of BSEP transport activity can lead to an increase in intracellular bile salt levels and liver injury. This review discusses the various in vitro assays currently available for assessing the effect of drugs or other chemical entities to modulate BSEP transport activity. BSEP transporter assays use one of the following platforms: Xenopus laevis oocytes; canalicular membrane vesicles (CMV); BSEP-expressed membrane vesicles; cell lines expressing BSEP; sandwich cultured hepatocytes (SCH); and hepatocytes in suspension. Two of these, BSEP-expressed insect membrane vesicles and sandwich cultured hepatocytes, are the most commonly used assays. BSEP membrane vesicles prepared from transfected insect cells are useful for assessing BSEP inhibition or substrate specificity and exploring mechanisms of BSEP-associated genetic diseases. This model can be applied in a high-throughput format for discovery-drug screening. However, experimental results from use of membrane vesicles may lack physiological relevance and the model does not allow for investigation of in situ metabolism in modulation of BSEP activity. Hepatocyte-based assays that use the SCH format provide results that are generally more physiologically relevant than membrane assays. The SCH model is useful in detailed studies of the biliary excretion of drugs and BSEP inhibition, but due to the complexity of SCH preparation, this model is used primarily for determining biliary clearance and BSEP inhibition in a limited number of compounds. The newly developed hepatocyte in suspension assay avoids many of the complexities of the SCH method. The use of pooled cryopreserved hepatocytes in suspension minimizes genetic variance and individual differences in BSEP activity and also provides the opportunity for higher throughput screening and cross

  10. A Study on the Application of the Information-Motivation-Behavioral Skills (IMB) Model on Rational Drug Use Behavior among Second-Level Hospital Outpatients in Anhui, China

    PubMed Central

    Wang, Heng; Li, Niannian; Wu, Jingya; Zhao, Yunwu; Li, Peng; Lu, Hua

    2015-01-01

    Background The high prevalence of risky irrational drug use behaviors mean that outpatients face high risks of drug resistance and even death. This study represents the first application of the Information-Motivation-Behavioral Skills (IMB) model on rational drug use behavior among second-level hospital outpatients from three prefecture-level cities in Anhui, China. Using the IMB model, our study examined predictors of rational drug use behavior and determined the associations between the model constructs. Methods This study was conducted with a sample of 1,214 outpatients aged 18 years and older in Anhui second-level hospitals and applied the structural equation model (SEM) to test predictive relations among the IMB model variables related to rational drug use behavior. Results Age, information and motivation had significant direct effects on rational drug use behavior. Behavioral skills as an intermediate variable also significantly predicted more rational drug use behavior. Female gender, higher educational level, more information and more motivation predicted more behavioral skills. In addition, there were significant indirect impacts on rational drug use behavior mediated through behavioral skills. Conclusions The IMB-based model explained the relationships between the constructs and rational drug use behavior of outpatients in detail, and it suggests that future interventions among second-level hospital outpatients should consider demographic characteristics and should focus on improving motivation and behavioral skills in addition to the publicity of knowledge. PMID:26275301

  11. Development of chiral praziquantel analogues as potential drug candidates with activity to juvenile Schistosoma japonicum.

    PubMed

    Zheng, Yang; Dong, LanLan; Hu, Changyan; Zhao, Bo; Yang, Chunhua; Xia, Chaoming; Sun, Dequn

    2014-09-01

    A series of chiral praziquantel analogues were synthesized and evaluated against Schistosoma japonicum both in vitro and in vivo. All compounds exhibited low to considerable good activity in vivo. Remarkably, worm reduction rate of R-3 was 60.0% at a single oral dose of 200mg/kg against juvenile stage of Schistosoma japonicum. The target compounds displayed in vivo antischistosomal activity against both Schistosoma japonicum and Schistosoma mansoni. Furthermore, all R-isomers displayed stronger antischistosomal activity than S-isomers in vivo, indicating R-isomers were the active enantiomers, while S-isomers were less active ones. This structure activity relationship (SAR) could have important implications in further drug development for schistosomiasis.

  12. Computational medicinal chemistry for rational drug design: Identification of novel chemical structures with potential anti-tuberculosis activity.

    PubMed

    Koseki, Yuji; Aoki, Shunsuke

    2014-01-01

    Tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis and is a common infectious disease with high mortality and morbidity. The increasing prevalence of drug-resistant strains of TB presents a major public health problem. Due to the lack of effective drugs to treat these drug-resistant strains, the discovery or development of novel anti-TB drugs is important. Computer-aided drug design has become an established strategy for the identification of novel active chemicals through a combination of several drug design tools. In this review, we summarise the current chemotherapy for TB, describe attractive target proteins for the development of antibiotics against TB, and detail several computational drug design strategies that may contribute to the further identification of active chemicals for the treatment of not only TB but also other diseases.

  13. Regulation of hepatic drug transporter activity and expression by organochlorine pesticides.

    PubMed

    Bucher, Simon; Le Vee, Marc; Jouan, Elodie; Fardel, Olivier

    2014-03-01

    Organochlorine (OC) pesticides constitute a major class of persistent and toxic organic pollutants, known to modulate drug-detoxifying enzymes. In the present study, OCs were demonstrated to also alter the activity and expression of human hepatic drug transporters. Activity of the sinusoidal influx transporter OCT1 (organic cation transporter 1) was thus inhibited by endosulfan, chlordane, heptachlor, lindane, and dieldrine, but not by dichlorodiphenyltrichloroethane isomers, whereas those of the canalicular efflux pumps MRP2 (multidrug resistance-associated protein 2) and BCRP (breast cancer resistance protein) were blocked by endosulfan, chlordane, heptachlor, and chlordecone; this latter OC additionally inhibited the multidrug resistance gene 1 (MDR1)/P-glycoprotein (P-gp) activity. OCs, except endosulfan, were next found to induce MDR1/P-gp and MRP2 mRNA expressions in hepatoma HepaRG cells; some of them also upregulated BCRP. By contrast, expression of sinusoidal transporters was not impaired (organic anion-transporting polypeptide (OATP) 1B1 and OATP2B1) or was downregulated (sodium taurocholate co-transporting polypeptide (NTCP) and OCT1). Such regulations of drug transporter activity and expression, depending on the respective nature of OCs and transporters, may contribute to the toxicity of OC pesticides.

  14. Is there a role for therapeutic drug monitoring of vitamin D level as a surrogate marker for fracture risk?

    PubMed

    Isenor, Jennifer E; Ensom, Mary H H

    2010-03-01

    Clinical studies have suggested a possible association of low serum vitamin D levels in patients with bone fractures. This, coupled with a high prevalence of fractures and increases in associated disability and mortality, begs the question, is there evidence to support a role for therapeutic drug monitoring of vitamin D levels to prevent bone fractures? We use a previously published nine-step decision-making algorithm to answer this question. Optimal dosages of vitamin D have not been determined, although daily intake guidelines are suggested. Current vitamin D assays yield varying results, making it challenging for clinicians to interpret results from clinical trials and apply them directly to patients and their specific serum level data. Fracture risk is not easily assessable clinically, with no clear relationship between vitamin D concentrations and bone mineral density. The existing primary literature shows no clear relationship between vitamin D concentrations and fracture risk; target concentrations are not well established. Although the pharmacokinetic parameters of vitamin D are unpredictable and vitamin D supplementation is frequently lifelong, results of a vitamin D assay are unlikely to make a significant difference in the clinical decision-making process (i.e., provide more information than clinical judgment alone). Most published studies on vitamin D levels and fracture risk did not control for other potential reasons to monitor levels, multifactorial risks for fractures, and other confounders. Given limited data to support a direct relation between vitamin D levels and clinical outcome of fracture, inconsistent between-assay results, and no consensus on optimal levels, there is insufficient evidence to recommend routine therapeutic drug monitoring of vitamin D for fracture prevention; however, other reasons for monitoring might exist that are beyond the scope of this review. Recent availability of vitamin D assay standards may lead to future

  15. Drug conjugated nanoparticles activated by cancer cell specific mRNA

    PubMed Central

    Li, Nan-Sheng; Zamora, Edward A.; Gordon, David J.; Piccirilli, Joseph A.; Gordon, Peter M.

