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Sample records for increasing drug half-life

  1. Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn

    PubMed Central

    Ying, Tianlei; Wang, Yanping; Feng, Yang; Prabakaran, Ponraj; Gong, Rui; Wang, Lili; Crowder, Karalyne; Dimitrov, Dimiter S

    2015-01-01

    Engineered antibody domains (eAds) are promising candidate therapeutics but their half-life is relatively short partly due to weak or absent binding to the neonatal Fc receptor (FcRn). We developed a novel approach to increase the eAd binding to FcRn based on a combination of structure-based design, computational modeling and phage display methodologies. By using this approach, we identified 2 IgG1 CH2-derived eAds fused to a short FcRn-binding motif derived from IgG1 CH3 that exhibited greatly enhanced FcRn binding with strict pH dependency. Importantly, the increased affinity resulted in significantly enhanced FcRn-mediated epithelial transcytosis and prolonged elimination half-life (mean 44.1 hours) in cynomolgus macaques. These results demonstrate for the first time that the half-life of isolated eAds can be prolonged (optimized) by increasing their binding to FcRn while maintaining their small size, which has important implications for development of therapeutics, including eAd-drug conjugates with enhanced penetration in solid tissues. PMID:26179052

  2. Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn.

    PubMed

    Ying, Tianlei; Wang, Yanping; Feng, Yang; Prabakaran, Ponraj; Gong, Rui; Wang, Lili; Crowder, Karalyne; Dimitrov, Dimiter S

    2015-01-01

    Engineered antibody domains (eAds) are promising candidate therapeutics but their half-life is relatively short partly due to weak or absent binding to the neonatal Fc receptor (FcRn). We developed a novel approach to increase the eAd binding to FcRn based on a combination of structure-based design, computational modeling and phage display methodologies. By using this approach, we identified 2 IgG1 CH2-derived eAds fused to a short FcRn-binding motif derived from IgG1 CH3 that exhibited greatly enhanced FcRn binding with strict pH dependency. Importantly, the increased affinity resulted in significantly enhanced FcRn-mediated epithelial transcytosis and prolonged elimination half-life (mean 44.1 hours) in cynomolgus macaques. These results demonstrate for the first time that the half-life of isolated eAds can be prolonged (optimized) by increasing their binding to FcRn while maintaining their small size, which has important implications for development of therapeutics, including eAd-drug conjugates with enhanced penetration in solid tissues.

  3. The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life

    PubMed Central

    Chen, Lei; Lu, Jing; Kong, XiangYin; Huang, Tao; Li, HaiPeng

    2016-01-01

    A drug’s biological half-life is defined as the time required for the human body to metabolize or eliminate 50% of the initial drug dosage. Correctly measuring the half-life of a given drug is helpful for the safe and accurate usage of the drug. In this study, we investigated which gene ontology (GO) terms and biological pathways were highly related to the determination of drug half-life. The investigated drugs, with known half-lives, were analyzed based on their enrichment scores for associated GO terms and KEGG pathways. These scores indicate which GO terms or KEGG pathways the drug targets. The feature selection method, minimum redundancy maximum relevance, was used to analyze these GO terms and KEGG pathways and to identify important GO terms and pathways, such as sodium-independent organic anion transmembrane transporter activity (GO:0015347), monoamine transmembrane transporter activity (GO:0008504), negative regulation of synaptic transmission (GO:0050805), neuroactive ligand-receptor interaction (hsa04080), serotonergic synapse (hsa04726), and linoleic acid metabolism (hsa00591), among others. This analysis confirmed our results and may show evidence for a new method in studying drug half-lives and building effective computational methods for the prediction of drug half-lives. PMID:27780226

  4. On the accuracy of a one-compartment approach for determination of drug terminal half-life.

    PubMed

    Berezhkovskiy, Leonid M

    2013-07-01

    The drug terminal half-life (t(1/2)) is commonly predicted by a simplified one-compartment approach (t(1/2) = ln 2V(ss)/CL), where V(ss) and CL are the steady-state volume of distribution and the total body clearance of drug, respectively. The analysis of the accuracy of this approach is provided. It turns out that most often a simplified one-compartment calculation underestimates t(1/2) by no more than 25% for human, 26% for dog, 20% for monkey, 19% for rat, and 23% for mouse. Thus, the application of a one-compartment calculation of t(1/2) is well justifiable, except for the rare cases of very high drug clearance (CL/(rQ) ≳ 0.5), where r is the equilibrium blood-plasma concentration ratio, and Q is the cardiac output.

  5. Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life.

    PubMed

    Shaughnessy, Maxwell J; Harsanyi, Antal; Li, Jingji; Bright, Tara; Murphy, Cormac D; Sandford, Graham

    2014-04-01

    In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug's metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti-inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4'-position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2' or 3' resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development.

  6. Bioconcentration, metabolism and half-life time of the human therapeutic drug diltiazem in rainbow trout Oncorhynchus mykiss.

    PubMed

    Steinbach, Christoph; Grabic, Roman; Fedorova, Ganna; Koba, Olga; Golovko, Oksana; Grabicova, Katerina; Kroupova, Hana Kocour

    2016-02-01

    Diltiazem is a human therapeutic drug and a member of the group of calcium channel blockers having widespread use in the treatment of angina pectoris and hypertension. The objective of the present study was to assess the bioconcentration, metabolism, and half-life time of diltiazem in rainbow trout Oncorhynchus mykiss. Juvenile trout were exposed for 21 and 42 days to three nominal concentrations of diltiazem: 0.03 µg L(-1) (environmentally relevant concentration), 3 µg L(-1), and 30 µg L(-1) (sub-lethal concentrations). The bioconcentration factor (BCF) of diltiazem was relatively low (0.5-194) in analysed tissues, following the order kidney > liver > muscle > blood plasma. The half-life of diltiazem in liver, kidney, and muscle was 1.5 h, 6.2 h, and 49 h, respectively. The rate of metabolism for diltiazem in liver, kidney, muscle, and blood plasma was estimated to be 85 ± 9%, 64 ± 14%, 46 ± 6%, and 41 ± 8%, respectively. Eight diltiazem metabolites were detected. The presence of desmethyl diltiazem (M1), desacetyl diltiazem (M2), and desacetyl desmethyl diltiazem (M3) suggests that rainbow trout metabolize diltiazem mainly via desmethylation and desacetylation, similar to mammals. In addition, diltiazem undergoes hydroxylation in fish. At environmentally relevant concentrations, diltiazem and its metabolites were identified in liver and kidney, indicating the potential for uptake and metabolism in non-target organisms in the aquatic environment.

  7. Dietary pectin shortens the biologic half-life of vitamin B-12 in rats by increasing fecal and urinary losses

    SciTech Connect

    Cullen, R.W.; Oace, S.M. )

    1989-08-01

    As little as 5% of pectin added to a fiber-free diet elevates urinary methylmalonic acid (MMA) severalfold in vitamin B-12--deprived rats. The present study examines whether increased urinary MMA reflects lower vitamin B-12 status or occurs only because of fermentation of pectin by intestinal bacteria and increased production of propionate, a precursor of MMA. By monitoring urinary and fecal excretion of {sup 57}Co after a tracer dose of ({sup 57}Co)vitamin B-12, we found the biologic half-life of vitamin B-12 to be 59 d for rats fed a fiber-free diet and only 19 d for rats fed a 5% pectin diet. Also, pectin-fed rats oxidized only 12% of a 1-mmol dose of ({sup 14}C)propionate to {sup 14}CO{sub 2} in 2 h, whereas rats fed the fiber-free diet expired 33% of the dose. Finally, high urinary MMA persisted even after the removal of pectin from the diet. We conclude that dietary pectin accelerates vitamin B-12 depletion in rats, possibly by interfering with enterohepatic recycling of vitamin B-12. By stimulating microbial propionate production, pectin and other fermentable fibers may also contribute to increased urinary MMA in vitamin B-12 deficiency, but a larger propionate pool does not account for the other effects of pectin on vitamin B-12 status.

  8. Hot-melts in buccoadhesive patches: an approach for bioavailability enhancement of highly-metabolized drugs with short elimination half-life.

    PubMed

    El Mahrouk, Galal M; ElGazayerly, Omaima N; Aboelwafa, Ahmed A; Taha, Maie S

    2014-11-01

    The present study deals with the inclusion or incorporation of hot-melts into buccoadhesive patches. Our aim is to develop a patient-friendly dosage form that is capable of extending release of short elimination half-life drugs so to decrease dosing frequency and to increase the bioavailability of highly-metabolized drugs with the ultimate aim of dose reduction. Tizanidine hydrochloride (TIZ) was used as a model drug.TIZ was incorporated into Compritol-based hot-melts, and then further formulated into buccal patches prepared using HPMC, PVA and Polyox. A Central Composite Face-centered Design was employed to statistically optimize the formulation variables; HPMC solution/PVA solution weight ratio, Compritol/TIZ ratio in the hot-melts and percentage Polyox. The optimized formula suggested by the software was successful in controlling drug release, where 85% of TIZ was released after 4 h and the patch showed acceptable mucoadhesion properties. Pharmacokinetic parameters of TIZ from the optimized formula were compared to those of the immediate release tablet, Sirdalud®, as reference in human volunteers using a randomized crossover design. Significant increase was observed for Cmax, Tmax, AUC(0-12) and AUC(0-1). The increase in relative bioavailability of TIZ from the optimized formula was 2.57 folds.

  9. Disease causing mutants of TDP-43 nucleic acid binding domains are resistant to aggregation and have increased stability and half-life

    PubMed Central

    Austin, James A.; Wright, Gareth S. A.; Watanabe, Seiji; Grossmann, J. Günter; Antonyuk, Svetlana V.; Yamanaka, Koji; Hasnain, S. Samar

    2014-01-01

    Over the last two decades many secrets of the age-related human neural proteinopathies have been revealed. A common feature of these diseases is abnormal, and possibly pathogenic, aggregation of specific proteins in the effected tissue often resulting from inherent or decreased structural stability. An archetype example of this is superoxide dismutase-1, the first genetic factor to be linked with amyotrophic lateral sclerosis (ALS). Mutant or posttranslationally modified TAR DNA binding protein-32 (TDP-43) is also strongly associated with ALS and an increasingly large number of other neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD). Cytoplasmic mislocalization and elevated half-life is a characteristic of mutant TDP-43. Furthermore, patient age at the onset of disease symptoms shows a good inverse correlation with mutant TDP-43 half-life. Here we show that ALS and FTLD-associated TDP-43 mutations in the central nucleic acid binding domains lead to elevated half-life and this is commensurate with increased thermal stability and inhibition of aggregation. It is achieved without impact on secondary, tertiary, or quaternary structure. We propose that tighter structural cohesion contributes to reduced protein turnover, increasingly abnormal proteostasis and, ultimately, faster onset of disease symptoms. These results contrast our perception of neurodegenerative diseases as misfolded proteinopathies and delineate a novel path from the molecular characteristics of mutant TDP-43 to aberrant cellular effects and patient phenotype. PMID:24591609

  10. Rapid viral expansion and short drug half-life explain the incomplete effectiveness of current herpes simplex virus 2-directed antiviral agents.

    PubMed

    Schiffer, Joshua T; Swan, David A; Corey, Lawrence; Wald, Anna

    2013-12-01

    The nucleoside analogues acyclovir (ACV) and famciclovir (FCV) reduce the frequency and severity of herpes simplex virus 2 (HSV-2) genital shedding, yet despite their high potency in vitro and a lack of induced drug resistance, frequent episodes of breakthrough mucosal shedding occur. We tested a published stochastic, spatial mathematical model of HSV-2 replication and spread, in concert with pharmacokinetic and pharmacodynamic equations, against virologic data from clinical trials of twice-daily acyclovir and famciclovir suppression. The model reproduced the key features of clinical trial data, including genital shedding episode rate, expansion and decay dynamics, and heterogeneous peak viral production and duration. In simulations, these agents shortened episode duration by limiting the extent of viral production by 1 to 2 log units and limiting the formation of secondary ulcers by ∼50%. However, drug concentrations were noninhibitory during 42% of the dosing cycle. Even if drug concentrations were high at episode initiation, prolonged episodes often ensued due to drug decay over ensuing hours and subsequent rebound of rapidly replicating HSV-2. The local CD8(+) T-cell density was more predictive of episode viral production (R(2) = 0.42) and duration (R(2) = 0.21) than the drug concentration at episode onset (R(2) = 0.14 and 0.05, respectively), though the model projected that an agent with an equivalent potency but a two times longer half-life would decrease shedding by 80% compared to that of standard twice-daily regimens. Therefore, long half-life is a key characteristic of any agent that might fully suppress HSV-2 reactivations.

  11. In silico prediction of brain exposure: drug free fraction, unbound brain to plasma concentration ratio and equilibrium half-life

    PubMed Central

    Spreafico, Morena; Jacobson, Matthew P.

    2014-01-01

    The focus of CNS drug pharmacokinetics programs has recently shifted from determining the total concentrations in brain and blood to considering also unbound fractions and concentrations. Unfortunately, assessing unbound brain exposure experimentally requires demanding in vivo and in vitro studies. We propose a physical model, based on lipid binding and pH partitioning, to predict in silico the unbound volume of distribution in the brain. The model takes into account the partition of a drug into lipids, interstitial fluid and intracellular compartments of the brain. The results are in good agreement with the experimental data, suggesting that the contributions of lipid binding and pH partitioning are important in determining drug exposure in brain. The predicted values are used, together with predictions for plasma protein binding, as corrective terms in a second model to derive the unbound brain to plasma concentration ratio starting from experimental values of total concentration ratio. The calculated values of brain free fraction and passive permeability are also used to qualitatively determine the brain to plasma equilibration time in a model that shows promising results but is limited to a very small set of compounds. The models we propose are a step forward in understanding and predicting pharmacologically relevant exposure in brain starting from compounds’ chemical structure and neuropharmacokinetics, by using experimental total brain to plasma ratios, in silico calculated properties and simple physics-based approaches. The models can be used in central nervous system drug discovery programs for a fast and cheap assessment of unbound brain exposure. For existing compounds, the unbound ratios can be derived from experimental values of total brain to plasma ratios. For both existing and hypothetical compounds, the unbound volume of distribution due to lipid binding and pH partitioning can be calculated starting only from the chemical structure. PMID:23578025

  12. In silico prediction of brain exposure: drug free fraction, unbound brain to plasma concentration ratio and equilibrium half-life.

    PubMed

    Spreafico, Morena; Jacobson, Matthew P

    2013-01-01

    The focus of CNS drug pharmacokinetics programs has recently shifted from determining the total concentrations in brain and blood to considering also unbound fractions and concentrations. Unfortunately, assessing unbound brain exposure experimentally requires demanding in vivo and in vitro studies. We propose a physical model, based on lipid binding and pH partitioning, to predict in silico the unbound volume of distribution in the brain. The model takes into account the partition of a drug into lipids, interstitial fluid and intracellular compartments of the brain. The results are in good agreement with the experimental data, suggesting that the contributions of lipid binding and pH partitioning are important in determining drug exposure in brain. The predicted values are used, together with predictions for plasma protein binding, as corrective terms in a second model to derive the unbound brain to plasma concentration ratio starting from experimental values of total concentration ratio. The calculated values of brain free fraction and passive permeability are also used to qualitatively determine the brain to plasma equilibration time in a model that shows promising results but is limited to a very small set of compounds. The models we propose are a step forward in understanding and predicting pharmacologically relevant exposure in brain starting from compounds' chemical structure and neuropharmacokinetics, by using experimental total brain to plasma ratios, in silico calculated properties and simple physics-based approaches. The models can be used in central nervous system drug discovery programs for a fast and cheap assessment of unbound brain exposure. For existing compounds, the unbound ratios can be derived from experimental values of total brain to plasma ratios. For both existing and hypothetical compounds, the unbound volume of distribution due to lipid binding and pH partitioning can be calculated starting only from the chemical structure. PMID:23578025

  13. Fusion of a Short Peptide that Binds Immunoglobulin G to a Recombinant Protein Substantially Increases Its Plasma Half-Life in Mice

    PubMed Central

    Sockolosky, Jonathan T.; Kivimäe, Saul; Szoka, Francis C.

    2014-01-01

    We explore a strategy to substantially increase the half-life of recombinant proteins by genetic fusion to FcIII, a 13-mer IgG-Fc domain binding peptide (IgGBP) originally identified by DeLano and co-workers at Genentech [DeLano WL, et al. (2000) Science 287∶1279–1283]. IgGBP fusion increases the in vivo half-life of proteins by enabling the fusion protein to bind serum IgG, a concept originally introduced by DeLano and co-workers in a patent but that to the best of our knowledge has never been pursued in the scientific literature. To further investigate the in vitro and in vivo properties of IgGBP fusion proteins, we fused FcIII to the C-terminus of a model fluorescent protein, monomeric Katushka (mKate). mKate-IgGBP fusions are easily expressed in Escherichia coli and bind specifically to human IgG with an affinity of ∼40 nM and ∼20 nM at pH 7.4 and pH 6, respectively, but not to mouse or rat IgG isotypes. mKate-IgGBP binds the Fc-domain of hIgG1 at a site overlapping the human neonatal Fc receptor (hFcRn) and as a consequence inhibits the binding of hIgG1 to hFcRn in vitro. High affinity binding to human IgG also endows mKate-IgGBP with a long circulation half-life of ∼8 hr in mice, a 75-fold increase compared to unmodified mKate. Thus, IgGBP fusion significantly reduces protein clearance by piggybacking on serum IgG without substantially increasing protein molecular weight due to the small size of the IgGBP. These attractive features could result in protein therapies with reduced dose frequency and improved patient compliance. PMID:25057984

  14. Effect of Truncating AUC at 12, 24 and 48 hr When Evaluating the Bioequivalence of Drugs with a Long Half-Life.

    PubMed

    Moreno, Isabel; Ochoa, Dolores; Román, Manuel; Cabaleiro, Teresa; Abad-Santos, Francisco

    2016-01-01

    Bioequivalence studies of drugs with a long half-life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC0-t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within-individual coefficient of variation (CVw) and on the ratio of the formulations was also analysed. Twenty-eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time-points. The degree of agreement of AUC0-72 in relation to AUC0-48 and AUC0-24, according to the Landis and Koch classification, was 'almost perfect'. Statistically significant differences were observed when the CVw of AUC truncated at 72, 48 and 24 hr was compared with the CVw of AUC0-12. There were no statistically significant differences in the AUC ratio at any time-point. Compared to AUC0-72, Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CVw was worse for AUC0-12 than AUC0-24 or AUC0-48. These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalent.

  15. Enhancing the circulating half-life and the antitumor effects of a tumor-selective cytotoxic peptide by exploiting endogenous serum albumin as a drug carrier.

    PubMed

    Su, Tao; Yang, Hao; Fan, Qing; Jia, Dianlong; Tao, Ze; Wan, Lin; Lu, Xiaofeng

    2016-02-29

    The elevated expression of bombesin receptors in many of the deadliest cancers has attracted special interest in developing bombesin-directed agents for tumor imaging and therapy. Previously, we constructed the chimeric peptide BB28 by fusing bombesin to a mitochondria-disrupting peptide. BB28 selectively induced the apoptosis of various tumor cells in vitro and showed promising in vivo antitumor effects. In general, a short circulating half-life limits the in vivo effect of peptides. To prolong the half-life of BB28, here, we generated the novel peptide ABB28 by fusing an albumin-binding domain (ABD) to the N-terminus of BB28. ABB28 exhibited much higher binding affinity for albumin than BB28, and this modification extended the peptide half-life from several minutes to 2 h. Optical imaging revealed that ABB28 accumulated in xenografted tumors within 1h post-injection and persisted at an evident level for up to 24 h. ABB28 exerted stronger tumor-suppressive effects than BB28. Significant differences in the tumor volumes (P<0.001) and the tumor weights (P=0.002) were observed between ABB28- and BB28-treated mice. Moreover, ABB28 exhibited tumor suppression comparable to that of PEGylated 5K-BB28 in vivo. These results suggest that half-life extension via ABD fusion represents a useful strategy for optimizing bombesin-directed pharmaceuticals for cancer-targeted therapy.

  16. Prediction of drug terminal half-life and terminal volume of distribution after intravenous dosing based on drug clearance, steady-state volume of distribution, and physiological parameters of the body.

    PubMed

    Berezhkovskiy, Leonid M

    2013-02-01

    The steady state, V(ss), terminal volume of distribution, V(β), and the terminal half-life, t(1/2), are commonly obtained from the drug plasma concentration-time profile, C(p)(t), following intravenous dosing. Unlike V(ss) that can be calculated based on the physicochemical properties of drugs considering the equilibrium partitioning between plasma and organ tissues, t(1/2) and V(β) cannot be calculated that way because they depend on the rates of drug transfer between blood and tissues. Considering the physiological pharmacokinetic model pertinent to the terminal phase of drug elimination, a novel equation that calculates t(1/2) (and consequently V(β)) was derived. It turns out that V(ss), the total body clearance, Cl, equilibrium blood-plasma concentration ratio, r; and the physiological parameters of the body such as cardiac output, and blood and tissue volumes are sufficient for determination of terminal kinetics. Calculation of t(1/2) by the obtained equation appears to be in good agreement with the experimentally observed vales of this parameter in pharmacokinetic studies in rat, monkey, dog, and human. The equation for the determination of the pre-exponent of the terminal phase of C(p)(t) is also found. The obtained equation allows to predict t(1/2) in human assuming that V(ss) and Cl were either obtained by allometric scaling or, respectively, calculated in silico or based on in vitro drug stability measurements. For compounds that have high clearance, the derived equation may be applied to calculate r just using the routine data on Cl, V(ss), and t(1/2), rather than doing the in vitro assay to measure this parameter.

  17. Mechanical Simulation of a Half-Life

    ERIC Educational Resources Information Center

    Grove, T. T.; Masters, M. F.

    2008-01-01

    The exponential function model of radioactive decay and the concept of a half-life are used in nuclear experiments that appear in introductory and intermediate laboratories. In our interactions with students, we have found that students at all levels have significant confusion about both the term exponential and what is meant by a half-life as…

  18. Up-regulation of microRNA-155 in macrophages contributes to increased tumor necrosis factor {alpha} (TNF{alpha}) production via increased mRNA half-life in alcoholic liver disease.

    PubMed

    Bala, Shashi; Marcos, Miguel; Kodys, Karen; Csak, Timea; Catalano, Donna; Mandrekar, Pranoti; Szabo, Gyongyi

    2011-01-14

    Activation of Kupffer cells (KCs) by gut-derived lipopolysaccharide (LPS) and Toll-Like Receptors 4 (TLR4)-LPS-mediated increase in TNFα production has a central role in the pathogenesis of alcoholic liver disease. Micro-RNA (miR)-125b, miR-146a, and miR-155 can regulate inflammatory responses to LPS. Here we evaluated the involvement of miRs in alcohol-induced macrophage activation. Chronic alcohol treatment in vitro resulted in a time-dependent increase in miR-155 but not miR-125b or miR-146a levels in RAW 264.7 macrophages. Furthermore, alcohol pretreatment augmented LPS-induced miR-155 expression in macrophages. We found a linear correlation between alcohol-induced increase in miR-155 and TNFα induction. In a mouse model of alcoholic liver disease, we found a significant increase in both miR-155 levels and TNFα production in isolated KCs when compared with pair-fed controls. The mechanistic role of miR-155 in TNFα regulation was indicated by decreased TNFα levels in alcohol-treated macrophages after inhibition of miR-155 and by increased TNFα production after miR-155 overexpression, respectively. We found that miR-155 affected TNFα mRNA stability because miR-155 inhibition decreased whereas miR-155 overexpression increased TNFα mRNA half-life. Using the NF-κB inhibitors, MG-132 or Bay11-7082, we demonstrated that NF-κB activation mediated the up-regulation of miR-155 by alcohol in KCs. In conclusion, our novel data demonstrate that chronic alcohol consumption increases miR-155 in macrophages via NF-κB and the increased miR-155 contributes to alcohol-induced elevation in TNFα production via increased mRNA stability. PMID:21062749

  19. Oritavancin: A Long-Half-Life Lipoglycopeptide.

    PubMed

    Saravolatz, Louis D; Stein, Gary E

    2015-08-15

    Oritavancin is a lipoglycopeptide antibiotic that has been shown to be effective for the treatment of acute bacterial skin and skin structure infections (ABSSSIs). This antibiotic has multiple mechanisms of action including inhibiting peptidoglycan cell wall synthesis and disrupting bacterial cell membrane, leading to cell death. Oritavancin is highly active against common gram-positive pathogens including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus, and vancomycin-resistant enterococci. The drug is administered as a single intravenous dose of 1200 mg over 3 hours in adult patients, and because of its terminal half-life of 393 hours, repeat dosing is not required in the treatment of ABSSIs. There is a very slow elimination from tissue sites, and no dosing adjustments are required for renal or hepatic insufficiency. Two clinical trials have demonstrated noninferiority compared with vancomycin in the treatment of ABSSSIs. Other than liver enzyme elevation and the occurrence of osteomyelitis, oritavancin has been associated with adverse events similar to those of vancomycin in follow-up for up to 60 days. Patients should be monitored for osteomyelitis and alternate therapy given in the case of confirmed or suspected osteomyelitis. Although oritavancin is an attractive antibiotic to consider in the outpatient area, its efficacy and safety in the treatment of other sites of infection are yet to be established.

  20. Half-life of DISC1 protein and its pathological significance under hypoxia stress.

    PubMed

    Barodia, Sandeep Kumar; Park, Sang Ki; Ishizuka, Koko; Sawa, Akira; Kamiya, Atsushi

    2015-08-01

    DISC1 (disrupted in schizophrenia 1) is an intracellular scaffolding molecule which regulates multiple signaling pathways for neural cell differentiation and function. Many biological studies utilizing animal models of DISC1 have indicated that loss of DISC1 functions are associated with pathological psychiatric conditions. Thus, DISC1 protein stability is a prerequisite to its goal in governing neural function, and modulating the protein stability of DISC1 may be a key target for understanding underlying pathology, as well promising drug discovery strategies. Nonetheless, a half-life of DISC1 protein has remained unexplored. Here, we determine for the first time the half-life of DISC1, which are regulated by ubiquitin-proteasome cascade. Overexpression of PDE4B2, a binding partner of DISC1, prolonged the half-life of DISC1, whereas NDEL1 does not alter DISC1 protein stability. Notably, the half-life of DISC1 is diminished under hypoxia stress by increasing protein degradation of DISC1, suggesting that alteration of DISC1 stability may be involved in hypoxia stress-mediated pathological conditions, such as ischemic stroke.

  1. Half-life of DISC1 protein and its pathological significance under hypoxia stress

    PubMed Central

    Barodia, Sandeep Kumar; Park, Sang Ki; Ishizuka, Koko; Sawa, Akira; Kamiya, Atsushi

    2015-01-01

    DISC1 (Disrupted in Schizophrenia 1) is an intracellular scaffolding molecule which regulates multiple signaling pathways for neural cell differentiation and function. Many biological studies utilizing animal models of DISC1 have indicated that loss of DISC1 functions are associated with pathological psychiatric conditions. Thus, DISC1 protein stability is a prerequisite to its goal in governing neural function, and modulating the protein stability of DISC1 may be a key target for understanding underlying pathology, as well promising drug discovery strategies. Nonetheless, a half-life of DISC1 protein has remained unexplored. Here, we determine for the first time the half-life of DISC1, which are regulated by ubiquitin-proteasome cascade. Overexpression of PDE4B2, a binding partner of DISC1, prolonged the half-life of DISC1, whereas NDEL1 does not alter DISC1 protein stability. Notably, the half-life of DISC1 is diminished under hypoxia stress by increasing protein degradation of DISC1, suggesting that alteration of DISC1 stability may be involved in hypoxia stress-mediated pathological conditions, such as ischemic stroke. PMID:25738396

  2. Half-life measurement of 124Sb.

    PubMed

    Paepen, J; Altzitzoglou, T; Van Ammel, R; Sibbens, G; Pommé, S

    2010-01-01

    The half-life of (124)Sb was determined experimentally by following the decay of a source from a radiopure solution with a Centronic IG12 ionisation chamber. Thousands of measurements were performed over a period of 358 days, i.e. about six half-life periods. However, the data analysis was restricted to the first 221 days, in order to limit the dominant uncertainty component associated with the hypothetical possibility of a systematic error on background subtraction. The resulting value for the (124)Sb half-life, 60.212 (11) days, is found to be in very good agreement with published values, but carries a lower uncertainty. Major uncertainty contributions pertain to possible systematic errors in background correction, long-term changes in source-detector geometry and medium- and long-term instability of the instrument. Additional measurements were performed with a high-purity germanium detector to confirm the above value.

  3. 57Co half-life determination.

    PubMed

    da Silva, C J; Iwahara, A; Moreira, D S; Delgado, J U; Gomes, R S

    2012-09-01

    The National Laboratory for Metrology of Ionizing Radiation (LNMRI)/Brazil participated in the last (57)Co activity measurement comparison organized by IAEA, in 2008. This was made in order to realize primary standardization of this radionuclide and to reduce the measuring uncertainties in the laboratory. Additionally, one sample with 2.6g was taken from the IAEA master solution of (57)Co and was prepared to be used in the measurement of the radionuclide's half-life in an ionization chamber system. The (57)Co half-life was measured to be 271.82 (17) days. PMID:22406221

  4. Half-life of {sup 44}Ti

    SciTech Connect

    Ahmad, I.; Kutschera, W.; Castagnoli, G.; Paul, M.

    1995-08-01

    The measurement of the {sup 44}Ti half-life, started 3 years ago, is still continuing. The goal of this measurement is to determine the half-life of {sup 44}Ti, which is {approximately}52 y, to a precision of {approximately}5%. An accurate value of this half-life is of interest to cosmologists who need it to determine the production of heavy elements in supernova. Three sets of samples - a pure 200-nCi {sup 44}Ti sample, a pure 300-nCi {sup 60}Co source, and a mixed {sup 44}Ti-{sup 60}Co source of similar strength - were prepared and their spectra are being measured with Ge spectrometers at Argonne, Torino and Jerusalem. Each sample is counted for a period of 2 days, at approximate intervals of 4 months. The room background is also measured for the same length of time. We hope to start data analysis at the end of summer and obtain a value for the {sup 44}Ti half-life.

  5. Remeasurement of (234)U Half-Life.

    PubMed

    Varga, Zsolt; Nicholl, Adrian; Wallenius, Maria; Mayer, Klaus

    2016-03-01

    The half-life of (234)U has been measured using a novel approach. In this method, a uranium material was chemically purified from its thorium decay product at a well-known time. The ingrowth of the (230)Th daughter product in the material was followed by measuring the accumulated (230)Th daughter product relative to its parent (234)U nuclide using inductively coupled plasma mass spectrometry. Then, the (234)U decay constant and the respective half-life could be calculated using the radioactive decay equations based on the n((230)Th)/n((234)U) amount ratio. The obtained (234)U half-life is 244 900 ± 670 years (k = 1), which is in good agreement with the previously reported results in the literature with comparable uncertainty. The main advantages of the proposed method are that it does not require the assumption of secular equilibrium between (234)U and (238)U. Moreover, the calculation is independent from the (238)U half-life value and its uncertainty. The suggested methodology can also be applied for the remeasurement of the half-lives of several other long-lived radionuclides. PMID:26823129

  6. Half-life of /sup 218/Po

    SciTech Connect

    Potapov, V.G.; Soloshenkov, P.S.

    1986-10-01

    The decay of Po 218 is accompanied by the emission of 6.00-MeV alpha particles. The most suitable method for studying it is the alphaspectrometric method. To generate radon, the source for RaA, the authors used a preparation of Ra 226 with a high degree of purity. Targets were prepared for measuring the half-life on a radon setup. Approximately 30 sec after holding in a radon atmosphere the target was placed with the polonium deposited on it into a vacuum chamber. It was noted that the intensity of the peak at 6.70 MeV decreases at the same rate as the decay of Po 218, and the ratio of the intensities of their peaks was equal to 0.037 +/- 0.007%. The spectra (alpha was analyzed on an LP-4900 analyzer. The values of the half-life that were obtained are in good agreement with the values obtained previously.

  7. A free cysteine prolongs the half-life of a homing peptide and improves its tumor-penetrating activity.

    PubMed

    Pang, Hong-Bo; Braun, Gary B; She, Zhi-Gang; Kotamraju, Venkata R; Sugahara, Kazuki N; Teesalu, Tambet; Ruoslahti, Erkki

    2014-02-10

    The accessibility of extravascular tumor tissue to drugs is critical for therapeutic efficacy. We previously described a tumor-targeting peptide (iRGD) that elicits active transport of drugs and macromolecules (covalently coupled or co-administered) across the vascular wall into tumor tissue. Short peptides (iRGD is a 9-amino acid cyclic peptide) generally have a plasma half-life measured in minutes. Since short half-life limits the window of activity obtained with a bolus injection of iRGD, we explored to extend the half-life of the peptide. We show here that addition of a cysteine residue prolongs the plasma half-life of iRGD and increases the accumulation of the peptide in tumors. This modification prolongs the activity of iRGD in inducing macromolecular extravasation and leads to greater drug accumulation in tumors than is obtained with the unmodified peptide. This effect is mediated by covalent binding of iRGD to plasma albumin through a disulfide bond. Our study provides a simple strategy to improve peptide pharmacokinetics and activity. Applied to RGD, it provides a means to increase the entry of therapeutic agents into tumors.

  8. The half-life of 237Np

    NASA Astrophysics Data System (ADS)

    Lowles, I. M.; Mac Mahon, T. D.; Wiltshire, R. A. P.; Crossley, D.; Fudge, A. J.

    1992-02-01

    The only available precise measurement of the half-life of 237Np is that of Brauer et al. (J. Inorg. Nucl. Chem. 12 (1960) 234), which dates from 1960. As a consequence of this radionuclide's importance in fission reactors, the IAEA-CRP requested a confirmatory measurement of the half-life of 237Np. In this present determination the specific activity of 37 sources, prepared from known masses of high purity 237Np solution, have been measured. Accurate concentration analysis of the solution was provided by controlled-potential coulometry. Source activities, in the range 1.0-1.9 kBq. were measured by α-particle counting in two gas flow proportional counters of known geometry. The measured specific activity was 26.03±0.08 Bq μg-1, which corresponds to a half-life of 2.144±0.007 × 106 years, in excellent agreement with the value reported by Brauer et al.

  9. sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo.

    PubMed

    Altiok, Eda I; Browne, Shane; Khuc, Emily; Moran, Elizabeth P; Qiu, Fangfang; Zhou, Kelu; Santiago-Ortiz, Jorge L; Ma, Jian-Xing; Chan, Matilda F; Healy, Kevin E

    2016-01-01

    Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life.

  10. sFlt Multivalent Conjugates Inhibit Angiogenesis and Improve Half-Life In Vivo

    PubMed Central

    Altiok, Eda I.; Browne, Shane; Khuc, Emily; Moran, Elizabeth P.; Qiu, Fangfang; Zhou, Kelu; Santiago-Ortiz, Jorge L.; Ma, Jian-xing; Chan, Matilda F.; Healy, Kevin E.

    2016-01-01

    Current anti-VEGF drugs for patients with diabetic retinopathy suffer from short residence time in the vitreous of the eye. In order to maintain biologically effective doses of drug for inhibiting retinal neovascularization, patients are required to receive regular monthly injections of drug, which often results in low patient compliance and progression of the disease. To improve the intravitreal residence time of anti-VEGF drugs, we have synthesized multivalent bioconjugates of an anti-VEGF protein, soluble fms-like tyrosine kinase-1 (sFlt) that is covalently grafted to chains of hyaluronic acid (HyA), conjugates that are termed mvsFlt. Using a mouse corneal angiogenesis assay, we demonstrate that covalent conjugation to HyA chains does not decrease the bioactivity of sFlt and that mvsFlt is equivalent to sFlt at inhibiting corneal angiogenesis. In a rat vitreous model, we observed that mvsFlt had significantly increased intravitreal residence time compared to the unconjugated sFlt after 2 days. The calculated intravitreal half-lives for sFlt and mvsFlt were 3.3 and 35 hours, respectively. Furthermore, we show that mvsFlt is more effective than the unconjugated form at inhibiting retinal neovascularization in an oxygen-induced retinopathy model, an effect that is most likely due to the longer half-life of mvsFlt in the vitreous. Taken together, our results indicate that conjugation of sFlt to HyA does not affect its affinity for VEGF and this conjugation significantly improves drug half-life. These in vivo results suggest that our strategy of multivalent conjugation could substantially improve upon drug half-life, and thus the efficacy of currently available drugs that are used in diseases such as diabetic retinopathy, thereby improving patient quality of life. PMID:27257918

  11. Half-life of 14O

    SciTech Connect

    Burke, Jason T.; Vetter, Paul A.; Freedman, Stuart J.; Fujikawa,Brian K.; Winter, Wesley T.

    2006-01-11

    We have measured the half-life of 14O, a superallowed (0+\\rightarrow 0+) \\beta decay isotope. The 14O was produced by the12C(3He,n)14O reaction using a carbon aerogel target. A low-energy ionbeam of 14O was mass separated and implanted in a thin beryllium foil.The beta particles were counted with plastic scintillator detectors. Wefind \\tau 1/2 = 70.696 +- 0.037\\sigma. This result is 2.0\\sigma higherthan an average value from six earlier experiments, but agrees moreclosely with the most recent previous measurment.

  12. The half-life of 18F.

    PubMed

    García-Toraño, Eduardo; Medina, Virginia Peyrés; Ibarra, Miguel Roteta

    2010-01-01

    The half-life of the positron-emitter (18)F has been measured by following the decay rate with three systems: ionization chambers, Ge detectors and coincidence with fast scintillators. The decay rate was measured for periods of time up to 9 half-lives. The combination of the results obtained with the three measuring systems gives a value of T(1/2)=1.82871 (18)h, in good agreement with recommended data and with an estimated uncertainty lower than any other previously reported value. PMID:20036570

  13. Half-life extension of the HIV-fusion inhibitor peptide TRI-1144 using a novel linker technology.

    PubMed

    Schneider, Eric L; Ashley, Gary W; Dillen, Lieve; Stoops, Bart; Austin, Nigel E; Malcolm, Bruce A; Santi, Daniel V

    2015-06-01

    We have previously developed a linker technology for half-life extension of peptides, proteins and small molecule drugs (1). The linkers undergo β-elimination reactions with predictable cleavage rates to release the native drug. Here we utilize this technology for half-life extension of the 38 amino acid HIV-1 fusion inhibitor TRI-1144. Conjugation of TRI-1144 to 40 kDa PEG by an appropriate β-eliminative linker and i.v. administration of the conjugate increased the in vivo half-life of the released peptide from 4 to 34 h in the rat, and the pharmacokinetic parameters were in excellent accord with a one-compartment model. From these data we simulated the pharmacokinetics of the PEG-TRI-1144 conjugate in humans, predicting a t1/2,β of 70 h for the released peptide, and that a serum concentration of 25 nM could be maintained by weekly doses of 8 μmol of the conjugate. Using a non-circulating carrier (2) similar simulations indicated a t1/2,β of 150 h for the peptide released from the conjugate and that dosing of only 1.8 μmol/week could maintain serum concentrations of TRI-1144 above 25 nM. Hence, releasable β-eliminative linkers provide significant half-life extension to TRI-1144 and would be expected to do likewise for related peptides.