    2016-01-01

    We describe a customizable approach to cancer therapy in which a gold nanoparticle (Au-NP) delivers a drug that is selectively activated within the cancer cell by the presence of an mRNA unique to the cancer cell. Fundamental to this approach is the observation that the amount of drug released from the Au-NP is proportional to both the presence and abundance of the cancer cell specific mRNA in a cell. As proof-of-principle, we demonstrate both the efficient delivery and selective release of the multi-kinase inhibitor dasatinib from Au-NPs in leukemia cells with resulting efficacy in vitro and in vivo. Furthermore, these Au-NPs reduce toxicity against hematopoietic stem cells and T-cells. This approach has the potential to improve the therapeutic efficacy of a drug and minimize toxicity while being highly customizable with respect to both the cancer cell specific mRNAs targeted and drugs activated. PMID:27203672

  16. High Affinity Inha Inhibitors with Activity Against Drug-Resistant Strains of Mycobacterium Tuberculosis

    SciTech Connect

    Sullivan,T.; Truglio, J.; Boyne, M.; Novichenok, P.; Zhang, X.; Stratton, C.; Li, H.; Kaur, T.; Amin, A.; et al.

    2006-01-01

    Novel chemotherapeutics for treating multidrug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) are required to combat the spread of tuberculosis, a disease that kills more than 2 million people annually. Using structure-based drug design, we have developed a series of alkyl diphenyl ethers that are uncompetitive inhibitors of InhA, the enoyl reductase enzyme in the MTB fatty acid biosynthesis pathway. The most potent compound has a Ki{prime} value of 1 nM for InhA and MIC{sub 99} values of 2-3 {micro}g mL{sup -1} (6-10 {micro}M) for both drug-sensitive and drug-resistant strains of MTB. Overexpression of InhA in MTB results in a 9-12-fold increase in MIC{sub 99}, consistent with the belief that these compounds target InhA within the cell. In addition, transcriptional response studies reveal that the alkyl diphenyl ethers fail to upregulate a putative efflux pump and aromatic dioxygenase, detoxification mechanisms that are triggered by the lead compound triclosan. These diphenyl ether-based InhA inhibitors do not require activation by the mycobacterial KatG enzyme, thereby circumventing the normal mechanism of resistance to the front line drug isoniazid (INH) and thus accounting for their activity against INH-resistant strains of MTB.

  17. Integration of active pharmaceutical ingredient solid form selection and particle engineering into drug product design.

    PubMed

    Ticehurst, Martyn David; Marziano, Ivan

    2015-06-01

    This review seeks to offer a broad perspective that encompasses an understanding of the drug product attributes affected by active pharmaceutical ingredient (API) physical properties, their link to solid form selection and the role of particle engineering. While the crucial role of active pharmaceutical ingredient (API) solid form selection is universally acknowledged in the pharmaceutical industry, the value of increasing effort to understanding the link between solid form, API physical properties and drug product formulation and manufacture is now also being recognised. A truly holistic strategy for drug product development should focus on connecting solid form selection, particle engineering and formulation design to both exploit opportunities to access simpler manufacturing operations and prevent failures. Modelling and predictive tools that assist in establishing these links early in product development are discussed. In addition, the potential for differences between the ingoing API physical properties and those in the final product caused by drug product processing is considered. The focus of this review is on oral solid dosage forms and dry powder inhaler products for lung delivery.

  18. Hot melt extrusion for amorphous solid dispersions: temperature and moisture activated drug-polymer interactions for enhanced stability.

    PubMed

    Sarode, Ashish L; Sandhu, Harpreet; Shah, Navnit; Malick, Waseem; Zia, Hossein

    2013-10-07

    Hot melt extrudates (HMEs) of indomethacin (IND) with Eudragit EPO and Kollidon VA 64 and those of itraconazole (ITZ) with HPMCAS-LF and Kollidon VA 64 were manufactured using a Leistritz twin screw extruder. The milled HMEs were stored at controlled temperature and humidity conditions. The samples were collected after specified time periods for 3 months. The stability of amorphous HMEs was assessed using moisture analysis, thermal evaluation, powder X-ray diffraction, FTIR, HPLC, and dissolution study. In general, the moisture content increased with time, temperature, and humidity levels. Amorphous ITZ was physically unstable at very high temperature and humidity levels, and its recrystallization was detected in the HMEs manufactured using Kollidon VA 64. Although physical stability of IND was better sustained by both Eudragit EPO and Kollidon VA 64, chemical degradation of the drug was identified in the stability samples of HMEs with Eudragit EPO stored at 50 °C. The dissolution rates and the supersaturation levels were significantly decreased for the stability samples in which crystallization was detected. Interestingly, the supersaturation was improved for the stability samples of IND:Eudragit EPO and ITZ:HPMCAS-LF, in which no physical or chemical instability was observed. This enhancement in supersaturation was attributed to the temperature and moisture activated electrostatic interactions between the drugs and their counterionic polymers.

  19. Postgraduation Activities: All Degree Levels in Pennsylvania, 1979.

    ERIC Educational Resources Information Center

    Donny, William F.

    The employment of graduates of all degree levels in Pennsylvania institutions of higher education in 1979 was examined, based on data for 44,875 graduates or 50.6 percent of all higher education graduates. Research was designed to determine what proportion of graduates in each degree field and degree level were employed in their fields of…

  20. Hepatoprotective activity of Moringa oleifera on antitubercular drug-induced liver damage in rats.

    PubMed

    Pari, L; Kumar, N Ashok

    2002-01-01

    Moringa oleifera Lam (Moringaceae), commonly known as "Drumstick," is used in Indian folk medicine for the treatment of various illness. We have evaluated the hepatoprotective effect of an ethanolic extract of M. oleifera leaves on liver damage induced by antitubercular drugs such as isoniazid (INH), rifampicin (RMP), and pyrazinamide (PZA) in rats. Oral administration of the extract showed a significant protective action made evident by its effect on the levels of glutamic oxaloacetic transaminase (aspartate aminotransferase), glutamic pyruvic transaminase (alanine aminotransferase), alkaline phosphatase, and bilirubin in the serum; lipids, and lipid peroxidation levels in liver. This observation was supplemented by histopathological examination of liver sections. The results of this study showed that treatment with M. oleifera extracts or silymarin (as a reference) appears to enhance the recovery from hepatic damage induced by antitubercular drugs.

  1. In vivo monitoring of intracellular ATP levels in Leishmania donovani promastigotes as a rapid method to screen drugs targeting bioenergetic metabolism.

    PubMed

    Luque-Ortega, J R; Rivero-Lezcano, O M; Croft, S L; Rivas, L

    2001-04-01

    A method for the rapid screening of drugs targeting the bioenergetic metabolism of Leishmania spp. was developed. The system is based on the monitoring of changes in the intracellular ATP levels of Leishmania donovani promastigotes that occur in vivo, as assessed by the luminescence produced by parasites transfected with a cytoplasmic form of Phothinus pyralis luciferase and incubated with free-membrane permeable D-luciferin analogue D-luciferin-[1-(4,5-dimethoxy-2-nitrophenyl) ethyl ester]. A significant correlation was obtained between the rapid inhibition of luminescence with parasite proliferation and the dissipation of changes in mitochondrial membrane potential (DeltaPsi(m)) produced by buparvaquone or plumbagin, two leishmanicidal inhibitors of oxidative phosphorylation. To further validate this test, a screen of 14 standard leishmanicidal drugs, using a 50 microM cutoff, was carried out. Despite its semiquantitative properties and restriction to the promastigote stage, this test compares favorably with other bioenergetic parameters with respect to time and cell number requirements for the screening of drugs that affect mitochondrial activity.

  2. Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.

    PubMed

    Barakat, Khaled H; Law, John; Prunotto, Alessio; Magee, Wendy C; Evans, David H; Tyrrell, D Lorne; Tuszynski, Jack; Houghton, Michael

    2013-11-25

    The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.

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

    PubMed Central

    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

  4. Evaluating a policing strategy intended to disrupt an illicit street-level drug market.

    PubMed

    Corsaro, Nicholas; Brunson, Rod K; McGarrell, Edmund F

    2010-12-01

    The authors examined a strategic policing initiative that was implemented in a high crime Nashville, Tennessee neighborhood by utilizing a mixed-methodological evaluation approach in order to provide (a) a descriptive process assessment of program fidelity; (b) an interrupted time-series analysis relying upon generalized linear models; (c) in-depth resident interviews. Results revealed that the initiative corresponded with a statistically significant reduction in drug and narcotics incidents as well as perceived changes in neighborhood disorder within the target community. There was less-clear evidence, however, of a significant impact on other outcomes examined. The implications that an intensive crime prevention strategy corresponded with a reduction in specific forms of neighborhood crime illustrates the complex considerations that law enforcement officials face when deciding to implement this type of crime prevention initiative.

  5. Distant Interactions and Their Effects on Children's Physical Activity Levels

    ERIC Educational Resources Information Center

    Patterson, Debra L.; van der Mars, Hans

    2008-01-01

    Background: It has been observed that physical activity patterns of health-related behavior are established in childhood and may continue into adulthood. Recent findings showing a relationship between the onset of chronic diseases and sedentary lifestyles support the importance of examining Moderate to Vigorous Physical Activity (MVPA). One…

  6. Derived Intervention Levels for Tritium Based on Food and Drug Administration Methodology

    SciTech Connect

    Blanchard, A.

    1998-12-21

    In 1998, the FDA released it recommendations for age-dependent derived intervention levels for several radionuclides involved in nuclear accidents. One radionuclide that is not included in that document is tritium.

  7. Assessment of additive/nonadditive effects in structure-activity relationships: implications for iterative drug design.

    PubMed

    Patel, Yogendra; Gillet, Valerie J; Howe, Trevor; Pastor, Joaquin; Oyarzabal, Julen; Willett, Peter

    2008-12-11

    Free-Wilson (FW) analysis is common practice in medicinal chemistry and is based on the assumption that the contributions to activity made by substituents at different substitution positions are additive. We analyze eight near complete combinatorial libraries assayed on several different biological response(s) (GPCR, ion channel, kinase and P450 targets) and show that only half-exhibit clear additive behavior, which leads us to question the concept of additivity that is widely taken for granted in drug discovery. Next, we report a series of retrospective experiments in which subsets are extracted from the libraries for FW analysis to determine the minimum attributes (size, distribution of substituents, and activity range) necessary to reach the same conclusion about additive/nonadditive effects. These attributes can provide guidelines on when it is appropriate to apply FW analysis as well as for library design, and they also have important implications for further steps in iterative drug design.

  8. Nylon-3 polymers active against drug-resistant Candida albicans biofilms.

    PubMed

    Liu, Runhui; Chen, Xinyu; Falk, Shaun P; Masters, Kristyn S; Weisblum, Bernard; Gellman, Samuel H

    2015-02-18

    Candida albicans is the most common fungal pathogen in humans, and most diseases produced by C. albicans are associated with biofilms. We previously developed nylon-3 polymers with potent activity against planktonic C. albicans and excellent C. albicans versus mammalian cell selectivity. Here we show that these nylon-3 polymers have strong and selective activity against drug-resistant C. albicans in biofilms, as manifested by inhibition of biofilm formation and by killing of C. albicans in mature biofilms. The best nylon-3 polymer (poly-βNM) is superior to the antifungal drug fluconazole for all three strains examined. This polymer is slightly less effective than amphotericin B (AmpB) for two strains, but the polymer is superior against an AmpB-resistant strain.

  9. In vitro activities of a wide panel of antifungal drugs against various Scopulariopsis and Microascus species.

    PubMed

    Skóra, Magdalena; Bulanda, Małgorzata; Jagielski, Tomasz

    2015-09-01

    The in vitro activities of 11 antifungal drugs against 68 Scopulariopsis and Microascus strains were investigated. Amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole, and ciclopirox showed no or poor antifungal effect. The best activities were exhibited by terbinafine and caspofungin, where the MIC and MEC (minimal effective concentration) ranges were 0.0313 to >16 μg/ml and 0.125 to 16 μg/ml, respectively. The MIC and MEC modes were both 1 µg/ml for terbinafine and caspofungin; the MIC50 and MEC50 were 1 µg/ml for both drugs, whereas the MIC90 and MEC90 were 4 µg/ml and 16 µg/ml, respectively.

  10. Cooperative autoinhibition and multi-level activation mechanisms of calcineurin

    PubMed Central

    Li, Sheng-Jie; Wang, Jue; Ma, Lei; Lu, Chang; Wang, Jie; Wu, Jia-Wei; Wang, Zhi-Xin

    2016-01-01

    The Ca2+/calmodulin-dependent protein phosphatase calcineurin (CN), a heterodimer composed of a catalytic subunit A and an essential regulatory subunit B, plays critical functions in various cellular processes such as cardiac hypertrophy and T cell activation. It is the target of the most widely used immunosuppressants for transplantation, tacrolimus (FK506) and cyclosporin A. However, the structure of a large part of the CNA regulatory region remains to be determined, and there has been considerable debate concerning the regulation of CN activity. Here, we report the crystal structure of full-length CN (β isoform), which revealed a novel autoinhibitory segment (AIS) in addition to the well-known autoinhibitory domain (AID). The AIS nestles in a hydrophobic intersubunit groove, which overlaps the recognition site for substrates and immunosuppressant-immunophilin complexes. Indeed, disruption of this AIS interaction results in partial stimulation of CN activity. More importantly, our biochemical studies demonstrate that calmodulin does not remove AID from the active site, but only regulates the orientation of AID with respect to the catalytic core, causing incomplete activation of CN. Our findings challenge the current model for CN activation, and provide a better understanding of molecular mechanisms of CN activity regulation. PMID:26794871

  11. Effect of the mechanical activation on size reduction of crystalline acetaminophen drug particles

    PubMed Central

    Biazar, Esmaeil; Beitollahi, Ali; Rezayat, S Mehdi; Forati, Tahmineh; Asefnejad, Azadeh; Rahimi, Mehdi; Zeinali, Reza; Ardeshir, Mahmoud; Hatamjafari, Farhad; Sahebalzamani, Ali; Heidari, Majid

    2009-01-01

    The decrease in particle size may offer new properties to drugs. In this study, we investigated the size reduction influence of the acetaminophen (C8H9O2N) particles by mechanical activation using a dry ball mill. The activated samples with the average size of 1 μm were then investigated in different time periods with the infrared (IR), inductively coupled plasma (ICP), atomic force microscopy (AFM), and X-ray diffraction (XRD) methods. The results of the IR and XRD images showed no change in the drug structure after the mechanical activation of all samples. With the peak height at full width at half maximum from XRD and the Scherrer equation, the size of the activated crystallite samples illustrated that the AFM images were in sound agreement with the Scherrer equation. According to the peaks of the AFM images, the average size of the particles in 30 hours of activation was 24 nm with a normal particle distribution. The ICP analysis demonstrated the presence of tungsten carbide particle impurities after activation from the powder sample impacting with the ball and jar. The greatest reduction in size was after milling for 30 hours. PMID:20054432

  12. Playground Designs to Increase Physical Activity Levels during School Recess: A Systematic Review

    ERIC Educational Resources Information Center

    Escalante, Yolanda; García-Hermoso, Antonio; Backx, Karianne; Saavedra, Jose M.