  14. Superior serum half life of albumin tagged TNF ligands

    SciTech Connect

    Mueller, Nicole; Schneider, Britta; Pfizenmaier, Klaus; Wajant, Harald

    2010-06-11

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  15. Improving the Precision of the Half Life of 34Ar

    NASA Astrophysics Data System (ADS)

    Iacob, V. E.; Hardy, J. C.; Bencomo, M.; Chen, L.; Horvat, V.; Nica, N.; Park, H. I.

    2016-03-01

    Currently, precise ft-values measured for superallowed 0+ -->0+ β transitions provide the most accurate value for Vud, the up-down quark mixing element of the Cabibbo-Kobayashi-Maskawa (CKM) matrix. This enables the most demanding test of CKM unitarity, one of the pillars of the Standard Model. Further improvements in precision are possible if the ft values for pairs of mirror 0+ -->0+ transitions can be measured with 0.1% precision or better. The decays of 34Ar and 34Cl are members of such a mirror pair, but so far the former is not known with sufficient precision. Since our 2006 publication of the half-life of 34Ar, we have improved significantly our acquisition and analysis techniques, adding refinements that have led to increased accuracy. The 34Cl half-life is about twice that of 34Ar. This obscures the 34Ar contribution to the decay in measurements such as ours, which detected the decay positrons and was thus unable to differentiate between the parent and daughter decays. We report here two experiments aiming to improve the half-life of 34Ar: The first detected positrons as in but with improved controls; the second measured γ rays in coincidence with positrons, thus achieving a clear separation of 34Ar decay from 34Cl.

  16. Stable Isotope Turnover and Half-Life in Animal Tissues: A Literature Synthesis

    PubMed Central

    Vander Zanden, M. Jake; Clayton, Murray K.; Moody, Eric K.; Solomon, Christopher T.; Weidel, Brian C.

    2015-01-01

    Stable isotopes of carbon, nitrogen, and sulfur are used as ecological tracers for a variety of applications, such as studies of animal migrations, energy sources, and food web pathways. Yet uncertainty relating to the time period integrated by isotopic measurement of animal tissues can confound the interpretation of isotopic data. There have been a large number of experimental isotopic diet shift studies aimed at quantifying animal tissue isotopic turnover rate λ (%·day-1, often expressed as isotopic half-life, ln(2)/λ, days). Yet no studies have evaluated or summarized the many individual half-life estimates in an effort to both seek broad-scale patterns and characterize the degree of variability. Here, we collect previously published half-life estimates, examine how half-life is related to body size, and test for tissue- and taxa-varying allometric relationships. Half-life generally increases with animal body mass, and is longer in muscle and blood compared to plasma and internal organs. Half-life was longest in ecotherms, followed by mammals, and finally birds. For ectotherms, different taxa-tissue combinations had similar allometric slopes that generally matched predictions of metabolic theory. Half-life for ectotherms can be approximated as: ln (half-life) = 0.22*ln (body mass) + group-specific intercept; n = 261, p<0.0001, r2 = 0.63. For endothermic groups, relationships with body mass were weak and model slopes and intercepts were heterogeneous. While isotopic half-life can be approximated using simple allometric relationships for some taxa and tissue types, there is also a high degree of unexplained variation in our models. Our study highlights several strong and general patterns, though accurate prediction of isotopic half-life from readily available variables such as animal body mass remains elusive. PMID:25635686

  17. Protein HESylation for half-life extension: synthesis, characterization and pharmacokinetics of HESylated anakinra.

    PubMed

    Liebner, Robert; Mathaes, Roman; Meyer, Martin; Hey, Thomas; Winter, Gerhard; Besheer, Ahmed

    2014-07-01

    Half-life extension (HLE) is becoming an essential component of the industrial development of small-sized therapeutic peptides and proteins. HESylation(®) is a HLE technology based on coupling drug molecules to the biodegradable hydroxyethyl starch (HES). In this study, we report on the synthesis, characterization and pharmacokinetics of HESylated anakinra, where anakinra was conjugated to propionaldehyde-HES using reductive amination, leading to a monoHESylated protein. Characterization using size exclusion chromatography and dynamic light scattering confirmed conjugation and the increase in molecular size, while Fourier transform infrared spectroscopy showed that the secondary structure of the conjugate was not affected by coupling. Meanwhile, microcalorimetry and aggregation studies showed a significant increase in protein stability. Surface plasmon resonance and microscale thermophoresis showed that the conjugate retained its nanomolar affinity, and finally, the pharmacokinetics of the HESylated protein exhibited a 6.5-fold increase in the half-life, and a 45-fold increase in the AUC. These results indicate that HESylation(®) is a promising HLE technology.

  18. Isolation of human anti-serum albumin Fab antibodies with an extended serum-half life.

    PubMed

    Kang, Hyeon-Ju; Kim, Hye-Jin; Cha, Sang-Hoon

    2016-01-01

    The serum albumin (SA) has been exploited to generate long-acting biotherapeutics by taking advantage of the FcRn-mediated recycling mechanism in a direct or an indirect way. Since Fab fragments have been proven to be clinically safe for human usage, we assumed that human anti-SA Fab antibodies could have a great potential as a carrier molecule to extend the serum half-life of therapeutic proteins. We, herein, had attempted to isolate anti-SA Fab antibodies from HuDVFab-8L antibody library via a phage display technology, and identified eight discrete human Fab antibodies. One of the Fab antibodies, SL335, showed the strongest binding reactivity to human SA with nM range of affinity at both pH 6 and pH 7.4, and cross-reacted to SAs from various species including rat, mouse, canine and monkey. The in vivo pharmacokinetic assay using a rat model indicated that SL335 has approximately 10 fold longer serum half-life and 26 to 44-fold increase in AUC0 → ∞ compared to the negative control Fab molecule in both intravenous and subcutaneous administrations. Knowing that Fabs have proven to be safe in clinics for a long time, SL335 seems to have a great potential in generating long-acting protein drugs by tagging effector molecules with either chemical conjugation or genetic fusion.

  19. PASylation of Murine Leptin Leads to Extended Plasma Half-Life and Enhanced in Vivo Efficacy.

    PubMed

    Morath, Volker; Bolze, Florian; Schlapschy, Martin; Schneider, Sarah; Sedlmayer, Ferdinand; Seyfarth, Katrin; Klingenspor, Martin; Skerra, Arne

    2015-05-01

    Leptin plays a central role in the control of energy homeostasis and appetite and, thus, has attracted attention for therapeutic approaches in spite of its limited pharmacological activity owing to the very short circulation in the body. To improve drug delivery and prolong plasma half-life, we have fused murine leptin with Pro/Ala/Ser (PAS) polypeptides of up to 600 residues, which adopt random coil conformation with expanded hydrodynamic volume in solution and, consequently, retard kidney filtration in a similar manner as polyethylene glycol (PEG). Relative to unmodified leptin, size exclusion chromatography and dynamic light scattering revealed an approximately 21-fold increase in apparent size and a much larger molecular diameter of around 18 nm for PAS(600)-leptin. High receptor-binding activity for all PASylated leptin versions was confirmed in BIAcore measurements and cell-based dual-luciferase assays. Pharmacokinetic studies in mice revealed a much extended plasma half-life after ip injection, from 26 min for the unmodified leptin to 19.6 h for the PAS(600) fusion. In vivo activity was investigated after single ip injection of equimolar doses of each leptin version. Strongly increased and prolonged hypothalamic STAT3 phosphorylation was detected for PAS(600)-leptin. Also, a reduction in daily food intake by up to 60% as well as loss in body weight of >10% lasting for >5 days was observed, whereas unmodified leptin was merely effective for 1 day. Notably, application of a PASylated superactive mouse leptin antagonist (SMLA) led to the opposite effects. Thus, PASylated leptin not only provides a promising reagent to study its physiological role in vivo but also may offer a superior drug candidate for clinical therapy. PMID:25811325

  20. PASylation of Murine Leptin Leads to Extended Plasma Half-Life and Enhanced in Vivo Efficacy.

    PubMed

    Morath, Volker; Bolze, Florian; Schlapschy, Martin; Schneider, Sarah; Sedlmayer, Ferdinand; Seyfarth, Katrin; Klingenspor, Martin; Skerra, Arne

    2015-05-01

    Leptin plays a central role in the control of energy homeostasis and appetite and, thus, has attracted attention for therapeutic approaches in spite of its limited pharmacological activity owing to the very short circulation in the body. To improve drug delivery and prolong plasma half-life, we have fused murine leptin with Pro/Ala/Ser (PAS) polypeptides of up to 600 residues, which adopt random coil conformation with expanded hydrodynamic volume in solution and, consequently, retard kidney filtration in a similar manner as polyethylene glycol (PEG). Relative to unmodified leptin, size exclusion chromatography and dynamic light scattering revealed an approximately 21-fold increase in apparent size and a much larger molecular diameter of around 18 nm for PAS(600)-leptin. High receptor-binding activity for all PASylated leptin versions was confirmed in BIAcore measurements and cell-based dual-luciferase assays. Pharmacokinetic studies in mice revealed a much extended plasma half-life after ip injection, from 26 min for the unmodified leptin to 19.6 h for the PAS(600) fusion. In vivo activity was investigated after single ip injection of equimolar doses of each leptin version. Strongly increased and prolonged hypothalamic STAT3 phosphorylation was detected for PAS(600)-leptin. Also, a reduction in daily food intake by up to 60% as well as loss in body weight of >10% lasting for >5 days was observed, whereas unmodified leptin was merely effective for 1 day. Notably, application of a PASylated superactive mouse leptin antagonist (SMLA) led to the opposite effects. Thus, PASylated leptin not only provides a promising reagent to study its physiological role in vivo but also may offer a superior drug candidate for clinical therapy.

  1. Effects of measurement error on estimating biological half-life

    SciTech Connect

    Caudill, S.P.; Pirkle, J.L.; Michalek, J.E. )

    1992-10-01

    Direct computation of the observed biological half-life of a toxic compound in a person can lead to an undefined estimate when subsequent concentration measurements are greater than or equal to previous measurements. The likelihood of such an occurrence depends upon the length of time between measurements and the variance (intra-subject biological and inter-sample analytical) associated with the measurements. If the compound is lipophilic the subject's percentage of body fat at the times of measurement can also affect this likelihood. We present formulas for computing a model-predicted half-life estimate and its variance; and we derive expressions for the effect of sample size, measurement error, time between measurements, and any relevant covariates on the variability in model-predicted half-life estimates. We also use statistical modeling to estimate the probability of obtaining an undefined half-life estimate and to compute the expected number of undefined half-life estimates for a sample from a study population. Finally, we illustrate our methods using data from a study of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure among 36 members of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of Agent Orange in Vietnam.

  2. Beta Decay Half-Life of 84Mo

    NASA Astrophysics Data System (ADS)

    Stoker, J. B.; Mantica, P. F.; Bazin, D.; Bickley, A.; Becerril, A.; Crawford, H.; Cruse, K.; Estrade, A.; Mosby, M.; Guess, C. J.; Hitt, G. W.; Lorusso, G.; Matos, M.; Meharchand, R.; Minamisono, K.; Montes, F.; Pereira, J.; Perdikakis, G.; Pinter, J. S.; Schatz, H.; Vredevoogd, J.; Zegers, R. G. T.

    2008-10-01

    The β-decay half-life ^84Mo governs leakage out of the Zr-Nb cycle, a high temperature rp-process endpoint in x-ray binaries [1]. Treatment of the background and the poor statistics accumulated during the previous half-life measurement leave questions about statistical and systematic errors. We have remeasured the half-life of ^84Mo using a concerted setup of the NSCL β-Counting System [3] and 16 detectors from the Segmented Germanium Array [4]. We will report the half-life for ^84Mo, deduced using 40 times the previous sample size. The application of the NSCL RF Fragment Separator to remove unwanted isotopes, and hence reduce background for the half-life measurement, will also be discussed. [1] H. Schatz et al., Phys. Rep. 294, 167 1998 [2] P. Kienle et al., Prog. Part. Nuc. Phys. 46, 73 2001 [3] J. Prisciandaro et al., NIM A 505, 140 2003 [4] W. Mueller et al., NIM A 466, 492 2001 [5] D. Gorelov et al. PAC 2005, Knoxville, TN, May 16-20

  3. Fusion Proteins for Half-Life Extension of Biologics as a Strategy to Make Biobetters.

    PubMed

    Strohl, William R

    2015-08-01

    The purpose of making a "biobetter" biologic is to improve on the salient characteristics of a known biologic for which there is, minimally, clinical proof of concept or, maximally, marketed product data. There already are several examples in which second-generation or biobetter biologics have been generated by improving the pharmacokinetic properties of an innovative drug, including Neulasta(®) [a PEGylated, longer-half-life version of Neupogen(®) (filgrastim)] and Aranesp(®) [a longer-half-life version of Epogen(®) (epoetin-α)]. This review describes the use of protein fusion technologies such as Fc fusion proteins, fusion to human serum albumin, fusion to carboxy-terminal peptide, and other polypeptide fusion approaches to make biobetter drugs with more desirable pharmacokinetic profiles.

  4. Measuring the Half Life of ^229mTh

    NASA Astrophysics Data System (ADS)

    Swanberg, E.; Burke, J. T.; Casperson, R. J.; Sheets, S. A.; Beck, B. R.; Scielzo, N. D.; Norman, E. B.

    2010-11-01

    ^229Th has the lowest known nuclear excited state at 7.6 ± 0.5 eV.ootnotetextB.R. Beck et al. (2007). ``Energy Splitting of the Ground-State Doublet in the Nucleus 229Th.'' Phys. Rev. Lett. 98: 142501 Decay to the ground state has never been directly observed, and the half life is unknown. Excitation from the ground state could allow applications such as a nuclear clock or a quantum computer. The half life, and hence the line width, are needed to pursue these applications. Due to the low energy, internal conversion (IC) is expected to be the dominant decay mode. The current experiment is attempting to measure the half life by searching for IC electrons or photons emitted as a result of IC. We have measured the IC electron emission of ^235mU (76 eV energy, 26 minute half life) to validate or setup. Results to date will be presented. Partially supported by the U.S. Department of Homeland Security. This work performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

  5. The Half-Life of the Chemical Literature.

    ERIC Educational Resources Information Center

    Brown, Pauline

    1980-01-01

    The average citation per article in chemistry by age of citation is related to the Poisson frequency distribution. This provides a formula for calculation of a half-life for chemistry which depends on the structure of the research front exhibited in the literature. (Author/FM)

  6. Estimation of Half-Life for Single Compartmental Elimination Models

    ERIC Educational Resources Information Center

    Mickens, R. E.; Rucker, S.

    2008-01-01

    A method is presented to calculate accurate approximations to the half-life values of elimination systems modelled by one compartment. The major advantage of this method is that only algebraic mathematical operations are required. The results will be of value not only to students beginning the study of elimination kinetics, but also to…

  7. On the half-life of {sup 44}Ti

    SciTech Connect

    Norman, E.B.; Browne, E.; Chan, Y.D.; Goldman, I.D.; Larimer, R.M.; Lesko, K.T.; Wietfeldt, F.E.; Zlimen, I.; Nelson, M.

    1996-06-19

    One of the few long-lived gamma-ray emitting radioisotopes expected to be produced in substantial quantities during a supernova explosion is {sup 44}Ti. The relevant portions of the decay schemes of {sup 44}Ti and its daughter {sup 44}Sc are shown. {sup 44}Ti decays to {sup 44}Sc emitting {gamma} rays of 68 and 78 keV. {sup 44}Sc subsequently decays with a 3.93-hour half life to {sup 44}Ca emitting an 1,157-keV {gamma}ray. This characteristic 1,157-keV {gamma} ray from the decay of {sup 44}Ti has recently been observed from the supernova remnant Cas A. In order to compare the predicted {gamma}-ray flux to that actually observed from this remnant, one must know the half-life of {sup 44}Ti. However, published values for this quantity range from 46.4 to 66.6 years. Given that the Cas A supernova is believed to have occurred approximately 300 years ago, this translates to an uncertainty by a factor of 4 in the amount of {sup 44}Ti ejected by this supernova. Thus, in order to provide an accurate and reliable value for this important quantity, the authors have performed a new experiment to determine the half-life of {sup 44}Ti. The authors produced {sup 44}Ti via the {sup 45}Sc(p,2n) reaction using 40 MeV protons from the Lawrence Berkeley National Laboratory`s 88-Inch Cyclotron. In the present experiment, the authors attempted to use all three {sup 44}Ti {gamma}-ray lines to determine its half life. However, analysis of the {sup 241}Am and {sup 137}Cs lines produced an incorrect value for the half life of each of these isotopes. On the other hand, the analysis of the {sup 22}Na line produced a result that agreed to within 0.5% of the known value of 2.603 years. Thus, they decided to concentrate their effort on the analysis of the 1,157-keV line. The half life of {sup 44}Ti that they deduce from this experiment is 63 {+-} 3 years.

  8. Secnidazole. A 5-nitroimidazole derivative with a long half-life.

    PubMed Central

    Videau, D; Niel, G; Siboulet, A; Catalan, F

    1978-01-01

    The therapeutic activity of a single 2 g dose of secnidazole was studied in patients with urogenital trichomoniasis. In 140 patients, 97% were cured and the drug was well tolerated. In the laboratory, tests on sensitivity were made and the minimal inhibitory concentration (MIC) and the minimal trichomonacidal concentration (MTC) were determined on cultures that had recently been isolated at the clinic, and the pharmacokinetic properties of secnidazole in man were compared with those of tinidazole. The therapeutic efficacy of all the metronidazole derivatives was reviewed and a single-dose treatment is recommended. Therapeutic and prophylactic treatment is achieved by products with a long half-life. Secnidazole, with a half-life of 14.3 +/- 1.3 h (women) and 20.2 +/- 3.1 h (men), is particularly suitable for this type of treatment. PMID:305808

  9. Quantitative pharmacological analyses of the interaction between flumazenil and midazolam in monkeys discriminating midazolam: Determination of the functional half life of flumazenil.

    PubMed

    Zanettini, Claudio; France, Charles P; Gerak, Lisa R

    2014-01-15

    The duration of action of a drug is commonly estimated using plasma concentration, which is not always practical to obtain or an accurate estimate of functional half life. For example, flumazenil is used clinically to reverse the effects of benzodiazepines like midazolam; however, its elimination can be altered by other drugs, including some benzodiazepines, thereby altering its half life. This study used Schild analyses to characterize antagonism of midazolam by flumazenil and determine the functional half life of flumazenil. Four monkeys discriminated 0.178mg/kg midazolam while responding under a fixed-ratio 10 schedule of stimulus-shock termination; flumazenil was given at various times before determination of a midazolam dose-effect curve. There was a time-related decrease in the magnitude of shift of the midazolam dose-effect curve as the interval between flumazenil and midazolam increased. The potency of flumazenil, estimated by apparent pA2 values (95% CI), was 7.30 (7.12, 7.49), 7.17 (7.03, 7.31), 6.91 (6.72, 7.10) and 6.80 (6.67, 6.92) at 15, 30, 60 and 120min after flumazenil administration, respectively. The functional half life of flumazenil, derived from potency estimates, was 57±13min. Thus, increasing the interval between flumazenil and midazolam causes orderly decreases in flumazenil potency; however, across a broad range of conditions, the qualitative nature of the interaction does not change, as indicated by slopes of Schild plots at all time points that are not different from unity. Differences in potency of flumazenil are therefore due to elimination of flumazenil and not due to pharmacodynamic changes over time.

  10. EFFECTIVE DOSIMETRIC HALF LIFE OF CESIUM 137 SOIL CONTAMINATION

    SciTech Connect

    Jannik, T; P Fledderman, P; Michael Paller, M

    2008-01-09

    In the early 1960s, an area of privately-owned swamp adjacent to the US Department of Energy's Savannah River Site (SRS), known as Creek Plantation, was contaminated by site operations. Studies conducted in 1974 estimated that approximately 925 GBq of {sup 137}Cs was deposited in the swamp. Subsequently, a series of surveys--composed of 52 monitoring locations--was initiated to characterize and trend the contaminated environment. The annual, potential, maximum doses to a hypothetical hunter were estimated by conservatively using the maximum {sup 137}Cs concentrations measured in the soil. The purpose of this report is to calculate an 'effective dosimetric' half-life for {sup 137}Cs in soil (based on the maximum concentrations) and compare it to the effective environmental half-life (based on the geometric mean concentrations).

  11. New Measurement of the {sup 60}Fe Half-Life

    SciTech Connect

    Rugel, G.; Faestermann, T.; Knie, K.; Korschinek, G.; Poutivtsev, M.; Schumann, D.; Kivel, N.; Guenther-Leopold, I.; Weinreich, R.; Wohlmuther, M.

    2009-08-14

    We have made a new determination of the half-life of the radioactive isotope {sup 60}Fe using high precision measurements of the number of {sup 60}Fe atoms and their activity in a sample containing over 10{sup 15} {sup 60}Fe atoms. Our new value for the half-life of {sup 60}Fe is (2.62+-0.04)x10{sup 6} yr, significantly above the previously reported value of (1.49+-0.27)x10{sup 6} yr. Our new measurement for the lifetime of {sup 60}Fe has significant implications for interpretations of galactic nucleosynthesis, for determinations of formation time scales of solids in the early Solar System, and for the interpretation of live {sup 60}Fe measurements from supernova-ejecta deposits on Earth.

  12. New Measurement of the 60Fe Half-Life.

    PubMed

    Rugel, G; Faestermann, T; Knie, K; Korschinek, G; Poutivtsev, M; Schumann, D; Kivel, N; Günther-Leopold, I; Weinreich, R; Wohlmuther, M

    2009-08-14

    We have made a new determination of the half-life of the radioactive isotope 60Fe using high precision measurements of the number of 60Fe atoms and their activity in a sample containing over 10(15) 60Fe atoms. Our new value for the half-life of 60Fe is (2.62+/-0.04) x 10(6) yr, significantly above the previously reported value of (1.49+/-0.27) x 10(6) yr. Our new measurement for the lifetime of 60Fe has significant implications for interpretations of galactic nucleosynthesis, for determinations of formation time scales of solids in the early Solar System, and for the interpretation of live 60Fe measurements from supernova-ejecta deposits on Earth. PMID:19792637

  13. Standardisation and half-life measurements of (111)In.

    PubMed

    Dziel, Tomasz; Listkowska, Anna; Tymiński, Zbigniew

    2016-03-01

    The standardisation of (111)In by 4π(LS)-γ coincidence and anticoincidence counting is presented. Absolute measurements were performed for samples with different concentrations of carrier solution and for different window settings in the gamma channel. The radioactive concentration of the master solution determined on the same reference date was consistent for all measurements performed. The evaluated typical uncertainty was 0.43%. The half-life of (111)In was determined using a time series of measurements performed with an ionisation chamber. A least squares fit of the measured data resulted in a half-life of 2.8067 (34) days consistent with Decay Data Evaluation Project recommended value (0.064% higher than the DDEP value). PMID:26651174

  14. A new determination of 79Se half-life.

    PubMed

    Bienvenu, Philippe; Cassette, Philippe; Andreoletti, Gilbert; Bé, Marie-Martine; Comte, Jérôme; Lépy, Marie-Christine

    2007-03-01

    A new value of (79)Se half-life was determined by the means of inductively coupled plasma mass spectrometry (ICP-MS) and liquid scintillation counting (LSC) on a sample source isolated from a nuclear reprocessing solution. The procedure used to extract Se from the complex sample solution consisted in liquid-liquid extraction and ion exchange chromatographic methods. The concentration of (79)Se was measured using ICP-MS coupled with electro-thermal vaporisation to eliminate potential isobaric interferences. The activity was measured using LSC after gamma-ray spectrometry to check the contribution of residual radioactive contaminants. From these results, the half-life of (79)Se was found to be 3.77 (19) x 10(5) a.

  15. On Double-Beta Decay Half-Life Time Systematics

    SciTech Connect

    Pritychenko, B.

    2010-04-14

    Recommended 2{beta}(2{nu}) half-life values and their systematics were analyzed in the framework of a simple empirical approach. T{sub 1/2}{sup 2{nu}} {approx} 1/E{sup 8} trend has been observed for {sup 128,130}Te recommended values. This trend was used to predict T{sub 1/2}{sup 2{nu}} for all isotopes of interest. Current results were compared with other theoretical and experimental works.

  16. Measurement of the 225Ac half-life.

    PubMed

    Pommé, S; Marouli, M; Suliman, G; Dikmen, H; Van Ammel, R; Jobbágy, V; Dirican, A; Stroh, H; Paepen, J; Bruchertseifer, F; Apostolidis, C; Morgenstern, A

    2012-11-01

    The (225)Ac half-life was determined by measuring the activity of (225)Ac sources as a function of time, using various detection techniques: α-particle counting with a planar silicon detector at a defined small solid angle and in a nearly-2π geometry, 4πα+β counting with a windowless CsI sandwich spectrometer and with a pressurised proportional counter, gamma-ray spectrometry with a HPGe detector and with a NaI(Tl) well detector. Depending on the technique, the decay was followed for 59-141 d, which is about 6-14 times the (225)Ac half-life. The six measurement results were in good mutual agreement and their mean value is T(1/2)((225)Ac)=9.920 (3)d. This half-life value is more precise and better documented than the currently recommended value of 10.0 d, based on two old measurements lacking uncertainty evaluations.

  17. Half-life of naled under three test scenarios.

    PubMed

    Tietze, N S; Shaffer, K R; Hester, P G

    1996-06-01

    Decline of naled residue on filter paper was studied after exposure to ultra-low volume droplets in a settling chamber. Naled-treated filter papers were stored under 3 treatment scenarios: 1) in a dark environmental chamber at an average relative humidity (RH) of 46.9% and temperature of 24 degrees C, 2) in a dark environmental chamber at an average RH of 87.7% and temperature of 24 degrees C, and, 3) in direct sunlight in the field. Decline of naled followed first order kinetics in all cases; consequently, half-life of naled under each treatment was determined from the slope of each line. Half-life (+/- 1 SD) of naled was 8.17 +/- 1.24, 4.81 +/- 1.18, and 1.37 +/- 0.24 h, for treatment scenarios 1, 2, and 3, respectively. In each test, a significant (P < 0.05) decline in naled residue occurred between initial assessment and 4 h postapplication. The half-life of each treatment scenario was significantly (P < 0.05) different from that of the other 2 scenarios, indicating that both humidity and sunlight affect naled degradation rates. PMID:8827601

  18. Measurement of the 225Ac half-life.

    PubMed

    Pommé, S; Marouli, M; Suliman, G; Dikmen, H; Van Ammel, R; Jobbágy, V; Dirican, A; Stroh, H; Paepen, J; Bruchertseifer, F; Apostolidis, C; Morgenstern, A

    2012-11-01

    The (225)Ac half-life was determined by measuring the activity of (225)Ac sources as a function of time, using various detection techniques: α-particle counting with a planar silicon detector at a defined small solid angle and in a nearly-2π geometry, 4πα+β counting with a windowless CsI sandwich spectrometer and with a pressurised proportional counter, gamma-ray spectrometry with a HPGe detector and with a NaI(Tl) well detector. Depending on the technique, the decay was followed for 59-141 d, which is about 6-14 times the (225)Ac half-life. The six measurement results were in good mutual agreement and their mean value is T(1/2)((225)Ac)=9.920 (3)d. This half-life value is more precise and better documented than the currently recommended value of 10.0 d, based on two old measurements lacking uncertainty evaluations. PMID:22940415

  19. Multivalent antiviral XTEN-peptide conjugates with long in vivo half-life and enhanced solubility.

    PubMed

    Ding, Sheng; Song, Michael; Sim, Bee-Cheng; Gu, Chen; Podust, Vladimir N; Wang, Chia-Wei; McLaughlin, Bryant; Shah, Trishul P; Lax, Rodney; Gast, Rainer; Sharan, Rahul; Vasek, Arthur; Hartman, M Amanda; Deniston, Colin; Srinivas, Prathna; Schellenberger, Volker

    2014-07-16

    XTENs are unstructured, nonrepetitive protein polymers designed to prolong the in vivo half-life of pharmaceuticals by introducing a bulking effect similar to that of poly(ethylene glycol). While XTEN can be expressed as a recombinant fusion protein with bioactive proteins and peptides, therapeutic molecules of interest can also be chemically conjugated to XTEN. Such an approach permits precise control over the positioning, spacing, and valency of bioactive moieties along the length of XTEN. We have demonstrated the attachment of T-20, an anti-retroviral peptide indicated for the treatment of HIV-1 patients with multidrug resistance, to XTEN. By reacting maleimide-functionalized T-20 with cysteine-containing XTENs and varying the number and positioning of cysteines in the XTENs, a library of different peptide-polymer combinations were produced. The T-20-XTEN conjugates were tested using an in vitro antiviral assay and were found to be effective in inhibiting HIV-1 entry and preventing cell death, with the copy number and spacing of the T-20 peptides influencing antiviral activity. The peptide-XTEN conjugates were also discovered to have enhanced solubilities in comparison with the native T-20 peptide. The pharmacokinetic profile of the most active T-20-XTEN conjugate was measured in rats, and it was found to exhibit an elimination half-life of 55.7 ± 17.7 h, almost 20 times longer than the reported half-life for T-20 dosed in rats. As the conjugation of T-20 to XTEN greatly improved the in vivo half-life and solubility of the peptide, the XTEN platform has been demonstrated to be a versatile tool for improving the properties of drugs and enabling the development of a class of next-generation therapeutics.

  20. Amino-acid mutations to extend the biological half-life of a therapeutically valuable mutant of human butyrylcholinesterase.

    PubMed

    Fang, Lei; Hou, Shurong; Xue, Liu; Zheng, Fang; Zhan, Chang-Guo

    2014-05-01

    Cocaine is a widely abused and addictive drug without an FDA-approved medication. Our recently designed and discovered cocaine hydrolase, particularly E12-7 engineered from human butyrylcholinesterase (BChE), has the promise of becoming a valuable cocaine abuse treatment. An ideal anti-cocaine therapeutic enzyme should have not only a high catalytic efficiency against cocaine, but also a sufficiently long biological half-life. However, recombinant human BChE and the known BChE mutants have a much shorter biological half-life compared to the native human BChE. The present study aimed to extend the biological half-life of the cocaine hydrolase without changing its high catalytic activity against cocaine. Our strategy was to design possible amino-acid mutations that can introduce cross-subunit disulfide bond(s) and, thus, change the distribution of the oligomeric forms and extend the biological half-life. Three new BChE mutants (E364-532, E377-516, and E535) were predicted to have a more stable dimer structure with the desirable cross-subunit disulfide bond(s) and, therefore, a different distribution of the oligomeric forms and a prolonged biological half-life. The rational design was followed by experimental tests in vitro and in vivo, confirming that the rationally designed new BChE mutants, i.e. E364-532, E377-516, and E535, indeed had a remarkably different distribution of the oligomeric forms and prolonged biological half-life in rats from ∼7 to ∼13h without significantly changing the catalytic activity against (-)-cocaine. This is the first demonstration that rationally designed amino-acid mutations can significantly prolong the biological half-life of a high-activity enzyme without significantly changing the catalytic activity.

  1. Precision half-life measurement of 17F

    NASA Astrophysics Data System (ADS)

    Brodeur, M.; Nicoloff, C.; Ahn, T.; Allen, J.; Bardayan, D. W.; Becchetti, F. D.; Gupta, Y. K.; Hall, M. R.; Hall, O.; Hu, J.; Kelly, J. M.; Kolata, J. J.; Long, J.; O'Malley, P.; Schultz, B. E.

    2016-02-01

    Background: The precise determination of f t values for superallowed mixed transitions between mirror nuclide are gaining attention as they could provide an avenue to test the theoretical corrections used to extract the Vu d matrix element from superallowed pure Fermi transitions. The 17F decay is particularly interesting as it proceeds completely to the ground state of 17O, removing the need for branching ratio measurements. The dominant uncertainty on the f t value of the 17F mirror transition stems from a number of conflicting half-life measurements. Purpose: A precision half-life measurement of 17F was performed and compared to previous results. Methods: The life-time was determined from the β counting of implanted 17F on a Ta foil that was removed from the beam for counting. The 17F beam was produced by transfers reaction and separated by the TwinSol facility of the Nuclear Science Laboratory of the University of Notre Dame. Results: The measured value of t1/2 new=64.402 (42) s is in agreement with several past measurements and represents one of the most precise measurements to date. In anticipation of future measurements of the correlation parameters for the decay and using the new world average t1/2 world=64.398 (61) s, we present a new estimate of the mixing ratio ρ for the mixed transition as well as the correlation parameters based on assuming Standard Model validity. Conclusions: The relative uncertainty on the new world average for the half-life is dominated by the large χ2=31 of the existing measurements. More precision measurements with different systematics are needed to remedy to the situation.

  2. The Half Life of {sup 193}Osbeta-decay

    SciTech Connect

    Zahn, Guilherme S.; Genezini, Frederico A.; Oliva, Jefferson W. M.; Zamboni, Cibele B.

    2010-05-21

    In this work, the half life of the beta{sup -} decay of {sup 193}Os was measured by following the activity of 25 5 mg {sup 192}Os-enriched samples for 20-60 h after they were irradiated in the IEA-R1 reactor of IPEN-CNEN/SP. Three different transitions associated with this beta decay were analyzed, and the results were then processed using three different statistical methods; the resulting values were compatible with the tabulated value, with an uncertainty of the same order of magnitude.

  3. The half-life of exogenous gastrin in the circulation

    PubMed Central

    Blair, E. L.; Farra, Yvonne; Richardson, Diana D.; Steinbok, P.

    1970-01-01

    1. A method of gastrin bio-assay is described which can be used on as little as 30 ng synthetic human gastrin I at a minimum concentration of 2·5 ng/ml. 2. Pentagastrin or synthetic human gastrin I added to cat plasma can be stored on ice or at 4° C, for periods up to 27 hr without apparent loss of gastrin activity. 3. Between 1½ and 13 min after the rapid I.V. injection of pentagastrin in the anaesthetized cat and between 1½ and 15 min after the injection of synthetic human gastrin I, there is a rapid reduction of the gastrin concentration in the arterial plasma. The data relating log10 gastrin concentration in arterial plasma with time can be fitted by a single term. 4. Studies in vitro show that over the periods of time involved in the in vivo studies, both pentagastrin and synthetic human gastrin I are stable in cat plasma at 37° C in concentrations which occurred in the circulating plasma. 5. The half-life of pentagastrin in the circulating arterial plasma of the anaesthetized cat is 1·50 min (S.E. ± 0·08) and the half-life of synthetic human gastrin I is 2·65 min (S.E. ± 0·09). ImagesFig. 5 PMID:5500725

  4. Half-life extension technologies for haemostatic agents.

    PubMed

    Mannucci, Pier Mannuccio

    2015-01-01

    The use of plasma-derived and recombinant coagulation factors for the treatment of haemophilia A and B is well established and permits patients to live a relatively normal life. In order to improve treatment options, several products are in development, which have a prolonged duration of action, thus enabling less frequent prophylactic dosing and aiming to reduce the burden of treatment. Several innovative approaches are being pursued to extend the half-life of factor VIIa, factor VIII and factor IX, utilising technologies such as Fc fusion, recombinant albumin fusion and addition of polyethyleneglycol (PEG) (PEGylation). These methods prolong the time in the circulation by reducing degradation and elimination. This review summarises the technologies and products in development and their stages of development, and also discusses their pros and cons.

  5. Biological Half-Life of Cardiolite®

    NASA Astrophysics Data System (ADS)

    Jesse, Kenneth

    2008-12-01

    I recently had a cardiac stress test. It was my fourth. Its purpose was to determine whether my heart is pumping an adequate quantity of blood during exercise. Additionally, is there a partial arterial blockage or damaged heart muscle? The test involves the patient receiving an injection of Cardiolite®, a substance containing a molecule to which Technetium-99m (Tc-99m) is attached, and then lying under a camera that detects gamma rays emanating from the interior heart wall and forms an image indicative of blood flow in the resting heart. This is followed by treadmill exercise, another injection of Cardiolite® during peak exercise, and then another image obtained with the camera indicating maximum blood flow. After the test, I decided to determine the biological half-life of Cardiolite®.

  6. The ecological half-life of ¹³⁷Cs in undisturbed silt soil.

    PubMed

    Drosg, M

    2012-08-01

    The time necessary to safely cultivate agricultural areas after they have been contaminated by radioactivity (e.g. after the Chernobyl accident) is not determined by the physical half-life of the radioactive isotopes in question but by their (usually much shorter) ecological half-life (Brisbin et al., 2002). This half-life not only depends on the type of soil but also on whether the soil was fertilized or not. Therefore it is not possible to determine an ecological half-life that is universally valid. However, the value for undisturbed, unfertilized soil should provide a general indication for the duration of ecological half-life. In a silt soil in Vienna, Austria, the ecological half-life of (137)Cs was determined to be 0.8 years, which is much shorter than the physical half-life of 30 years.

  7. Half-life determination of the ground state decay of ¹¹¹Ag.

    PubMed

    Collins, S M; Harms, A V; Regan, P H

    2016-02-01

    The radioactive decay half-life of the β(-)-emitter (111)Ag has been measured using decay transitions identified using a high purity germanium γ-ray spectrometer. The time series of measurements of the net peak areas of the 96.8 keV, 245.4 keV and 342.1 keV γ-ray emissions following the β(-) decay of (111)Ag were made over approximately 23 days, i.e. ~3 half-life periods. The measured half-life of the ground state decay of (111)Ag was determined as 7.423 (13) days which is consistent with the Evaluated Nuclear Structure Data File (ENSDF) recommended half-life of 7.45 (1) days at k=2. Utilising all available experimental half-life values, a revised recommended half-life of 7.452 (12) days has been determined. PMID:26720263

  8. Half-life determination of the ground state decay of ¹¹¹Ag.

    PubMed

    Collins, S M; Harms, A V; Regan, P H

    2016-02-01

    The radioactive decay half-life of the β(-)-emitter (111)Ag has been measured using decay transitions identified using a high purity germanium γ-ray spectrometer. The time series of measurements of the net peak areas of the 96.8 keV, 245.4 keV and 342.1 keV γ-ray emissions following the β(-) decay of (111)Ag were made over approximately 23 days, i.e. ~3 half-life periods. The measured half-life of the ground state decay of (111)Ag was determined as 7.423 (13) days which is consistent with the Evaluated Nuclear Structure Data File (ENSDF) recommended half-life of 7.45 (1) days at k=2. Utilising all available experimental half-life values, a revised recommended half-life of 7.452 (12) days has been determined.

  9. Lunatic fringe protein processing by proprotein convertases may contribute to the short protein half-life in the segmentation clock.

    PubMed

    Shifley, Emily T; Cole, Susan E

    2008-12-01

    During vertebrate segmentation, oscillatory activation of Notch signaling is important in the clock that regulates the timing of somitogenesis. In mice, the cyclic activation of NOTCH1 requires the periodic expression of Lunatic fringe (Lfng). For LFNG to play a role in the segmentation clock, its cyclic transcription must be coupled with post-translational mechanisms that confer a short protein half-life. LFNG protein is cleaved and released into the extracellular space, and here we examine the hypothesis that this secretion contributes to a short LFNG intracellular half-life, facilitating rapid oscillations within the segmentation clock. We localize N-terminal protein sequences that control the secretory behavior of fringe proteins and find that LFNG processing is promoted by specific proprotein convertases including furin and SPC6. Mutations that alter LFNG processing increase its intracellular half-life without preventing its secretion. These mutations do not affect the specificity of LFNG function in the Notch pathway, thus regulation of protein half-life affects the duration of LFNG activity without altering its function. Finally, the embryonic expression pattern of Spc6 suggests a role in terminating LFNG activity during somite patterning. These results have important implications for the mechanisms that contribute to the tight control of Notch signaling during vertebrate segmentation.

  10. Fusion of an albumin-binding domain extends the half-life of immunotoxins.

    PubMed

    Guo, Rui; Guo, Wenjun; Cao, Li; Liu, Hui; Liu, Jieyu; Xu, Hua; Huang, Weiqiang; Wang, Fengwei; Hong, Zhangyong

    2016-09-10

    Immunotoxins have documented potential as a cancer treatment due to their extreme potency; a single toxin molecule delivered to the cytosol may be sufficient to kill a cell. However, their short half-life in the circulatory system may be one of the key problems associated with the clinical use of immunotoxins and may continue to limit their therapeutic activity. Herein, we genetically fused an albumin-binding domain (ABD) to the human epidermal growth factor receptor 2 (HER2)-specific immunotoxin ZHER2-PE38 to extend the circulation time and thus improve the therapeutic outcome of this immunotoxin. Furthermore, the fusion of an ABD to the immunotoxin was found to promote non-covalent interactions between the immunotoxin and serum albumin, which rescue the immunotoxin from lysosomal degradation through a serum albumin-mediated interaction with the neonatal Fc receptor (FcRn). This manuscript reports the construction, purification, and characterization of the ABD-fused HER2-specific immunotoxin, ABD-ZHER2-PE38, both in vitro and in vivo. Compared with non-fused ZHER2-PE38, this new construct exhibits a clearly increased half-life in plasma (330.8 versus 13.5min, approximately 24.4-fold extension) and remarkably improved antitumor effects in an NCI-N87 subcutaneous xenograft model. Therefore, the new construct represents a potentially attractive therapeutic modality, and the proposed strategy may also have useful applications for current immunotoxin designs.

  11. Study of the dependence of (198) Au half-life on source geometry

    SciTech Connect

    Greene, Geoffrey L; Jenkins, J. H.; Fischbach, E.; Buncher, J.B.; Krause, D.E.; Mattes, J.J.; Lindstrom, R.M.; Yue, A.; Krause, D.E.

    2010-01-01

    We report the results of an experiment to determine whether the half-life of {sup 198}Au depends on the shape of the source. This study was motivated by recent suggestions that nuclear decay rates may be affected by solar activity, perhaps arising from solar neutrinos. If this were the case then the {beta}-decay rates, or half-lives, of a thin foil sample and a spherical sample of gold of the same mass and activity could be different. We find for {sup 198}Au, (T{sub 1/2}){sub foil}/(T{sub 1/2}){sub sphere} = 0.999 {+-} 0.002, where T{sub 1/2} is the mean half-life. The maximum neutrino flux at the sample in our experiments was several times greater than the flux of solar neutrinos at the surface of the Earth. We show that this increase in flux leads to a significant improvement in the limits that can be inferred on a possible solar contribution to nuclear decays.

  12. Fusion of an albumin-binding domain extends the half-life of immunotoxins.

    PubMed

    Guo, Rui; Guo, Wenjun; Cao, Li; Liu, Hui; Liu, Jieyu; Xu, Hua; Huang, Weiqiang; Wang, Fengwei; Hong, Zhangyong

    2016-09-10

    Immunotoxins have documented potential as a cancer treatment due to their extreme potency; a single toxin molecule delivered to the cytosol may be sufficient to kill a cell. However, their short half-life in the circulatory system may be one of the key problems associated with the clinical use of immunotoxins and may continue to limit their therapeutic activity. Herein, we genetically fused an albumin-binding domain (ABD) to the human epidermal growth factor receptor 2 (HER2)-specific immunotoxin ZHER2-PE38 to extend the circulation time and thus improve the therapeutic outcome of this immunotoxin. Furthermore, the fusion of an ABD to the immunotoxin was found to promote non-covalent interactions between the immunotoxin and serum albumin, which rescue the immunotoxin from lysosomal degradation through a serum albumin-mediated interaction with the neonatal Fc receptor (FcRn). This manuscript reports the construction, purification, and characterization of the ABD-fused HER2-specific immunotoxin, ABD-ZHER2-PE38, both in vitro and in vivo. Compared with non-fused ZHER2-PE38, this new construct exhibits a clearly increased half-life in plasma (330.8 versus 13.5min, approximately 24.4-fold extension) and remarkably improved antitumor effects in an NCI-N87 subcutaneous xenograft model. Therefore, the new construct represents a potentially attractive therapeutic modality, and the proposed strategy may also have useful applications for current immunotoxin designs. PMID:27457423

  13. Orthogonal assembly of a designed ankyrin repeat protein-cytotoxin conjugate with a clickable serum albumin module for half-life extension.

    PubMed

    Simon, Manuel; Frey, Raphael; Zangemeister-Wittke, Uwe; Plückthun, Andreas

    2013-11-20

    The generation of drug conjugates for safe and effective tumor targeting requires binding proteins tolerant to functionalization by rational engineering. Here, we show that Designed Ankyrin Repeat Proteins (DARPins), a novel class of binding proteins not derived from antibodies, can be used as building blocks for facile orthogonal assembly of bioconjugates for tumor targeting with tailored properties. DARPin Ec1, which targets the Epithelial Cell Adhesion Molecule (EpCAM), was genetically modified with a C-terminal cysteine for conjugation of the small molecule cytotoxin monomethylauristatin F (MMAF). In addition, it was N-terminally functionalized by metabolic introduction of the non-natural amino acid azidohomoalanine to enable linkage of site-specifically dibenzocyclooctyne-modified mouse serum albumin (MSA) for half-life extension using Cu(I)-free click chemistry. The conjugate MSA-Ec1-MMAF was assembled to obtain high yields of a pure and stable drug conjugate as confirmed by various analytical methods and in functional assays. The orthogonality of the assembly led to a defined reaction product and preserved the functional properties of all modules, including EpCAM-specific binding and internalization, FcRn binding mediated by MSA, and cytotoxic potency. Linkage of MMAF to the DARPin increased receptor-specific uptake of the drug while decreasing nonspecific uptake, and further coupling of the conjugate to MSA enhanced this effect. In mice, albumin conjugation increased the serum half-life from 11 min to 17.4 h, resulting in a more than 22-fold increase in the area-under-the-curve (AUC). Our data demonstrate the promise of the DARPin format for facile modular assembly of drug conjugates with improved pharmacokinetic performance for tumor targeting.

  14. Ubiquitin-fusion as a strategy to modulate protein half-life: A3G antiviral activity revisited

    SciTech Connect

    Cadima-Couto, Iris; Freitas-Vieira, Acilino; Nowarski, Roni; Britan-Rosich, Elena; Kotler, Moshe; Goncalves, Joao

    2009-10-25

    The human APOBEC3G (A3G) is a potent inhibitor of HIV-1 replication and its activity is suppressed by HIV-1 virion infectivity factor (Vif). Vif neutralizes A3G mainly by inducing its degradation in the proteasome and blocking its incorporation into HIV-1 virions. Assessing the time needed for A3G incorporation into virions is, therefore, important to determine how quickly Vif must act to induce its degradation. We show that modelling the intracellular half-life of A3G can induce its Vif-independent targeting to the ubiquitin-proteasome system. By using various amino acids (X) in a cleavable ubiquitin-X-A3G fusion, we demonstrate that the half-life (t1/2) of X-A3G can be manipulated. We show that A3G molecules with a half-life of 13 min are incorporated into virions, whereas those with a half-life shorter than 5 min were not. The amount of X-A3G incorporated into virions increases from 13 min (Phe-A3G) to 85 min (Asn-A3G) and remains constant after this time period. Interestingly, despite the presence of similar levels of Arg-A3G (t1/2 = 28 min) and Asp-A3G (t1/2 = 65 min) into HIV-1 DELTAvif virions, inhibition of viral infectivity was only evident in the presence of A3G proteins with a longer half-life (t1/2 >= 65 min).

  15. Comparative pharmacokinetics of factor VIII and recombinant factor IX: for which coagulation factors should half-life change with age?

    PubMed

    Björkman, S

    2013-11-01

    The half-life of factor VIII (FVIII) increases with the age of the patient, while studies on recombinant factor IX (rFIX) and factor VIIa (rFVIIa) have not demonstrated corresponding age-related changes. The purpose of this analysis was to relate the changes in FVIII and rFIX pharmacokinetics (PK) with age to developmental changes in body size and fluid volumes and explain why the elimination half-life of FVIII, but not of rFIX, would change with age, and to consider how the findings could be applied prospectively to other coagulation factors. Published PK data for FVIII from 186 patients aged 1-74 years and for rFIX from 56 patients aged 4-56 years were used. The relationships of FVIII and rFIX clearance (CL) with body weight could be described by allometric expressions. Relative changes in CL with age or weight were similar for FVIII and rFIX. The age-related change in volume of distribution at steady state (V(ss)) of rFIX was parallel to the change in CL in the children while for FVIII the change was much less pronounced. Elimination half-life was clearly age-dependent for FVIII while only a very weak trend could be seen for rFIX. Limited data suggest that rFVIIa in this respect resembles rFIX, with parallel changes in CL and V(ss) producing insignificant change in half-life. To what extent the elimination half-life of a coagulation factor would show a correlation with age can in principle be predicted from the characteristics of its CL and distribution.

  16. Adenosine monophosphate deaminase 3 activation shortens erythrocyte half-life and provides malaria resistance in mice.

    PubMed

    Hortle, Elinor; Nijagal, Brunda; Bauer, Denis C; Jensen, Lora M; Ahn, Seong Beom; Cockburn, Ian A; Lampkin, Shelley; Tull, Dedreia; McConville, Malcolm J; McMorran, Brendan J; Foote, Simon J; Burgio, Gaetan

    2016-09-01

    The factors that determine red blood cell (RBC) lifespan and the rate of RBC aging have not been fully elucidated. In several genetic conditions, including sickle cell disease, thalassemia, and G6PD deficiency, erythrocyte lifespan is significantly shortened. Many of these diseases are also associated with protection from severe malaria, suggesting a role for accelerated RBC senescence and clearance in malaria resistance. Here, we report a novel, N-ethyl-N-nitrosourea-induced mutation that causes a gain of function in adenosine 5'-monophosphate deaminase (AMPD3). Mice carrying the mutation exhibit rapid RBC turnover, with increased erythropoiesis, dramatically shortened RBC lifespan, and signs of increased RBC senescence/eryptosis, suggesting a key role for AMPD3 in determining RBC half-life. Mice were also found to be resistant to infection with the rodent malaria Plasmodium chabaudi. We propose that resistance to P. chabaudi is mediated by increased RBC turnover and higher rates of erythropoiesis during infection. PMID:27465915

  17. Recombinant human lactoferrin-Fc fusion with an improved plasma half-life.

    PubMed

    Shiga, Yuki; Oshima, Yuta; Kojima, Yoshinori; Sugimoto, Akinori; Tamaki, Naomi; Murata, Daisuke; Takeuchi, Takashi; Sato, Atsushi

    2015-01-25

    Lactoferrin (LF), an 80-kDa iron-binding glycoprotein found in mammalian exocrine secretions, has potential therapeutic efficacy due to its extensive health-promoting effects. However, LF is rapidly cleared from the circulation (∼12.6min half-life for recombinant human LF [rhLF] in rats), which limits its therapeutic potential. Therefore, to improve plasma stability, we developed a recombinant human LF (hLF)-immunoglobulin G1 (IgG1) fragment crystallizable domain (Fc) fusion (hLF-hinge-CH2-CH3) expressed in a Chinese Hamster Ovary cell (CHO) expression system and evaluated the in vitro bioactivities and pharmacokinetic properties of the purified fusion. CHO DG44 cells were transfected with an expression vector coding for recombinant hLF-hinge-CH2-CH3. Iron binding, Caco-2 uptake, and thermal stability were investigated in vitro, and pharmacokinetic parameters were investigated in vivo. hLF-hinge-CH2-CH3 was significantly expressed in CHO cells (∼100mg/l culture), was readily purified, and exhibited 98.3% of the non-fused rhLF iron-binding activity. Caco-2 uptake and thermal stability were improved for hLF-Fc fusion relative to rhLF. Moreover, hLF-hinge-CH2-CH3 demonstrated a plasma half-life that was 9.1-fold longer than that of rhLF as well as longer than that of the PEGylated bovine LFs that we previously developed. Thus, CHO-derived hLF-hinge-CH2-CH3, with enhanced pharmacokinetic properties, is a promising candidate drug for potential parenteral administration.

  18. Esculetin Downregulates the Expression of AML1-ETO and C-Kit in Kasumi-1 Cell Line by Decreasing Half-Life of mRNA.

    PubMed

    Sawney, Sharad; Arora, Rashi; Aggarwal, Kamal K; Saluja, Daman

    2015-01-01

    One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis. We illustrate the potential use of esculetin on leukemic cell line, Kasumi-1, bearing t(8;21) translocation and mutated C-Kit gene. Esculetin decreases the expression of AML1-ETO at both protein and transcript level within 24 hours of treatment. Half-life of AML1-ETO mRNA was reduced from 7 hours to 1.5 hours. Similarly half-life of C-Kit mRNA was reduced to 2 hours from 5 hours in esculetin treated cells. Esculetin also perturbed the expression of ectopically expressed AML1-ETO in U937 cells. The decreased expression of AML1-ETO chimeric gene was associated with increased expression of LAT1 and RUNX3 genes, targets of AML1. We envisage that discovery of a drug candidate which could target both these mutated genes would be a considerable breakthrough for future application.

  19. Esculetin Downregulates the Expression of AML1-ETO and C-Kit in Kasumi-1 Cell Line by Decreasing Half-Life of mRNA

    PubMed Central

    Sawney, Sharad; Arora, Rashi; Aggarwal, Kamal K.; Saluja, Daman

    2015-01-01

    One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis. We illustrate the potential use of esculetin on leukemic cell line, Kasumi-1, bearing t(8;21) translocation and mutated C-Kit gene. Esculetin decreases the expression of AML1-ETO at both protein and transcript level within 24 hours of treatment. Half-life of AML1-ETO mRNA was reduced from 7 hours to 1.5 hours. Similarly half-life of C-Kit mRNA was reduced to 2 hours from 5 hours in esculetin treated cells. Esculetin also perturbed the expression of ectopically expressed AML1-ETO in U937 cells. The decreased expression of AML1-ETO chimeric gene was associated with increased expression of LAT1 and RUNX3 genes, targets of AML1. We envisage that discovery of a drug candidate which could target both these mutated genes would be a considerable breakthrough for future application. PMID:25861270

  20. A biomimetic approach for enhancing the in vivo half-life of peptides.

    PubMed

    Penchala, Sravan C; Miller, Mark R; Pal, Arindom; Dong, Jin; Madadi, Nikhil R; Xie, Jinghang; Joo, Hyun; Tsai, Jerry; Batoon, Patrick; Samoshin, Vyacheslav; Franz, Andreas; Cox, Trever; Miles, Jesse; Chan, William K; Park, Miki S; Alhamadsheh, Mamoun M

    2015-10-01

    The tremendous therapeutic potential of peptides has not yet been realized, mainly owing to their short in vivo half-life. Although conjugation to macromolecules has been a mainstay approach for enhancing protein half-life, the steric hindrance of macromolecules often harms the binding of peptides to target receptors, compromising the in vivo efficacy. Here we report a new strategy for enhancing the in vivo half-life of peptides without compromising their potency. Our approach involves endowing peptides with a small molecule that binds reversibly to the serum protein transthyretin. Although there are a few molecules that bind albumin reversibly, we are unaware of designed small molecules that reversibly bind other serum proteins and are used for half-life extension in vivo. We show here that our strategy was effective in enhancing the half-life of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior in vivo efficacy.

  1. Extending half-life by indirect targeting of the neonatal Fc receptor (FcRn) using a minimal albumin binding domain.

    PubMed

    Andersen, Jan Terje; Pehrson, Rikard; Tolmachev, Vladimir; Daba, Muluneh Bekele; Abrahmsén, Lars; Ekblad, Caroline

    2011-02-18

    The therapeutic and diagnostic efficiency of engineered small proteins, peptides, and chemical drug candidates is hampered by short in vivo serum half-life. Thus, strategies to tailor their biodistribution and serum persistence are highly needed. An attractive approach is to take advantage of the exceptionally long circulation half-life of serum albumin or IgG, which is attributed to a pH-dependent interaction with the neonatal Fc receptor (FcRn) rescuing these proteins from intracellular degradation. Here, we present molecular evidence that a minimal albumin binding domain (ABD) derived from streptococcal protein G can be used for efficient half-life extension by indirect targeting of FcRn. We show that ABD, and ABD recombinantly fused to an Affibody molecule, in complex with albumin does not interfere with the strictly pH-dependent FcRn-albumin binding kinetics. The same result was obtained in the presence of IgG. An in vivo study performed in rat confirmed that the clinically relevant human epidermal growth factor 2 (HER2)-targeting Affibody molecule fused to ABD has a similar half-life and biodistribution profile as serum albumin. The proof-of-concept described may be broadly applicable to extend the in vivo half-life of short lived biological or chemical drugs ultimately resulting in enhanced therapeutic or diagnostic efficiency, a more favorable dosing regimen, and improved patient compliance.

  2. Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies.

    PubMed

    Wang, Weirong; Vlasak, Josef; Li, Yunsong; Pristatsky, Pavlo; Fang, Yulin; Pittman, Tamara; Roman, Jeanette; Wang, Yang; Prueksaritanont, Thomayant; Ionescu, Roxana

    2011-03-01

    IgG monoclonal antibodies (mAbs) consist of two Fab fragments and one Fc fragment. The Fab fragments contain the variable regions and are responsible for drug specificity (via antigen binding); the Fc fragment contains constant regions and is responsible for effector functions (via interactions with Fcγ receptors) and extended serum half-life (via interaction with the neonatal Fc receptor, FcRn). There are two conserved methionine (Met) residues located in the FcRn binding site of the Fc fragment. It has been shown previously that oxidation of these two Met residues decreases the binding affinity to FcRn. We have further evaluated the impact of Met oxidation on serum half-lives of two humanized IgG1 mAbs in transgenic mice with human FcRn. Variable oxidation levels were obtained by several procedures: exposure to an oxidizing agent, accumulation during extended refrigerated storage, or chromatographic separation. Our results show that Met oxidation can result in a significant reduction of the serum circulation half-life and the magnitude of the change correlates well with the extent of Met oxidation and changes in FcRn binding affinities. The relatively low levels of Met oxidation accumulated during 3 years of refrigerated storage had minimal impact on FcRn binding and no detectable impact on the serum half-life.

  3. A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life.

    PubMed

    Lindgren, Joel; Refai, Essam; Zaitsev, Sergei V; Abrahmsén, Lars; Berggren, Per-Olof; Karlström, Amelie Eriksson

    2014-05-01

    Glucagon-like peptide 1 (GLP-1) and related peptide agonists have been extensively investigated for glycaemic control in Type 2 diabetes, and may also have therapeutic applications for other diseases. Due to the short half-life (t1/2  < 2 min) of the endogenous peptide, caused by proteolytic degradation and renal clearance, different strategies for half-life extension and sustained release have been explored. In the present study, conjugates between a GLP-1 analogue and a 5 kDa albumin-binding domain (ABD) derived from streptococcal protein G have been chemically synthesized and evaluated. ABD binds with high affinity to human serum albumin, which is highly abundant in plasma and functions as a drug carrier in the circulation. Three different GLP-1-ABD conjugates, with the two peptides connected by linkers of two, four, and six PEG units, respectively, were synthesized and tested in mouse pancreatic islets at high (11 mM) and low (3 mM) glucose concentration. Insulin release upon stimulation was shown to be glucose-dependent, showing no significant difference between the three different GLP-1-ABD conjugates and unconjugated GLP-1 analogue. The biological activity, in combination with the high affinity binding to albumin, make the GLP-1-ABD conjugates promising GLP-1 receptor agonists expected to show extended in vivo half-life.

  4. Influence of soil half-life on risk assessment of carcinogens.

    PubMed

    Borgert, C J; Roberts, S M; Harbison, R D; James, R C

    1995-10-01

    Risk estimates for contaminants in soil are currently calculated assuming that concentrations remain unchanged over time. In reality, biological and physicochemical processes can substantially diminish contaminant concentrations in soil. For exposure periods typically evaluated in USEPA risk assessments, failure to consider the decline in contaminant levels from environmental transport and degradation can result in a significant overestimation of the average daily dose of toxicant. This overestimation may be up to 2- to 3-fold for compounds with long half-lives (15-20 years) in soil and as much as 40-fold for compounds with short half-lives (0.5 years). Overestimation of dosages affects estimation of cancer risks because of the assumption that the probability of cancer increases directly with the cumulative dose of carcinogen. Thus, assuming static contaminant concentrations in soil adds unacknowledged conservatism to cancer risk estimates and target concentration limits. Furthermore, as significant time may elapse before future-use scenarios could possibly occur, soil half-life can affect the estimation of noncarcinogenic health hazards as well. Therefore, an increase in target concentration limits for some compounds could be allowed and corresponding remediation costs reduced by considering how soil half-life changes the dosage calculation. Specific examples of the influence of soil degradation rates on estimates of cancer risk are presented and the degree of added conservatism imparted to risk assessments through assumption of static site contaminant levels is discussed. Considering the potential importance of this parameter for risk assessment and risk management decisions, soil degradation of contaminants under site-specific conditions should be performed whenever possible and incorporated into the risk assessment exercise. When the soil degradation rate cannot be measured or reliably predicted, an estimate of the degree of conservatism should be made to

  5. Estimation of the Biological Half-Life of Methylmercury Using a Population Toxicokinetic Model.

    PubMed

    Jo, Seongil; Woo, Hae Dong; Kwon, Ho-Jang; Oh, Se-Young; Park, Jung-Duck; Hong, Young-Seoub; Pyo, Heesoo; Park, Kyung Su; Ha, Mina; Kim, Ho; Sohn, Seok-Joon; Kim, Yu-Mi; Lim, Ji-Ae; Lee, Sang-Ah; Eom, Sang-Yong; Kim, Byoung-Gwon; Lee, Kyoung-Mu; Lee, Jong-Hyeon; Hwang, Myung Sil; Kim, Jeongseon

    2015-07-31

    Methylmercury is well known for causing adverse health effects in the brain and nervous system. Estimating the elimination constant derived from the biological half-life of methylmercury in the blood or hair is an important part of calculating guidelines for methylmercury intake. Thus, this study was conducted to estimate the biological half-life of methylmercury in Korean adults. We used a one-compartment model with a direct relationship between methylmercury concentrations in the blood and daily dietary intake of methylmercury. We quantified the between-person variability of the methylmercury half-life in the population, and informative priors were used to estimate the parameters in the model. The population half-life of methylmercury was estimated to be 80.2 ± 8.6 days. The population mean of the methylmercury half-life was 81.6 ± 8.4 days for men and 78.9 ± 8.6 days for women. The standard deviation of the half-life was estimated at 25.0 ± 8.6 days. Using the direct relationship between methylmercury concentrations in blood and methylmercury intake, the biological half-life in this study was estimated to be longer than indicated by the earlier studies that have been used to set guideline values.

  6. Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody

    PubMed Central

    Monnet, Céline; Jorieux, Sylvie; Souyris, Nathalie; Zaki, Ouafa; Jacquet, Alexandra; Fournier, Nathalie; Crozet, Fabien; de Romeuf, Christophe; Bouayadi, Khalil; Urbain, Rémi; Behrens, Christian K; Mondon, Philippe; Fontayne, Alexandre

    2014-01-01

    While glyco-engineered monoclonal antibodies (mAbs) with improved antibody-dependent cell-mediated cytotoxicity (ADCC) are reaching the market, extensive efforts have also been made to improve their pharmacokinetic properties to generate biologically superior molecules. Most therapeutic mAbs are human or humanized IgG molecules whose half-life is dependent on the neonatal Fc receptor FcRn. FcRn reduces IgG catabolism by binding to the Fc domain of endocytosed IgG in acidic lysosomal compartments, allowing them to be recycled into the blood. Fc-engineered mAbs with increased FcRn affinity resulted in longer in vivo half-life in animal models, but also in healthy humans. These Fc-engineered mAbs were obtained by alanine scanning, directed mutagenesis or in silico approach of the FcRn binding site. In our approach, we applied a random mutagenesis technology (MutaGenTM) to generate mutations evenly distributed over the whole Fc sequence of human IgG1. IgG variants with improved FcRn-binding were then isolated from these Fc-libraries using a pH-dependent phage display selection process. Two successive rounds of mutagenesis and selection were performed to identify several mutations that dramatically improve FcRn binding. Notably, many of these mutations were unpredictable by rational design as they were located distantly from the FcRn binding site, validating our random molecular approach. When produced on the EMABling® platform allowing effector function increase, our IgG variants retained both higher ADCC and higher FcRn binding. Moreover, these IgG variants exhibited longer half-life in human FcRn transgenic mice. These results clearly demonstrate that glyco-engineering to improve cytotoxicity and protein-engineering to increase half-life can be combined to further optimize therapeutic mAbs. PMID:24492301

  7. The novel benzopyran class of selective cyclooxygenase-2 inhibitors. Part 2: The second clinical candidate having a shorter and favorable human half-life

    SciTech Connect

    Wang, Jane L.; Limburg, David; Graneto, Matthew J.; Springer, John; Hamper, Joseph Rogier Bruce; Liao, Subo; Pawlitz, Jennifer L.; Kurumbail, Ravi G.; Maziasz, Timothy; Talley, John J.; Kiefer, James R.; Carter, Jeffery

    2012-05-29

    In this Letter, we provide the structure-activity relationships, optimization of design, testing criteria, and human half-life data for a series of selective COX-2 inhibitors. During the course of our structure-based drug design efforts, we discovered two distinct binding modes within the COX-2 active site for differently substituted members of this class. The challenge of a undesirably long human half-life for the first clinical candidate 1t{sub 1/2} = 360 h was addressed by multiple strategies, leading to the discovery of 29b-(S) (SC-75416) with t{sub 1/2} = 34 h.

  8. Update of NIST half-life results corrected for ionization chamber source-holder instability.

    PubMed

    Unterweger, M P; Fitzgerald, R

    2014-05-01

    As reported at the ICRM 2011, it was discovered that the source holder used for calibrations in the NIST 4πγ ionization chamber (IC) was not stable. This has affected a large number of half-life measurement results previously reported and used in compilations of nuclear data. Corrections have been made on all of the half-life data based on the assumption that the changes to the ionization chamber response were gradual. The corrections are energy dependent and therefore radionuclide specific. This presentation will review our results and present the recommended changes in half-life values and/or uncertainties.

  9. Age- and Concentration-Dependent Elimination Half-Life of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Seveso Children

    PubMed Central

    Kerger, Brent D.; Leung, Hon-Wing; Scott, Paul; Paustenbach, Dennis J.; Needham, Larry L.; Patterson, Donald G.; Gerthoux, Pier M.; Mocarelli, Paolo

    2006-01-01

    Objective Pharmacokinetic and statistical analyses are reported to elucidate key variables affecting 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) elimination in children and adolescents. Design We used blood concentrations to calculate TCDD elimination half-life. Variables examined by statistical analysis include age, latency from exposure, sex, TCDD concentration and quantity in the body, severity of chloracne response, body mass index, and body fat mass. Participants Blood was collected from 1976 to 1993 from residents of Seveso, Italy, who were < 18 years of age at the time of a nearby trichlorophenol reactor explosion in July 1976. Results TCDD half-life in persons < 18 years of age averaged 1.6 years while those ≥18 years of age averaged 3.2 years. Half-life is strongly associated with age, showing a cohort average increase of 0.12 year half-life per year of age or time since exposure. A significant concentration-dependency is also identified, showing shorter half-lives for TCDD concentrations > 400 ppt for children < 12 years of age and 700 ppt when including adults. Moderate correlations are also observed between half-life and body mass index, body fat mass, TCDD mass, and chloracne response. Conclusions Children and adolescents have shorter TCDD half-lives and a slower rate of increase in half-life than adults, and this effect is augmented at higher body burdens. Relevance Modeling of TCDD blood concentrations or body burden in humans should take into account the markedly shorter elimination half-life observed in children and adolescents and concentration-dependent effects observed in persons > 400–700 ppt. PMID:17035149

  10. Measurement of the {sup 44}Ti half-life and its significance for supernova.

    SciTech Connect

    Ahmad, I.; Greene, J. P.; Kutschera, W.; Paul, M.

    1999-08-28

    In 1998, we reported the three-laboratory measurement of the {sup 44}Ti half-life which was determined relative to the well known value (5.2714 {+-} 0.0005 yr) of the {sup 60}Co half-life. We have continued the measurement at Argonne and Jerusalem and inclusion of data points for additional two years does not change our published value of 59.0 {+-} 0.6 yr.

  11. Dependence of the half-life of {sup 221}Fr on the implantation environment

    SciTech Connect

    Olaizola, B.; Fraile, L. M.; Riisager, K.; Jeppesen, H.; Skovbo, K.; Thomsen, L. A.; Correia, J. G.; Johnston, K.; Fynbo, H. O. U.; Kirsebom, O.

    2010-04-26

    The possible dependence of the half-life of {sup 221}Fr on the solid-state environment has been investigated by the simultaneous measurement of implanted {sup 221}Fr ions in an insulator (Si) and a metallic substrate (Au) at the ISOLDE facility at CERN. Our results indicate that, if existing, the difference in half-life does not follow a systematic trend and it is well below 1%.

  12. Insomnia in generalized anxiety disorder: polysomnographic, psychometric and clinical investigations before, during and after therapy with a long- versus a short-half-life benzodiazepine (quazepam versus triazolam).

    PubMed

    Saletu, B; Anderer, P; Brandstätter, N; Frey, R; Grünberger, J; Klösch, G; Mandl, M; Wetter, T; Zeitlhofer, J

    1994-01-01

    Within a double-blind, comparative study on the effects of the long-half-life benzodiazepine (BDZ), quazepam, and the short-half-life BDZ, triazolam, on clinical symptomatology, sleep and anxiety of 45 patients with insomnia based on a mild to moderate generalized anxiety disorder (GAD) (ICD-9 code: 307.42-1, 300,0; ASDC-APSS-Code: A.2.a), we compared, in a first step at baseline, drug-free polysomnographic and psychometric data of 22 patients recorded in the laboratory (L-group) and 21 patients recorded by the Oxford Medilog 9000 system at home (H-group) with those of normal controls. Sleep efficiency, total sleep time, wake within total sleep period (middle insomnia) and wake before buzzer (late insomnia) were significantly deteriorated in both patient groups as compared with controls, while sleep induction time only differed significantly in home recordings. Regarding sleep architecture, stage (S)2 was reduced, S3 and S4 increased in the H-group only, while no intergroup differences were seen in S1, SREM and REM latency. Subjective sleep quality was reduced in both patient groups, but not awakening quality. Psychometric tests in the morning demonstrated for the noopsyche, only a significantly deteriorated psychomotor activity in both patient groups. In the thymopsyche, evening well-being and mood in the morning were reduced in both the L- and H-group, affectivity and morning well-being only in the H-group. The psychopharmacological part of the study was completed by 40 patients (there were 4 drop-outs in the triazolam, 1 in the quazepam group). They were treated after 1 week placebo with either 15-30 mg (median 15 mg) quazepam or 0.25-0.5 mg (median 0.25 mg) triazolam for 4 weeks, and thereafter for 2 weeks with placebo. Anxiety (rated by HAMA and SAS) improved significantly with both drugs and remained improved throughout 2 weeks post-drug placebo, with quazepam being slightly superior to triazolam. Polysomnography demonstrated a shortened sleep onset only

  13. Drug and Alcohol Arrests Increased in 1999.

    ERIC Educational Resources Information Center

    Nicklin, Julie L.

    2001-01-01

    U.S. Department of Education (DOE) data showed a 1999 increase in drug and alcohol arrests on college campuses. Also, the number of reported sex offenses rose by 6 percent from 1998-99. Some experts question the validity of the year-to-year comparisons and the DOE data. Presents statistics on sex offenses, drug use, and drinking and football. (SM)

  14. A biomimetic approach for enhancing the in vivo half-life of peptides

    PubMed Central

    Penchala, Sravan C; Miller, Mark R; Pal, Arindom; Dong, Jin; Madadi, Nikhil R.; Xie, Jinghang; Joo, Hyun; Tsai, Jerry; Batoon, Patrick; Samoshin, Vyacheslav; Franz, Andreas; Cox, Trever; Miles, Jesse; Chan, William K; Park, Miki S; Alhamadsheh, Mamoun M

    2015-01-01

    The tremendous therapeutic potential of peptides has not yet been realized, mainly due to their short in vivo half-life. While conjugation to macromolecules has been a mainstay approach for enhancing the half-life of proteins, the steric hindrance of macromolecules often harms the binding of peptides to target receptors, compromising the in vivo efficacy. Here we report a new strategy for enhancing the in vivo half-life of peptides without compromising their potency. Our approach involves endowing peptides with a small-molecule that binds reversibly to the serum protein, transthyretin. Although there are few reversible albumin-binding molecules, we are unaware of designed small molecules that bind reversibly to other serum proteins and are used for half-life extension in vivo. We show here that our strategy was indeed effective in enhancing the half-life of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior in vivo efficacy. PMID:26344696

  15. Using gamma distribution to determine half-life of rotenone, applied in freshwater.

    PubMed

    Rohan, Maheswaran; Fairweather, Alastair; Grainger, Natasha

    2015-09-15

    Following the use of rotenone to eradicate invasive pest fish, a dynamic first-order kinetic model is usually used to determine the half-life and rate at which rotenone dissipated from the treated waterbody. In this study, we investigate the use of a stochastic gamma model for determining the half-life and rate at which rotenone dissipates from waterbodies. The first-order kinetic and gamma models produced similar values for the half-life (4.45 days and 5.33 days respectively) and days to complete dissipation (51.2 days and 52.48 days respectively). However, the gamma model fitted the data better and was more flexible than the first-order kinetic model, allowing us to use covariates and to predict a possible range for the half-life of rotenone. These benefits are particularly important when examining the influence that different environmental factors have on rotenone dissipation and when trying to predict the rate at which rotenone will dissipate during future operations. We therefore recommend that in future the gamma distribution model is used when calculating the half-life of rotenone in preference to the dynamic first-order kinetics model. PMID:25965037

  16. Role of enhanced half-life factor VIII and IX in the treatment of haemophilia.

    PubMed

    Mahdi, Ali J; Obaji, Samya G; Collins, Peter W

    2015-06-01

    Treatment of congenital haemophilia with factor VIII and IX concentrates often requires frequent infusions. This has obvious implications in establishing effective administration strategies and, in turn, adherence. To overcome these issues, three main technologies--polyethylene-glycol, Fc-neonatal IgG1 and albumin fusion products--have emerged into various stages of clinical development. Published data indicates an approximately 1·5- and fivefold increase in half-life of factor VIII and IX, respectively, compared to standard recombinant concentrates. Studies into efficacy and safety are starting to be published. Monitoring and optimal use of these new concentrates remains unknown. Weekly factor IX prophylaxis appears to be a feasible prophylactic regimen in haemophilia B patients. Weekly longer-acting FVIII is unlikely to provide adequate prophylaxis in most patients with haemophilia A but may reduce the frequency of infusions. Ongoing clinical trials and real life experience will help shape how these products can be used in practice and their cost effectiveness. The drive for convenience however should not overshadow the ultimate goal of prophylaxis, namely, preventing bleeding and arthropathy.

  17. Determination of the half-life of 213Fr with high precision

    NASA Astrophysics Data System (ADS)

    Fisichella, M.; Musumarra, A.; Farinon, F.; Nociforo, C.; Del Zoppo, A.; Figuera, P.; La Cognata, M.; Pellegriti, M. G.; Scuderi, V.; Torresi, D.; Strano, E.

    2013-07-01

    High-precision measurement of half-life and Qα value of neutral and highly charged α emitters is a major subject of investigation currently. In this framework, we recently pushed half-life measurements of neutral emitters to a precision of a few per mil. This result was achieved by using different techniques and apparatuses at Istituto Nazionale di Fisica Nucleare Laboratori Nazionali del Sud (INFN-LNS) and GSI Darmstadt. Here we report on 213Fr half-life determination [T1/2(213Fr) = 34.14±0.06 s] at INFN-LNS, detailing the measurement protocol used. Direct comparison with the accepted value in the literature shows a discrepancy of more than three sigma. We propose this new value as a reference, discussing previous experiments.