    2014-01-01

    School recess provides a major opportunity to increase children's physical activity levels. Various studies have described strategies to increase levels of physical activity. The purpose of this systematic review is therefore to examine the interventions proposed as forms of increasing children's physical activity levels during recess. A…

  13. Changes of Nitric Oxide and Peroxynitrite Serum Levels during Drug Therapy in Patients with Obsessive-Compulsive Disorder

    PubMed Central

    Aghakoochakzadeh, Maryam

    2016-01-01

    Objectives. Some studies have shown that increased nitric oxide (NO) concentrations may be associated with obsessive-compulsive disorder (OCD). In a few animal researches, enhanced synthesis of NO had reversed the effect of selective serotonin reuptake inhibitors (SSRIs). The present study tries to find the effect of treatment with SSRIs on NO serum levels and its product peroxynitrite. Patients and Methods. Patients diagnosed with OCD who are candidates of receiving SSRIs entered this study. Two blood samples were taken from subjects, prior to drug therapy and after the patients had shown some improvements due to their regimen. Serum NO and peroxynitrite levels were measured and their correlation with SSRI use was assessed. Results. 31 patients completed this study. Mean concentrations of NO and peroxynitrite prior to drug therapy were 28.63 ± 16.9 and 5.73 ± 2.5 μmol/L, respectively. These values were 18.87 ± 7.55 and 2.15 ± 0.94 μmol/L at the second blood test. With p values < 0.05, these differences were considered significant. Conclusion. Patients, who showed improvement of OCD symptoms after a mean duration of SSRI monotherapy of 3.531 ± 0.64 months, had lower values of NO and peroxynitrite in their sera compared to their levels prior to therapy. Such results can be helpful in finding a predictive factor of response to therapy and augmentation therapy with future drugs that target NO synthesis. PMID:27822492

  14. Effects of common buffer systems on drug activity: the case of clerocidin.

    PubMed

    Richter, Sara; Fabris, Daniele; Binaschi, Monica; Gatto, Barbara; Capranico, Giovanni; Palumbo, Manlio

    2004-04-01

    Two widely used biological buffers [tris(hydroxymethyl)aminomethane (TRIS) and phosphate] covalently react with the topoisomerase II inhibitor clerocidin, affecting the drug's reactivity profile. Comprehensive analytical and structural analysis obtained by LC/MS, MS/MS, NMR, and IR techniques shows that these buffers form reversible and irreversible adducts through reactions with chemical groups, such as carbonyls, aldehydes, and epoxide. Analysis of the kinetic data on adducts formation suggests two parallel mechanisms for the inhibition of drug activity. The first involves modulation of the reactivity of the epoxide group obtained by elimination of the spiro system and relief of ring strain. This effect does not abolish epoxide reactivity and is more evident for the TRIS adduct, which can count on intramolecular stabilization of the form devoid of the spiro system. The second mechanism involves the slow nucleophilic attack to the epoxide ring, which results in permanent deactivation of the functional group responsible for topoisomerase II inhibition. This effect is predominant in phosphate buffer and is more evident for longer reaction times. These results provide a compelling reminder that the activity of chemically complex drugs in biological systems can be severely altered by buffer interactions, which may not be immediately predictable from the identity of the active group(s) and may require a more detailed knowledge of the subtle effects induced by vicinal groups.

  15. Active wound dressings based on bacterial nanocellulose as drug delivery system for octenidine.

    PubMed

    Moritz, Sebastian; Wiegand, Cornelia; Wesarg, Falko; Hessler, Nadine; Müller, Frank A; Kralisch, Dana; Hipler, Uta-Christina; Fischer, Dagmar

    2014-08-25

    Although bacterial nanocellulose (BNC) may serve as an ideal wound dressing, it exhibits no antibacterial properties by itself. Therefore, in the present study BNC was functionalized with the antiseptic drug octenidine. Drug loading and release, mechanical characteristics, biocompatibility, and antimicrobial efficacy were investigated. Octenidine release was based on diffusion and swelling according to the Ritger-Peppas equation and characterized by a time dependent biphasic release profile, with a rapid release in the first 8h, followed by a slower release rate up to 96 h. The comparison between lab-scale and up-scale BNC identified thickness, water content, and the surface area to volume ratio as parameters which have an impact on the control of the release characteristics. Compression and tensile strength remained unchanged upon incorporation of octenidine in BNC. In biological assays, drug-loaded BNC demonstrated high biocompatibility in human keratinocytes and antimicrobial activity against Staphylococcus aureus. In a long-term storage test, the octenidine loaded in BNC was found to be stable, releasable, and biologically active over a period of 6 months without changes. In conclusion, octenidine loaded BNC presents a ready-to-use wound dressing for the treatment of infected wounds that can be stored over 6 months without losing its antibacterial activity.

  16. Quantitative analysis of drug effects at the whole-body level: a case study for glucose metabolism in malaria patients.

    PubMed

    Snoep, Jacky L; Green, Kathleen; Eicher, Johann; Palm, Daniel C; Penkler, Gerald; du Toit, Francois; Walters, Nicolas; Burger, Robert; Westerhoff, Hans V; van Niekerk, David D

    2015-12-01

    We propose a hierarchical modelling approach to construct models for disease states at the whole-body level. Such models can simulate effects of drug-induced inhibition of reaction steps on the whole-body physiology. We illustrate the approach for glucose metabolism in malaria patients, by merging two detailed kinetic models for glucose metabolism in the parasite Plasmodium falciparum and the human red blood cell with a coarse-grained model for whole-body glucose metabolism. In addition we use a genome-scale metabolic model for the parasite to predict amino acid production profiles by the malaria parasite that can be used as a complex biomarker.

  17. A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation.

    PubMed

    Artemov, Artem; Aliper, Alexander; Korzinkin, Michael; Lezhnina, Ksenia; Jellen, Leslie; Zhukov, Nikolay; Roumiantsev, Sergey; Gaifullin, Nurshat; Zhavoronkov, Alex; Borisov, Nicolas; Buzdin, Anton

    2015-10-06

    A new generation of anticancer therapeutics called target drugs has quickly developed in the 21st century. These drugs are tailored to inhibit cancer cell growth, proliferation, and viability by specific interactions with one or a few target proteins. However, despite formally known molecular targets for every "target" drug, patient response to treatment remains largely individual and unpredictable. Choosing the most effective personalized treatment remains a major challenge in oncology and is still largely trial and error. Here we present a novel approach for predicting target drug efficacy based on the gene expression signature of the individual tumor sample(s). The enclosed bioinformatic algorithm detects activation of intracellular regulatory pathways in the tumor in comparison to the corresponding normal tissues. According to the nature of the molecular targets of a drug, it predicts whether the drug can prevent cancer growth and survival in each individual case by blocking the abnormally activated tumor-promoting pathways or by reinforcing internal tumor suppressor cascades. To validate the method, we compared the distribution of predicted drug efficacy scores for five drugs (Sorafenib, Bevacizumab, Cetuximab, Sorafenib, Imatinib, Sunitinib) and seven cancer types (Clear Cell Renal Cell Carcinoma, Colon cancer, Lung adenocarcinoma, non-Hodgkin Lymphoma, Thyroid cancer and Sarcoma) with the available clinical trials data for the respective cancer types and drugs. The percent of responders to a drug treatment correlated significantly (Pearson's correlation 0.77 p = 0.023) with the percent of tumors showing high drug scores calculated with the current algorithm.