  18. Measurement of the (211)Pb half-life using recoil atoms from (219)Rn decay.

    PubMed

    Aitken-Smith, P M; Collins, S M

    2016-04-01

    The radioactive half-life of (211)Pb was measured, by α-particle counting of samples of radiochemically pure (211)Pb in equilibrium with its α-emitting progeny, (211)Bi and (211)Po. The samples were prepared by the collection of (215)Po recoil atoms from the decay of the (219)Rn decay progeny produced from a (223)Ra sample onto stainless steel discs. The radioactive decay of the (211)Pb was measured utilising a 2π proportional counter operating on the α plateau. A half-life of 36.164 (13)min was determined, which is in agreement with currently available literature. A full uncertainty budget is presented. A recommended half-life of T1/2((211)Pb)=36.161 (17)min has been evaluated from the current literature values. PMID:26773817

  19. β-decay half-life of V50 calculated by the shell model

    NASA Astrophysics Data System (ADS)

    Haaranen, M.; Srivastava, P. C.; Suhonen, J.; Zuber, K.

    2014-10-01

    In this work we survey the detectability of the β- channel of 2350V leading to the first excited 2+ state in 2450Cr. The electron-capture (EC) half-life corresponding to the transition of 2350V to the first excited 2+ state in 2250Ti had been measured earlier. Both of the mentioned transitions are 4th-forbidden non-unique. We have performed calculations of all the involved wave functions by using the nuclear shell model with the GXPF1A interaction in the full f-p shell. The computed half-life of the EC branch is in good agreement with the measured one. The predicted half-life for the β- branch is in the range ≈2×1019 yr whereas the present experimental lower limit is 1.5×1018 yr. We discuss also the experimental lay-out needed to detect the β--branch decay.

  20. Measurement of the (211)Pb half-life using recoil atoms from (219)Rn decay.

    PubMed

    Aitken-Smith, P M; Collins, S M

    2016-04-01

    The radioactive half-life of (211)Pb was measured, by α-particle counting of samples of radiochemically pure (211)Pb in equilibrium with its α-emitting progeny, (211)Bi and (211)Po. The samples were prepared by the collection of (215)Po recoil atoms from the decay of the (219)Rn decay progeny produced from a (223)Ra sample onto stainless steel discs. The radioactive decay of the (211)Pb was measured utilising a 2π proportional counter operating on the α plateau. A half-life of 36.164 (13)min was determined, which is in agreement with currently available literature. A full uncertainty budget is presented. A recommended half-life of T1/2((211)Pb)=36.161 (17)min has been evaluated from the current literature values.

  1. Half life of chromium in serum and urine in a former plasma cutter of stainless steel

    PubMed Central

    Petersen, R.; Thomsen, J. F.; Jorgensen, N. K.; Mikkelsen, S.

    2000-01-01

    For 8 years chromium in serum and urine has been followed up in a former plasma cutter of stainless steel who was exposed to airborne dust and fumes containing chromium during this work. After the first examination for serum chromium the exposure ended. Serum chromium concentration has been measured seven times during the period and was initially very high and has subsequently dropped slowly. The half life was 40 months in serum. Urinary chromium has been measured five times. The half life was 129 months in urine. The study shows that exposure to airborne dust and fumes containing chromium may cause accumulation of chromium in the body, and that when exposure ends, elimination of chromium is very slow. Previous studies suggest that chromium mainly accumulates in the lungs.


Keywords: chromium half life; plasma cutting; stainless steel PMID:10711283

  2. Measurement of the {sup 214}Po half-life by the DEVIS track setup

    SciTech Connect

    Belov, V. A.; Brakhman, E. V.; Zeldovich, O. Ya.; Karelin, A. K.; Kirichenko, V. V.; Kobyakin, A. S. Kozodaeva, O. M.; Kuchenkov, A. V.; Tsvetkova, T. N.

    2013-04-15

    Measurement of the {sup 214}Po half-life with the DEVIS track setup at the Institute of Theoretical and Experimental Physics (ITEP, Moscow) by means of a procedure based on determining lifetimes of individual nuclei is described. The value obtained for the {sup 214}Po half-life is 163.8 {+-} 3.0 Micro-Sign s. The possibility of reaching the accuracy of the measurements that is required for testing the statement that the decay of some nuclei has a nonexponential character and the source intensity necessary for this are discussed.

  3. Half-life measurements of lutetium-176 using underground HPGe-detectors.

    PubMed

    Hult, Mikael; Vidmar, Tim; Rosengård, Ulf; Marissens, Gerd; Lutter, Guillaume; Sahin, Namik

    2014-05-01

    The half-life of (176)Lu was determined by measuring the (176)Lu activity in metallic lutetium foils. Three different HPGe-detectors located 225 m underground were employed for the study. Measurements using the sum-peak method were performed and resulted in an average massic activity of (52.61±0.36) Bq g(-1). The foils were of natural isotopic abundance so using the massic activity and the value of the natural isotopic abundance of (2.59±0.01)%, a half-life of (3.722±0.029)×10(10)a could be calculated.

  4. Direct Determination of the Half-Life of ^4^1Ca

    NASA Astrophysics Data System (ADS)

    Jörg, G.; Amelin, Y.; Kossert, K.; v. Gostomski, C. L.

    2012-03-01

    The half-life of ^4^1Ca is determined at 9937 ± 146 years using double spike isotope dilution TIMS, and liquid scintillation counting using triple-to-double coincidence ratio method on a radiochemically pure, carrier-free ^4^1Ca.

  5. Intrinsically disordered segments and the evolution of protein half-life

    NASA Astrophysics Data System (ADS)

    Babu, M.

    2013-03-01

    Precise turnover of proteins is essential for cellular homeostasis and is primarily mediated by the proteasome. Thus, a fundamental question is: What features make a protein an efficient substrate for degradation? Here I will present results that proteins with a long terminal disordered segment or internal disordered segments have a significantly shorter half-life in yeast. This relationship appears to be evolutionarily conserved in mouse and human. Furthermore, upon gene duplication, divergence in the length of terminal disorder or variation in the number of internal disordered segments results in significant alteration of the half-life of yeast paralogs. Many proteins that exhibit such changes participate in signaling, where altered protein half-life will likely influence their activity. We suggest that variation in the length and number of disordered segments could serve as a remarkably simple means to evolve protein half-life and may serve as an underappreciated source of genetic variation with important phenotypic consequences. MMB acknowledges the Medical Research Council for funding his research program.

  6. Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution

    PubMed Central

    van der Lee, Robin; Lang, Benjamin; Kruse, Kai; Gsponer, Jörg; Sánchez de Groot, Natalia; Huynen, Martijn A.; Matouschek, Andreas; Fuxreiter, Monika; Babu, M. Madan

    2014-01-01

    Summary Precise control of protein turnover is essential for cellular homeostasis. The ubiquitin-proteasome system is well established as a major regulator of protein degradation, but an understanding of how inherent structural features influence the lifetimes of proteins is lacking. We report that yeast, mouse, and human proteins with terminal or internal intrinsically disordered segments have significantly shorter half-lives than proteins without these features. The lengths of the disordered segments that affect protein half-life are compatible with the structure of the proteasome. Divergence in terminal and internal disordered segments in yeast proteins originating from gene duplication leads to significantly altered half-life. Many paralogs that are affected by such changes participate in signaling, where altered protein half-life will directly impact cellular processes and function. Thus, natural variation in the length and position of disordered segments may affect protein half-life and could serve as an underappreciated source of genetic variation with important phenotypic consequences. PMID:25220455

  7. The "Radioactive Dice" Experiment: Why Is the "Half-Life" Slightly Wrong?

    ERIC Educational Resources Information Center

    Murray, Arthur; Hart, Ian

    2012-01-01

    The "radioactive dice" experiment is a commonly used classroom analogue to model the decay of radioactive nuclei. However, the value of the half-life obtained from this experiment differs significantly from that calculated for real nuclei decaying exponentially with the same decay constant. This article attempts to explain the discrepancy and…

  8. Site-specific fatty acid-conjugation to prolong protein half-life in vivo.

    PubMed

    Lim, Sung In; Mizuta, Yukina; Takasu, Akinori; Hahn, Young S; Kim, Yong Hwan; Kwon, Inchan

    2013-09-10

    Therapeutic proteins are indispensable in treating numerous human diseases. However, therapeutic proteins often suffer short serum half-life. In order to extend the serum half-life, a natural albumin ligand (a fatty acid) has been conjugated to small therapeutic peptides resulting in a prolonged serum half-life via binding to patients' serum albumin in vivo. However, fatty acid-conjugation has limited applicability due to lack of site-specificity resulting in the heterogeneity of conjugated proteins and a significant loss in pharmaceutical activity. In order to address these issues, we exploited the site-specific fatty acid-conjugation to a permissive site of a protein, using copper-catalyzed alkyne-azide cycloaddition, by linking a fatty acid derivative to p-ethynylphenylalanine incorporated into a protein using an engineered pair of yeast tRNA/aminoacyl tRNA synthetase. As a proof-of-concept, we show that single palmitic acid conjugated to superfolder green fluorescent protein (sfGFP) in a site-specific manner enhanced a protein's albumin-binding in vitro about 20 times and the serum half-life in vivo 5 times when compared to those of the unmodified sfGFP. Furthermore, the fatty acid conjugation did not cause a significant reduction in the fluorescence of sfGFP. Therefore, these results clearly indicate that the site-specific fatty acid-conjugation is a very promising strategy to prolong protein serum half-life in vivo without compromising its folded structure and activity.

  9. Effective half-life of caesium-137 in various environmental media at the Savannah river site.

    PubMed

    Paller, M H; Jannik, G T; Baker, R A

    2014-05-01

    During the operational history of the Savannah River Site (SRS), many different radionuclides have been released from site facilities into the SRS environment. However, only a relatively small number of pathways, most importantly (137)Cs in fish and deer, have contributed significantly to doses and risks to the public. The "effective" half-lives (Te) of (137)Cs (which include both physical decay and environmental dispersion) in Savannah River floodplain soil and vegetation and in fish and white-tailed deer from the SRS were estimated using long-term monitoring data. For 1974-2011, the Tes of (137)Cs in Savannah River floodplain soil and vegetation were 17.0 years (95% CI = 14.2-19.9) and 13.4 years (95% CI = 10.8-16.0), respectively. These Tes were greater than in a previous study that used data collected only through 2005 as a likely result of changes in the flood regime of the Savannah River. Field analyses of (137)Cs concentrations in deer collected during yearly controlled hunts at the SRS indicated an overall Te of 15.9 years (95% CI = 12.3-19.6) for 1965-2011; however, the Te for 1990-2011 was significantly shorter (11.8 years, 95% CI = 4.8-18.8) due to an increase in the rate of (137)Cs removal. The shortest Tes were for fish in SRS streams and the Savannah River (3.5-9.0 years), where dilution and dispersal resulted in rapid (137)Cs removal. Long-term data show that Tes are significantly shorter than the physical half-life of (137)Cs in the SRS environment but that they can change over time. Therefore, it is desirable have a long period of record for calculating Tes and risky to extrapolate Tes beyond this period unless the processes governing (137)Cs removal are clearly understood.

  10. Crosslinking of micropatterned collagen-based nerve guides to modulate the expected half-life.

    PubMed

    Salvatore, L; Madaghiele, M; Parisi, C; Gatti, F; Sannino, A

    2014-12-01

    The microstructural, mechanical, compositional, and degradative properties of a nerve conduit are known to strongly affect the regenerative process of the injured peripheral nerve. Starting from the fabrication of micropatterned collagen-based nerve guides, according to a spin-casting process reported in the literature, this study further investigates the possibility to modulate the degradation rate of the scaffolds over a wide time frame, in an attempt to match different rates of nerve regeneration that might be encountered in vivo. To this aim, three different crosslinking methods, that is, dehydrothermal (DHT), carbodiimide-based (EDAC), and glutaraldehyde-based (GTA) crosslinking, were selected. The elastically effective degree of crosslinking, attained by each method and evaluated according to the classical rubber elasticity theory, was found to significantly tune the in vitro half-life (t1/2 ) of the matrices, with an exponential dependence of the latter on the crosslink density. The high crosslinking efficacy of EDAC and GTA treatments, respectively threefold and fourfold when compared to the one attained by DHT, led to a sharp increase of the corresponding in vitro half-lives (ca., 10, 172, and 690 h, for DHT, EDAC, and GTA treated matrices, respectively). As shown by cell viability assays, the cytocompatibility of both DHT and EDAC treatments, as opposed to the toxicity of GTA, suggests that such methods are suitable to crosslink collagen-based scaffolds conceived for clinical use. In particular, nerve guides with expected high residence times in vivo might be produced by finely controlling the biocompatible reaction(s) adopted for crosslinking.

  11. PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins

    PubMed Central

    Schlapschy, Martin; Binder, Uli; Börger, Claudia; Theobald, Ina; Wachinger, Klaus; Kisling, Sigrid; Haller, Dirk; Skerra, Arne

    2013-01-01

    A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjugation to drugs is an established method for plasma half-life extension. In contrast, PAS polypeptides offer fusion to a therapeutic protein on the genetic level, permitting Escherichia coli production of fully active proteins and obviating in vitro coupling or modification steps. Furthermore, they are biodegradable, thus avoiding organ accumulation, while showing stability in serum and lacking toxicity or immunogenicity in mice. We demonstrate that PASylation bestows typical biologics, such as interferon, growth hormone or Fab fragments, with considerably prolonged circulation and boosts bioactivity in vivo. PMID:23754528

  12. Immunoglobulin Fc domain fusion to apolipoprotein(a) kringle V significantly prolongs plasma half-life without affecting its anti-angiogenic activity.

    PubMed

    Yu, Hyun-Kyung; Lee, Ho-Jeong; Ahn, Jin-Hyung; Lim, In-Hwan; Moon, Jae-Hoon; Yoon, Yeup; Yi, Lee S H; Kim, Sun Jin; Kim, Jang-Seong

    2013-06-01

    Angiogenesis is crucial for tumor growth and metastasis. Blocking this process is, therefore, a potentially powerful approach for the treatment of cancer. Human apolipoprotein(a) kringle V (rhLK8) is an angiogenesis inhibitor and is currently under development as an anti-cancer therapeutic. However, a relatively short in vivo half-life limits its widespread clinical use. This study was performed to evaluate whether fusion of an Fc domain to rhLK8 can extend plasma half-life. RhLK8-Fc fusion protein was expressed in CHO DG44 cells as a dimer and was readily purified by protein G affinity chromatography. The anti-angiogenic activity of rhLK8-Fc was similar to that of rhLK8, as determined by migration and tube formation assays with endothelial cells in vitro and a chorioallantoic membrane assay in vivo. Pharmacokinetic profiles in mice after single intravenous administration of rhLK8 or rhLK8-Fc showed that Fc fusion significantly increased the elimination half-life (t(½)) and the systemic exposure (AUC(inf)) of the protein, in parallel with a significant decrease in total clearance (CL). These data suggest that Fc fusion to rhLK8 is a powerful strategy for extending the plasma half-life of rhLK8 without affecting its anti-angiogenic activity, and could thus improve the clinical applicability of rhLK8.

  13. Dual Constant Domain-Fab: A novel strategy to improve half-life and potency of a Met therapeutic antibody.

    PubMed

    Cignetto, Simona; Modica, Chiara; Chiriaco, Cristina; Fontani, Lara; Milla, Paola; Michieli, Paolo; Comoglio, Paolo M; Vigna, Elisa

    2016-06-01

    The kinase receptor encoded by the Met oncogene is a sensible target for cancer therapy. The chimeric monovalent Fab fragment of the DN30 monoclonal antibody (MvDN30) has an odd mechanism of action, based on cell surface removal of Met via activation of specific plasma membrane proteases. However, the short half-life of the Fab, due to its low molecular weight, is a severe limitation for the deployment in therapy. This issue was addressed by increasing the Fab molecular weight above the glomerular filtration threshold through the duplication of the constant domains, in tandem (DCD-1) or reciprocally swapped (DCD-2). The two newly engineered molecules showed biochemical properties comparable to the original MvDN30 in vitro, acting as full Met antagonists, impairing Met phosphorylation and activation of downstream signaling pathways. As a consequence, Met-mediated biological responses were inhibited, including anchorage-dependent and -independent cell growth. In vivo DCD-1 and DCD-2 showed a pharmacokinetic profile significantly improved over the original MvDN30, doubling the circulating half-life and reducing the clearance. In pre-clinical models of cancer, generated by injection of tumor cells or implant of patient-derived samples, systemic administration of the engineered molecules inhibited the growth of Met-addicted tumors.

  14. Half-life of Th232 and the branching ratio of Bi212

    USGS Publications Warehouse

    Senftle, F.E.; Farley, T.A.; Lazar, N.

    1956-01-01

    The half-life of Th232 has been calculated by determining an absolute gamma-disintegration rate for Tl208 in equilibrium with Th232 for three old thorium nitrate salts and one natural thorite sample. The branching ratio, ??(??+??), for Bi212, a necessary parameter in the calculation, was also measured. The half-life of Th232 was found to be 1.42??1010 years within an estimated error of 5%, which is essentially in agreement with the presently accepted value. The branching ratio, ??(??+??), of Bi212 was found to be 0.362??0.006, about 7.4% higher than the currently accepted value. ?? 1956 The American Physical Society.

  15. Half-life extended factor VIII for the treatment of hemophilia A.

    PubMed

    Tiede, A

    2015-06-01

    Prophylactic infusion of factor VIII (FVIII) prevents joint bleeding and other hemorrhages in patients with hemophilia A. Conventional FVIII concentrates have a short half-life, with an average of about 12 h in adults, ranging in individual patients between 6 and 24 h, and even shorter in younger children. Therefore, effective prophylaxis requires frequent intravenous injection, usually three times per week or every other day. Several technologies are currently under investigation to extend the half-life of FVIII, including Fc fusion (Eloctate, Elocta, efmoroctocog alfa), addition of polyethylene glycol (turoctocog alfa pegol [N8-GP], BAY 94-9027, BAX 855), and a single-chain construct (CSL627). This review summarizes characteristics of products in clinical development and discusses their potential benefits.

  16. A New Method to Determine the Half-Life for Penicillin Using Microcalorimeter

    NASA Astrophysics Data System (ADS)

    Li, Z. X.; Zhao, W. W.

    2015-01-01

    The dissolution process of penicillin in normal saline and isotonic glucose solution was reported using a microcalorimeter. Both the integral and differential heats of solution were measured. The quantitative relationships between the amount of heat released and the quantity of dissolved penicillin were established. Meanwhile, the kinetics and the half-life of the dissolution processes as well as the enthalpy of solution, the entropy of dissolution, and the free energy of dissolution were determined. The results showed that a change of the solvent from normal saline to isotonic glucose solution had little effect on the half-life of penicillin in the dissolution process, and there was no significant difference between the stabilities of penicillin in isotonic glucose solution and normal saline. Moreover, the dissolution process of penicillin in isotonic glucose solution followed the first-order kinetics. These results could provide a theoretical basis for the clinical applications of penicillin.

  17. Interspecies comparisons of plasma half-life of trimethoprim in relation to body mass.

    PubMed

    Pashov, D A; Lashev, L D; Matev, I B; Kanelov, I N

    1997-02-01

    The relationship between body mass and plasma half-life of trimethoprim was studied in 10 different species of animals and man using published data. Log half-life was positively and significantly correlated to log body mass based on individual measurements in herbivorous animals (n = 23, P < 0.01), in herbivorous animals+pigs (n = 29, P < 0.01), in ungulates (n = 27, P < 0.01), in ruminants (n = 16, P < 0.01) and in non-herbivorous mammals, except pigs (n = 6, P < 0.05). The correlation was described by the allometric equations: t 1/2 beta = 27 W0.26 in herbivorous animals and t 1/2 beta = 125 W0.32 in non-herbivorous animals except pigs. PMID:9049949

  18. Precision half-life measurement of the 4-fold forbidden β decay of V50

    NASA Astrophysics Data System (ADS)

    Dombrowski, H.; Neumaier, S.; Zuber, K.

    2011-05-01

    A sensitive search of the 4-fold forbidden nonunique decay of V50 has been performed. A total mass measuring time product of 186 kg d has been accumulated. A reliable half-life value with the highest precision so far of (2.29±0.25)×1017 years of the electron capture decay of V50 into the first excited state of Ti50 could be obtained. A photon emission line following the β decay into the first excited state of Cr50 could not be observed, resulting in a lower limit on the half-life of the β-decay branch of 1.7×1018 years. This is not in good agreement with a claimed observation of this decay branch published in 1989.

  19. Precision half-life measurement of the 4-fold forbidden {beta} decay of {sup 50}V

    SciTech Connect

    Dombrowski, H.; Neumaier, S.; Zuber, K.

    2011-05-15

    A sensitive search of the 4-fold forbidden nonunique decay of {sup 50}V has been performed. A total mass measuring time product of 186 kg d has been accumulated. A reliable half-life value with the highest precision so far of (2.29{+-}0.25)x10{sup 17} years of the electron capture decay of {sup 50}V into the first excited state of {sup 50}Ti could be obtained. A photon emission line following the {beta} decay into the first excited state of {sup 50}Cr could not be observed, resulting in a lower limit on the half-life of the {beta}-decay branch of 1.7x10{sup 18} years. This is not in good agreement with a claimed observation of this decay branch published in 1989.

  20. A new value for the half-life of 10Be by Heavy-Ion Elastic Recoil Detection and liquid scintillation counting

    NASA Astrophysics Data System (ADS)

    Korschinek, G.; Bergmaier, A.; Faestermann, T.; Gerstmann, U. C.; Knie, K.; Rugel, G.; Wallner, A.; Dillmann, I.; Dollinger, G.; von Gostomski, Ch. Lierse; Kossert, K.; Maiti, M.; Poutivtsev, M.; Remmert, A.

    2010-01-01

    The importance of 10Be in different applications of accelerator mass spectrometry (AMS) is well-known. In this context the half-life of 10Be has a crucial impact, and an accurate and precise determination of the half-life is a prerequisite for many of the applications of 10Be in cosmic-ray and earth science research. Recently, the value of the 10Be half-life has been the centre of much debate. In order to overcome uncertainties inherent in previous determinations, we introduced a new method of high accuracy and precision. An aliquot of our highly enriched 10Be master solution was serially diluted with increasing well-known masses of 9Be. We then determined the initial 10Be concentration by least square fit to the series of measurements of the resultant 10Be/ 9Be ratio. In order to minimize uncertainties because of mass bias which plague other low-energy mass spectrometric methods, we used for the first time Heavy-Ion Elastic Recoil Detection (HI-ERD) for the determination of the 10Be/ 9Be isotopic ratios, a technique which does not suffer from difficult to control mass fractionation. The specific activity of the master solution was measured by means of accurate liquid scintillation counting (LSC). The resultant combination of the 10Be concentration and activity yields a 10Be half-life of T1/2 = 1.388 ± 0.018 (1 s, 1.30%) Ma. In a parallel but independent study (Chmeleff et al. [11]), found a value of 1.386 ± 0.016 (1.15%) Ma. Our recommended weighted mean and mean standard error for the new value for 10Be half-life based on these two independent measurements is 1.387 ± 0.012 (0.87%) Ma.

  1. Neutron activation analyses and half-life measurements at the usgs triga reactor

    NASA Astrophysics Data System (ADS)

    Larson, Robert E.

    Neutron activation of materials followed by gamma spectroscopy using high-purity germanium detectors is an effective method for making measurements of nuclear beta decay half-lives and for detecting trace amounts of elements present in materials. This research explores applications of neutron activation analysis (NAA) in two parts. Part 1. High Precision Methods for Measuring Decay Half-Lives, Chapters 1 through 8 Part one develops research methods and data analysis techniques for making high precision measurements of nuclear beta decay half-lives. The change in the electron capture half-life of 51Cr in pure chromium versus chromium mixed in a gold lattice structure is explored, and the 97Ru electron capture decay half-life are compared for ruthenium in a pure crystal versus ruthenium in a rutile oxide state, RuO2. In addition, the beta-minus decay half-life of 71mZn is measured and compared with new high precision findings. Density Functional Theory is used to explain the measured magnitude of changes in electron capture half-life from changes in the surrounding lattice electron configuration. Part 2. Debris Collection Nuclear Diagnostic at the National Ignition Facility, Chapters 9 through 11 Part two explores the design and development of a solid debris collector for use as a diagnostic tool at the National Ignition Facility (NIF). NAA measurements are performed on NIF post-shot debris collected on witness plates in the NIF chamber. In this application NAA is used to detect and quantify the amount of trace amounts of gold from the hohlraum and germanium from the pellet present in the debris collected after a NIF shot. The design of a solid debris collector based on material x-ray ablation properties is given, and calculations are done to predict performance and results for the collection and measurements of trace amounts of gold and germanium from dissociated hohlraum debris.

  2. Extending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albumin.

    PubMed

    Metzner, H J; Pipe, S W; Weimer, T; Schulte, S

    2013-11-01

    The prophylactic treatment of haemophilia B and the management of haemophilia A or B with inhibitors demand frequent administrations of coagulation factors due to the suboptimal half-lives of the products commercially available and currently in use, e.g. recombinant factor IX (rFIX) and recombinant factor VIIa (rFVIIa), respectively. The extension of the half-lives of rFIX and rFVIIa could allow for longer intervals between infusions and could thereby improve adherence and clinical outcomes and may improve quality of life. Albumin fusion is one of a number of different techniques currently being examined to prolong the half-life of rFIX and rFVIIa. Results from a phase I clinical trial demonstrated that the recombinant fusion protein linking FIX to albumin (rIX-FP) has a five-times longer half-life than rFIX, and preclinical studies with the recombinant fusion protein linking FVIIa to albumin (rVIIa-FP) suggest that rVIIa-FP possesses a significantly extended half-life versus rFVIIa. In this review, we describe albumin fusion technology and examine the recent progress in the development of rIX-FP and rVIIa-FP.

  3. Precise and direct determination of the half-life of 41Ca

    NASA Astrophysics Data System (ADS)

    Jörg, Gerhard; Amelin, Yuri; Kossert, Karsten; Lierse v. Gostomski, Christoph

    2012-07-01

    Calcium-41 plays an important role in the long-term evaluation of the safety of final repositories for nuclear waste and is used to study the fine-scale chronology of the formation of the Solar System. Both applications are hindered by insufficient precision and poor consistency of previous determinations of the half-life. This work reports a half-life for 41Ca of (9.94 ± 0.15) × 104 years, which was determined with a combination of methods, chosen to provide the best possible precision. The activity was measured by liquid scintillation counting (LSC) exploiting the triple-to-double coincidence ratio method (TDCR); the absolute isotopic composition was determined by thermal ionization mass spectrometry (TIMS) and isotope dilution. Enhanced precision and accuracy of the 41Ca half-life will allow the improvement of safety analyses for final deposit sites of nuclear waste and of dating first solids, and better constrain the stellar environment of the formation of the Solar System.

  4. Radionuclide biological half-life values for terrestrial and aquatic wildlife.

    PubMed

    Beresford, N A; Beaugelin-Seiller, K; Burgos, J; Cujic, M; Fesenko, S; Kryshev, A; Pachal, N; Real, A; Su, B S; Tagami, K; Vives i Batlle, J; Vives-Lynch, S; Wells, C; Wood, M D

    2015-12-01

    The equilibrium concentration ratio is typically the parameter used to estimate organism activity concentrations within wildlife dose assessment tools. Whilst this is assumed to be fit for purpose, there are scenarios such as accidental or irregular, fluctuating, releases from licensed facilities when this might not be the case. In such circumstances, the concentration ratio approach may under- or over-estimate radiation exposure depending upon the time since the release. To carrying out assessments for such releases, a dynamic approach is needed. The simplest and most practical option is representing the uptake and turnover processes by first-order kinetics, for which organism- and element-specific biological half-life data are required. In this paper we describe the development of a freely available international database of radionuclide biological half-life values. The database includes 1907 entries for terrestrial, freshwater, riparian and marine organisms. Biological half-life values are reported for 52 elements across a range of wildlife groups (marine = 9, freshwater = 10, terrestrial = 7 and riparian = 3 groups). Potential applications and limitations of the database are discussed. PMID:26378959

  5. EFFECTIVE HALF-LIFE OF CESIUM-137 IN VARIOUS ENVIRONMENTAL MEDIA AT THE SAVANNAH RIVER SITE

    SciTech Connect

    Jannik, T.; Paller, M.; Baker, R.

    2013-12-12

    During the operational history of the Savannah River Site (SRS), many different radionuclides have been released from site facilities into the SRS environment. However, only a relatively small number of pathways, most importantly {sup 137}Cs in fish and deer, have contributed significantly to doses and risks to the public. The “effective” half-lives (T{sub e}) of {sup 137}Cs (which include both physical decay and environmental dispersion) in Savannah River floodplain soil and vegetation and in fish and white-tailed deer from the SRS were estimated using long-term monitoring data. For 1974–2011, the T{sub e}s of {sup 137}Cs in Savannah River floodplain soil and vegetation were 17.0 years (95% CI = 14.2–19.9) and 13.4 years (95% CI = 10.8–16.0), respectively. These T{sub e}s were greater than in a previous study that used data collected only through 2005 as a likely result of changes in the flood regime of the Savannah River. Field analyses of {sup 137}Cs concentrations in deer collected during yearly controlled hunts at the SRS indicated an overall T{sub e} of 15.9 years (95% CI = 12.3–19.6) for 1965–2011; however, the T{sub e} for 1990–2011 was significantly shorter (11.8 years, 95% CI = 4.8–18.8) due to an increase in the rate of {sup 137}Cs removal. The shortest T{sub e}s were for fish in SRS streams and the Savannah River (3.5–9.0 years), where dilution and dispersal resulted in rapid {sup 137}Cs removal. Long-term data show that T{sub e}s are significantly shorter than the physical half-life of {sup 137}Cs in the SRS environment but that they can change over time. Therefore, it is desirable have a long period of record for calculating Tes and risky to extrapolate T{sub e}s beyond this period unless the processes governing {sup 137}Cs removal are clearly understood.

  6. The designer leptin antagonist peptide Allo-aca compensates for short serum half-life with very tight binding to the receptor.

    PubMed

    Otvos, Laszlo; Vetter, Stefan W; Koladia, Mohit; Knappe, Daniel; Schmidt, Rico; Ostorhazi, Eszter; Kovalszky, Ilona; Bionda, Nina; Cudic, Predrag; Surmacz, Eva; Wade, John D; Hoffmann, Ralf

    2014-04-01

    The leptin receptor antagonist peptide Allo-aca exhibits picomolar activities in various cellular systems and sub-mg/kg subcutaneous efficacies in animal models making it a prime drug candidate and target validation tool. Here we identified the biochemical basis for its remarkable in vivo activity. Allo-aca decomposed within 30 min in pooled human serum and was undetectable beyond the same time period from mouse plasma during pharmacokinetic measurements. The C max of 8.9 μg/mL at 5 min corresponds to approximately 22% injected peptide present in the circulation. The half-life was extended to over 2 h in bovine vitreous fluid and 10 h in human tears suggesting potential efficacy in ophthalmic diseases. The peptide retained picomolar anti-proliferation activity against a chronic myeloid leukemia cell line; addition of a C-terminal biotin label increased the IC50 value by approximately 200-fold. In surface plasmon resonance assays with the biotin-labeled peptide immobilized to a NeutrAvidin-coated chip, Allo-aca exhibited exceptionally tight binding to the binding domain of the human leptin receptor with ka = 5 × 10(5) M(-1) s(-1) and kdiss = 1.5 × 10(-4) s(-1) values. Peptides excel in terms of high activity and selectivity to their targets, and may activate or inactivate receptor functions considerably longer than molecular turnovers that take place in experimental animals.

  7. A novel exendin-4 human serum albumin fusion protein, E2HSA, with an extended half-life and good glucoregulatory effect in healthy rhesus monkeys.

    PubMed

    Zhang, Ling; Wang, Lin; Meng, Zhiyun; Gan, Hui; Gu, Ruolan; Wu, Zhuona; Gao, Lei; Zhu, Xiaoxia; Sun, Wenzhong; Li, Jian; Zheng, Ying; Dou, Guifang

    2014-03-01

    Glucagon-like peptide-1 (GLP-1) has attracted considerable research interest in terms of the treatment of type 2 diabetes due to their multiple glucoregulatory functions. However, the short half-life, rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native incretin hormone. Therefore, efforts are being made to develop the long-acting incretin mimetics via modifying its structure. Here we report a novel recombinant exendin-4 human serum albumin fusion protein E2HSA with HSA molecule extends their circulatory half-life in vivo while still retaining exendin-4 biological activity and therapeutic properties. In vitro comparisons of E2HSA and exendin-4 showed similar insulinotropic activity on rat pancreatic islets and GLP-1R-dependent biological activity on RIN-m5F cells, although E2HSA was less potent than exendin-4. E2HSA had a terminal elimation half-life of approximate 54 h in healthy rhesus monkeys. Furthermore, E2HSA could reduce postprandial glucose excursion and control fasting glucose level, dose-dependent suppress food intake. Improvement in glucose-dependent insulin secretion and control serum glucose excursions were observed during hyperglycemic clamp test (18 h) and oral glucose tolerance test (42 h) respectively. Thus the improved physiological characterization of E2HSA make it a new potent anti-diabetic drug for type 2 diabetes therapy.

  8. A novel exendin-4 human serum albumin fusion protein, E2HSA, with an extended half-life and good glucoregulatory effect in healthy rhesus monkeys

    SciTech Connect

    Zhang, Ling; Wang, Lin; Meng, Zhiyun; Gan, Hui; Gu, Ruolan; Wu, Zhuona; Gao, Lei; Zhu, Xiaoxia; Sun, Wenzhong; Li, Jian; Zheng, Ying; Dou, Guifang

    2014-03-07

    Highlights: • E2HSA has an extended half-life and good plasma stability. • E2HSA could improve glucose-dependent insulin secretion. • E2HSA has excellent glucoregulatory effects in vivo. • E2HSA could potentially be used as a new long-acting GLP-1 receptor agonist for type 2 diabetes management. - Abstract: Glucagon-like peptide-1 (GLP-1) has attracted considerable research interest in terms of the treatment of type 2 diabetes due to their multiple glucoregulatory functions. However, the short half-life, rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native incretin hormone. Therefore, efforts are being made to develop the long-acting incretin mimetics via modifying its structure. Here we report a novel recombinant exendin-4 human serum albumin fusion protein E2HSA with HSA molecule extends their circulatory half-life in vivo while still retaining exendin-4 biological activity and therapeutic properties. In vitro comparisons of E2HSA and exendin-4 showed similar insulinotropic activity on rat pancreatic islets and GLP-1R-dependent biological activity on RIN-m5F cells, although E2HSA was less potent than exendin-4. E2HSA had a terminal elimation half-life of approximate 54 h in healthy rhesus monkeys. Furthermore, E2HSA could reduce postprandial glucose excursion and control fasting glucose level, dose-dependent suppress food intake. Improvement in glucose-dependent insulin secretion and control serum glucose excursions were observed during hyperglycemic clamp test (18 h) and oral glucose tolerance test (42 h) respectively. Thus the improved physiological characterization of E2HSA make it a new potent anti-diabetic drug for type 2 diabetes therapy.

  9. Change in the observed half-life of an excited nuclear state under conditions of a resonance environment

    SciTech Connect

    Loginov, Yu. E.

    2010-01-15

    A model description of the increase in the observed value of the half-life of isomeric nuclei {sup 119m1}Sn (E = 23.8 keV, T{sub 1/2} {approx} 18 ns) in a resonance environment created by stable nuclei of {sup 119}Sn is proposed. According to the model used, the observed effect is due to gamma radiation from isomeric nuclei {sup 119m1}Sn newly produced upon the resonance capture of gamma rays emitted in {sup 119m1}Sn decay by stable nuclei of {sup 119}Sn. On the basis of T{sub 1/2} values that were measured previously, the radiative shift of the position of an excited nuclear state (nuclear analog of the Lamb shift in an atom), {Delta}{omega}{sub 0}, was estimated at 1.5(2) x 10{sup 11} s{sup -1} for the isomer {sup 119m1}Sn.

  10. The half-life of lead with respect to spontaneous fission

    SciTech Connect

    Zakharova, V.P.; Zenkevich, V.S.; Funshtein, V.B.

    1995-04-01

    The authors report results of an experiment to measure the half life of lead 208 against fission. The impetus for this work is earlier work in the case of fermium isotopes, where it was found that addition of two neutrons to fermium, producing isotopes which could decay to fragments with near magic numbers, resulted in tremendous decreases in fission lifetimes. The authors had assumed the same effect could be seen in lead 208. This experiment has put a lower bound of 2{times}10{sup 19} yr on this decay in lead 208.

  11. Calculation of the Aluminosilicate Half-Life Formation Time in the 2H Evaporator

    SciTech Connect

    Fondeur, F.F.

    2000-09-21

    The 2H Evaporator contains large quantities of aluminosilicate solids deposited on internal fixtures. The proposed cleaning operations will dissolve the solids in nitric acid. Operations will then neutralize the waste prior to transfer to a waste tank. Combining recent calculations of heat transfer for the 2H Evaporator cleaning operations and laboratory experiments for dissolution of solid samples from the pot, the authors estimated the re-formation rate for aluminosilicates during cooling. The results indicate a half-life formation of 17 hours when evaporator solution cools from 60 degrees C and 9 hours when cooled from 90 degrees C.

  12. Standardisation and precise determination of the half-life of (44)Sc.

    PubMed

    García-Toraño, E; Peyrés, V; Roteta, M; Sánchez-Cabezudo, A I; Romero, E; Martínez Ortega, A

    2016-03-01

    The half-life of the positron-emitter (44)Sc has been determined by following the decay rate with two measurement systems; an Ionisation Chamber and a HPGe detector. The combination of seven results gives a value of T1/2=4.042 (25)h, about 2% higher than the recommended value of T1/2=3.97 (4)h (Browne, 2011) and with a lower uncertainty. This radionuclide has also been standardised by coincidence counting, and liquid scintillation counting techniques. A (44)Ti/(44)Sc generator developed at CIEMAT was used to obtain the (44)Sc solutions used in all measurements. PMID:26701659

  13. Measurement of the half-life of ⁶⁸Ga.

    PubMed

    García-Toraño, Eduardo; Peyrés Medina, Virginia; Romero, Eduardo; Roteta, Miguel

    2014-05-01

    The half-life of the positron-emitter (68)Ga has been measured by following the decay rate with two systems based on ionization chamber and Ge detectors. The decay rate was measured for periods of time up to 10 half-lives. The combination of the 6 results obtained with both systems gives a value of T1/2=67.845(18) min, in good agreement with recommended data and with an uncertainty lower than any other previously reported value. PMID:24342557

  14. Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer.

    PubMed

    Singh, K; Stempora, L; Harvey, R D; Kirk, A D; Larsen, C P; Blazar, B R; Kean, L S

    2014-12-01

    Many critical issues remain concerning how best to deploy adoptive regulatory T cell (Treg) immunotherapy to the clinic. These include a determination of their pharmacokinetic characteristics, their optimal dose, their phenotypic stability and the best therapies with which to pair Tregs. By performing a CFSE-labeled autologous Treg pulse experiment, we determined that the accessible peripheral blood Treg pool in rhesus macaques is quite large (75 ± 11 × 10(6) Tregs/kg). Pharmacokinetic analysis revealed that Tregs have two phases of elimination: an α phase, with a T1/2 in the peripheral blood of 32.4 ± 11.3 h and a β phase with a T1/2 of 120.4 ± 19.7 h. In addition to their short initial half-life, Tregs underwent rapid phenotypic shifts after infusion, with significant loss of both CD25 and FoxP3 by day +6. While tacrolimus stabilized CD25 expression, it did not improve T1/2 , nor mitigate the loss of FoxP3. In contrast, rapamycin significantly stabilized both CD25 and FoxP3, and supported an increased half-life, with an α phase of 67.7 ± 6.9 h and a β phase of 252.1 ± 54.9 h. These results suggest that rapamycin may be a necessary addition to Treg immunotherapy, and that tacrolimus may be deleterious to Treg integrity posttransfer.

  15. Half-life of {sup 221}Fr in Si and Au at 4 K and at millikelvin temperatures

    SciTech Connect

    Wauters, F.; Breitenfeldt, M.; De Leebeeck, V.; Kozlov, V. Yu.; Kraev, I.; Roccia, S.; Soti, G.; Tandecki, M.; Traykov, E.; Van Gorp, S.; Severijns, N.; Verstichel, B.; Zakoucky, D.

    2010-12-15

    The half-life of the {alpha}-decaying nucleus {sup 221}Fr was determined in different environments, that is, embedded in Si at 4 K, and embedded in Au at 4 K and about 20 mK. No differences in half-life for these different conditions were observed within 0.1%. Furthermore, we quote a value for the absolute half-life of {sup 221}Fr of t{sub 1/2}=286.1(10) s that is of comparable precision to the most precise value available in the literature.

  16. Settling the half-life of 60Fe: fundamental for a versatile astrophysical chronometer.

    PubMed

    Wallner, A; Bichler, M; Buczak, K; Dressler, R; Fifield, L K; Schumann, D; Sterba, J H; Tims, S G; Wallner, G; Kutschera, W

    2015-01-30

    In order to resolve a recent discrepancy in the half-life of 60Fe, we performed an independent measurement with a new method that determines the 60Fe content of a material relative to 55Fe (t1/2=2.744  yr) with accelerator mass spectrometry. Our result of (2.50±0.12)×10(6)  yr clearly favors the recently reported value (2.62±0.04)×10(6)  yr, and rules out the older result of (1.49±0.27)×10(6)  yr. The present weighted mean half-life value of (2.60±0.05)×10(6)  yr substantially improves the reliability as an important chronometer for astrophysical applications in the million-year time range. This includes its use as a sensitive probe for studying recent chemical evolution of our Galaxy, the formation of the early Solar System, nucleosynthesis processes in massive stars, and as an indicator of a recent nearby supernova.

  17. Half-life determination for {sup 108}Ag and {sup 110}Ag

    SciTech Connect

    Zahn, Guilherme S.; Genezini, Frederico A.

    2014-11-11

    In this work, the half-life of the short-lived silver radionuclides {sup 108}Ag and {sup 110}Ag were measured by following the activity of samples after they were irradiated in the IEA-R1 reactor. The results were then fitted using a non-paralizable dead time correction to the regular exponential decay and the individual half-life values obtained were then analyzed using both the Normalized Residuals and the Rajeval techniques, in order to reach the most exact and precise final values. To check the validity of dead-time correction, a second correction method was also employed by means of counting a long-lived {sup 60}Co radioactive source together with the samples as a livetime chronometer. The final half-live values obtained using both dead-time correction methods were in good agreement, showing that the correction was properly assessed. The results obtained are partially compatible with the literature values, but with a lower uncertainty, and allow a discussion on the last ENSDF compilations' values.

  18. Settling the half-life of 60Fe: fundamental for a versatile astrophysical chronometer.

    PubMed

    Wallner, A; Bichler, M; Buczak, K; Dressler, R; Fifield, L K; Schumann, D; Sterba, J H; Tims, S G; Wallner, G; Kutschera, W

    2015-01-30

    In order to resolve a recent discrepancy in the half-life of 60Fe, we performed an independent measurement with a new method that determines the 60Fe content of a material relative to 55Fe (t1/2=2.744  yr) with accelerator mass spectrometry. Our result of (2.50±0.12)×10(6)  yr clearly favors the recently reported value (2.62±0.04)×10(6)  yr, and rules out the older result of (1.49±0.27)×10(6)  yr. The present weighted mean half-life value of (2.60±0.05)×10(6)  yr substantially improves the reliability as an important chronometer for astrophysical applications in the million-year time range. This includes its use as a sensitive probe for studying recent chemical evolution of our Galaxy, the formation of the early Solar System, nucleosynthesis processes in massive stars, and as an indicator of a recent nearby supernova. PMID:25679883

  19. Half-life Measurements of Excited Levels in Fission Products around Mass Number 150

    SciTech Connect

    Kojima, Y.; Shima, Y.; Hayashi, H.; Taniguchi, A.; Shibata, M.

    2014-06-15

    A spectrometer to measure nuclear level half-lives has been installed at the on-line isotope separator of the Kyoto University Reactor. This spectrometer consists of a LaBr3 scintillator, a thin plastic scintillator and an HPGe detector. Half-lives are deduced using the β-γ-γ delayed coincidence method. The prompt-time distribution curves measured with the spectrometer give a time resolution (FWHM) of 600 ps for 100-keV γ rays. This resolution means that half-lives down to the subnanosecond range or shorter can be measured. We reported recent measurements of the half-life of {sup 149}Pr and {sup 149}Nd. Some of the more interesting results include the first determination of the half-lives of {sup 149}Pr levels at 86.5 and 125.6 keV, which are 4.2(5) ns and 1.0(2) ns, respectively. In addition, the data indicate that the half-life of the 270.8-keV level in {sup 149}Nd is not 5.1(3) ns as reported previously, but 0.42(3) ns.

  20. Settling the Half-Life of 60Fe: Fundamental for a Versatile Astrophysical Chronometer

    NASA Astrophysics Data System (ADS)

    Wallner, A.; Bichler, M.; Buczak, K.; Dressler, R.; Fifield, L. K.; Schumann, D.; Sterba, J. H.; Tims, S. G.; Wallner, G.; Kutschera, W.

    2015-01-01

    In order to resolve a recent discrepancy in the half-life of 60Fe, we performed an independent measurement with a new method that determines the 60Fe content of a material relative to 55Fe (t1 /2=2.744 yr ) with accelerator mass spectrometry. Our result of (2.50 ±0.12 )×106 yr clearly favors the recently reported value (2.62 ±0.04 )×106 yr , and rules out the older result of (1.49 ±0.27 )×106 yr . The present weighted mean half-life value of (2.60 ±0.05 )×106 yr substantially improves the reliability as an important chronometer for astrophysical applications in the million-year time range. This includes its use as a sensitive probe for studying recent chemical evolution of our Galaxy, the formation of the early Solar System, nucleosynthesis processes in massive stars, and as an indicator of a recent nearby supernova.

  1. Site-Specific Albumination as an Alternative to PEGylation for the Enhanced Serum Half-Life in Vivo.

    PubMed

    Yang, Byungseop; Lim, Sung In; Kim, Jong Chul; Tae, Giyoong; Kwon, Inchan

    2016-05-01

    Polyethylene glycol (PEG) has been widely used as a serum half-life extender of therapeutic proteins. However, due to immune responses and low degradability of PEG, developing serum half-life extender alternatives to PEG is required. Human serum albumin (HSA) has several beneficial features as a serum half-life extender, including a very long serum half-life, good degradability, and low immune responses. In order to further evaluate the efficacy of HSA, we compared the extent of serum half-life extension of a target protein, superfolder green fluorescent protein (sfGFP), upon HSA conjugation with PEG conjugation side-by-side. Combination of site-specific incorporation of p-azido-l-phenylalanine into sfGFP and copper-free click chemistry achieved the site-specific conjugation of a single HSA, 20 kDa PEG, or 30 kDa PEG to sfGFP. These sfGFP conjugates exhibited the fluorescence comparable to or even greater than that of wild-type sfGFP (sfGFP-WT). In mice, HSA-conjugation to sfGFP extended the serum half-life 9.0 times compared to that of unmodified sfGFP, which is comparable to those of PEG-conjugated sfGFPs (7.3 times for 20 kDa PEG and 9.5 times for 30 kDa PEG). These results clearly demonstrated that HSA was as effective as PEG in extending the serum half-life of a target protein. Therefore, with the additional favorable features, HSA is a good serum half-life extender of a (therapeutic) protein as an alternative to PEG. PMID:27050863

  2. Development of a time-variable nuclear pulser for half life measurements

    SciTech Connect

    Zahn, Guilherme S.; Domienikan, Claudio; Carvalhaes, Roberto P. M.; Genezini, Frederico A.

    2013-05-06

    In this work a time-variable pulser system with an exponentially-decaying pulse frequency is presented, which was developed using the low-cost, open-source Arduino microcontroler plataform. In this system, the microcontroller produces a TTL signal in the selected rate and a pulse shaper board adjusts it to be entered in an amplifier as a conventional pulser signal; both the decay constant and the initial pulse rate can be adjusted using a user-friendly control software, and the pulse amplitude can be adjusted using a potentiometer in the pulse shaper board. The pulser was tested using several combinations of initial pulse rate and decay constant, and the results show that the system is stable and reliable, and is suitable to be used in half-life measurements.

  3. Transferrin Fusion Technology: A Novel Approach to Prolonging Biological Half-Life of Insulinotropic Peptides

    PubMed Central

    Kim, Byung-Joon; Zhou, Jie; Martin, Bronwen; Carlson, Olga D.; Maudsley, Stuart; Greig, Nigel H.; Mattson, Mark P.; Ladenheim, Ellen E.; Wustner, Jay; Turner, Andrew; Sadeghi, Homayoun

    2010-01-01

    Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic β-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides. PMID:20498254

  4. Development of a time-variable nuclear pulser for half life measurements

    NASA Astrophysics Data System (ADS)

    Zahn, Guilherme S.; Domienikan, Claudio; Carvalhaes, Roberto P. M.; Genezini, Frederico A.

    2013-05-01

    In this work a time-variable pulser system with an exponentially-decaying pulse frequency is presented, which was developed using the low-cost, open-source Arduino microcontroler plataform. In this system, the microcontroller produces a TTL signal in the selected rate and a pulse shaper board adjusts it to be entered in an amplifier as a conventional pulser signal; both the decay constant and the initial pulse rate can be adjusted using a user-friendly control software, and the pulse amplitude can be adjusted using a potentiometer in the pulse shaper board. The pulser was tested using several combinations of initial pulse rate and decay constant, and the results show that the system is stable and reliable, and is suitable to be used in half-life measurements.

  5. Short half-life activation analysis in biomedical and scientific research

    SciTech Connect

    Becker, D.A.

    1996-12-31

    There are a number of elements that upon neutron irradiation produce very short-lived activation products, which are potentially useful for neutron activation analysis (NAA). In some cases these nuclides may be the only available activation product (e.g., for fluorine, oxygen, and lead). In other cases, the nuclides are activation products that provide improved sensitivity, accuracy, or ease of determination (e.g., for selenium, silver, and rhodium). The existing pneumatic tubes in the National Institute of Standards and Technology (NIST) nuclear reactor have relatively long transfer times (3 to 15 s) and have no accurate timing capability. These deficiencies make them relatively useless for the measurement of very short half-life activation products.

  6. A new measurement of the half-life of (166m)Ho.

    PubMed

    Nedjadi, Y; Bailat, C; Caffari, Y; Froidevaux, P; Wastiel, C; Kivel, N; Guenther-Leopold, I; Triscone, G; Jaquenod, F; Bochud, F

    2012-09-01

    The work presented here is a new and precise measurement of the half-life of (166m)Ho by determining the activity concentration, using an ionisation chamber calibrated for this nuclide, and measuring the number of (166m)Ho atoms using multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). Since the isotope (166)Er interferes with the mass spectrometric measurement, Er has to be eliminated from the (166m)Ho radioactive solution. The elimination was achieved using ion-exchange chromatography with the cation exchange resin Dowex AG 50W-X8 and 2-Hydroxybutanoic acid as the mobile phase. After a first transit through the chromatographic column, the purified (166m)Ho eluate was spiked with natural Er to get a resulting Er isotopic composition close to that of natural Er at better than 99.5%, and then it underwent two further separations to eliminate the Er. The activity concentration of this Er-free radioactive (166m)Ho solution was measured in our reference ionisation chamber calibrated for this nuclide by means of the 4πβ(PC)-γ and 4πβ(PS)-4πγ coincidence techniques and integral counting with a well-type NaI(Tl) detector and Monte Carlo efficiencies. An aliquot of this standardized solution was sent to the Paul Scherrer Institute (PSI) for mass concentration determination using an isotope dilution MC-ICP-MS approach. The mass concentration of (166m)Ho in this solution was determined with 0.25% relative standard uncertainty. This value was corroborated by two other independent measurements. The new half-life of (166m)Ho, 1132.6(39) years (k=1), is compatible with the value determined in 1965, but is 5.6% shorter and about 43 times more precise. PMID:22421399

  7. Calculation of chemical elimination half-life from blood with an ongoing exposure source: the example of perfluorooctanoic acid (PFOA).

    PubMed

    Russell, Mark H; Waterland, Robert L; Wong, Fiona

    2015-06-01

    Determination of the chemical clearance rate from human blood is a critical component of toxicokinetic exposure assessment. Analysis of temporal biomonitoring data without consideration of ongoing exposure results in calculation of apparent elimination half-life values that are longer than the intrinsic value. The intrinsic elimination half-life is solely a function of the rate of elimination while the apparent elimination half-life reflects the processes of both elimination and ongoing exposure. Confusion between intrinsic and apparent half-life values can lead to misinterpretation of biomonitoring data and can result in exaggerated predictions in subsequent modeling efforts. This work provides a review of the first-order equations that have been developed to calculate intrinsic and apparent half-life values and the potential bias that can result from confusing these two values. Published human biomonitoring data for perfluorooctanoic acid (PFOA) are analyzed using these equations to provide examples of low, medium and high bias in determination of the intrinsic elimination half-life from plasma or serum, the components of blood typically analyzed for PFOA. An approach is also provided to estimate the extent of exposure reduction that is indicated by declining longitudinal or cross-sectional biomonitoring data. Based on the evaluation methodology presented in this work, the intrinsic elimination half-life of PFOA in humans is 2.4years, representing the average of independent estimates of 2.5years (95% CI, 2.4-2.7) and 2.3years (95% CI, 2.1-2.4). The declining concentration of PFOA in blood of the general USA adult population represents an estimated exposure reduction of 20-30% over the period 1999-2008. PMID:25149361

  8. High-Precision Half-Life Measurements for the Superallowed β^{+} Emitter ^{10}C: Implications for Weak Scalar Currents.

    PubMed

    Dunlop, M R; Svensson, C E; Ball, G C; Grinyer, G F; Leslie, J R; Andreoiu, C; Austin, R A E; Ballast, T; Bender, P C; Bildstein, V; Diaz Varela, A; Dunlop, R; Garnsworthy, A B; Garrett, P E; Hackman, G; Hadinia, B; Jamieson, D S; Laffoley, A T; MacLean, A D; Miller, D M; Mills, W J; Park, J; Radich, A J; Rajabali, M M; Rand, E T; Unsworth, C; Valencik, A; Wang, Z M; Zganjar, E F

    2016-04-29

    Precision measurements of superallowed Fermi β-decay transitions, particularly for the lightest superallowed emitters ^{10}C and ^{14}O, set stringent limits on possible scalar current contributions to the weak interaction. In the present work, a discrepancy between recent measurements of the ^{10}C half-life is addressed through two high-precision half-life measurements, via γ-ray photopeak and β counting, that yield consistent results for the ^{10}C half-life of T_{1/2}=19.2969±0.0074  s and T_{1/2}=19.3009±0.0017  s, respectively. The latter is the most precise superallowed β-decay half-life measurement reported to date and the first to achieve a relative precision below 10^{-4}. A fit to the world superallowed β-decay data including the ^{10}C half-life measurements reported here yields b_{F}=-0.0018±0.0021 (68% C.L.) for the Fierz interference term and C_{S}/C_{V}=+0.0009±0.0011 for the ratio of the weak scalar to vector couplings assuming left-handed neutrinos. PMID:27176517

  9. High-Precision Half-Life Measurements for the Superallowed β+ Emitter 10C: Implications for Weak Scalar Currents

    NASA Astrophysics Data System (ADS)

    Dunlop, M. R.; Svensson, C. E.; Ball, G. C.; Grinyer, G. F.; Leslie, J. R.; Andreoiu, C.; Austin, R. A. E.; Ballast, T.; Bender, P. C.; Bildstein, V.; Diaz Varela, A.; Dunlop, R.; Garnsworthy, A. B.; Garrett, P. E.; Hackman, G.; Hadinia, B.; Jamieson, D. S.; Laffoley, A. T.; MacLean, A. D.; Miller, D. M.; Mills, W. J.; Park, J.; Radich, A. J.; Rajabali, M. M.; Rand, E. T.; Unsworth, C.; Valencik, A.; Wang, Z. M.; Zganjar, E. F.

    2016-04-01

    Precision measurements of superallowed Fermi β -decay transitions, particularly for the lightest superallowed emitters 10C and 14O, set stringent limits on possible scalar current contributions to the weak interaction. In the present work, a discrepancy between recent measurements of the 10C half-life is addressed through two high-precision half-life measurements, via γ -ray photopeak and β counting, that yield consistent results for the 10C half-life of T1 /2=19.2969 ±0.0074 s and T1 /2=19.3009 ±0.0017 s , respectively. The latter is the most precise superallowed β -decay half-life measurement reported to date and the first to achieve a relative precision below 10-4 . A fit to the world superallowed β -decay data including the 10C half-life measurements reported here yields bF=-0.0018 ±0.0021 (68% C.L.) for the Fierz interference term and CS/CV=+0.0009 ±0.0011 for the ratio of the weak scalar to vector couplings assuming left-handed neutrinos.

  10. Half-life of porcine antibodies absorbed from a colostrum supplement containing porcine immunoglobulins.

    PubMed

    Polo, J; Campbell, J M; Crenshaw, J; Rodríguez, C; Pujol, N; Navarro, N; Pujols, J

    2012-12-01

    Absorption of immunoglobulins (Ig) at birth from colostrum is essential for piglet survival. The objective was to evaluate the half-life of antibodies absorbed in the bloodstream of newborn piglets orally fed a colostrum supplement (CS) containing energy (fat and carbohydrates) and IgG from porcine plasma. Viable piglets (n = 23; 900 to 1,800 g BW) from 6 sows were colostrum deprived and blood sampled and within the next 2 h of life randomly allocated to either control group (n = 9) providing 30 mL of Ig-free milk replacer or a group (n = 14) receiving 30 mL of CS by oral gavage. Piglets were transported to a Biosafety Level 3 facility (Centre de Recerca en Sanitat Animal, Spain) and fed Ig-free milk replacer every 3 to 4 h for 15 d. Survival, weight, plasma IgG content by radial immunodiffusion (RID), and antibodies against porcine circovirus type 2 (PCV2), porcine parvovirus (PPV), porcine reproductive and respiratory syndrome (PRRS), Mycoplasma hyopneumoniae (Mhy), and swine influenza virus (SIV) were determined by specific ELISA before treatment administration, at 24 h, and weekly for 56 d. Clinical symptoms were not observed for either group. Mortality index was lower (17 vs. 38%; P < 0.02) and BW higher (17.7 vs. 15.3 kg; P = 0.035) for pigs supplemented with CS than piglets in the control group. At 24 h postadministration, the CS group had a plasma IgG mean of 7.6 ± 0.06 vs. 0.14 ± 0.03 mg/mL for the control group. The IgG levels in the CS group decayed until day 21 when de novo synthesis of IgG was detected in 25% of piglets. Half-life of antibody concentration (HLAC) by RID was 6.2 d. In the CS group, efficiency of PCV2 and PPV antibody transfer was high. For PCV2, all animals remained positive by day 56 and the calculated HLAC was 17.7 d. For PPV, 72.7% of piglets were ELISA positive by day 35 and HLAC was 12.0 d. For PRRS, all piglets remained positive by day 14 and the calculated HLAC was 11.9 d. For Mhy and SIV the calculated HLAC were 8.4 and 3.0 d

  11. Extending the half-life of a fab fragment through generation of a humanized anti-human serum albumin Fv domain: An investigation into the correlation between affinity and serum half-life

    PubMed Central

    Adams, Ralph; Griffin, Laura; Compson, Joanne E.; Jairaj, Mark; Baker, Terry; Ceska, Tom; West, Shauna; Zaccheo, Oliver; Davé, Emma; Lawson, Alastair DG.; Humphreys, David P.; Heywood, Sam

    2016-01-01

    ABSTRACT We generated an anti-albumin antibody, CA645, to link its Fv domain to an antigen-binding fragment (Fab), thereby extending the serum half-life of the Fab. CA645 was demonstrated to bind human, cynomolgus, and mouse serum albumin with similar affinity (1–7 nM), and to bind human serum albumin (HSA) when it is in complex with common known ligands. Importantly for half-life extension, CA645 binds HSA with similar affinity within the physiologically relevant range of pH 5.0 – pH 7.4, and does not have a deleterious effect on the binding of HSA to neonatal Fc receptor (FcRn). A crystal structure of humanized CA645 Fab in complex with HSA was solved and showed that CA645 Fab binds to domain II of HSA. Superimposition with the crystal structure of FcRn bound to HSA confirmed that CA645 does not block HSA binding to FcRn. In mice, the serum half-life of humanized CA645 Fab is 84.2 h. This is a significant extension in comparison with < 1 h for a non-HSA binding CA645 Fab variant. The Fab-HSA structure was used to design a series of mutants with reduced affinity to investigate the correlation between the affinity for albumin and serum half-life. Reduction in the affinity for MSA by 144-fold from 2.2 nM to 316 nM had no effect on serum half-life. Strikingly, despite a reduction in affinity to 62 µM, an extension in serum half-life of 26.4 h was still obtained. CA645 Fab and the CA645 Fab-HSA complex have been deposited in the Protein Data Bank (PDB) with accession codes, 5FUZ and 5FUO, respectively. PMID:27315033

  12. The increasing challenge of discovering asthma drugs.

    PubMed

    Mullane, Kevin

    2011-09-15

    The prevalence of asthma continues to rise. Current drugs provide symptomatic relief to some, but not all, patients. Despite the need for new therapeutics, and a huge research effort, only four novel agents from two classes of drugs - the antileukotrienes and an anti-IgE antibody - have been approved in the last 30 years. This review highlights three particular issues that contribute to the challenge of identifying new therapeutics. First is an over-reliance on animal models of allergy to define targets and expectations of efficacy that has met with poor translation to the clinical setting. While sensitivity to particular aeroallergens is one key risk factor for asthma, atopy and asthma are not synonymous, and while about half of adult asthmatics are atopic the incidence of allergic asthma is probably <50%. The second issue is a fundamental disconnect between the directions of basic research and clinical research. Basic research has developed a detailed, reductive, unifying mechanism of antigen-induced, T helper type 2 cell-mediated airway inflammation as the root cause of asthma. In contrast, clinical research has started to identify multiple asthma phenotypes with differing cellular components, mediators and sensitivities to asthma drugs, and probably varying underlying factors including susceptibility genes. Finally, different features of asthma - bronchoconstriction, symptoms, and exacerbations - respond diversely to treatment; effects that are not captured in animal models which do not develop asthma per se, but utilize unvalidated surrogate markers. Basic research needs to better integrate and utilize the clinical research findings to improve its relevance to drug discovery efforts. PMID:21745459

  13. Towards a Measurement of the Half-Life of {sup 60}Fe for Stellar and Early Solar System Models

    SciTech Connect

    Ostdiek, K.; Anderson, T.; Bauder, W.; Bowers, M.; Collon, P.; Dressler, R.; Greene, J.; Kutschera, W.; Lu, W.; Paul, M.

    2015-10-15

    Radioisotopes, produced in stars and ejected into the Interstellar Medium, are important for constraining stellar and early Solar System (ESS) models. In particular, the half-life of the radioisotope, Fe-60, can have an impact on calculations for the timing for ESS events, the distance to nearby Supernovae, and the brightness of individual, non-steady-state Fe gamma ray sources in the Galaxy. A half-life measurement has been undertaken at the University of Notre Dame and measurements of the Fe-60/Fe-56 concentration of our samples using Accelerator Mass Spectrometry has begun. This result will be coupled with an activity measurement of the isomeric decay in Co-60, which is the decay product of Fe. Preliminary half-life estimates of (2.53 +/- 0.24) x 10(6) years seem to confirm the recent measurement by Rugel et al. (2009). (C) 2015 Elsevier B.V. All rights reserved.

  14. The half-life of DNA in bone: measuring decay kinetics in 158 dated fossils.

    PubMed

    Allentoft, Morten E; Collins, Matthew; Harker, David; Haile, James; Oskam, Charlotte L; Hale, Marie L; Campos, Paula F; Samaniego, Jose A; Gilbert, M Thomas P; Willerslev, Eske; Zhang, Guojie; Scofield, R Paul; Holdaway, Richard N; Bunce, Michael

    2012-12-01

    Claims of extreme survival of DNA have emphasized the need for reliable models of DNA degradation through time. By analysing mitochondrial DNA (mtDNA) from 158 radiocarbon-dated bones of the extinct New Zealand moa, we confirm empirically a long-hypothesized exponential decay relationship. The average DNA half-life within this geographically constrained fossil assemblage was estimated to be 521 years for a 242 bp mtDNA sequence, corresponding to a per nucleotide fragmentation rate (k) of 5.50 × 10(-6) per year. With an effective burial temperature of 13.1°C, the rate is almost 400 times slower than predicted from published kinetic data of in vitro DNA depurination at pH 5. Although best described by an exponential model (R(2) = 0.39), considerable sample-to-sample variance in DNA preservation could not be accounted for by geologic age. This variation likely derives from differences in taphonomy and bone diagenesis, which have confounded previous, less spatially constrained attempts to study DNA decay kinetics. Lastly, by calculating DNA fragmentation rates on Illumina HiSeq data, we show that nuclear DNA has degraded at least twice as fast as mtDNA. These results provide a baseline for predicting long-term DNA survival in bone.

  15. The half-life of Ascaris lumbricoides prevalence in Japanese school children.

    PubMed

    Kurosawa, Carmen Miwa; Ito, Takehiko; Takaki, Jiro; Wang, Bin-Ling; Wang, Da-Hong; Takigawa, Tomoko; Ogino, Keiki

    2008-10-01

    In the present study, we examined the dynamic of school-health-based parasite control and the related socio-economic influences. This is an ecological study based on data from 46 prefectures in Japan. The exponential decay of Ascaris lumbricoides prevalence was calculated by iterative least-squares method. Pearson's correlation and multiple linear regression model analysis were performed to assess the associations between the prevalence of Ascaris lumbricoides in Japanese school children and socio-economic variables such as the prefecture income per capita, the percentage of primary industry, the population density per 1 km2, the diffusion rate of population under water supply, and the percentage of upper secondary school enrollment. The results indicated that the parasite carrier rate was higher in younger students. The half-life of Ascaris lumbricoides prevalence was approximately 3 years with significant variation among prefectures. Multiple regression analyses showed that the decrease of infection in elementary and lower secondary school children had a significant positive association with primary industry and a significant negative association with prefecture income per capita. The school-health-based parasite intervention differs by prefecture and has changed over time according to the respective prefectural stage of economic development.

  16. Kinetic modeling and half life study on bioremediation of crude oil dispersed by Corexit 9500.

    PubMed

    Zahed, Mohammad Ali; Aziz, Hamidi Abdul; Isa, Mohamed Hasnain; Mohajeri, Leila; Mohajeri, Soraya; Kutty, Shamsul Rahman Mohamed

    2011-01-30

    Hydrocarbon pollution in marine ecosystems occurs mainly by accidental oil spills, deliberate discharge of ballast waters from oil tankers and bilge waste discharges; causing site pollution and serious adverse effects on aquatic environments as well as human health. A large number of petroleum hydrocarbons are biodegradable, thus bioremediation has become an important method for the restoration of oil polluted areas. In this research, a series of natural attenuation, crude oil (CO) and dispersed crude oil (DCO) bioremediation experiments of artificially crude oil contaminated seawater was carried out. Bacterial consortiums were identified as Acinetobacter, Alcaligenes, Bacillus, Pseudomonas and Vibrio. First order kinetics described the biodegradation of crude oil. Under abiotic conditions, oil removal was 19.9% while a maximum of 31.8% total petroleum hydrocarbons (TPH) removal was obtained in natural attenuation experiment. All DCO bioreactors demonstrated higher and faster removal than CO bioreactors. Half life times were 28, 32, 38 and 58 days for DCO and 31, 40, 50 and 75 days for CO with oil concentrations of 100, 500, 1000 and 2000 mg/L, respectively. The effectiveness of Corexit 9500 dispersant was monitored in the 45 day study; the results indicated that it improved the crude oil biodegradation rate.

  17. Energy level and half-life determinations from photonuclear reaction on Ga target

    NASA Astrophysics Data System (ADS)

    Akkoyun, Serkan; Bayram, Tuncay; Dulger, Fatih; Đapo, Haris; Boztosun, Ismail

    2016-06-01

    Photonuclear reactions are important tools in the understanding of the nucleus. These reactions are also interesting for realizing the element creation processes in stellar environment. The use of bremsstrahlung photons generated from clinic linear accelerator is practical for performing these type of reactions. In this study, the bremsstrahlung photons with endpoint energy of 18MeV have been used for activating gallium target material. After irradiation, the transition energies and half-lives associated with the decay of 68Ga, 70Ga and 72Ga isotopes have been determined The values obtained for half-life of 68Ga, 70Ga and 72Ga isotopes are 67.5±0.9min, 21.1±0.9min and 13.8±0.4h, respectively. It has been seen that the values are consistent with the present literature values. In addition, the new measurements of gamma-ray energies for transition energies have been obtained comparable to the literature values with good uncertainties.

  18. Ecological half-life of 137Cs in plants associated with a contaminated stream.

    PubMed

    Peles, John D; Smith, Michael H; Brisbin, I Lehr

    2002-01-01

    Ecological half-life (Te) is a useful measure for studying the long-term decline of contaminants, such as radionuclides, in natural systems. The current investigation determined levels of radiocesium (137Cs) in two aquatic (Polygonum punctatum, Sagittaria latifolia) and three terrestrial (Alnus serrulata, Myrica cerifera, Salix nigra) plant species from a contaminated stream and floodplain on the U.S. Department of Energy's Savannah River Site. Current 137Cs levels in plants were used in conjunction with historical data to determine Te of 137Cs in each species. Median concentrations of 137Cs were highest in S. latifolia (0.84 Bq g(-1)) and lowest in M. cerifera (0.10 Bq g(-1)). Te's ranged from 4.85 yr in M. cerifera to 8.35 yr in S. nigra, both terrestrial species. Te's for all aquatic (6.30 yr) and all terrestrial (5.87) species combined were very similar. The Te's of the two aquatic primary producers (P. punctatum and S. latifolia) in the Steel Creek ecosystem were somewhat longer than Te values previously reported for some consumers from this ecosystem.

  19. Precise measurement of the half-life of the Fermi {beta} decay of {sup 26}Al{sup m}

    SciTech Connect

    Scott, Rebecca J.; Thompson, Maxwell N.; Rassool, Roger P.; O'Keefe, Graeme J.

    2011-08-15

    State-of-the-art signal digitization and analysis techniques have been used to measure the half-life of the Fermi {beta} decay of {sup 26}Al{sup m}. The half-life was determined to be 6347.8 {+-} 2.5 ms. This new datum contributes to the experimental testing of the conserved-vector-current hypothesis and the required unitarity of the Cabibbo-Kobayashi-Maskawa matrix: two essential components of the standard model. Detailed discussion of the experimental techniques and data analysis and a thorough investigation of the statistical and systematic uncertainties are presented.

  20. Hair-to-blood ratio and biological half-life of mercury: experimental study of methylmercury exposure through fish consumption in humans.

    PubMed

    Yaginuma-Sakurai, Kozue; Murata, Katsuyuki; Iwai-Shimada, Miyuki; Nakai, Kunihiko; Kurokawa, Naoyuki; Tatsuta, Nozomi; Satoh, Hiroshi

    2012-02-01

    The hair-to-blood ratio and biological half-life of methylmercury in a one-compartment model seem to differ between past and recent studies. To reevaluate them, 27 healthy volunteers were exposed to methylmercury at the provisional tolerable weekly intake (3.4 µg/kg body weight/week) for adults through fish consumption for 14 weeks, followed by a 15-week washout period after the cessation of exposure. Blood was collected every 1 or 2 weeks, and hair was cut every 4 weeks. Total mercury (T-Hg) concentrations were analyzed in blood and hair. The T-Hg levels of blood and hair changed with time (p < 0.001). The mean concentrations increased from 6.7 ng/g at week 0 to 26.9 ng/g at week 14 in blood, and from 2.3 to 8.8 µg/g in hair. The mean hair-to-blood ratio after the adjustment for the time lag from blood to hair was 344 ± 54 (S.D.) for the entire period. The half-lives of T-Hg were calculated from raw data to be 94 ± 23 days for blood and 102 ± 31 days for hair, but the half-lives recalculated after subtracting the background levels from the raw data were 57 ± 18 and 64 ± 22 days, respectively. In conclusion, the hair-to-blood ratio of methylmercury, based on past studies, appears to be underestimated in light of recent studies. The crude half-life may be preferred rather than the recalculated one because of the practicability and uncertainties of the background level, though the latter half-life may approximate the conventional one.

  1. Oral delivery of octreotide acetate in Intravail® improves uptake, half-life, and bioavailability over subcutaneous administration in male Swiss webster mice.

    PubMed

    Maggio, Edward T; Grasso, Patricia

    2011-04-11

    The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogs. Octreotide acetate is a synthetic analog of somatostatin, with similar effects but a prolonged duration of action. Octreotide acetate is routinely given by subcutaneous (s.c.) or intramuscular injection. In the present study, we examined the feasibility of oral delivery of octreotide acetate reconstituted with increasing concentrations (0.5%, 1.5% and 3.0%) of Intravail®, a patented alkylsaccharide transmucosal absorption enhancing agent. The pharmacokinetics of orally delivered (by gavage) octreotide acetate in Intravail® were compared to those of octreotide acetate administered subcutaneously in sodium acetate buffer to male Swiss Webster mice. Oral delivery of octreotide acetate in 0.5% Intravail® significantly enhanced total uptake (1254.08ng/ml/min vs. 311.63ng/ml/min, respectively), serum half-life (52.1min vs. 1.3min, respectively), and relative bioavailability (4.0 vs. 1.0, respectively) when compared to delivery by s.c. injection. Higher concentrations of Intravail ®did not further enhance uptake, serum half-life, or bioavailability. The results of this study indicate that oral delivery of octreotide acetate in Intravail®is feasible, and is an effective method of administration which significantly improves uptake, bioavailability and half-life when compared to s.c. injection. Thus, oral delivery of octreotide acetate in Intravail® may have significant potential as a novel, non-invasive approach to the treatment of acromegaly and octreotide-mediated symptoms of carcinoid and VIP-secreting tumors.

  2. Half-life measurements of chemical inducers for recombinant gene expression

    PubMed Central

    2014-01-01

    Background Inducible promoters are widely spread genetic tools for triggering, tuning and optimizing the expression of recombinant genes in engineered biological systems. Most of them are controlled by the addition of a specific exogenous chemical inducer that indirectly regulates the promoter transcription rate in a concentration-dependent fashion. In order to have a robust and predictable degree of control on promoter activity, the degradation rate of such chemicals should be considered in many applications like recombinant protein production. Results In this work, we use whole-cell biosensors to assess the half-life of three commonly used chemical inducers for recombinant Escherichia coli: Isopropyl β-D-1-thiogalactopyranoside (IPTG), anhydrotetracycline (ATc) and N-(3-oxohexanoyl)-L-homoserine lactone (HSL). A factorial study was conducted to investigate the conditions that significantly contribute to the decay rate of these inducers. Temperature has been found to be the major factor affecting ATc, while medium and pH have been found to highly affect HSL. Finally, no significant degradation was observed for IPTG among the tested conditions. Conclusions We have quantified the decay rate of IPTG, ATc and HSL in many conditions, some of which were not previously tested in the literature, and the main effects affecting their degradation were identified via a statistics-based framework. Whole-cell biosensors were successfully used to conduct this study, yielding reproducible measurements via simple multiwell-compatible assays. The knowledge of inducer degradation rate in several contexts has to be considered in the rational design of synthetic biological systems for improving the predictability of induction effects, especially for prolonged experiments. PMID:24485151

  3. Precise measurement of the 222Rn half-life: A probe to monitor the stability of radioactivity

    NASA Astrophysics Data System (ADS)

    Bellotti, E.; Broggini, C.; Di Carlo, G.; Laubenstein, M.; Menegazzo, R.