  18. In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni

    PubMed Central

    Neves, Bruno J.; Braga, Rodolpho C.; Bezerra, José C. B.; Cravo, Pedro V. L.; Andrade, Carolina H.

    2015-01-01

    Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. PMID:25569258

  19. In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni.

    PubMed

    Neves, Bruno J; Braga, Rodolpho C; Bezerra, José C B; Cravo, Pedro V L; Andrade, Carolina H

    2015-01-01

    Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes.

  20. Patterns of drug distribution: implications and issues.

    PubMed

    Johnson, Bruce D

    2003-01-01

    This article delineates various patterns of illicit sales of drugs, especially at the retail (and near-retail) level, addressing a variety of central issues about drug sales and distribution documented during the past 30 years. including: a) the links between drug consumption and drug distribution activities; b) the various distribution roles; c) various levels of the distribution hierarchy; d) types of retail and wholesale markets; e) the association of drug distribution with nondrug associated criminality and violence. The article also will address the implications of drug distribution: whether various public policies such as supply reduction and source interdiction affect illicit drug markets, and how policing strategies and various law enforcement strategies can influence the involvement of individual participation in drug distribution activities. The overlooked contribution of treatment for "drug abuse" to reducing drug sales and distribution activities also will be considered as will other critical unresolved issues.

  1. Patterns of Drug Distribution: Implications and Issues#

    PubMed Central

    Johnson, Bruce D.

    2007-01-01

    This article delineates various patterns of illicit sales of drugs, especially at the retail (and near-retail) level, addressing a variety of central issues about drug sales and distribution documented during the past 30 years, including: a) the links between drug consumption and drug distribution activities; b) the various distribution roles; c) various levels of the distribution hierarchy; d) types of retail and wholesale markets; e) the association of drug distribution with nondrug associated criminality and violence. The article also will address the implications of drug distribution: whether various public policies such as supply reduction and source interdiction affect illicit drug markets, and how policing strategies and various law enforcement strategies can influence the involvement of individual participation in drug distribution activities. The overlooked contribution of treatment for “drug abuse” to reducing drug sales and distribution activities also will be considered as will other critical unresolved issues. PMID:14582578

  2. 75 FR 12756 - Agency Information Collection Activities: Proposed Collection; Comment Request; Prescription Drug...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-17

    ... Collection; Comment Request; Prescription Drug Advertisements AGENCY: Food and Drug Administration, HHS..., contained in FDA's regulations on prescription drug advertisements. DATES: Submit written or electronic... of information technology. Prescription Drug Advertisements--21 CFR 202.1 (OMB Control Number...

  3. The role of antiepileptic drugs in free radicals generation and antioxidant levels in epileptic patients.

    PubMed

    Eldin, Essam Eldin Mohamed Nour; Elshebiny, Hosam Abdel-Fattah; Mohamed, Tarek Mostafa; Abdel-Aziz, Mohamed Abdel-Azim; El-Readi, Mahmoud Zaki

    2016-01-01

    Many risk factors are encountered during the pathogenesis of epilepsy. In this study, the effect of seizure frequency on free radical generation and antioxidants levels in epileptic patients was evaluated. This study was carried out on 15 healthy controls (GI) and 60 epileptic patients treated with mono- or poly-therapy of carbamazepine, valproic acid, or phenytoin. The treated epileptic patients were divided into 2 main groups according to the seizure frequency: controlled seizure patients GII (n = 30) and uncontrolled seizure patients GIII (n = 30). GII included the GIIA subgroup (n = 15) which had been seizure free for more than 12 months and the GIIB subgroup (n = 15) which had been seizure free for a period from 6 to12 months. GIII included GIIIA (n = 15) and GIIIB (n = 15) for patients which had a seizure frequency of less than and more than four times/month, respectively. In comparison to the control group (GI), the levels of nitric oxide (NO) and malondialdehyde/creatinine ratio were significantly increased in GIIB, GIIIA, and GIIIB, while vitamins A and E levels were significantly decreased in GIIIB. Serum NO levels had significant negative correlations with serum vitamin E in the GIIA and GIIB groups, and with vitamin A in the GIIIA and GIIIB groups. However, serum NO had positive correlation with urinary MDA/Cr ratio. The imbalance between free radical generation and antioxidant system in epileptic patients may be a factor in seizure frequency.

  4. Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo

    PubMed Central

    Liu, Yancheng; Tan, Shumin; Huang, Lu; Abramovitch, Robert B.; Rohde, Kyle H.; Zimmerman, Matthew D.; Chen, Chao; Dartois, Véronique; VanderVen, Brian C.

    2016-01-01

    Successful chemotherapy against Mycobacterium tuberculosis (Mtb) must eradicate the bacterium within the context of its host cell. However, our understanding of the impact of this environment on antimycobacterial drug action remains incomplete. Intriguingly, we find that Mtb in myeloid cells isolated from the lungs of experimentally infected mice exhibit tolerance to both isoniazid and rifampin to a degree proportional to the activation status of the host cells. These data are confirmed by in vitro infections of resting versus activated macrophages where cytokine-mediated activation renders Mtb tolerant to four frontline drugs. Transcriptional analysis of intracellular Mtb exposed to drugs identified a set of genes common to all four drugs. The data imply a causal linkage between a loss of fitness caused by drug action and Mtb’s sensitivity to host-derived stresses. Interestingly, the environmental context exerts a more dominant impact on Mtb gene expression than the pressure on the drugs’ primary targets. Mtb’s stress responses to drugs resemble those mobilized after cytokine activation of the host cell. Although host-derived stresses are antimicrobial in nature, they negatively affect drug efficacy. Together, our findings demonstrate that the macrophage environment dominates Mtb’s response to drug pressure and suggest novel routes for future drug discovery programs. PMID:27114608

  5. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug

    PubMed Central

    Sharpe, Martyn A.; Livingston, Andrew D.; Gist, Taylor L.; Ghosh, Pardip; Han, Junyan; Baskin, David S.

    2015-01-01

    The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P+-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models. PMID:26501110

  6. Self-Nanoemulsified Drug Delivery System of Hydrochlorothiazide for Increasing Dissolution Rate and Diuretic Activity.

    PubMed

    Mendes, Cassiana; Buttchevitz, Aline; Kruger, Jéssica Henriques; Caon, Thiago; de Oliveira Benedet, Patricia; Lemos-Senna, Elenara; Silva, Marcos Antônio Segatto

    2017-02-17

    Hydrochlorothiazide (HCTZ) is a class IV drug according to the Biopharmaceutical Classification System. This study aimed the development of self-nanoemulsifying drug delivery system (SNEDDS) for HCTZ as an approach to overcome the biopharmaceutical limitations. Pre-formulation screening and ternary phase diagrams were carried out to select the oil phase, the surfactant, and the co-surfactant as the amount of each constituent. The optimized formulations, with reduced amount of surfactant, and composed of medium chain triglycerides, Cremophor EL and Transcutol P did not affect the pH or show drug incompatibilities. The SNEDDS were stabilized by the nanoscale globules and high negative zeta potential. All the physicochemical characterization assays were performed in biorelevant media to better predict the in vivo performance. The enhanced dissolution rate of the SNEDDS reflected in the in vivo diuretic activity, presenting a natriuresis, kaliuresis, and chloriuresis at early stages and an increased volume of total urine compared with HCTZ alone. The designed SNEDDS produced an improvement in the pharmacodynamics due to high dissolution and probable inhibition of intestinal efflux protein by Cremophor EL. The use of SNEDDS demonstrated to be an efficient approach to modulate the absorption of HCTZ and drug therapeutics.

  7. Magnetic field activated drug release system based on magnetic PLGA microspheres for chemo-thermal therapy.

    PubMed

    Fang, Kun; Song, Lina; Gu, Zhuxiao; Yang, Fang; Zhang, Yu; Gu, Ning

    2015-12-01

    Controlled drug delivery systems have been extensively investigated for cancer therapy in order to obtain better specific targeting and therapeutic efficiency. Herein, we developed doxorubicin-loaded magnetic PLGA microspheres (DOX-MMS), in which DOX was encapsulated in the core and high contents (28.3 wt%) of γ-Fe2O3 nanoparticles (IOs) were electrostatically assembled on the surface of microsphere to ensure the high sensitivity to response of an external alternating current magnetic field (ACMF). The IOs in PLGA shell can both induce the heat effect and trigger shell permeability enhancement to release drugs when DOX-MMs was activated by ACMF. Results show that the cumulative drug release from DOX-MMs exposed to ACMF for 30 min (21.6%) was significantly higher (approximately 7 times higher) than that not exposed to ACMF (2.8%). The combination of hyperthermia and enhanced DOX release from DOX-MMS is beneficial for in vitro 4T1 breast cancer cell apoptosis as well as effective inhibition of tumor growth in 4T1 tumor xenografts. Therefore, the DOX-MMS can be optimized as powerful delivery system for efficient magnetic responsive drug release and chemo-thermal therapy.

  8. The biological and clinical activity of anti-malarial drugs in autoimmune disorders.

    PubMed

    Taherian, Elham; Rao, Anshul; Malemud, Charles J; Askari, Ali D

    2013-01-01

    Chloroquine and hydroxychloroquine are 4-aminoquinoline compounds commonly employed as anti-malarial drugs. Chloroquine and its synthetic analogue, hydroxychloroquine also belong to the disease-modifying anti-rheumatic drug class because these drugs are immunosuppressive. The immunosuppressive activity of chloroquine and hydroxychloroquine is likely to account for their capacity to reduce T-cell and B-cell hyperactivity as well as pro-inflammatory cytokine gene expression. This review evaluated experimental and clinical trials results as well as clinical response data relative to the use of chloroquine and/or hydroxychloroquine as first-line medical therapies in systemic lupus erythematosus, rheumatoid arthritis, primary Sjogren's syndrome, the anti-phospholipid syndrome and in the treatment of sarcoidosis. A primary outcomes measure in these clinical trials was the extent to which chloroquine and/or hydroxychloroquine reduced disease progression or exacerbations and/or the use and dosage of corticosteroids. The relative efficacy of chloroquine and hydroxychloroquine in modifying the clinical course of these autoimmune disorders is balanced against evidence that these drugs induce adverse effects which may reduce their use and effectiveness in the therapy of autoimmune disorders.

  9. Phytochemicals increase the antibacterial activity of antibiotics by acting on a drug efflux pump

    PubMed Central

    Ohene-Agyei, Thelma; Mowla, Rumana; Rahman, Taufiq; Venter, Henrietta

    2014-01-01

    Drug efflux pumps confer resistance upon bacteria to a wide range of antibiotics from various classes. The expression of efflux pumps are also implicated in virulence and biofilm formation. Moreover, organisms can only acquire resistance in the presence of active drug efflux pumps. Therefore, efflux pump inhibitors (EPIs) are attractive compounds to reverse multidrug resistance and to prevent the development of resistance in clinically relevant bacterial pathogens. We investigated the potential of pure compounds isolated from plants to act as EPIs. In silico screening was used to predict the bioactivity of plant compounds and to compare that with the known EPI, phe-arg-β-naphthylamide (PAβN). Subsequently, promising products have been tested for their ability to inhibit efflux. Plumbagin nordihydroguaretic acid (NDGA) and to a lesser degree shikonin, acted as sensitizers of drug-resistant bacteria to currently used antibiotics and were able to inhibit the efflux pump-mediated removal of substrate from cells. We demonstrated the feasibility of in silico screening to identify compounds that potentiate the action of antibiotics against drug-resistant strains and which might be potentially useful lead compounds for an EPI discovery program. PMID:25224951

  10. A new targeted drug delivery method using ultrasound and acoustically active lipospheres

    NASA Astrophysics Data System (ADS)

    Shortencarier, Michaelann; Bloch, Susannah; Dayton, Paul; Ferrara, Kathy; Matsunaga, Terry; Labell, Rachel; Schumann, Patricia

    2005-04-01

    The goal is to create a strategy for localized drug delivery using engineered delivery vehicles and ultrasound energy. These drug delivery vehicles, referred to as acoustically active lipospheres (AALs), consist of small gas bubbles surrounded by thick oil shells (where drugs can be carried) and are enclosed by an outermost lipid layer. Ultrasound radiation force can be used to displace these vehicles near the blood vessel wall, after which a higher intensity pulse can fragment the vehicle and transfer its contents to the endothelium. Blood velocity ranges from 1 to 10 mm/s in the microvasculature. Therefore, agents in capillaries insonified by a transducer with a 1 mm focal beam width for 0.1 to 1 seconds can be displaced of 1 to 2 mm. Delivery vehicles containing various fluorescent dyes within the oil layer are exposed to ultrasound in cell chambers or flowing vessels. Fluorescence intensity increases more than 10-fold with application of radiation force and fragmentation, both over no exposure and over fragmentation pulses alone (both P<0.001). This implies radiation force is necessary to bring AALs into proximity of the cell monolayer before their destruction in order for drug delivery to occur.

  11. Successful Treatment of Intracranial Glioblastoma Xenografts With a Monoamine Oxidase B-Activated Pro-Drug.

    PubMed

    Sharpe, Martyn A; Livingston, Andrew D; Gist, Taylor L; Ghosh, Pardip; Han, Junyan; Baskin, David S

    2015-09-01

    The last major advance in the treatment of glioblastoma multiforme (GBM) was the introduction of temozolomide in 1999. Treatment with temozolomide following surgical debulking extends survival rate compared to radiotherapy and debulking alone. However, virtually all glioblastoma patients experience disease progression within 7 to 10 months. Although many salvage treatments, including bevacizumab, rechallenge with temozolomide, and other alkylating agents, have been evaluated, none of these clearly improves survival. Monoamine oxidase B (MAOB) is highly expressed in glioblastoma cell mitochondria, and mitochondrial function is intimately tied to treatment-resistant glioblastoma progression. These glioblastoma properties provide a strong rationale for pursuing a MAOB-selective pro-drug treatment approach that, upon drug activation, targets glioblastoma mitochondria, especially mitochondrial DNA. MP-MUS is the lead compound in a family of pro-drugs designed to treat GBM that is converted into the mature, mitochondria-targeting drug, P(+)-MUS, by MAOB. We show that MP-MUS can successfully kill primary gliomas in vitro and in vivo mouse xenograft models.