    2015-04-01

    We give the results of a study on the 222Rn decay we performed in the Gran Sasso Laboratory (LNGS) by detecting the gamma rays from the radon progeny. The motivation was to monitor the stability of radioactivity measuring several times per year the half-life of a short lifetime (days) source instead of measuring over a long period the activity of a long lifetime (tens or hundreds of years) source. In particular, we give a possible reason of the large periodical fluctuations in the count rate of the gamma rays due to radon inside a closed canister which has been described in literature and which has been attributed to a possible influence of a component in the solar irradiation affecting the nuclear decay rates. We then provide the result of four half-life measurements we performed underground at LNGS in the period from May 2014 to January 2015 with radon diffused into olive oil. Briefly, we did not measure any change of the 222Rn half-life with a 8 ṡ10-5 precision. Finally, we provide the most precise value for the 222Rn half-life: 3.82146(16)stat(4)syst days.

  4. Developing a support vector machine based QSPR model for prediction of half-life of some herbicides.

    PubMed

    Samghani, Kobra; HosseinFatemi, Mohammad

    2016-07-01

    The half-life (t1/2) of 58 herbicides were modeled by quantitative structure-property relationship (QSPR) based molecular structure descriptors. After calculation and the screening of a large number of molecular descriptors, the most relevant those ones selected by stepwise multiple linear regression were used for developing linear and nonlinear models which developed by using multiple linear regression and support vector machine, respectively. Comparison between statistical parameters of linear and nonlinear models indicates the suitability of SVM over MLR model for predicting the half-life of herbicides. The statistical parameters of R(2) and standard error for training set of SVM model were; 0.96 and 0.087, respectively, and were 0.93 and 0.092 for the test set. The SVM model was evaluated by leave one out cross validation test, which its result indicates the robustness and predictability of the model. The established SVM model was used for predicting the half-life of other herbicides that are located in the applicability domain of model that were determined via leverage approach. The results of this study indicate that the relationship among selected molecular descriptors and herbicide's half-life is non-linear. These results emphases that the process of degradation of herbicides in the environment is very complex and can be affected by various environmental and structural features, therefore simple linear model cannot be able to successfully predict it. PMID:26970881

  5. Screening and ranking of POPs for global half-life: QSAR approaches for prioritization based on molecular structure.

    PubMed

    Gramatica, Paola; Papa, Ester

    2007-04-15

    Persistence in the environment is an important criterion in prioritizing hazardous chemicals and in identifying new persistent organic pollutants (POPs). Degradation half-life in various compartments is among the more commonly used criteria for studying environmental persistence, but the limited availability of experimental data or reliable estimates is a serious problem. Available half-life data for degradation in air, water, sediment, and soil, for a set of 250 organic POP-type chemicals, were combined in a multivariate approach by principal component analysis to obtain a ranking of the studied organic pollutants according to their relative overall half-life. A global half-life index (GHLI) applicable for POP screening purposes is proposed. The reliability of this index was verified in comparison with multimedia model results. This global index was then modeled as a cumulative end-point using a QSAR approach based on few theoretical molecular descriptors, and a simple and robust regression model externally validated for its predictive ability was derived. The application of this model could allow a fast preliminary identification and prioritization of not yet known POPs, just from the knowledge of their molecular structure. This model can be applied a priori also in the chemical design of safer and alternative non-POP compounds.

  6. Poly(butylcyanoacrylate) and Poly(ε-caprolactone) Nanoparticles Loaded with 5-Fluorouracil Increase the Cytotoxic Effect of the Drug in Experimental Colon Cancer.

    PubMed

    Ortiz, Raúl; Cabeza, Laura; Arias, José L; Melguizo, Consolación; Álvarez, Pablo J; Vélez, Celia; Clares, Beatriz; Áranega, Antonia; Prados, Jose

    2015-07-01

    The clinical use of 5-fluorouracil, one of the drugs of choice in colon cancer therapy, is limited by a nonuniform oral absorption, a short plasma half-life, and by the development of drug resistances by malignant cells. We hypothesized that the formulation of biodegradable nanocarriers for the efficient delivery of this antitumor drug may improve its therapeutic effect against advanced or recurrent colon cancer. Hence, we have engineered two 5-fluorouracil-loaded nanoparticulate systems based on the biodegradable polymers poly(butylcyanoacrylate) and poly(ε-caprolactone). Drug incorporation to the nanosystems was accomplished by entrapment (encapsulation/dispersion) within the polymeric network during nanoparticle synthesis, i.e., by anionic polymerization of the monomer and interfacial polymer disposition, respectively. Main factors determining 5-fluorouracil incorporation within the polymeric nanomatrices were investigated. These nanocarriers were characterized by high drug entrapment efficiencies and sustained drug-release profiles. In vitro studies using human and murine colon cancer cell lines demonstrated that both types of nanocarriers significantly increased the antiproliferative effect of the encapsulated drug. In addition, both nanoformulations produced in vivo an intense tumor growth inhibition and increased the mice survival rate, being the greater tumor volume reduction obtained when using the poly(ε-caprolactone)-based formulation. These results suggest that these nanocarriers may improve the antitumor activity of 5-fluorouracil and could be used against advanced or recurrent colon cancer.

  7. Determining thyroid {sup 131}I effective half-life for the treatment planning of Graves' disease

    SciTech Connect

    Willegaignon, Jose; Sapienza, Marcelo T.; Barberio Coura Filho, George; Buchpiguel, Carlos A.; Traino, Antonio C.

    2013-02-15

    Purpose: Thyroid {sup 131}I effective half-life (T{sub eff}) is an essential parameter in patient therapy when accurate radiation dose is desirable for producing an intended therapeutic outcome. Multiple {sup 131}I uptake measurements and resources from patients themselves and from nuclear medicine facilities are requisites for determining T{sub eff}, these being limiting factors when implementing the treatment planning of Graves' disease (GD) in radionuclide therapy. With the aim of optimizing this process, this study presents a practical, propitious, and accurate method of determining T{sub eff} for dosimetric purposes. Methods: A total of 50 patients with GD were included in this prospective study. Thyroidal {sup 131}I uptake was measured at 2-h, 6-h, 24-h, 48-h, 96-h, and 220-h postradioiodine administration. T{sub eff} was calculated by considering sets of two measured points (24-48-h, 24-96-h, and 24-220-h), sets of three (24-48-96-h, 24-48-220-h, and 24-96-220-h), and sets of four (24-48-96-220-h). Results: When considering all the measured points, the representative T{sub eff} for all the patients was 6.95 ({+-}0.81) days, whereas when using such sets of points as (24-220-h), (24-96-220-h), and (24-48-220-h), this was 6.85 ({+-}0.81), 6.90 ({+-}0.81), and 6.95 ({+-}0.81) days, respectively. According to the mean deviations 2.2 ({+-}2.4)%, 2.1 ({+-}2.0)%, and 0.04 ({+-}0.09)% found in T{sub eff}, calculated based on all the measured points in time, and with methods using the (24-220-h), (24-48-220-h), and (24-96-220-h) sets, respectively, no meaningful statistical difference was noted among the three methods (p > 0.500, t test). Conclusions: T{sub eff} obtained from only two thyroid {sup 131}I uptakes measured at 24-h and 220-h, besides proving to be sufficient, accurate enough, and easily applicable, attributes additional major cost-benefits for patients, and facilitates the application of the method for dosimetric purposes in the treatment planning of

  8. Design of the INHIBIT trial: preventing inhibitors by avoiding 'danger', prolonging half-life and promoting tolerance.

    PubMed

    Ragni, Margaret V; Malec, Lynn M

    2014-12-01

    Inhibitor formation is among the most serious complications of hemophilia treatment. With the US FDA licensure of the novel long-lasting recombinant factor VIII (FVIII) Fc fusion protein, Eloctate, which prolongs FVIII half-life, we propose an innovative approach to prevent inhibitor formation. In this paper, we describe a multicenter, Phase II, single-arm, 48-week trial, the INHIBIT trial, to determine if Eloctate, begun before a bleed and continued as once weekly prophylaxis, will reduce inhibitor formation in children with hemophilia A. We hypothesize that avoiding 'danger,' that is, immune activation by a bleed at first factor exposure and prolonging FVIII half-life will prevent inhibitors and promote FVIII-specific T-cell tolerance. If successful, this approach will suggest a new paradigm in clinical practice.

  9. Half-life of the Iπ = 4- Intruder State in 34P Using LaBr3:Ce Fast Timing

    NASA Astrophysics Data System (ADS)

    Mason, P. J. R.; Alharbi, T.; Regan, P. H.; Mǎrginean, N.; Podolyàk, Zs; Alkhomashi, N.; Bender, P. C.; Bowry, M.; Bostan, M.; Bucurescu, D.; Bruce, A. M.; Cǎta-Danil, G.; Cǎta-Danil, I.; Chakrabarti, R.; Deleanu, D.; Detistov, P.; Erduran, M. N.; Filipescu, D.; Garg, U.; Glodariu, T.; Ghiţǎ, D.; Ghugre, S. S.; Kusoglu, A.; Mǎrginean, R.; Mihai, C.; Nakhostin, M.; Negret, A.; Pascu, S.; Rodríguez Triguero, C.; Sava, T.; Simpson, E. C.; Sinha, A. K.; Stroe, L.; Suliman, G.; Zamfir, N. V.

    2012-09-01

    The half-life of the Iπ = 4- intruder state at 2305 keV in 3415P19 has been measured using γ-ray coincident fast timing with LaBr3:Ce scintillation detectors. Excited states in 34P were populated in the 18O(18O,pn)34P reaction at a beam energy of 36 MeV at the Tandem Laboratory at the National Institute of Physics and Nuclear Engineering, Bucharest, Romania. A half-life of t1/2 ~ 2 ns was obtained for the 4- state, giving an M2 reduced transition probability consistent with similar transitions in this mass region and confirming the intruder-parity nature of the state.

  10. Macromolecular prodrug that provides the irinotecan (CPT-11) active-metabolite SN-38 with ultralong half-life, low C(max), and low glucuronide formation.

    PubMed

    Santi, Daniel V; Schneider, Eric L; Ashley, Gary W

    2014-03-27

    We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.

  11. The Delta F508 mutation shortens the biochemical half-life of plasma membrane CFTR in polarized epithelial cells.

    PubMed

    Heda, G D; Tanwani, M; Marino, C R

    2001-01-01

    Although the biosynthetic arrest of the DeltaF508 mutant of cystic fibrosis transmembrane conductance regulator (CFTR) can be partially reversed by physical and chemical means, recent evidence suggests that the functional stability of the mutant protein after reaching the cell surface is compromised. To understand the molecular basis for this observation, the current study directly measured the half-life of Delta F508 and wild-type CFTR at the cell surface of transfected LLC-PK(1) cells. Plasma membrane CFTR expression over time was characterized biochemically and functionally in these polarized epithelial cells. Surface biotinylation, streptavidin extraction, and quantitative immunoblot analysis determined the biochemical half-life of plasma membrane DeltaF508 CFTR to be approximately 4 h, whereas the plasma membrane half-life of wild-type CFTR exceeded 48 h. This difference in biochemical stability correlated with CFTR-mediated transport function. These findings indicate that the Delta F508 mutation decreases the biochemical stability of CFTR at the cell surface. We conclude that the Delta F508 mutation triggers more rapid internalization of CFTR and/or its preferential sorting to a pathway of rapid degradation. PMID:11121388

  12. Extension of in vivo half-life of biologically active peptides via chemical conjugation to XTEN protein polymer.

    PubMed

    Podust, Vladimir N; Sim, Bee-Cheng; Kothari, Dharti; Henthorn, Lana; Gu, Chen; Wang, Chia-wei; McLaughlin, Bryant; Schellenberger, Volker

    2013-11-01

    XTEN, unstructured biodegradable proteins, have been used to extend the in vivo half-life of genetically fused therapeutic proteins and peptides. To expand the applications of XTEN technology to half-life extension of other classes of molecules, XTEN protein polymers and methods for chemical XTENylation were developed. Two XTEN precursors were engineered to contain enzymatically removable purification tags. The proteins were readily expressed in bacteria and purified to homogeneity by chromatography techniques. As proof-of-principle, GLP2-2G peptide was chemically conjugated to each of the two XTEN protein polymers using maleimide-thiol chemistry. The monodisperse nature of XTEN protein polymer enabled reaction monitoring as well as the detection of peptide modifications in the conjugated state using reverse phase-high performance liquid chromatography (RP-HPLC) and electrospray ionization mass spectrometry. The resulting GLP2-2G-XTEN conjugates were purified by preparative RP-HPLC to homogeneity. In comparison with recombinantly fused GLP2-2G-XTEN, chemically conjugated GLP2-2G-XTEN molecules exhibited comparable in vitro activity, in vitro plasma stability and pharmacokinetics in rats. These data suggest that chemical XTENylation could effectively extend the half-life of a wide spectrum of biologically active molecules, therefore broadening its applicability.

  13. Drug use patterns among Thai illicit drug injectors amidst increased police presence.

    PubMed

    Werb, Dan; Hayashi, Kanna; Fairbairn, Nadia; Kaplan, Karyn; Suwannawong, Paisan; Lai, Calvin; Kerr, Thomas

    2009-07-21

    Thailand has traditionally pursued an aggressive enforcement-based anti-illicit drug policy in an effort to make the country "drug-free." In light of this ongoing approach, we sought to assess impacts of enforcement on drug use behaviors among a cohort of injection drug users (IDU) in Thailand. We examined drug use patterns among IDU participating in a cross-sectional study conducted in Bangkok (n = 252). Participants were asked to provide data regarding patterns of drug use in the previous six months, including types of drugs consumed, method of consumption, frequency of use, and weekly income spent on drugs. We also conducted bivariate analyses to identify a possible effect of a reported increase in police presence on measures of drug use and related risk behaviors among study participants. One hundred fifty-five (61.5%) individuals reported injection heroin use and 132 (52.4%) individuals reported injection midazolam use at least daily in the past six months. Additionally, 86 (34.1%) individuals reported at least daily injection Yaba and Ice (i.e., methamphetamine) use. Participants in our study reported high levels of illicit drug use, including the injection of both illicit and licit drugs. In bivariate analyses, no association between increased police presence and drug use behaviors was observed. These findings demonstrate high ongoing rates of drug injecting in Thailand despite reports of increased levels of strict enforcement and enforcement-related violence, and raise questions regarding the merits of this approach.

  14. Drug use patterns among Thai illicit drug injectors amidst increased police presence

    PubMed Central

    Werb, Dan; Hayashi, Kanna; Fairbairn, Nadia; Kaplan, Karyn; Suwannawong, Paisan; Lai, Calvin; Kerr, Thomas

    2009-01-01

    Thailand has traditionally pursued an aggressive enforcement-based anti-illicit drug policy in an effort to make the country "drug-free." In light of this ongoing approach, we sought to assess impacts of enforcement on drug use behaviors among a cohort of injection drug users (IDU) in Thailand. We examined drug use patterns among IDU participating in a cross-sectional study conducted in Bangkok (n = 252). Participants were asked to provide data regarding patterns of drug use in the previous six months, including types of drugs consumed, method of consumption, frequency of use, and weekly income spent on drugs. We also conducted bivariate analyses to identify a possible effect of a reported increase in police presence on measures of drug use and related risk behaviors among study participants. One hundred fifty-five (61.5%) individuals reported injection heroin use and 132 (52.4%) individuals reported injection midazolam use at least daily in the past six months. Additionally, 86 (34.1%) individuals reported at least daily injection Yaba and Ice (i.e., methamphetamine) use. Participants in our study reported high levels of illicit drug use, including the injection of both illicit and licit drugs. In bivariate analyses, no association between increased police presence and drug use behaviors was observed. These findings demonstrate high ongoing rates of drug injecting in Thailand despite reports of increased levels of strict enforcement and enforcement-related violence, and raise questions regarding the merits of this approach. PMID:19622171

  15. Refinements on the age-dependent half-life model for estimating child body burdens of polychlorodibenzodioxins and dibenzofurans.

    PubMed

    Kerger, Brent D; Leung, Hon-Wing; Scott, Paul K; Paustenbach, Dennis J

    2007-04-01

    We modified our prior age-dependent half-life model to characterize the range of child (ages 0-7) body burdens associated with dietary and environmental exposure to polychlorodibenzodioxins and furans (PCDD/Fs). Several exposure scenarios were evaluated. Infants were assumed to be either breast-fed or formula-fed from birth to 6 months of age. They then received intakes of PCDD/Fs through age 7 from foods based on weighted means estimates [JECFA, 2001. Joint FAO/WHO Committee on Food Additives. Fifty-seventh meeting, Rome, June 5-14 , 2001, pp. 24-40], and with or without exposures (ingestion and dermal) to urban residential soils at 1ppb TCDD toxic equivalents (TEQ). A one-compartment (adipose volume) toxicokinetic model for TCDD described by Kreuzer [Kreuzer, P.F., Csanady, Gy.A., et al., 1997. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and congeners in infants. A toxicokinetic model of human lifetime body burden by TCDD with special emphasis on its uptake by nutrition. Arch. Toxicol. 71, 383-400] was expanded to include the key non-TCDD congeners in human breast milk and adipose tissues, and two model parameter refinements were examined: (1) use of updated and more detailed age-correlated body fat mass data [CDC, 2000. Centers for Disease Control. CDC Growth Charts: United States. Advance Data from Vital and Health Statistics of the Centers for Disease Control and Prevention, National Center for Health Statistics, Number 314, December 2000]; (2) use of breast milk PCDD/F concentration data from sampling completed in 2000-2003 [Wittsiepe, J., Fürst, P., et al., 2004. PCDD/F and dioxin-like PCB in human blood and milk from German mothers. Organohalogen Compd. 66, 2865-2872]. The updated body fat mass data nearly halved the predicted peak body burden for breast-feeding and lowered the time-weighted average (TWA) body burdens from ages 0-7 by 30-40% for breast-fed and formula-fed infants. Combined use of the updated breast milk PCDD/F concentration and body fat

  16. Microneedles: a valuable physical enhancer to increase transdermal drug delivery.

    PubMed

    Escobar-Chávez, José Juan; Bonilla-Martínez, Dalia; Villegas-González, Martha Angélica; Molina-Trinidad, Eva; Casas-Alancaster, Norma; Revilla-Vázquez, Alma Luisa

    2011-07-01

    Transdermal drug delivery offers an attractive alternative to the conventional drug delivery methods of oral administration and injection. However, the stratum corneum acts as a barrier that limits the penetration of substances through the skin. Recently, the use of micron-scale needles in increasing skin permeability has been proposed and shown to dramatically increase transdermal delivery. Microneedles have been fabricated with a range of sizes, shapes, and materials. Most in vitro drug delivery studies have shown these needles to increase skin permeability to a broad range of drugs that differ in molecular size and weight. In vivo studies have demonstrated satisfactory release of oligonucleotides and insulin and the induction of immune responses from protein and DNA vaccines. Microneedles inserted into the skin of human subjects were reported to be painless. For all these reasons, microneedles are a promising technology to deliver drugs into the skin. This review presents the main findings concerning the use of microneedles in transdermal drug delivery. It also covers types of microneedles, their advantages and disadvantages, enhancement mechanisms, and trends in transdermal drug delivery.

  17. Half-life of the yrast 2+ state in 188W: Evolution of deformation and collectivity in neutron-rich tungsten isotopes

    NASA Astrophysics Data System (ADS)

    Mason, P. J. R.; Podolyák, Zs.; Mărginean, N.; Regan, P. H.; Stevenson, P. D.; Werner, V.; Alexander, T.; Algora, A.; Alharbi, T.; Bowry, M.; Britton, R.; Bruce, A. M.; Bucurescu, D.; Bunce, M.; Căta-Danil, G.; Căta-Danil, I.; Cooper, N.; Deleanu, D.; Delion, D.; Filipescu, D.; Gelletly, W.; Ghiţă, D.; Gheorghe, I.; Glodariu, T.; Ilie, G.; Ivanova, D.; Kisyov, S.; Lalkovski, S.; Lica, R.; Liddick, S. N.; Mărginean, R.; Mihai, C.; Mulholland, K.; Nita, C. R.; Negret, A.; Pascu, S.; Rice, S.; Roberts, O. J.; Sava, T.; Smith, J. F.; Söderström, P.-A.; Stroe, L.; Suliman, G.; Suvaila, R.; Toma, S.; Townsley, C.; Wilson, E.; Wood, R. T.; Zhekova, M.; Zhou, C.

    2013-10-01

    The half-life of the yrast Iπ=2+ state in the neutron-rich nucleus 188W has been measured using fast-timing techniques with the HPGe and LaBr3:Ce array at the National Institute of Physics and Nuclear Engineering, Bucharest. The resulting value of t1/2=0.87(12) ns is equivalent to a reduced transition probability of B(E2;21+→01+)=85(12) W.u. for this transition. The B(E2;21+→01+) is compared to neighboring tungsten isotopes and nuclei in the Hf, Os, and Pt isotopic chains. Woods-Saxon potential energy surface (PES) calculations have been performed for nuclei in the tungsten isotopic chain and predict prolate deformed minima with rapidly increasing γ softness for 184-192W and an oblate minimum for 194W.

  18. Enhanced in vivo efficacy of a type I interferon superagonist with extended plasma half-life in a mouse model of multiple sclerosis.

    PubMed

    Harari, Daniel; Kuhn, Nadine; Abramovich, Renne; Sasson, Keren; Zozulya, Alla L; Smith, Paul; Schlapschy, Martin; Aharoni, Rina; Köster, Mario; Eilam, Raya; Skerra, Arne; Schreiber, Gideon

    2014-10-17

    IFNβ is a common therapeutic option to treat multiple sclerosis. It is unique among the family of type I IFNs in that it binds to the interferon receptors with high affinity, conferring exceptional biological properties. We have previously reported the generation of an interferon superagonist (dubbed YNSα8) that is built on the backbone of a low affinity IFNα but modified to exhibit higher receptor affinity than even for IFNβ. Here, YNSα8 was fused with a 600-residue hydrophilic, unstructured N-terminal polypeptide chain comprising proline, alanine, and serine (PAS) to prolong its plasma half-life via "PASylation." PAS-YNSα8 exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors, notably without any detectable loss in biological potency or bioavailability. This long-lived superagonist conferred significantly improved protection from MOG35-55-induced experimental autoimmune encephalomyelitis compared with IFNβ, despite being injected with a 4-fold less frequency and at an overall 16-fold lower dosage. These data were corroborated by FACS measurements showing a decrease of CD11b(+)/CD45(hi) myeloid lineage cells detectable in the CNS, as well as a decrease in IBA(+) cells in spinal cord sections determined by immunohistochemistry for PAS-YNSα8-treated animals. Importantly, PAS-YNSα8 did not induce antibodies upon repeated administration, and its biological efficacy remained unchanged after 21 days of treatment. A striking correlation between increased levels of CD274 (PD-L1) transcripts from spleen-derived CD4(+) cells and improved clinical response to autoimmune encephalomyelitis was observed, indicating that, at least in this mouse model of multiple sclerosis, CD274 may serve as a biomarker to predict the effectiveness of IFN therapy to treat this complex disease.

  19. Enhanced in Vivo Efficacy of a Type I Interferon Superagonist with Extended Plasma Half-life in a Mouse Model of Multiple Sclerosis*

    PubMed Central

    Harari, Daniel; Kuhn, Nadine; Abramovich, Renne; Sasson, Keren; Zozulya, Alla L.; Smith, Paul; Schlapschy, Martin; Aharoni, Rina; Köster, Mario; Eilam, Raya; Skerra, Arne; Schreiber, Gideon

    2014-01-01

    IFNβ is a common therapeutic option to treat multiple sclerosis. It is unique among the family of type I IFNs in that it binds to the interferon receptors with high affinity, conferring exceptional biological properties. We have previously reported the generation of an interferon superagonist (dubbed YNSα8) that is built on the backbone of a low affinity IFNα but modified to exhibit higher receptor affinity than even for IFNβ. Here, YNSα8 was fused with a 600-residue hydrophilic, unstructured N-terminal polypeptide chain comprising proline, alanine, and serine (PAS) to prolong its plasma half-life via “PASylation.” PAS-YNSα8 exhibited a 10-fold increased half-life in both pharmacodynamic and pharmacokinetic assays in a transgenic mouse model harboring the human receptors, notably without any detectable loss in biological potency or bioavailability. This long-lived superagonist conferred significantly improved protection from MOG35–55-induced experimental autoimmune encephalomyelitis compared with IFNβ, despite being injected with a 4-fold less frequency and at an overall 16-fold lower dosage. These data were corroborated by FACS measurements showing a decrease of CD11b+/CD45hi myeloid lineage cells detectable in the CNS, as well as a decrease in IBA+ cells in spinal cord sections determined by immunohistochemistry for PAS-YNSα8-treated animals. Importantly, PAS-YNSα8 did not induce antibodies upon repeated administration, and its biological efficacy remained unchanged after 21 days of treatment. A striking correlation between increased levels of CD274 (PD-L1) transcripts from spleen-derived CD4+ cells and improved clinical response to autoimmune encephalomyelitis was observed, indicating that, at least in this mouse model of multiple sclerosis, CD274 may serve as a biomarker to predict the effectiveness of IFN therapy to treat this complex disease. PMID:25193661

  20. A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life

    PubMed Central

    Souders, Colby A; Nelson, Stuart C; Wang, Yang; Crowley, Andrew R; Klempner, Mark S; Thomas, William

    2015-01-01

    Immunoglobulin G (IgG) has an unusually long serum half-life in comparison to proteins of a similar size. It is well-known that this phenomenon is due to IgG's ability to bind the neonatal Fc receptor (FcRn) in a pH-dependent manner. FcRn binding properties can vary among IgGs, resulting in altered in vivo half-lives, and therefore it would be beneficial to accurately predict the FcRn binding properties of therapeutic IgG monoclonal antibodies (mAbs). Here we describe the development of an in vitro model capable of predicting the in vivo half-life of human IgG. Using a high-throughput biolayer interferometry (BLI) platform, the human FcRn association rate at acidic pH and subsequent dissociation rate at physiological pH was determined for 5 human IgG1 mAbs. Comparing the combined FcRn association and dissociation rates to the Phase 1 clinical study half-lives of the mAbs resulted in a strong correlation. The correlation was also verified in vivo using mice transgenic for human FcRn. The model was used to characterize various factors that may influence FcRn-mAb binding, including mAb variable region sequence differences and constant region glycosylation patterns. Results indicated that the complementarity-determining regions of the heavy chain significantly influence the mAb's FcRn binding properties, while the absence of glycosylation does not alter mAb-FcRn binding. Development of this high-throughput FcRn binding model could potentially predict the half-life of therapeutic IgGs and aid in selection of lead candidates while also serving as a screening tool for the development of mAbs with desired pharmacokinetic properties. PMID:26018774

  1. An inter-comparison of 10Be and 26Al AMS reference standards and the 10Be half-life

    NASA Astrophysics Data System (ADS)

    Fink, David; Smith, Andrew

    2007-06-01

    We have completed a survey and inter-comparison of several 10Be and 26Al standard reference materials (SRMs) that are in routine use at various AMS laboratories to assess their relative values and the accuracy of their quoted nominal ratios. The accelerator measurement cycle, analysis procedure and setup used at the ANTARES AMS facility for this survey are described. We focused on a new set of 10Be and 26Al serial dilutions of standard reference materials (SRMs) prepared by Kuni Nishiizumii at the University of California, Berkeley, and found excellent systematic reproducibility and internal consistency. For other standard materials, minor deviations are evident even when the results have been recalibrated to a common half-life. In particular, we confirm that the NIST 10Be SRM-4325 has a 14% greater 10Be/Be ratio than that certified by NIST when it is calibrated against other SRMs whose ratios have been normalized to a common 1.5 Ma 10Be half-life. In order to investigate this apparent discrepancy, we report on the results of an absolute, normalization independent, measure of the NIST-4325 10Be/Be ratio. Within the constraints of this type of measurement and its systematic errors, we determine an absolute value for the 10Be/Be SRM-4325 ratio in the range 26,050 to 24,800 × 10-15 in support of the certified value of 26,800 × 10-15 given by NIST. We hesitate to directly infer as a consequence that the 10Be half-life is 1.34 Ma because such an inference is contingent on a direct and accurate specific activity in the parent solution, which at present is not available.

  2. Innovative methodology for intercomparison of radionuclide calibrators using short half-life in situ prepared radioactive sources

    SciTech Connect

    Oliveira, P. A.; Santos, J. A. M.

    2014-07-15

    Purpose: An original radionuclide calibrator method for activity determination is presented. The method could be used for intercomparison surveys for short half-life radioactive sources used in Nuclear Medicine, such as{sup 99m}Tc or most positron emission tomography radiopharmaceuticals. Methods: By evaluation of the resulting net optical density (netOD) using a standardized scanning method of irradiated Gafchromic XRQA2 film, a comparison of the netOD measurement with a previously determined calibration curve can be made and the difference between the tested radionuclide calibrator and a radionuclide calibrator used as reference device can be calculated. To estimate the total expected measurement uncertainties, a careful analysis of the methodology, for the case of{sup 99m}Tc, was performed: reproducibility determination, scanning conditions, and possible fadeout effects. Since every factor of the activity measurement procedure can influence the final result, the method also evaluates correct syringe positioning inside the radionuclide calibrator. Results: As an alternative to using a calibrated source sent to the surveyed site, which requires a relatively long half-life of the nuclide, or sending a portable calibrated radionuclide calibrator, the proposed method uses a source preparedin situ. An indirect activity determination is achieved by the irradiation of a radiochromic film using {sup 99m}Tc under strictly controlled conditions, and cumulated activity calculation from the initial activity and total irradiation time. The irradiated Gafchromic film and the irradiator, without the source, can then be sent to a National Metrology Institute for evaluation of the results. Conclusions: The methodology described in this paper showed to have a good potential for accurate (3%) radionuclide calibrators intercomparison studies for{sup 99m}Tc between Nuclear Medicine centers without source transfer and can easily be adapted to other short half-life radionuclides.

  3. Improved measurement of the half-life of the Jπ = 8- nuclear isomer 152m2 Eu

    DOE PAGES

    Humby, Peter; Simon, Anna; Beausang, C. W.; Ross, T. J.; Hughes, R. O.; Burke, J. T.; Casperson, R. J.; Koglin, J.; Ota, S.; Allmond, James M.; et al

    2015-02-23

    The standard γ-ray energy calibration source 152Eu is well known based on the 13.5 y decay of its ground state. Nevertheless, in addition to this decay 152Eu also has two relatively long-lived isomeric states: a 9 h Jπ=0- state at E*=46 keV and a 96 min Jπ=8- state at E*=148 keV. Here we report a new measurement of the half-lives of both of these isomeric states. Excited states in 152Eu were populated following the 154Sm (p,3n) reaction using a 25 MeV proton beam from the K-150 cyclotron at the Cyclotron Institute of Texas A&M University. Post irradiation, γ rays frommore » the de-excitation of the long lived isomeric states were measured using the six BGO shielded high-purity germanium (HPGe) clover detectors that are part of the STARLiTeR array. The half-life of the Jπ=8- isomer 152m2Eu was obtained by measuring the decrease in intensity of the 90 keV γ ray from the cascade to the ground state. The half-life of this state was measured to be 95.8(4) min which is in agreement with and significantly more precise than the previously measured value of 96(1) min. In a manner similar to the ground state the second long-lived isomer 151m1Eu, the Jπ=0- state at 46 keV, β decays to excited states in 152Gd and 152Sm. Also, the half-life of this state was measured to be 9.39(7) h using five γ-ray transitions.« less

  4. Improved measurement of the half-life of the Jπ=8- nuclear isomer 152Eu m2

    NASA Astrophysics Data System (ADS)

    Humby, P.; Simon, A.; Beausang, C. W.; Ross, T. J.; Hughes, R. O.; Burke, J. T.; Casperson, R. J.; Koglin, J.; Ota, S.; Allmond, J. M.; McCleskey, M.; McCleskey, E.; Saastamoinen, A.; Chyzh, R.; Dag, M.; Gell, K.; Tarlow, T.; Vyas, G.

    2015-02-01

    The standard γ -ray energy calibration source 152Eu is well known based on the 13.5 y decay of its ground state. However, in addition to this decay 152Eu also has two relatively long-lived isomeric states: a 9 h Jπ=0- state at E*=46 keV and a 96 min Jπ=8- state at E*=148 keV. Here we report a new measurement of the half-lives of both of these isomeric states. Excited states in 152Eu were populated following the 154Sm(p ,3 n ) reaction using a 25 MeV proton beam from the K-150 cyclotron at the Cyclotron Institute of Texas A&M University. Post irradiation, γ rays from the de-excitation of the long lived isomeric states were measured using the six BGO shielded high-purity germanium (HPGe) clover detectors that are part of the STARLiTeR array. The half-life of the Jπ=8- isomer 152Eu m2 was obtained by measuring the decrease in intensity of the 90 keV γ ray from the cascade to the ground state. The half-life of this state was measured to be 95.8(4) min which is in agreement with and significantly more precise than the previously measured value of 96(1) min. In a manner similar to the ground state the second long-lived isomer 151Eu m1, the Jπ=0- state at 46 keV, β decays to excited states in 152Gd and 152Sm. The half-life of this state was measured to be 9.39(7) h using five γ -ray transitions.

  5. The effective and environmental half-life of 137Cs at Coral Islands at the former US nuclear test site.

    PubMed

    Robison, William L; Conrado, Cynthia L; Bogen, Kenneth T; Stoker, A Carol

    2003-01-01

    The United States (US) conducted nuclear weapons testing from 1946 to 1958 at Bikini and Enewetak Atolls in the northern Marshall Islands. Based on previous detailed dose assessments for Bikini, Enewetak, Rongelap, and Utirik Atolls over a period of 28 years, cesium-137 (137Cs) at Bikini Atoll contributes about 85-89% of the total estimated dose through the terrestrial food chain as a result of uptake of 137Cs by food crops. The estimated integral 30, 50, and 70-year doses were based on the radiological decay of 137Cs (30-year half-life) and other radionuclides. However, there is a continuing inventory of 137Cs and 90Sr in the fresh water portion of the groundwater at all contaminated atolls even though the turnover rate of the fresh groundwater is about 5 years. This is evidence that a portion of the soluble fraction of 137Cs and 90Sr inventory in the soil is lost by transport to groundwater when rainfall is heavy enough to cause recharge of the lens, resulting in loss of 137Cs from the soil column and root zone of the plants. This loss is in addition to that caused by radioactive decay. The effective rate of loss was determined by two methods: (1) indirectly, from time-dependent studies of the 137Cs concentration in leaves of Pisonia grandis, Guettarda specosia, Tournefortia argentea (also called Messerschmidia), Scaevola taccada, and fruit from Pandanus and coconut trees (Cocos nucifera L.), and (2) more directly, by evaluating the 137Cs/90Sr ratios at Bikini Atoll. The mean (and its lower and upper 95% confidence limits) for effective half-life and for environmental-loss half-life (ELH) based on all the trees studied on Rongelap, Bikini, and Enewetak Atolls are 8.5 years (8.0 years, 9.8 years), and 12 years (11 years, 15 years), respectively. The ELH based on the 137Cs/90Sr ratios in soil in 1987 relative to the 137Cs/90Sr ratios at the time of deposition in 1954 is less than 17 years. The magnitude of the decrease below 17 years depends on the ELH for 90Sr

  6. The effective and environmental half-life of 137Cs at Coral Islands at the former US nuclear test site.

    PubMed

    Robison, William L; Conrado, Cynthia L; Bogen, Kenneth T; Stoker, A Carol

    2003-01-01

    The United States (US) conducted nuclear weapons testing from 1946 to 1958 at Bikini and Enewetak Atolls in the northern Marshall Islands. Based on previous detailed dose assessments for Bikini, Enewetak, Rongelap, and Utirik Atolls over a period of 28 years, cesium-137 (137Cs) at Bikini Atoll contributes about 85-89% of the total estimated dose through the terrestrial food chain as a result of uptake of 137Cs by food crops. The estimated integral 30, 50, and 70-year doses were based on the radiological decay of 137Cs (30-year half-life) and other radionuclides. However, there is a continuing inventory of 137Cs and 90Sr in the fresh water portion of the groundwater at all contaminated atolls even though the turnover rate of the fresh groundwater is about 5 years. This is evidence that a portion of the soluble fraction of 137Cs and 90Sr inventory in the soil is lost by transport to groundwater when rainfall is heavy enough to cause recharge of the lens, resulting in loss of 137Cs from the soil column and root zone of the plants. This loss is in addition to that caused by radioactive decay. The effective rate of loss was determined by two methods: (1) indirectly, from time-dependent studies of the 137Cs concentration in leaves of Pisonia grandis, Guettarda specosia, Tournefortia argentea (also called Messerschmidia), Scaevola taccada, and fruit from Pandanus and coconut trees (Cocos nucifera L.), and (2) more directly, by evaluating the 137Cs/90Sr ratios at Bikini Atoll. The mean (and its lower and upper 95% confidence limits) for effective half-life and for environmental-loss half-life (ELH) based on all the trees studied on Rongelap, Bikini, and Enewetak Atolls are 8.5 years (8.0 years, 9.8 years), and 12 years (11 years, 15 years), respectively. The ELH based on the 137Cs/90Sr ratios in soil in 1987 relative to the 137Cs/90Sr ratios at the time of deposition in 1954 is less than 17 years. The magnitude of the decrease below 17 years depends on the ELH for 90Sr

  7. The half-life of the HSV-1 1.5-kb LAT intron is similar to the half-life of the 2.0-kb LAT intron.

    PubMed

    Brinkman, Kerry K; Mishra, Prakhar; Fraser, Nigel W

    2013-02-01

    Herpes simplex virus type 1 establishes a latent infection in the sensory neurons of the peripheral nervous system of humans. Although about 80 genes are expressed during the lytic cycle of the virus infection, essentially only one gene is expressed during the latent cycle. This gene is known as the latency-associated transcript (LAT), and it appears to play a role in the latency cycle through an anti-apoptotic function in the 5' end of the gene and miRNA encoded along the length of the transcript which downregulate some of the viral immediate-early gene products. The LAT gene is about 8.3 kb long and consists of two exons separated by an unusual intron. The intron between the exons consists of two nested introns. This arrangement of introns has been called a twintron. Furthermore, the larger (2 kb) intron has been shown to be very stable. In this study, we measure the stability of the shorter 1.5-kb nested intron and find its half-life is similar to the longer intron. This was achieved by deleting the 0.5-kb overlapping intron from a plasmid construct designed to express the LAT transcript from a tet-inducible promoter and measuring the half-life of the 1.5-kb intron in tissue culture cells. This finding supports the hypothesis that it is the common branch-point region of these nested introns that is responsible for their stability.

  8. The half-life of the HSV-1 1.5-kb LAT intron is similar to the half-life of the 2.0-kb LAT intron.

    PubMed

    Brinkman, Kerry K; Mishra, Prakhar; Fraser, Nigel W

    2013-02-01

    Herpes simplex virus type 1 establishes a latent infection in the sensory neurons of the peripheral nervous system of humans. Although about 80 genes are expressed during the lytic cycle of the virus infection, essentially only one gene is expressed during the latent cycle. This gene is known as the latency-associated transcript (LAT), and it appears to play a role in the latency cycle through an anti-apoptotic function in the 5' end of the gene and miRNA encoded along the length of the transcript which downregulate some of the viral immediate-early gene products. The LAT gene is about 8.3 kb long and consists of two exons separated by an unusual intron. The intron between the exons consists of two nested introns. This arrangement of introns has been called a twintron. Furthermore, the larger (2 kb) intron has been shown to be very stable. In this study, we measure the stability of the shorter 1.5-kb nested intron and find its half-life is similar to the longer intron. This was achieved by deleting the 0.5-kb overlapping intron from a plasmid construct designed to express the LAT transcript from a tet-inducible promoter and measuring the half-life of the 1.5-kb intron in tissue culture cells. This finding supports the hypothesis that it is the common branch-point region of these nested introns that is responsible for their stability. PMID:23335177

  9. Fab-dsFv: A bispecific antibody format with extended serum half-life through albumin binding

    PubMed Central

    Davé, Emma; Adams, Ralph; Zaccheo, Oliver; Carrington, Bruce; Compson, Joanne E.; Dugdale, Sarah; Airey, Michael; Malcolm, Sarah; Hailu, Hanna; Wild, Gavin; Turner, Alison; Heads, James; Sarkar, Kaushik; Ventom, Andrew; Marshall, Diane; Jairaj, Mark; Kopotsha, Tim; Christodoulou, Louis; Zamacona, Miren; Lawson, Alastair D.; Heywood, Sam; Humphreys, David P.

    2016-01-01

    ABSTRACT An antibody format, termed Fab-dsFv, has been designed for clinical indications that require monovalent target binding in the absence of direct Fc receptor (FcR) binding while retaining substantial serum presence. The variable fragment (Fv) domain of a humanized albumin-binding antibody was fused to the C-termini of Fab constant domains, such that the VL and VH domains were individually connected to the Cκ and CH1 domains by peptide linkers, respectively. The anti-albumin Fv was selected for properties thought to be desirable to ensure a durable serum half-life mediated via FcRn. The Fv domain was further stabilized by an inter-domain disulfide bond. The bispecific format was shown to be thermodynamically and biophysically stable, and retained good affinity and efficacy to both antigens simultaneously. In in vivo studies, the serum half-life of Fab-dsFv, 2.6 d in mice and 7.9 d in cynomolgus monkeys, was equivalent to Fab'-PEG. PMID:27532598

  10. RBC-/Cr-51/ half-life and albumin turnover in growing Beagle dogs during chronic radial acceleration

    NASA Technical Reports Server (NTRS)

    Beckman, D. A.; Evans, J. W.; Oyama, J.

    1979-01-01

    The effects of chronic centrifugation on growing Beagle dogs exposed to -2 or -2.6 Gx on albumin and RBC turnover rates, albumin concentration and space, and total blood volume were determined and compared with caged and run control of animals. Albumin-(I-125) and autologous RBC-(Cr-51) preparations were injected into all dogs at day 82 of the centrifugation periods, and the disappearance curves were determined by successive bleedings of the animals over the next 35 d, during which the centrifugation was continued. There were no differences in albumin turnover rates or space. Two populations of RBCs were found in both centrifugated groups, one with a normal half-life of 27 + or - 1 S.E.M. d, and one with a significantly (p less than 0.01) shorter half-life of 15 + or - 2 S.E.M. d. An absolute polycythemia was also observed in both centrifuged groups. The results suggest that chronic centrifugation acts through some as-yet unknown mechanism to affect RBC population kinetics.

  11. Biological half-life and oxidative stress effects in mice with low-level, oral exposure to tritium.

    PubMed

    Kelsey-Wall, Angel; Seaman, John C; Jagoe, Charles H; Dallas, Cham E

    2006-02-01

    Tritium ((3)H) may enter the environment from human activities, particularly at production, processing, or waste storage sites such as the Department of Energy's Savannah River Site, a former nuclear production facility in South Carolina. Understanding the dynamics and potential adverse effects of tritium in exposed organisms is critical to evaluating risks of tritium releases at such sites. Previous studies estimated the biological half-life of tritium in mice to be approximately 1.13 d; however, these laboratory studies were not conducted under environmentally realistic conditions. In this study, designed to be more representative of environmental exposure, mice were allowed to drink water containing tritium (activity about 300 Bq/ml) for a period of 2 wk. The induction of oxidative stress from tritium exposure was evaluated by comparing the activities of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase) in exposed and control mice. From this experiment, the biological half-life of tritium was determined to be 2.26 +/- 0.04 d, almost double previous estimates. While positive controls (x-ray irradiated mice) showed responses in antioxidant enzyme activity, there was no indication of oxidative stress induction in mice exposed to tritium at this concentration. PMID:16263691

  12. Extension of the in vivo half-life of endostatin and its improved anti-tumor activities upon fusion to a humanized antibody against tumor-associated glycoprotein 72 in a mouse model of human colorectal carcinoma.

    PubMed

    Lee, Sang-Hyun; Jeung, In Cheul; Park, Tae Woo; Lee, Kyungmin; Lee, Dong Gwang; Cho, Young-Lai; Lee, Tae Sup; Na, Hee-Jun; Park, Young-Jun; Lee, Hee Gu; Jeong, Mun Sik; Bae, Kwang-Hee; Lee, Sang Chul; Lee, Hyo Jin; Kwon, Young-Guen; Hong, Hyo Jeong; Kim, Jang-Seong; Min, Jeong-Ki

    2015-03-30

    Endostatin is an endogenous angiogenesis inhibitor that exhibits potential anti-tumor efficacy in various preclinical animal models. However, its relatively short in vivo half-life and the long-term, frequent administration of high doses limit its widespread clinical use. In this study, we evaluated whether a fusion protein of murine endostatin (mEndo) to a humanized antibody against tumor-associated glycoprotein 72 (TAG-72), which is highly expressed in several human tumor tissues including colon cancer, can extend the serum half-life and improve the anti-tumor efficacy of endostatin by targeted delivery to the tumor mass. The fusion protein (3E8-mEndo) and mEndo showed improved anti-angiogenic activity in vitro and in vivo, predominantly by interfering with pro-angiogenic signaling triggered by vascular endothelial growth factor (VEGF). Moreover, in mice treated with 3E8-mEndo, we observed a markedly prolonged serum half-life and significantly inhibited tumor growth. The improved anti-tumor activity of 3E8-mEndo can be partially explained by increased local concentration in the tumor mass due to targeted delivery of 3E8-mEndo to implanted colon tumors. Collectively, our data clearly indicate that tumor-targeting antibody fusions to endostatin are a powerful strategy that improves the poor pharmacokinetic profile and anti-tumor efficacy of endostatin.

  13. Use of a GM counter to measure the half-life of Ba-137m generated by using an isotope generator

    NASA Astrophysics Data System (ADS)

    Kweon, Dae Cheol; Choi, Jiwon; Dong, Kyung-Rae; Chung, Woon-Kwan; Song, Hyeon-Je; Kim, Young-Jae

    2014-08-01

    A Cs-137/Ba-137m isotope generator is used to demonstrate the properties of radioactive decay. In this experiment, we investigate and verify the random behavior of radioactive decay and determine the half-life of a radioactive isotope. The half-life of a radioisotope is measured in this experiment. The purpose of this experiment is to determine the half-life of Ba-137m by using several methods and to determine the percent error for each determination. Ba-137m decays by gamma emission (662 keV) with a half-life of 2.6 minutes to the stable Ba-137 element. During elution, Ba-137m is selectively "milked" from the generator, leaving behind the Cs-137 parent. Each generator is supplied with 250 mL of an eluting solution (0.9% NaCl in 0.04M HCl). A Geiger counter interfaced with a computer is used to acquire and record the activity at set time intervals. The half-life of the radioactive isotope Ba-137m is determined by measuring the activity of a sample as it decays. The half-life of Ba-137m, which has been extracted from the radioisotope Cs-137, is detected by using AktivLab. The theoretical half-life of Ba-137m is approximately 2.56 minutes, and the result from the experiment is 2.6 minutes. In summary, a radioisotope generator containing Cs-137 produces Ba-137m, which is extracted in a solution. The Ba-137m has a half-life of about 2.6 minutes as measured during this research.

  14. Models for Prediction of Factor VIII Half-Life in Severe Haemophiliacs: Distinct Approaches for Blood Group O and Non-O Patients

    PubMed Central

    Fischer, Kathelijn; van Dijk, Karin; Denis, Cécile V.; van den Berg, H. Marijke; Lenting, Peter J.

    2009-01-01

    Background Von Willebrand factor (VWF) is critical for the in vivo survival of factor VIII (FVIII). Since FVIII half-life correlates with VWF-antigen pre-infusion levels, we hypothesized that VWF levels are useful to predict FVIII half-life. Methodology Standardized half-life studies and analysis of pre-infusion VWF and VWF-propeptide levels were performed in a cohort of 38 patients with severe haemophilia A (FVIII <1 IU/ml), aged 15–44 years. Nineteen patients had blood-group O. Using multivariate linear regression-analysis (MVLR-analysis), the association of VWF-antigen, VWF-propeptide, age and body-weight with FVIII half-life was evaluated. Principal Findings FVIII half-life was shorter in blood-group O-patients compared to non-O-patients (11.5±2.6 h versus 14.3±3.0 h; p = 0.004). VWF-antigen levels correlated with FVIII half-life considerably better in patients with blood-group non-O than O (Pearson-rank = 0.70 and 0.47, respectively). Separate prediction models evolved from MVLR-analysis for blood-group O and non-O patients, based on VWF-antigen and VWF/propeptide ratio. Predicted half-lives deviated less than 3 h of observed half-life in 34/38 patients (89%) or less than 20% in 31/38 patients (82%). Conclusion Our approach may identify patients with shorter FVIII half-lives, and adapt treatment protocols when half-life studies are unavailable. In addition, our data indicate that survival of FVIII is determined by survival of endogenous VWF rather than VWF levels per se. PMID:19707594

  15. Increasing the Structural Coverage of Tuberculosis Drug Targets

    PubMed Central

    Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; Fox, David; Dieterich, Shellie H.; Staker, Bart L.; Gardberg, Anna S.; Choi, Ryan; Hewitt, Stephen N.; Napuli, Alberto J.; Myers, Janette; Barrett, Lynn K.; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W.; Stacy, Robin; Stewart, Lance J.; Edwards, Thomas E.; Van Voorhis, Wesley C.; Myler, Peter J.

    2015-01-01

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. Of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases. PMID:25613812

  16. Increasing the structural coverage of tuberculosis drug targets

    SciTech Connect

    Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; Fox, David; Dieterich, Shellie H.; Staker, Bart L.; Gardberg, Anna S.; Choi, Ryan; Hewitt, Stephen N.; Napuli, Alberto J.; Myers, Janette; Barrett, Lynn K.; Zhang, Yang; Ferrell, Micah; Mundt, Elizabeth; Thompkins, Katie; Tran, Ngoc; Lyons-Abbott, Sally; Abramov, Ariel; Sekar, Aarthi; Serbzhinskiy, Dmitri; Lorimer, Don; Buchko, Garry W.; Stacy, Robin; Stewart, Lance J.; Edwards, Thomas E.; Van Voorhis, Wesley C.; Myler, Peter J.

    2014-12-19

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.

  17. Increasing the structural coverage of tuberculosis drug targets

    DOE PAGES

    Baugh, Loren; Phan, Isabelle; Begley, Darren W.; Clifton, Matthew C.; Armour, Brianna; Dranow, David M.; Taylor, Brandy M.; Muruthi, Marvin M.; Abendroth, Jan; Fairman, James W.; et al

    2014-12-19

    High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structuresmore » would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target, thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less

  18. Relationship between isotope half-life and prostatic edema for optimal prostate dose coverage in permanent seed implants

    SciTech Connect

    Villeneuve, Maxime; Leclerc, Ghyslain; Lessard, Etienne; Pouliot, Jean; Beaulieu, Luc

    2008-05-15

    The robustness of treatment planning to prostatic edema for three different isotopes ({sup 125}I, {sup 103}Pd, and {sup 131}Cs) is explored using dynamical dose calculations on 25 different clinical prostate cases. The treatment plans were made using the inverse planning by simulated annealing (IPSA) algorithm. The prescription was 144, 127, and 125 Gy for {sup 125}I, {sup 131}Cs, and {sup 103}Pd, respectively. For each isotope, three dose distribution schemes were used to impose different protection levels to the urethra: V{sub 120}=0%, V{sub 150}=0%, and V{sub 150}=30%. Eleven initial edema values were considered ranging from 1.0 (no edema) to 2.0 (100%). The edema was assumed to resolve exponentially with time. The prostate volume, seed positions, and seed activity were dynamically tracked to produce the final dose distribution. Edema decay half-lives of 10, 30, and 50 days were used. A total of 675 dynamical calculations were performed for each initial edema value. For the {sup 125}I isotope, limiting the urethra V{sub 120} to 0% leads to a prostate D{sub 90} under 140 Gy for initial edema values above 1.5. Planning with urethra V{sub 150} at 0% provides a good response to the edema; the prostate D{sub 90} remains higher than 140 Gy for edema values up to 1.8 and a half-life of 30 days or less. For {sup 103}Pd, the prostate D{sub 90} is under 97% of the prescription dose for approximately 66%, 40%, and 30% of edema values for urethra V{sub 120}=0%, V{sub 150}=0%, and V{sub 150}=30%, respectively. Similar behavior is seen for {sup 131}Cs and the center of the prostate becomes 'cold' for almost all edema scenarios. The magnitude of the edema following prostate brachytherapy, as well as the half-life of the isotope used and that of the edema resorption, all have important impacts on the dose distribution. The {sup 125}I isotope with its longer half-life is more robust to prostatic edema. Setting up good planning objectives can provide an adequate compromise

  19. Half-life of Zn-80 - The first measurement for an r-process waiting-point nucleus

    NASA Astrophysics Data System (ADS)

    Gill, R. L.; Casten, R. F.; Warner, D. D.; Piotrowski, A.; Mach, H.

    1986-04-01

    The first measurement of beta decay in Zn-80, a critical N = 50 waiting-point nucleus in the evaluation of different models of r-process environments and exposure times, is reported. Using the TRISTAN mass separator on line to the Brookhaven high-flux beam reactor, a half-life of 0.55 + or - 0.02 was measured for the neutron-rich fission product nucleus Zn-80(50). A Q-beta value for the decay of Zn-80 of 7.15 + or - 0.15 MeV, and a decay scheme for Zn-80 comprising low-lying levels and prominent gamma rays in Ga-80, are also deduced. A mass excess of -52.28 + or - 0.46 MeV is obtained for Zn-80.

  20. Alprolix (recombinant Factor IX Fc fusion protein): extended half-life product for the prophylaxis and treatment of hemophilia B.

    PubMed

    Ducore, Jonathan M; Miguelino, Maricel G; Powell, Jerry S

    2014-10-01

    Hemophilia B is a genetic disease caused by mutation of the gene for coagulation protein Factor IX. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic recombinant or plasma-derived protein concentrates containing Factor IX. Alprolix™ (recombinant Factor IX Fc fusion protein), is a therapeutic Factor IX preparation that has been engineered for a prolonged half-life in circulation, has completed pivotal clinical trials and has been approved recently in the USA, Canada, Australia and Japan for use in the clinic for patients with hemophilia B. This promising therapy should allow patients to use fewer infusions to maintain appropriate Factor IX activity levels in all clinical settings, and its use may be indicated in both on demand and prophylactic treatments.

  1. Developments in human growth hormone preparations: sustained-release, prolonged half-life, novel injection devices, and alternative delivery routes

    PubMed Central

    Cai, Yunpeng; Xu, Mingxin; Yuan, Minglu; Liu, Zhenguo; Yuan, Weien

    2014-01-01

    Since the availability of recombinant human growth hormone (rhGH) enabled the application of human growth hormone both in clinical and research use in the 1980s, millions of patients were prescribed a daily injection of rhGH, but noncompliance rates were high. To address the problem of noncompliance, numerous studies have been carried out, involving: sustained-release preparations, prolonged half-life derivatives, new injectors that cause less pain, and other noninvasive delivery methods such as intranasal, pulmonary and transdermal deliveries. Some accomplishments have been made and launched already, such as the Nutropin Depot® microsphere and injectors (Zomajet®, Serojet®, and NordiFlex®). Here, we provide a review of the different technologies and illustrate the key points of these studies to achieve an improved rhGH product. PMID:25114523

  2. Accurate Determination of Radionuclidic Purity and Half-Life of Reactor Produced LU-177G for Metabolic Radioimmunotherapy

    NASA Astrophysics Data System (ADS)

    Groppi, F.; Canella, L.; Bonardi, M. L.; Zona, C.; Morzenti, S.; Menapace, E.; Alfassi, Z. B.; Chinol, M.; Papi, S.; Tosi, G.

    2006-04-01

    The accurate determination of radionuclidic purity and half-life of the beta emitter 177gLu used for metabolic radioimmunotherapy is presented. High-resolution gamma spectrometry, as well as deconvolution of beta decay curve measured by spectrometry with liquid scintillation counting, have been adopted for quality control of different samples available on the market. A simple method was developed to distinguish between the different methods available for production of 177gLu: i.e. either direct (n,γ) reactions of enriched 176Lu or indirect (n,γ) activation of enriched 176Yb followed by β- decay. In the first case, the long-lived metastable level 177mLu is present in the radioactive preparation and a low specific activity radionuclide is obtained, in the latter a very high purity and high specific activity 177gLu is produced.

  3. Drugged Driving: Increased Traffic Risks Involving Licit and Illicit Substances

    ERIC Educational Resources Information Center

    Pilkinton, Melinda W.; Robertson, Angela; McCluskey, D. Lee

    2013-01-01

    Driving under the influence of drugs poses risks for traffic safety. Most research attention has been focused on the most prevalent drugs of abuse, such as alcohol, illegal drugs, and prescription drugs with high abuse potential. The objectives of this study were to determine the types of drugs used by convicted DUI offenders on the day of their…

  4. Increasing Infectious Endocarditis Admissions Among Young People Who Inject Drugs

    PubMed Central

    Wurcel, Alysse G.; Anderson, Jordan E.; Chui, Kenneth K. H.; Skinner, Sally; Knox, Tamsin A.; Snydman, David R.; Stopka, Thomas J.

    2016-01-01

    People who inject drugs (PWID) are at risk for infective endocarditis (IE). Hospitalization rates related to misuse of prescription opioids and heroin have increased in recent years, but there are no recent investigations into rates of hospitalizations from injection drug use-related IE (IDU-IE). Using the Health Care and Utilization Project National Inpatient Sample (HCUP-NIS) dataset, we found that the proportion of IE hospitalizations from IDU-IE increased from 7% to 12.1% between 2000 and 2013. Over this time period, we detected a significant increase in the percentages of IDU-IE hospitalizations among 15- to 34-year-olds (27.1%–42.0%; P < .001) and among whites (40.2%–68.9%; P < .001). Female gender was less common when examining all the IDU-IE (40.9%), but it was more common in the 15- to 34-year-old age group (53%). Our findings suggest that the demographics of inpatients hospitalized with IDU-IE are shifting to reflect younger PWID who are more likely to be white and female than previously reported. Future studies to investigate risk behaviors associated with IDU-IE and targeted harm reduction strategies are needed to avoid further increases in morbidity and mortality in this rapidly growing population of young PWID. PMID:27800528

  5. Comparison of serum immunoglobulin G half-life in dairy calves fed colostrum, colostrum replacer or administered with intravenous bovine plasma.

    PubMed

    Murphy, Jacob M; Hagey, Jill V; Chigerwe, Munashe

    2014-04-15

    In calves, passive immunity of immunoglobulins can be acquired through ingestion of colostrum or colostrum replacers. Plasma can been used to supplement immunoglobulins in healthy or sick calves. Serum half-life of colostral derived immuglobulin G (IgG) is estimated to be 20 days. Half-life of IgG is important in determining response to antigens and timing of vaccination in calves. To date studies evaluating half-life of colostrum replacer or plasma derived IgG are lacking. The objectives of this study were to compare the serum half-life of IgG derived from colostrum, colostrum replacer and plasma in dairy calves reared up to 35 days of age. Thirty Jersey calves were randomly assigned to receive colostrum or colostrum replacer by oroesophageal tubing or plasma by intravenous administration. Serum samples were collected at 2, 5, 7, 10, 14, 21, 28 and 35 days. Serum IgG concentrations were determined by radial immunodiffusion. The results indicated that half-life for IgG in colostrum fed (28.5 days) or plasma transfused calves (27.3 days) was longer than colostrum replacer fed calves (19.1 days). Further studies are required to evaluate pathogen specific immunoglobulins in order to recommend vaccination timing in calves fed colostrum replacers. PMID:24534145

  6. Label-free Fab and Fc affinity/avidity profiling of the antibody complex half-life for polyclonal and monoclonal efficacy screening.

    PubMed

    Read, Thomas; Olkhov, Rouslan V; Williamson, E Diane; Shaw, Andrew M

    2015-09-01

    A unified approach to affinity screening for Fab and Fc interactions of an antibody for its antigen and FcγR receptor has been developed. An antigen array is used for the Fab affinity and cross-reactivity screening and protein A/G proxy is the FcγR receptor. The affinities are derived using a simple 1:1 binding model with a consistent error analysis. The association and dissociation kinetics are measured over optimised times for accurate determination. The Fab/Fc affinities are derived for ten antibodies: mAb-actin (mouse), pAb-BSA (sheep), pAb-collagen V (rabbit), pAb-CRP (goat), mAb-F1 (mouse), mAbs (mouse) 7.3, 12.3, 29.3, 36.3 and 46.3 raised against LcrV in Yersinia pestis. The rate of the dissociation of antigen-antibody complexes relates directly to their immunological function as does the Fc-FcγR complex and a new half-life plot has been defined with a Fab/Fc half-life range of 17-470 min. The upper half-life value points to surface avidity. Two antibodies that are protective as an immunotherapy define a Fab half-life >250 min and an Fc half-life >50 min as characteristics of ideal interactions which can form the basis of an antibody screen for immunotherapy.

  7. Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of operation ranch hand

    SciTech Connect

    Pirkle, J.L.; Wolfe, W.H.; Patterson, D.G.; Needham, L.L.; Philips, D.L. ); Michalek, J.E.; Miner, J.C.; Peterson, M.R. )

    1989-01-01

    A half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; commonly known as dioxin) in serum has been measured in 36 Air Force Vietnam Veterans of Operation Ranch Hand, which was the operation that aerially sprayed the herbicide Agent Orange in Vietnam. From serum specimens taken in 1982 and 1987, the median half-life of 2,3,7,8-TCDD in these Ranch Hand veterans was found to be 7.1 yr (95% confidence interval about the median of 5.8-9.6 yr). These veterans reported no civilian exposure to dioxin or herbicides. Concentrations of 2,3,7,8-TCDD in the 1982 serum specimens from these veterans ranged from 16.9 to 423 parts per trillion on a lipid weight basis. The half-life estimates were not associated with the concentration of 2,3,7,8-TCDD in the 1982 serum specimens. This half-life of 7.1 yr is much longer than the half-life of 2,3,7,8-TCDD reported in animals but is consistent with recent evidence from other human exposures to 2,3,7,8-TCDD.

  8. Solubility increases associated with crystalline drug nanoparticles: methodologies and significance.

    PubMed

    Van Eerdenbrugh, Bernard; Vermant, Jan; Martens, Johan A; Froyen, Ludo; Humbeeck, Jan Van; Van den Mooter, Guy; Augustijns, Patrick

    2010-10-01

    In this manuscript, the determination of solubility of crystalline drug nanosuspensions by a range of methods is critically investigated. As the determinations of solubility were performed in the presence of the solubilizing nanosuspension stabilizer d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), the potential effects of this excipient on the measurements were studied first. Solubility data of nanosuspensions of itraconazole, loviride, phenytoin and naproxen were generated using different methodologies. Data obtained using separation-based methodologies (centrifugation, filtration and ultracentrifugation) proved to be of limited use, due to poor nanoparticle separation efficiencies and/or significant adsorption of TPGS onto the nanoparticle surfaces. Light scattering and turbidity were found to be more suitable for the determination of nanosuspension solubility. The obtained data show that, unlike earlier reports, the solubility increases due to nanosizing are small, with measured increases of only 15%. These solubility increases are in fair agreement with what would be predicted based on the Ostwald-Freundlich equation.

  9. Digoxin is a selective modifier increasing platinum drug anticancer activity.

    PubMed

    Bogush, T A; Chernov, V Yu; Dudko, E A; Shprakh, Z S; Bogush, E A; Polotsky, B E; Tjulandin, S A; Davydov, M I

    2016-05-01

    Using the model of breast cancer Ehrlich ascites tumor in mice, we showed that a sigle intraperitoneal injection of cardiac glycoside digoxin 1 h before the intraperitoneal injection of cisplatin increased the anticancer effect of the cytostatic drug more than twice when recalculated for the dose. It is assumed that the modifying effect of digoxin is determined by the direct inhibition of glycolysis in tumor cells. Taking into account the design of the study, we consider promising the clinical evaluation of the effectiveness of digoxin as a modifier of cisplatin efficiency in intracavitary therapy of ascites cancers with pleural and abdominal dissenmination. PMID:27417726

  10. Maximizing Accuracy in Half Life Measurements, by Minimizing Error, with Application to BISMUTH-212 and POLONIUM-218

    NASA Astrophysics Data System (ADS)

    Poupaki, Irene

    1990-01-01

    Radon and short-lived progeny existing in all three primordial series, namely uranium, thorium and actinium, are of most significance for human exposure, since their inhalation is implicated in bronchogenic carcinoma. Because the dosimetric calculations utilize half-life, it is important to know this parameter with the maximum possible accuracy. The half-lives of Po-218 and Bi-212, radon-222 and radon-220 progeny, were measured as 3.078 +/- 0.01 min and 59.81 +/- 0.23 min respectively. Experimental data collected by alpha-counting included background from both the counter and the intrinsic radioactivity. A comparison of all mathematical methods presently employed in the analysis of experimental radioactivity decay is presented. The most commonly used methods are, the least squares, the weighted least squares with different weighting factors and the maximum likelihood (Peierls) method. Artificial data corresponding to three different nuclides, different total experimental duration, and different counting time intervals were generated. Testing these data showed that the WLSQ with the correct weighting factor gives the higher accuracy and precision. Without spectrometry, it is impossible to measure the quantity or half-life of Po-218 unless correction is made for the Po-214 daughter. For the measurement of Po-218, samples containing the short-lived radon-222 daughters were collected electrostatically. A method used to estimate the initial radon daughters concentration in air based on regression analysis is proposed. The comparison of this with the well known Thomas method using artificial data showed that the regression analysis method leads to more accurate results. The Bi-212 samples were prepared from a Th-228 solution by spontaneous electrodeposition on platinum and nickel disks. Corrections for the curve stripping have been applied. The methods developed here have general application to the measurement of any radioactive nuclides. A review of the measured half

  11. Drug Synergy Drives Conserved Pathways to Increase Fission Yeast Lifespan

    PubMed Central

    Huang, Xinhe; Leggas, Markos; Dickson, Robert C.

    2015-01-01

    Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker’s yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms. PMID:25786258

  12. Manganese accumulation in bone following chronic exposure in rats: steady-state concentration and half-life in bone.

    PubMed

    O'Neal, Stefanie L; Hong, Lan; Fu, Sherleen; Jiang, Wendy; Jones, Alexander; Nie, Linda H; Zheng, Wei

    2014-08-17

    Literature data indicate that bone is a major storage organ for manganese (Mn), accounting for 43% of total body Mn. However, the kinetic nature of Mn in bone, especially the half-life (t(1/2)), remained unknown. This study was designed to understand the time-dependence of Mn distribution in rat bone after chronic oral exposure. Adult male rats received 50 mg Mn/kg (as MnCl2) by oral gavage, 5 days per week, for up to 10 weeks. Animals were sacrificed every 2 weeks during Mn administration for the uptake study, and on day 1, week 2, 4, 8, or 12 after the cessation at 6-week Mn exposure for the t(1/2) study. Mn concentrations in bone (MnBn) were determined by AAS analysis. By the end of 6-week's treatment, MnBn appeared to reach the steady state (T(ss)) level, about 2-3.2 fold higher than MnBn at day 0. Kinetic calculation revealed t(1/2)s of Mn in femur, tibia, and humerus bone of 77 (r=0.978), 263 (r=0.988), and 429 (r=0.994) days, respectively; the average t(1/2) in rat skeleton was about 143 days, equivalent to 8.5 years in human bone. Moreover, MnBn were correlated with Mn levels in striatum, hippocampus, and CSF. These data support MnBn to be a useful biomarker of Mn exposure.

  13. New and Emerging Agents for the Treatment of Hemophilia: Focus on Extended Half-Life Recombinant Clotting Proteins.

    PubMed

    Ragni, Margaret V

    2015-09-01

    Hemophilia A and B are X-linked disorders caused by deficient or defective clotting factor VIII (FVIII) or IX factor (FIX) proteins, and characterized by spontaneous or traumatic bleeding into joints and muscles. Previous use of plasma and plasma-derived clotting factors that lacked appropriate viral inactivation steps in manufacturing led to significant morbidity associated with transfusion-transmitted HIV and hepatitis C virus (HCV). The development of recombinant proteins revolutionized their treatment, and, with no new HIV or HCV infection via clotting proteins for nearly 30 years, greatly improved their lifespan, which now approaches that of the general population, and with the same risks for aging complications. Novel long-acting factor proteins are being licensed to extend FVIII and FIX half-life, thereby reducing infusion frequency and potentially bleed frequency and associated morbidity. Further, novel therapeutics which take advantage of new technologies, including siRNA, monoclonal antibody, and small peptide inhibition technologies, have the potential to simplify treatment and improve outcomes for those with inhibitors.

  14. Acetylcholinesterase-Fc Fusion Protein (AChE-Fc): A Novel Potential Organophosphate Bioscavenger with Extended Plasma Half-Life.

    PubMed

    Noy-Porat, Tal; Cohen, Ofer; Ehrlich, Sharon; Epstein, Eyal; Alcalay, Ron; Mazor, Ohad

    2015-08-19

    Acetylcholinesterase (AChE) is the physiological target of organophosphate nerve agent compounds. Currently, the development of a formulation for prophylactic administration of cholinesterases as bioscavengers in established risk situations of exposure to nerve agents is the incentive for many efforts. While cholinesterase bioscavengers were found to be highly effective in conferring protection against nerve agent exposure in animal models, their therapeutic use is complicated by short circulatory residence time. To create a bioscavenger with prolonged plasma half-life, compatible with biotechnological production and purification, a chimeric recombinant molecule of HuAChE coupled to the Fc region of human IgG1 was designed. The novel fusion protein, expressed in cultured cells under optimized conditions, maintains its full enzymatic activity, at levels similar to those of the recombinant AChE enzyme. Thus, this novel fusion product retained its binding affinity toward BW284c5 and propidium, and its bioscavenging reactivity toward the organophosphate-AChE inhibitors sarin and VX. Furthermore, when administered to mice, AChE-Fc exhibits exceptional circulatory residence longevity (MRT of 6000 min), superior to any other known cholinesterase-based recombinant bioscavengers. Owing to its optimized pharmacokinetic performance, high reactivity toward nerve agents, and ease of production, AChE-Fc emerges as a promising next-generation organophosphate bioscavenger.

  15. Perfluorooctane Sulfonate Plasma Half-Life Determination and Long-Term Tissue Distribution in Beef Cattle (Bos taurus).

    PubMed

    Lupton, Sara J; Dearfield, Kerry L; Johnston, John J; Wagner, Sarah; Huwe, Janice K

    2015-12-30

    Perfluorooctane sulfonate (PFOS) is used in consumer products as a surfactant and is found in industrial and consumer waste, which ends up in wastewater treatment plants (WWTPs). PFOS does not breakdown during WWTP processes and accumulates in the biosolids. Common practices include application of biosolids to pastures and croplands used for feed, and as a result, animals such as beef cattle are exposed to PFOS. To determine plasma and tissue depletion kinetics in cattle, 2 steers and 4 heifers were dosed with PFOS at 0.098 mg/kg body weight and 9.1 mg/kg, respectively. Plasma depletion half-lives for steers and heifers were 120 ± 4.1 and 106 ± 23.1 days, respectively. Specific tissue depletion half-lives ranged from 36 to 385 days for intraperitoneal fat, back fat, muscle, liver, bone, and kidney. These data indicate that PFOS in beef cattle has a sufficiently long depletion half-life to permit accumulation in edible tissues.

  16. Depression of nuclear transcription and extension of mRNA half-life under anoxia in Artemia franciscana embryos.

    PubMed

    van Breukelen, F; Maier, R; Hand, S C

    2000-04-01

    Transcriptional activity, as assessed by nuclear run-on assays, was constant during 10 h of normoxic development for embryos of the brine shrimp Artemia franciscana. Exposure of embryos to only 4 h of anoxia resulted in a 79.3+/-1 % decrease in levels of in-vivo-initiated transcripts, and transcription was depressed by 88. 2+/-0.7 % compared with normoxic controls after 24 h of anoxia (means +/- s.e.m., N=3). Initiation of transcription was fully restored after 1 h of normoxic recovery. Artificially lowering the intracellular pH of aerobic embryos to the value reflective of anoxia (pH 6.7) showed that acidification alone explained over half the transcriptional arrest. Initiation of transcription was not rescued by application of 80 % carbon monoxide under anoxia, which suggests that heme-based oxygen sensing is not involved in this global arrest. When these transcriptional data are combined with the finding that mRNA levels are unchanged for at least 6 h of anoxia, it is clear that the half-life of mRNA is extended at least 8.5-fold compared with that in aerobic embryos. In contrast to the activation of compensatory mechanisms to cope with anoxia that occurs in mammalian cells, A. franciscana embryos enter a metabolically depressed state in which gene expression and mRNA turnover are cellular costs apparently not compatible with survival and in which extended tolerance supercedes the requirement for continued metabolic function. PMID:10708633

  17. Perfluorooctane Sulfonate Plasma Half-Life Determination and Long-Term Tissue Distribution in Beef Cattle (Bos taurus).

    PubMed

    Lupton, Sara J; Dearfield, Kerry L; Johnston, John J; Wagner, Sarah; Huwe, Janice K

    2015-12-30

    Perfluorooctane sulfonate (PFOS) is used in consumer products as a surfactant and is found in industrial and consumer waste, which ends up in wastewater treatment plants (WWTPs). PFOS does not breakdown during WWTP processes and accumulates in the biosolids. Common practices include application of biosolids to pastures and croplands used for feed, and as a result, animals such as beef cattle are exposed to PFOS. To determine plasma and tissue depletion kinetics in cattle, 2 steers and 4 heifers were dosed with PFOS at 0.098 mg/kg body weight and 9.1 mg/kg, respectively. Plasma depletion half-lives for steers and heifers were 120 ± 4.1 and 106 ± 23.1 days, respectively. Specific tissue depletion half-lives ranged from 36 to 385 days for intraperitoneal fat, back fat, muscle, liver, bone, and kidney. These data indicate that PFOS in beef cattle has a sufficiently long depletion half-life to permit accumulation in edible tissues. PMID:26684745

  18. Correlations between changes in conformational dynamics and physical stability in a mutant IgG1 mAb engineered for extended serum half-life

    PubMed Central

    Majumdar, Ranajoy; Esfandiary, Reza; Bishop, Steven M; Samra, Hardeep S; Middaugh, C Russell; Volkin, David B; Weis, David D

    2015-01-01

    This study compares the local conformational dynamics and physical stability of an IgG1 mAb (mAb-A) with its corresponding YTE (M255Y/S257T/T259E) mutant (mAb-E), which was engineered for extended half-life in vivo. Structural dynamics was measured using hydrogen/deuterium (H/D) exchange mass spectrometry while protein stability was measured with differential scanning calorimetry (DSC) and size exclusion chromatography (SEC). The YTE mutation induced differences in H/D exchange kinetics at both pH 6.0 and 7.4. Segments covering the YTE mutation sites and the FcRn binding epitopes showed either subtle or no observable differences in local flexibility. Surprisingly, several adjacent segments in the CH2 and distant segments in the VH, CH1, and VL domains had significantly increased flexibility in the YTE mutant. Most notable among the observed differences is increased flexibility of the 244–254 segment of the CH2 domain, where increased flexibility has been shown previously to correlate with decreased conformational stability and increased aggregation propensity in other IgG1 mAbs (e.g., presence of destabilizing additives as well as upon de-glycosylation or methionine oxidation). DSC analysis showed decreases in both thermal onset (Tonset) and unfolding (Tm1) temperatures of 7°C and 6.7°C, respectively, for the CH2 domain of the YTE mutant. In addition, mAb-E aggregated faster than mAb-A under accelerated stability conditions as measured by SEC analysis. Hence, the relatively lower physical stability of the YTE mutant correlates with increased local flexibility of the 244–254 segment, providing a site-directed mutant example that this segment of the CH2 domain is an aggregation hot spot in IgG1 mAbs. PMID:25524268

  19. Ecological half-life of 137Cs in fish from a stream contaminated by nuclear reactor effluents

    SciTech Connect

    Peles, J.; BryanJr, A.; Garten Jr, Charles T; Ribble, D.; Smith, M.