  12. High-throughput mapping of brain-wide activity in awake and drug-responsive vertebrates.

    PubMed

    Lin, Xudong; Wang, Shiqi; Yu, Xudong; Liu, Zhuguo; Wang, Fei; Li, Wai Tsun; Cheng, Shuk Han; Dai, Qiuyun; Shi, Peng

    2015-02-07

    The reconstruction of neural activity across complete neural circuits, or brain activity mapping, has great potential in both fundamental and translational neuroscience research. Larval zebrafish, a vertebrate model, has recently been demonstrated to be amenable to whole brain activity mapping in behaving animals. Here we demonstrate a microfluidic array system ("Fish-Trap") that enables high-throughput mapping of brain-wide activity in awake larval zebrafish. Unlike the commonly practiced larva-processing methods using a rigid gel or a capillary tube, which are laborious and time-consuming, the hydrodynamic design of our microfluidic chip allows automatic, gel-free, and anesthetic-free processing of tens of larvae for microscopic imaging with single-cell resolution. Notably, this system provides the capability to directly couple pharmaceutical stimuli with real-time recording of neural activity in a large number of animals, and the local and global effects of pharmacoactive drugs on the nervous system can be directly visualized and evaluated by analyzing drug-induced functional perturbation within or across different brain regions. Using this technology, we tested a set of neurotoxin peptides and obtained new insights into how to exploit neurotoxin derivatives as therapeutic agents. The novel and versatile "Fish-Trap" technology can be readily unitized to study other stimulus (optical, acoustic, or physical) associated functional brain circuits using similar experimental strategies.

  13. Surgical treatment of infective endocarditis in active intravenous drug users: a justified procedure?

    PubMed Central

    2014-01-01

    Background Infective endocarditis is a life threatening complication of intravenous drug abuse, which continues to be a major burden with inadequately characterised long-term outcomes. We reviewed our institutional experience of surgical treatment of infective endocarditis in active intravenous drug abusers with the aim of identifying the determinants long-term outcome of this distinct subgroup of infective endocarditis patients. Methods A total of 451 patients underwent surgery for infective endocarditis between January 1993 and July 2013 at the University Hospital of Heidelberg. Of these patients, 20 (7 female, mean age 35 ± 7.7 years) underwent surgery for infective endocarditis with a history of active intravenous drug abuse. Mean follow-up was 2504 ± 1842 days. Results Staphylococcus aureus was the most common pathogen detected in preoperative blood cultures. Two patients (10%) died before postoperative day 30. Survival at 1, 5 and 10 years was 90%, 85% and 85%, respectively. Freedom from reoperation was 100%. Higher NYHA functional class, higher EuroSCORE II, HIV infection, longer operating time, postoperative fever and higher requirement for red blood cell transfusion were associated with 90-day mortality. Conclusions In active intravenous drug abusers, surgical treatment for infective endocarditis should be performed as extensively as possible and be followed by an aggressive postoperative antibiotic therapy to avoid high mortality. Early surgical intervention is advisable in patients with precipitous cardiac deterioration and under conditions of staphylococcal endocarditis. However, larger studies are necessary to confirm our preliminary results. PMID:24661344

  14. Effect of Pluronic P85 on ATPase Activity of Drug Efflux Transporters

    PubMed Central

    Batrakova, Elena V.; Li, Shu; Li, Yili; Alakhov, Valery Yu.; Kabanov, Alexander V.

    2009-01-01

    Purpose Pluronic block copolymers are potent sensitizers of multi-drug resistant (MDR) cancer cells. The sensitization effect by Pluronics is a result of two processes acting in concert: i) intracellular ATP depletion, and ii) inhibition of ATPase activity of drug efflux proteins. This work characterizes effects of Pluronic P85 on ATPase activities of Pgp, MRP1, and MRP2 drug efflux transport proteins and interaction of these proteins with their substrates, vinblastine, and leucotriene C4. Methods Using membranes overexpressing Pgp, MRP1, and MRP2, the current study evaluates effects of Pluronic P85 (P85) on the kinetic parameters (Vmax, Km, Vmax/Km) of ATP hydrolysis by these ATPases. Results The decreases in the maximal reaction rates (Vmax) and increases in apparent Michaelis constants (Km) for these transporters in the presence of various concentrations of P85 were observed. The mechanism of these effects may involve i) conformational changes of the transporter due to membrane fluidization and/or ii) nonspecific steric hindrance of the drug-binding sites by P85 chains embedded into cellular membranes. The extent of these alterations was increased in the row MRP1 < MRP2 << Pgp. Conclusions These data suggest that there are unifying pathways for the inhibition of Pgp and MRPs by the block copolymer. However, the effect of P85 on Pgp ATPase activity is considerably greater compared with the effects on MRP1 and MRP2 ATPases. This may be a reason for greater inhibitory effects of Pluronic in Pgp- compared with MRP-overexpressing cells. PMID:15648254

  15. Online Activity Levels Are Related to Caffeine Dependency.

    PubMed

    Phillips, James G; Landhuis, C Erik; Shepherd, Daniel; Ogeil, Rowan P

    2016-05-01

    Online activity could serve in the future as behavioral markers of emotional states for computer systems (i.e., affective computing). Hence, this study considered relationships between self-reported stimulant use and online study patterns. Sixty-two undergraduate psychology students estimated their daily caffeine use, and this was related to study patterns as tracked by their use of a Learning Management System (Blackboard). Caffeine dependency was associated with less time spent online, lower rates of file access, and fewer online activities completed. Reduced breadth or depth of processing during work/study could be used as a behavioral marker of stimulant use.

  16. Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach.

    PubMed

    Mathialagan, Sumathy; Piotrowski, Mary A; Tess, David A; Feng, Bo; Litchfield, John; Varma, Manthena V

    2017-04-01

    Organic anion transporters (OATs) are important in the renal secretion, and thus, the clearance, of many drugs; and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured in vitro using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir), and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance (after physiologic scaling) to in vivo secretory clearance. Using the estimated RAFs (0.64, 7.3, and 4.1, respectively, for OAT1, OAT2, and OAT3, respectively) and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with average fold errors (AFEs) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play a predominant role in renal secretion for 22 of the 31 drugs evaluated. This mechanistic static approach was further applied to quantitatively predict renal drug-drug interactions (AFE ∼1.6) of the substrate drugs with probenecid, a clinical probe OAT inhibitor. In conclusion, the proposed in vitro-in vivo extrapolation approach is the first comprehensive attempt toward mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.

  17. Intermedilysin release by Streptococcus intermedius: effects of various antibacterial drugs at sub-MIC levels.

    PubMed

    Taylor, Mark B; Oh, Janice H L; Kang, K L; Chow, Vincent T K

    2005-02-15

    Intermedilysin is a cytolytic toxin produced by Streptococcus intermedius, a pathogen of humans. In vitro studies showed that exposure of S. intermedius to sub-minimum inhibitory concentration (MIC) levels (1/2 MIC) of protein-inhibiting antibiotics and nucleic acid-inhibiting antibiotics decreased intermedilysin release by S. intermedius. The most potent antibiotic was clindamycin. On the other hand, exposure to cell wall-inhibiting antibiotics generally showed insignificant changes in intermedilysin release at sub-MIC concentrations. Investigations into possible mechanisms underlying this sub-MIC effect with clindamycin showed that there was selective decrease in biosynthesis and release of toxin after exposure to 1/2 MIC condition. However, no significant differences in the mRNA levels of the intermedilysin gene were observed.

  18. Chemical proteomic probes for profiling cytochrome P450 activities and drug interactions in vivo

    PubMed Central

    Wright, Aaron T.; Cravatt, Benjamin F.

    2007-01-01

    The cytochrome P450 (P450) superfamily metabolizes many endogenous signaling molecules and drugs. P450 enzymes are regulated by post-translational mechanisms in vivo, which hinders their functional characterization by conventional genomic or proteomic methods. Here, we describe a chemical proteomic strategy to profile P450 activities directly in living systems. Derivatization of a mechanism-based inhibitor with a “clickable” handle provided an activity-based probe that labels multiple P450s both in proteomic extracts and in vivo. This probe was used to record alterations in liver P450 activities triggered by chemical agents, including inducers of P450 expression and direct P450 inhibitors. The chemical proteomic strategy described herein thus offers a versatile method to monitor P450 activities and small molecule interactions in any biological system and, through doing so, should facilitate the functional characterization of this large and diverse enzyme class. PMID:17884636

  19. Mid-level Features Improve Recognition of Interactive Activities

    DTIC Science & Technology

    2012-11-14

    Recognizing action as clouds of space-time interest points. In CVPR, 2009. [5] W. Brendel, A. Fern , and S. Todorovic. Probabilistic event logic for interval...context. In CVPR, 2009. [27] R. Messing, C. Pal, and H. Kautz. Activity recognition using the velocity histories of tracked keypoints. In ICCV, 2009

  20. Highlands County Energy Education Activities--High School Level.

    ERIC Educational Resources Information Center

    Allen, Rodney F., Ed.

    Presented are five instructional units, developed by the Tri-County Teacher Education Center, for the purpose of educating secondary school students on Florida's unique energy problems. Unit one provides a series of value clarification and awareness activities as an introduction to energy. Unit two uses mathematics exercises to examine energy…

  1. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... mental health services for children with disabilities; (iv) To improve the use of technology in the classroom by children with disabilities to enhance learning; (v) To support the use of technology, including... training; (ii) To support paperwork reduction activities, including expanding the use of technology in...

  2. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... mental health services for children with disabilities; (iv) To improve the use of technology in the classroom by children with disabilities to enhance learning; (v) To support the use of technology, including... training; (ii) To support paperwork reduction activities, including expanding the use of technology in...

  3. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... mental health services for children with disabilities; (iv) To improve the use of technology in the classroom by children with disabilities to enhance learning; (v) To support the use of technology, including... training; (ii) To support paperwork reduction activities, including expanding the use of technology in...

  4. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... mental health services for children with disabilities; (iv) To improve the use of technology in the classroom by children with disabilities to enhance learning; (v) To support the use of technology, including... training; (ii) To support paperwork reduction activities, including expanding the use of technology in...

  5. 34 CFR 300.704 - State-level activities.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... certify to the Secretary that the arrangements to establish responsibility for services pursuant to... transition of students with disabilities to postsecondary activities; (vii) To assist LEAs in meeting... State Medicaid program under Title XIX of the Social Security Act. (9) Funds reserved under paragraph...

  6. Motoneuron and sensory neuron plasticity to varying neuromuscular activity levels

    NASA Technical Reports Server (NTRS)

    Ishihara, Akihiko; Roy, Roland R.; Ohira, Yoshinobu; Edgerton, V. Reggie

    2002-01-01

    The size and phenotypic properties of the neural and muscular elements of the neuromuscular unit are matched under normal conditions. When subjected to chronic decreases or increases in neuromuscular activity, however, the adaptations in these properties are much more limited in the neural compared with the muscular elements.

  7. Drug delivery from hydrophobic-modified mesoporous silicas: Control via modification level and site-selective modification

    SciTech Connect

    Tang Qunli; Chen Yuxi; Chen Jianghua; Li Jin; Xu Yao; Wu Dong; Sun Yuhan

    2010-01-15

    Dimethylsilyl (DMS) modified mesoporous silicas were successfully prepared via co-condensation and post-grafting modification methods. The post-grafting modification was carried out by the reaction of the as-synthesized MCM-41 material (before CTAB removal) with diethoxydimethylsinale (DEDMS). N{sub 2} adsorption-desorption and {sup 29}Si MAS NMR characterization demonstrated that different amount of DMS groups were successfully incorporated into the co-condensation modified samples, and the functional DMS groups were placed selectively on the pore openings and external pore surfaces in the post-grafting modified samples. Subsequently, the controlled drug delivery properties from the resulting DMS-modified mesoporous silicas were investigated in detail. The drug adsorption experiments showed that the adsorption capacities were mainly depended on the content of silanol group (CSG) in the corresponding carriers. The in vitro tests exhibited that the incorporation of DMS groups greatly retarded the ibuprofen release rate. Moreover, the ibuprofen release profiles could be well modulated by varying DMS modification levels and site-selective distribution of functional groups in mesoporous carriers. - The distribution of DMS groups on the pore surfaces of the mesostructures strongly affects the drug release rate. The P-M41-1 and the P-M41-2 possess the close DMS modification levels as the C-M41-10, but the ibuprofen release rates from the P-M41-1 and P-M41-2 are much slower than that from the C-M41-10.

  8. Evaluation of the Presence and Levels of Enrofloxacin, Ciprofloxacin, Sulfaquinoxaline and Oxytetracycline in Broiler Chickens after Drug Administration

    PubMed Central

    da Silva, Guilherme Resende; Lanza, Isabela Pereira; Ribeiro, Ana Cláudia dos Santos Rossi; Lana, Ângela Maria Quintão; Lara, Leonardo José Camargos

    2016-01-01

    The depletion times of enrofloxacin and its metabolite ciprofloxacin as well as sulfaquinoxaline and oxytetracycline were evaluated in broiler chickens that had been subjected to pharmacological treatment. The presence and residue levels of these drugs in muscle tissue were evaluated using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method that was validated in this work. The results showed the presence of all antimicrobial residues; however, the presence of residues at concentrations higher than the drugs’ maximum residue limit (MRL) of 100 μg kg-1 was found only during the treatment period for oxytetracycline and until two days after discontinuation of the medication for enrofloxacin, ciprofloxacin and sulfaquinoxaline. It was concluded that the residues of all antimicrobials were rapidly metabolized from the broiler muscles; after four days of withdrawal, the levels were lower than the limit of quantification (LOQ) of the method for the studied analytes. PMID:27846314

  9. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain.

    PubMed

    Valjent, Emmanuel; Pagès, Christiane; Hervé, Denis; Girault, Jean-Antoine; Caboche, Jocelyne

    2004-04-01

    A major goal of research on addiction is to identify the molecular mechanisms of long-lasting behavioural alterations induced by drugs of abuse. Cocaine and delta-9-tetrahydrocannabinol (THC) activate extracellular signal-regulated kinase (ERK) in the striatum and blockade of the ERK pathway prevents establishment of conditioned place preference to these drugs. However, it is not known whether activation of ERK in the striatum is specific for these two drugs and/or this brain region. We studied the appearance of phospho-ERK immunoreactive neurons in CD-1 mouse brain following acute administration of drugs commonly abused by humans, cocaine, morphine, nicotine and THC, or of other psychoactive compounds including caffeine, scopolamine, antidepressants and antipsychotics. Each drug generated a distinct regional pattern of ERK activation. All drugs of abuse increased ERK phosphorylation in nucleus accumbens, lateral bed nucleus of the stria terminalis, central amygdala and deep layers of prefrontal cortex, through a dopamine D1 receptor-dependent mechanism. Although some non-addictive drugs moderately activated ERK in a few of these areas, they never induced this combined pattern of strong activation. Antidepressants and caffeine activated ERK in hippocampus and cerebral cortex. Typical antipsychotics mildly activated ERK in dorsal striatum and superficial prefrontal cortex, whereas clozapine had no effect in the striatum, but more widespread effects in cortex and amygdala. Our results outline a subset of structures in which ERK activation might specifically contribute to the long-term effects of drugs of abuse, and suggest mapping ERK activation in