    2000-12-01

    Radiocesium ({sup 137}Cs) concentrations were determined during 1974, 1981 and 1998 for seven species of fish inhabiting a stream (Steel Creek) contaminated by effluents from a nuclear reactor to examine the decline of this radionuclide in a natural ecosystem. Median {sup 137}Cs concentrations were highest in Micropterus salmoides (largemouth bass) during each year of the investigation (1974 = 6.67 Bq g{sup -1} dry wt. of whole body; 1981 = 3.72 Bq g{sup -1}; 1998 = 0.35 Bq g{sup -1}), but no patterns of differences were observed among Aphredoderus sayanus (pirate perch), Esox americanus (redfin pickerel), Lepomis auritus (redbreast sunfish), L. gulosus (warmouth), L. punctatus (spotted sunfish), and Notropis cummingsae (dusky shiner). Results demonstrated a rapid decline in {sup 137}Cs within fish from Steel Creek during the 24-year period. For example, {sup 137}Cs concentrations in all fish species declined significantly among years, even after accounting for radioactive decay. The observed percent declines in {sup 137}Cs concentrations of individual species were 3-4 times greater between 1974 and 1981 compared to that expected by physical decay alone, and 2-3 times greater during 1981-1998. Ecological half-lives (EHLs) of {sup 137}Cs in fish ranged from 4.43 years in A. sayanus to 6.53 years in L. gulosus. The EHL for {sup 137}Cs in all fish species combined was 5.54 years. Current levels of {sup 137}Cs in fish from Steel Creek (1.16 Bq g{sup -1} dry wt. of whole body to below detection limits) indicate that the consumption of fish from this ecosystem poses little risk to humans and sensitive wildlife species. These results demonstrate the importance of incorporating the concept of ecological half-life into determinations concerning the length and severity of potential risks associated with radiocontaminants.

  20. Ecological half-life of 137Cs in fish from a stream contaminated by nuclear reactor effluents.

    PubMed

    Peles, J D; Bryan, A L; Garten, C T; Ribble, D O; Smith, M H

    2000-12-18

    Radiocesium (137Cs) concentrations were determined during 1974, 1981 and 1998 for seven species of fish inhabiting a stream (Steel Creek) contaminated by effluents from a nuclear reactor to examine the decline of this radionuclide in a natural ecosystem. Median 137Cs concentrations were highest in Micropterus salmoides (largemouth bass) during each year of the investigation (1974 = 6.67 Bq g(-1) dry wt. of whole body; 1981 = 3.72 Bq g(-1); 1998 = 0.35 Bq g(-1)), but no patterns of differences were observed among Aphredoderus sayanus (pirate perch), Esox americanus (redfin pickerel), Lepomis auritus (redbreast sunfish), L. gulosus (warmouth), L. punctatus (spotted sunfish), and Notropis cummingsae (dusky shiner). Results demonstrated a rapid decline in 137Cs within fish from Steel Creek during the 24-year period. For example, 137Cs concentrations in all fish species declined significantly among years, even after accounting for radioactive decay. The observed percent declines in 137Cs concentrations of individual species were 3-4 times greater between 1974 and 1981 compared to that expected by physical decay alone, and 2-3 times greater during 1981-1998. Ecological half-lives (EHLs) of 137Cs in fish ranged from 4.43 years in A. sayanus to 6.53 years in L. gulosus. The EHL for 137Cs in all fish species combined was 5.54 years. Current levels of 137Cs in fish from Steel Creek (1.16 Bq g(-1) dry wt. of whole body to below detection limits) indicate that the consumption of fish from this ecosystem poses little risk to humans and sensitive wildlife species. These results demonstrate the importance of incorporating the concept of ecological half-life into determinations concerning the length and severity of potential risks associated with radiocontaminants.

  1. Biodegradation of Deep-Sea Oil Spill at the Gulf of Mexico: an Estimate of Half Life Time

    NASA Astrophysics Data System (ADS)

    Vilcaez, J.; Li, L.; Hubbard, S. S.; Hazen, T.

    2010-12-01

    The deep-sea oil spill has generated an anthropogenic disaster with severe urgency. One big question being raised is how fast the spilled oil can be biodegraded in the seawater with native bacteria. The rate of biodegradation depends on many factors, including, for example, the concentration of oil and oil degrading microbes. In the oil leakage event at the Gulf of Mexico, because of the large amount of oil spill and the addition of chemical dispersants, oil can exist either in the form of oil droplets that are separated from water phase, or as dissolved oil. This work aims to estimate the time scale of oil biodegradation for both of these forms. In the former case, the size distribution of oil droplets can be critical because it determines the amount of contact area between bacteria and oil. It has been observed that oil droplets biodegradation occurs when microbes adheres to the oil-water interface. Here we formulated a model that incorporates effects of the oil droplets size distribution and microbial activity in the water-oil interface into a shrinking-core model. The growth of microbes and the corresponding rates of biodegradation were represented by the Monod’s equation. The model was calibrated using experimental results of previous studies on dispersed oil biodegradation. Our results show that biodegradation rates of oil droplets depend largely on oil droplet size distribution and on the biodegradation rate constant. For the oil and microbes’ concentration levels reported for the Gulf of Mexico oil spill, the half life time of the spilled oil is within one week, which is consistent with experimental findings using field seawater samples collected from the Gulf of Mexico. However, it takes much longer to biodegrade the remaining 50%. Depending on the oil droplets size distribution, the remaining 50% can last for months. This does not happen with dissolved oil biodegradation which, according to our results, is readily biodegraded at rates 2-3 times faster

  2. Time scale dependence of the center of pressure entropy: What characteristics of the neuromuscular postural control system influence stabilographic entropic half-life?

    PubMed

    Federolf, Peter; Zandiyeh, Payam; von Tscharner, Vinzenz

    2015-12-01

    The center of pressure (COP) movement in studies of postural control reveals a highly regular structure (low entropy) over short time periods and a highly irregular structure over large time scales (high entropy). Entropic half-life (EnHL) is a novel measure that quantifies the time over which short-term temporal correlations in a time series deteriorate to an uncorrelated, random structure. The current study suggested and tested three hypotheses about how characteristics of the neuromuscular postural control system may affect stabilometric EnHL: (H1) control system activity hypothesis: EnHL decreases with increased frequency of control system interventions adjusting COP motion; (H2) abundance of states hypothesis: EnHL decreases with increased number of mechanically equivalent states available to the postural system; and (H3) neurologic process hierarchy hypothesis: EnHL increases if postural control functions shift from the spinal level to the motor cortex. Thirty healthy participants performed quiet stance tests for 90 s in 18 different conditions: stance (bipedal, one-legged, and tandem); footwear (bare foot, regular sports shoe, and rocker sole shoes); and simultaneous cognitive task (two-back working memory task, no challenge). A four-way repeated-measures ANOVA revealed significant changes in EnHL for the different stance positions and for different movement directions (medio-lateral, anterior-posterior). These changes support H1 and H2. Significant differences were also found between rocker sole shoes and normal or barefoot standing, which supports H3. This study contributes to the understanding of how and why EnHL is a useful measure to monitor neuromuscular control of balance.

  3. Measurement of the half-life of /sup 60/Fe using the Argonne FN tandem-superconducting Linac system as an accelerator mass spectrometer

    SciTech Connect

    Kutschera, W.; Billquist, P.J.; Frekers, D.

    1983-01-01

    An experiment to improve the accuracy in the half-life value of /sup 60/Fe by measuring both the amount of /sup 60/Fe nuclei and the decay-rate of a spallation produced sample using the relation dN/dt = -lambda N is briefly discussed. (WHK)

  4. Database for mRNA half-life of 19 977 genes obtained by DNA microarray analysis of pluripotent and differentiating mouse embryonic stem cells.

    PubMed

    Sharova, Lioudmila V; Sharov, Alexei A; Nedorezov, Timur; Piao, Yulan; Shaik, Nabeebi; Ko, Minoru S H

    2009-02-01

    Degradation of mRNA is one of the key processes that control the steady-state level of gene expression. However, the rate of mRNA decay for the majority of genes is not known. We successfully obtained the rate of mRNA decay for 19 977 non-redundant genes by microarray analysis of RNA samples obtained from mouse embryonic stem (ES) cells. Median estimated half-life was 7.1 h and only <100 genes, including Prdm1, Myc, Gadd45 g, Foxa2, Hes5 and Trib1, showed half-life less than 1 h. In general, mRNA species with short half-life were enriched among genes with regulatory functions (transcription factors), whereas mRNA species with long half-life were enriched among genes related to metabolism and structure (extracellular matrix, cytoskeleton). The stability of mRNAs correlated more significantly with the structural features of genes than the function of genes: mRNA stability showed the most significant positive correlation with the number of exon junctions per open reading frame length, and negative correlation with the presence of PUF-binding motifs and AU-rich elements in 3'-untranslated region (UTR) and CpG di-nucleotides in the 5'-UTR. The mRNA decay rates presented in this report are the largest data set for mammals and the first for ES cells.

  5. Unfounded Attribution of the "Half-Life" Index-Number of Literature Obsolescence to Burton and Kebler: A Literature Science Study.

    ERIC Educational Resources Information Center

    Szava-Kovats, Endre

    2002-01-01

    The term and notion of the "half-life" index-number of literature obsolescence, and their borrowing from nuclear physics and adaptation into the literature of literature obsolescence, have up to now been attributed to the librarian Burton and the physicist Kebler and to their 1960 journal article. This article presents evidence to show it is…

  6. ANALYSIS OF WATER AND NAPL SATURATION, DEGRADATION HALF-LIFE, AND LOWER BOUNDARY CONDITIONS ON VOC TRANSPORT MODELING: IMPLICATIONS FOR SOIL VENTING CLOSURE

    EPA Science Inventory

    Simulations using a one-dimensional, analytical, vadose zone, solute transport screening code (VFLUX) are conducted to assess the effect of water saturation, NAPL saturation, degradation half-life, and first-type, time-dependent and second-type, zero-gradient boundary conditions ...

  7. Improved in vivo anti-tumor effects of IgA-Her2 antibodies through half-life extension and serum exposure enhancement by FcRn targeting.

    PubMed

    Meyer, Saskia; Nederend, Maaike; Jansen, J H Marco; Reiding, Karli R; Jacobino, Shamir R; Meeldijk, Jan; Bovenschen, Niels; Wuhrer, Manfred; Valerius, Thomas; Ubink, Ruud; Boross, Peter; Rouwendal, Gerard; Leusen, Jeanette H W

    2016-01-01

    Antibody therapy is a validated treatment approach for several malignancies. All currently clinically applied therapeutic antibodies (Abs) are of the IgG isotype. However, not all patients respond to this therapy and relapses can occur. IgA represents an alternative isotype for antibody therapy that engages FcαRI expressing myeloid effector cells, such as neutrophils and monocytes. IgA Abs have been shown to effectively kill tumor cells both in vitro and in vivo. However, due to the short half-life of IgA Abs in mice, daily injections are required to reach an effect comparable to IgG Abs. The relatively long half-life of IgG Abs and serum albumin arises from their capability of interacting with the neonatal Fc receptor (FcRn). As IgA Abs lack a binding site for FcRn, we generated IgA Abs with the variable regions of the Her2-specific Ab trastuzumab and attached an albumin-binding domain (ABD) to the heavy or light chain (HCABD/LCABD) to extend their serum half-life. These modified Abs were able to bind albumin from different species in vitro. Furthermore, tumor cell lysis of IgA-Her2-LCABD Abs in vitro was similar to unmodified IgA-Her2 Abs. Pharmacokinetic studies in mice revealed that the serum exposure and half-life of the modified IgA-Her2 Abs was extended. In a xenograft mouse model, the modified IgA1 Abs exhibited a slightly, but significantly, improved anti-tumor response compared to the unmodified Ab. In conclusion, empowering IgA Abs with albumin-binding capacity results in in vitro and in vivo functional Abs with an enhanced exposure and prolonged half-life.

  8. Improved in vivo anti-tumor effects of IgA-Her2 antibodies through half-life extension and serum exposure enhancement by FcRn targeting

    PubMed Central

    Meyer, Saskia; Nederend, Maaike; Jansen, J.H. Marco; Reiding, Karli R.; Jacobino, Shamir R.; Meeldijk, Jan; Bovenschen, Niels; Wuhrer, Manfred; Valerius, Thomas; Ubink, Ruud; Boross, Peter; Rouwendal, Gerard; Leusen, Jeanette H.W.

    2016-01-01

    Antibody therapy is a validated treatment approach for several malignancies. All currently clinically applied therapeutic antibodies (Abs) are of the IgG isotype. However, not all patients respond to this therapy and relapses can occur. IgA represents an alternative isotype for antibody therapy that engages FcαRI expressing myeloid effector cells, such as neutrophils and monocytes. IgA Abs have been shown to effectively kill tumor cells both in vitro and in vivo. However, due to the short half-life of IgA Abs in mice, daily injections are required to reach an effect comparable to IgG Abs. The relatively long half-life of IgG Abs and serum albumin arises from their capability of interacting with the neonatal Fc receptor (FcRn). As IgA Abs lack a binding site for FcRn, we generated IgA Abs with the variable regions of the Her2-specific Ab trastuzumab and attached an albumin-binding domain (ABD) to the heavy or light chain (HCABD/LCABD) to extend their serum half-life. These modified Abs were able to bind albumin from different species in vitro. Furthermore, tumor cell lysis of IgA-Her2-LCABD Abs in vitro was similar to unmodified IgA-Her2 Abs. Pharmacokinetic studies in mice revealed that the serum exposure and half-life of the modified IgA-Her2 Abs was extended. In a xenograft mouse model, the modified IgA1 Abs exhibited a slightly, but significantly, improved anti-tumor response compared to the unmodified Ab. In conclusion, empowering IgA Abs with albumin-binding capacity results in in vitro and in vivo functional Abs with an enhanced exposure and prolonged half-life. PMID:26466856

  9. The adenovirus type 5 i-leader open reading frame functions in cis to reduce the half-life of L1 mRNAs.

    PubMed Central

    Soloway, P D; Shenk, T

    1990-01-01

    The 440-nucleotide adenovirus type 5 i-leader sequence, encoding a 13.6-kilodalton protein, is located between the second and third components of the tripartite leader sequence. It appears primarily on the L1 family of mRNAs. To study its function, we constructed two point mutations within the i leader. pm382 lacks the wild-type i-leader splice acceptor and failed to splice the leader onto L1 mRNAs. pm383 lacks the ATG used for translation of the i-leader protein; it synthesized i-leader-containing mRNAs, but failed to produce detectable levels of the polypeptide. Both mutants exhibited modestly reduced yields in some but not all cell lines tested and accumulated slightly elevated levels of L1 mRNA and L1 52- and 55-kilodalton proteins in infected cells. Mutant phenotypes were consistently more pronounced in pm382- than in pm383-infected cells. In wild-type virus-infected cells, L1 mRNAs lacking the i leader displayed a half-life of about 26 h, whereas L1 mRNAs containing the leader were much less stable, with a half-life of less than 4 h. In pm383-infected cells (ATG mutant), L1 mRNAs containing the i leader exhibited a half-life of 26 h. The abnormally long half-life of pm383-encoded L1 mRNAs containing a mutant i leader was not reduced by coinfection with wild-type virus, suggesting that synthesis of the i-leader protein leads to destabilization of the i-leader-containing L1 mRNA undergoing translation. Images PMID:2296076

  10. Absorption and biological half-life in humans of intrinsic and extrinsic sup 54 Mn tracers from foods of plant origin

    SciTech Connect

    Johnson, P.E.; Lykken, G.I.; Korynta, E.D. )

    1991-05-01

    Absorption and biological half-life of {sup 54}Mn were measured in adult men and women fed foods labeled intrinsically or extrinsically with {sup 54}Mn. Each subject consumed a series of three test meals consisting of a food labeled intrinsically, a food labeled extrinsically or MnCl{sub 2} (control) served in random order. The foods tested were lettuce, spinach, wheat and sunflower seeds. Lettuce meals and their controls contained 9.65 mumol Mn; other meals contained 22.50 mumol Mn. In addition to the test food or MnCl{sub 2}, each meal consisted of vegetable oil (5 g), salt (NaCl, 0.15 g) and crackers (10 g), which provided 0.55 mumol Mn. There were no differences in percentage of Mn absorption or biological half-life of {sup 54}Mn for any of the intrinsically/extrinsically labeled food pairs. Absorption of {sup 54}Mn from MnCl{sub 2} (8.90%) was greater than from lettuce (5.20%), spinach (3.81%), wheat (2.16%) or sunflower seeds (1.71%), but the biological half-life did not vary with the source of Mn. Absorption of {sup 54}Mn from lettuce was significantly (P less than 0.05) greater than from wheat or sunflower seeds. Although the Mn dose in the test meal was less for lettuce than for the other foods, there was no difference in Mn absorption from MnCl{sub 2} between the subjects fed lettuce and subjects fed other foods. There was no correlation of either {sup 54}Mn absorption or biological half-life with whole blood or plasma Mn.

  11. Pile-up corrections for high-precision superallowed β decay half-life measurements via γ-ray photopeak counting

    NASA Astrophysics Data System (ADS)

    Grinyer, G. F.; Svensson, C. E.; Andreoiu, C.; Andreyev, A. N.; Austin, R. A. E.; Ball, G. C.; Bandyopadhyay, D.; Chakrawarthy, R. S.; Finlay, P.; Garrett, P. E.; Hackman, G.; Hyland, B.; Kulp, W. D.; Leach, K. G.; Leslie, J. R.; Morton, A. C.; Pearson, C. J.; Phillips, A. A.; Sarazin, F.; Schumaker, M. A.; Smith, M. B.; Valiente-Dobón, J. J.; Waddington, J. C.; Williams, S. J.; Wong, J.; Wood, J. L.; Zganjar, E. F.

    2007-09-01

    A general technique that corrects γ-ray gated β decay-curve data for detector pulse pile-up is presented. The method includes corrections for non-zero time-resolution and energy-threshold effects in addition to a special treatment of saturating events due to cosmic rays. This technique is verified through a Monte Carlo simulation and experimental data using radioactive beams of Na26 implanted at the center of the 8π γ-ray spectrometer at the ISAC facility at TRIUMF in Vancouver, Canada. The β-decay half-life of Na26 obtained from counting 1809-keV γ-ray photopeaks emitted by the daughter Mg26 was determined to be T=1.07167±0.00055 s following a 27σ correction for detector pulse pile-up. This result is in excellent agreement with the result of a previous measurement that employed direct β counting and demonstrates the feasibility of high-precision β-decay half-life measurements through the use of high-purity germanium γ-ray detectors. The technique presented here, while motivated by superallowed-Fermi β decay studies, is general and can be used for all half-life determinations (e.g. α-, β-, X-ray, fission) in which a γ-ray photopeak is used to select the decays of a particular isotope.

  12. Measurement of the double-{beta} decay half-life of {sup 150}Nd and search for neutrinoless decay modes with the NEMO-3 detector

    SciTech Connect

    Argyriades, J.; Augier, C.; Bongrand, M.; Jullian, S.; Lalanne, D.; Sarazin, X.; Simard, L.; Szklarz, G.; Barabash, A. S.; Konovalov, S. I.; Umatov, V.; Vanyushin, I.; Basharina-Freshville, A.; Daraktchieva, Z.; Flack, R.; Kauer, M.; King, S.

    2009-09-15

    The half-life for double-{beta} decay of {sup 150}Nd has been measured by the NEMO-3 experiment at the Modane Underground Laboratory. Using 924.7 days of data recorded with 36.55 g of {sup 150}Nd, we measured the half-life for 2{nu}{beta}{beta} decay to be T{sub 1/2}{sup 2{nu}}=(9.11{sub -0.22}{sup +0.25}(stat.){+-}0.63(syst.))x10{sup 18} yr. The observed limit on the half-life for neutrinoless double-{beta} decay is found to be T{sub 1/2}{sup 0{nu}}>1.8x10{sup 22} yr at 90% confidence level. This translates into a limit on the effective Majorana neutrino mass of <4.0-6.3 eV if the nuclear deformation is taken into account. We also set limits on models involving Majoron emission, right-handed currents, and transitions to excited states.

  13. Sources of the systematic errors in measurements of 214Po decay half-life time variations at the Baksan deep underground experiments

    NASA Astrophysics Data System (ADS)

    Alexeyev, E. N.; Gavrilyuk, Yu. M.; Gangapshev, A. M.; Kazalov, V. V.; Kuzminov, V. V.; Panasenko, S. I.; Ratkevich, S. S.

    2015-03-01

    The design changes of the Baksan low-background TAU-1 and TAU-2 set-ups allowed to improve a sensitivity of 214Po half-life (τ) measurements up to the 2.5 × 10-4 are described. Different possible sources of systematic errors influencing on the τ-value are studied. An annual variation of 214Po half-life time measurements with an amplitude of A = (6.9 ± 3) × 10-4 and a phase of φ = 93 ± 10 days was found in a sequence of the week-collected τ-values obtained from the TAU-2 data sample with total duration of 480 days. 24 hours' variation of the t-value measurements with an amplitude of A = (10.0 ± 2.6) × 10-4 and phase of φ = 1 ± 0.5 hours was found in a solar day 1 hour step t-value sequence formed from the same data sample. It was found that the 214Po half-life averaged at 480 days is equal to 163.45 ± 0.04 μs.

  14. Consideration on the Long Ecological Half-Life Component of (137)Cs in Demersal Fish Based on Field Observation Results Obtained after the Fukushima Accident.

    PubMed

    Tagami, Keiko; Uchida, Shigeo

    2016-02-16

    Radiocesium concentrations in most marine fish collected off the coast of Fukushima and surrounding prefectures have decreased with time, and four years after the Fukushima Daiichi Nuclear Power Plant accident occurred, radiocesium concentrations have generally fallen below the detectable level (ca. < 10 Bq kg(-1)-raw). Only in some demersal fish species have detectable concentration levels still been found, and even these species have showed slow radiocesium decreases. The food web was considered as the major factor causing this phenomenon; however, slow elimination rates of radiocesium from these fish species also could be the cause. The latter effect was examined by considering that the (137)Cs concentration decreasing trend in fish could be fit with a set of three exponentially decreasing components; that is, having short, intermediate, and long biological half-lives. The long ecological half-life component was calculated using a 400-1500 d period of monitoring results for Japanese rockfish (Sebastes cheni) and compared with previous reported laboratory results for biological half-life. The obtained ecological half-lives ranged from 274-365 d, and these values agreed with the biological half-life of this fish species. This result implied that the long biological half-lives of radiocesium in some demersal fish species made their radiocesium contamination periods longer.

  15. Consideration on the Long Ecological Half-Life Component of (137)Cs in Demersal Fish Based on Field Observation Results Obtained after the Fukushima Accident.

    PubMed

    Tagami, Keiko; Uchida, Shigeo

    2016-02-16

    Radiocesium concentrations in most marine fish collected off the coast of Fukushima and surrounding prefectures have decreased with time, and four years after the Fukushima Daiichi Nuclear Power Plant accident occurred, radiocesium concentrations have generally fallen below the detectable level (ca. < 10 Bq kg(-1)-raw). Only in some demersal fish species have detectable concentration levels still been found, and even these species have showed slow radiocesium decreases. The food web was considered as the major factor causing this phenomenon; however, slow elimination rates of radiocesium from these fish species also could be the cause. The latter effect was examined by considering that the (137)Cs concentration decreasing trend in fish could be fit with a set of three exponentially decreasing components; that is, having short, intermediate, and long biological half-lives. The long ecological half-life component was calculated using a 400-1500 d period of monitoring results for Japanese rockfish (Sebastes cheni) and compared with previous reported laboratory results for biological half-life. The obtained ecological half-lives ranged from 274-365 d, and these values agreed with the biological half-life of this fish species. This result implied that the long biological half-lives of radiocesium in some demersal fish species made their radiocesium contamination periods longer. PMID:26828695

  16. Ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2 inhibition.

    PubMed

    Kovarik, John M; Dole, Kiran; Riviere, Gilles-Jacques; Pommier, Francoise; Maton, Steve; Jin, Yi; Lasseter, Kenneth C; Schmouder, Robert L

    2009-02-01

    The sphingosine-1-phosphate receptor modulator fingolimod is predominantly hydroxylated by cytochrome CYP4F2. In vitro experiments showed that ketoconazole significantly inhibited the oxidative metabolism of fingolimod by human liver microsomes and by recombinant CYP4F2. The authors used ketoconazole as a putative CYP4F2 inhibitor to quantify its influence on fingolimod pharmacokinetics in healthy subjects. In a 2-period, single-sequence, crossover study, 22 healthy subjects received a single 5-mg dose of fingolimod in period 1. In period 2, subjects received ketoconazole 200 mg twice daily for 9 days and a single 5-mg dose of fingolimod coadministered on the 4th day of ketoconazole treatment. Ketoconazole did not affect fingolimod t(max) or half-life, but there was a weak average increase in C(max) of 1.22-fold (90% confidence interval, 1.15-1.30). The AUC over the 5 days of ketoconazole coadministration increased 1.40-fold (1.31-1.50), and the full AUC to infinity increased 1.71-fold (1.53-1.91). The AUC of the active metabolite fingolimod-phosphate was increased to a similar extent by 1.67-fold (1.50-1.85). Ketoconazole predose plasma levels were not altered by fingolimod. The magnitude of this interaction suggests that a proactive dose reduction of fingolimod is not necessary when adding ketoconazole to a fingolimod regimen. The clinician, however, should be aware of this interaction and bear in mind the possibility of a fingolimod dose reduction based on clinical monitoring. PMID:19118083

  17. Pharmacokinetics of repeated sodium salicylate administration to laying hens: evidence for time dependent increase in drug elimination from plasma and eggs.

    PubMed

    Poźniak, Błażej; Grabowski, Tomasz; Motykiewicz-Pers, Karolina; Bobrek, Kamila; Rak, Lech; Bobusia, Katarzyna; Gaweł, Andrzej; Świtała, Marcin

    2015-01-01

    Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs) to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus) salicylate (SA) may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS) to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1st, 7th and 14th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT), minimal plasma concentration (Cmin, C16h) and elimination half-life (T1/2el) of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (ClB) increased. Layers administered with the higher dose showed a decrease only in the T1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment. PMID:25893240

  18. Pharmacokinetic and Pharmacodynamic Characterisation of an Anti-Mouse TNF Receptor 1 Domain Antibody Formatted for In Vivo Half-Life Extension.

    PubMed

    Goodall, Laura J; Ovecka, Milan; Rycroft, Daniel; Friel, Sarah L; Sanderson, Andrew; Mistry, Prafull; Davies, Marie L; Stoop, A Allart

    2015-01-01

    Tumour Necrosis Factor-α (TNF-α) inhibition has been transformational in the treatment of patients with inflammatory disease, e.g. rheumatoid arthritis. Intriguingly, TNF-α signals through two receptors, TNFR1 and TNFR2, which have been associated with detrimental inflammatory and beneficial immune-regulatory processes, respectively. To investigate if selective TNFR1 inhibition might provide benefits over pan TNF-α inhibition, tools to investigate the potential impact of pharmacological intervention are needed. Receptor-deficient mice have been very insightful, but are not reversible and could distort receptor cross-talk, while inhibitory anti-TNFR1 monoclonal antibodies have a propensity to induce receptor agonism. Therefore, we set out to characterise a monovalent anti-TNFR1 domain antibody (dAb) formatted for in vivo use. The mouse TNFR1 antagonist (DMS5540) is a genetic fusion product of an anti-TNFR1 dAb with an albumin-binding dAb (AlbudAb). It bound mouse TNFR1, but not human TNFR1, and was an antagonist of TNF-α-mediated cytotoxicity in a L929 cell assay. Surprisingly, the dAb did not compete with TNF-α for TNFR1-binding. This was supported by additional data showing the anti-TNFR1 epitope mapped to a single residue in the first domain of TNFR1. Pharmacokinetic studies of DMS5540 in mice over three doses (0.1, 1.0 and 10 mg/kg) confirmed extended in vivo half-life, mediated by the AlbudAb, and demonstrated non-linear clearance of DMS5540. Target engagement was further confirmed by dose-dependent increases in total soluble TNFR1 levels. Functional in vivo activity was demonstrated in a mouse challenge study, where DMS5540 provided dose-dependent inhibition of serum IL-6 increases in response to bolus mouse TNF-α injections. Hence, DMS5540 is a potent mouse TNFR1 antagonist with in vivo pharmacokinetic and pharmacodynamic properties compatible with use in pre-clinical disease models and could provide a useful tool to dissect the individual

  19. Biological half-life of radioactive cesium in Japanese rockfish Sebastes cheni contaminated by the Fukushima Daiichi nuclear power plant accident.

    PubMed

    Matsumoto, Akira; Shigeoka, Yu; Arakawa, Hisayuki; Hirakawa, Naoto; Morioka, Yoshiaki; Mizuno, Takuji

    2015-12-01

    Since the Fukushima accident in March 2011 the concentration of radioactive cesium in Japanese rockfish (Sebastes cheni) has been decreasing slower than other fish species. The aim of this study was therefore to investigate the possibility of slow elimination rate (i.e., relatively longer Tb) as one of the reasons for the slow decrease in (137)Cs concentrations in Japanese rockfish (S. cheni). To do this, we reared twenty-three individuals of this species for a period of about 1 year, during which time we measured the (137)Cs concentrations and γ-ray spectra 14 times by using a high-efficiency NaI(Tl) scintillator. We then examined the relationship between the (137)Cs concentrations and the total length of each individual. We estimated the biological half-life (Tb, day) for each individual using the total number of (137)Cs counts in the energy region, and examined the effects of total length and (137)Cs concentration on Tb by generalized linear model (GLM). We also examined the effect of sex, total length, seawater temperature, and the (137)Cs concentration of seawater on temporal changes in the (137)Cs count reduction rate by GLM. There was no clear relationship between the corrected whole-body (137)Cs concentrations and the total length in females, however there was a significant positive correlation between these two variables in males. The difference between males and females may be attributable to variation in the degree of dilution because of variable growth of individuals, and suggests that the (137)Cs concentrations of small individuals may be greatly diluted because of faster growth. However, there was no significant difference in Tb between sexes. The mean Tb (±SD) in all individuals was 269 (±39) days; this Tb value is 2.7-5.4 times longer than past Tb values (marine fish: 50-100 days), and is thought to be one of the reasons for the slower decrease in (137)Cs concentrations in this species than other fish species on the coast of Fukushima. The GLM

  20. Potential strategies for increasing drug-discovery productivity.

    PubMed

    Cumming, John G; Finlay, M Raymond V; Giordanetto, Fabrizio; Hemmerling, Martin; Lister, Troy; Sanganee, Hitesh; Waring, Michael J

    2014-04-01

    The productivity challenge facing the pharmaceutical industry is well documented. Strategies to improve productivity have mainly focused on enhancing efficiency, such as the application of Lean Six Sigma process improvement methods and the introduction of modeling and simulation in place of 'wet' experiments. While these strategies have their benefits, the real challenge is to improve effectiveness by reducing clinical failure rates. We advocate redesigning the screening cascade to identify and optimize novel compounds with improved efficacy against disease, not just with improved potency against the target. There should be greater use of disease-relevant phenotypic screens in conjunction with target-based assays to drive medicinal chemistry optimization. An opportunistic approach to polypharmacology is recommended. There should also be more emphasis on optimization of the molecular mechanism of action incorporating understanding of binding kinetics, consideration of covalent drug strategies and targeting allosteric modulators.

  1. Increased introduction, advertising, and sales of preventive drugs during 1986-2002 in Sweden.

    PubMed

    Nilsson, J Lars G; Melander, Arne

    2006-01-01

    The objective of this study was to survey how introduction of new drugs and promotional activities influence drug sales in Sweden. All drugs on the Swedish market were categorized as curative, symptom-alleviating, substitutive, or preventive. The number of new drugs introduced, drug sales in volume and value, and the number of drug advertisements appearing in the major Swedish medical journal during 1986-2002 were determined for each of the 4 drug categories. Between 1986 and 1998, the relative shares of the 4 drug categories were relatively constant. From 1998 to 2002, the share of new preventive drugs increased from 24% to 30%, their share of advertisements increased from 20% to 35%, and their sales value increased from 25% to 30%. During the same period, the shares of other drugs decreased correspondingly. Pharmaceutical companies have shifted their attention to the introduction, advertising, and sales of preventive drugs in an attempt to exploit preventive medicine. This might lead to waste of resources when expensive preventive drugs are used by numerous patients over many years, as the benefit of preventive drugs for the individual patient cannot be judged easily. PMID:16788360

  2. Drug-likeness and increased hydrophobicity of commercially available compound libraries for drug screening.

    PubMed

    Zuegg, Johannes; Cooper, Matthew A

    2012-01-01

    Most drug discovery programs today originate by selection of 'hit' molecules resulting from assays against large compound screening libraries. The chemical space in which these hits reside has implications for its biological activity in vivo and likelihood of progression to a drug candidate. We have created a database of commercially available screening compounds and natural products in order to analyse the drug- and lead-likeness of commercial screening compounds and compare them with i) orally administered drugs, ii) non-orally administered drugs, and iii) compounds with significant biological activity but unspecified or not yet determined route of administration from the public databases DrugBank and ChEMBL. The data set contained 15.5 million entries from 102 vendors, which resulted in just over 8 million unique chemical structures. We review these data for current drug/lead-likeness, then utilise substructure-based filters for promiscuity and unwanted groups, and finally compare chemical properties for structures within the different sub-sets. While the majority of the commercial compounds satisfy various drug-likeness rules, they show a larger molecular weight and higher hydrophobicity compared to orally available drugs, with generally higher aromaticity and lower solubility. This 'right shift' of chemical properties has also been found in the majority of the compounds with significant biological activity in ChEMBL, reflecting a common trend in current drug discovery, towards larger, more hydrophobic compounds and fewer drug-like compounds. In particular, successful drugs were found to possess much lower median logD values than those found for compound collections. In addition, commercial compounds show a quite narrow distribution in molecular weight, with a median absolute deviation of only 78 Da around a median of 387 Da. For high-throughput screening a highly stringent combination of several lead-likeness and substructure filters against unwanted groups

  3. Drug-likeness and increased hydrophobicity of commercially available compound libraries for drug screening.

    PubMed

    Zuegg, Johannes; Cooper, Matthew A

    2012-01-01

    Most drug discovery programs today originate by selection of 'hit' molecules resulting from assays against large compound screening libraries. The chemical space in which these hits reside has implications for its biological activity in vivo and likelihood of progression to a drug candidate. We have created a database of commercially available screening compounds and natural products in order to analyse the drug- and lead-likeness of commercial screening compounds and compare them with i) orally administered drugs, ii) non-orally administered drugs, and iii) compounds with significant biological activity but unspecified or not yet determined route of administration from the public databases DrugBank and ChEMBL. The data set contained 15.5 million entries from 102 vendors, which resulted in just over 8 million unique chemical structures. We review these data for current drug/lead-likeness, then utilise substructure-based filters for promiscuity and unwanted groups, and finally compare chemical properties for structures within the different sub-sets. While the majority of the commercial compounds satisfy various drug-likeness rules, they show a larger molecular weight and higher hydrophobicity compared to orally available drugs, with generally higher aromaticity and lower solubility. This 'right shift' of chemical properties has also been found in the majority of the compounds with significant biological activity in ChEMBL, reflecting a common trend in current drug discovery, towards larger, more hydrophobic compounds and fewer drug-like compounds. In particular, successful drugs were found to possess much lower median logD values than those found for compound collections. In addition, commercial compounds show a quite narrow distribution in molecular weight, with a median absolute deviation of only 78 Da around a median of 387 Da. For high-throughput screening a highly stringent combination of several lead-likeness and substructure filters against unwanted groups

  4. {alpha}-decay half-life of {sup 253}Es in metallic Fe at temperatures between 4 K and 50 mK

    SciTech Connect

    Severijns, N.; Golovko, V. V.; Kraev, I. S.; Phalet, T.; Wauters, F.; Belyaev, A. A.; Lukhanin, A. A.; Noga, V. I.; Erzinkyan, A. L.; Parfenova, V. P.; Eversheim, P.-D.; Herzog, P.; Tramm, C.; Filimonov, V. T.; Toporov, Yu. G.; Zotov, E.; Gurevich, G. M.; Rusakov, A. V.; Vyachin, V. N.; Zakoucky, D.

    2007-08-15

    It has been claimed recently that half-lives of radioactive nuclei embedded in metals would be significantly affected by electron screening provided by the metal. The effect would further be strengthened at low temperatures. We have determined the half-life-of {sup 253}Es nuclei embedded in iron at temperatures between 4 K and 50 mK. Our results agree with the room temperature literature value within about 2% and show no dependence on temperature over a range of almost two orders of magnitude.

  5. Measurements of the half-life of 246Cm and the alpha-decay emission probabilities of 246Cm and 250Cf.

    PubMed

    Kondev, F G; Ahmad, I; Greene, J P; Kellett, M A; Nichols, A L

    2007-03-01

    The alpha-decay half-life of Cm246 has been measured to be T(1/2)=4706 (40)yr by means of the alpha-counting of ingrowth activity following the decay of a mass separated source of the Cf250 parent nuclide. The alpha-decay emission probabilities of Cm246 and Cf250 have also been determined with high precision and have been compared with results from previous measurements. A new alpha-decay branch of Cm246 to the 4(+) level of the ground-state band of the Pu242 daughter nucleus has been identified and characterized.

  6. [Increased consumption of drugs among the elderly results in greater risk of problems].

    PubMed

    Fastbom, J

    2001-04-01

    With aging comes an increasing prevalence of diseases and symptoms that frequently require pharmaceutical treatment. However, aging also brings about bodily changes that result in increased effects and prolonged action of many drugs. Multiple drug use--often termed polypharmacy--seen in many elderly individuals, is the most important risk factor for adverse drug reactions (ADR) and increases the risk of drug interactions and poor compliance. ADR's are responsible for about 10% of all hospital admissions of elderly patients. The drugs most commonly involved are cardiovascular, psychotropics and anti-inflammatory agents. Many of these ADR's are dose-dependent and preventable. Drug use has increased over the last few years, largely thanks to the availability of new and effective agents. This calls for increased vigilance and prudence in prescribing for the elderly. PMID:11379169

  7. Isolation of invasive Plasmodium yoelii merozoites with a long half-life to evaluate invasion dynamics and potential invasion inhibitors.

    PubMed

    Mutungi, Joe Kimanthi; Yahata, Kazuhide; Sakaguchi, Miako; Kaneko, Osamu

    2015-11-01

    Malaria symptoms and pathogenesis are caused by blood stage parasite burdens of Plasmodium spp., for which invasion of red blood cells (RBCs) by merozoites is essential. Successful targeting by either drugs or vaccines directed against the whole merozoite or its antigens during its transient extracellular status would contribute to malaria control by impeding RBC invasion. To understand merozoite invasion biology and mechanisms, it is desired to obtain merozoites that retain their invasion activity in vitro. Accordingly, methods have been developed to isolate invasive Plasmodium knowlesi and Plasmodium falciparum merozoites. Rodent malaria parasite models offer ease in laboratory maintenance and experimental genetic modifications; however, no methods have been reported regarding isolation of high numbers of invasive rodent malaria merozoites. In this study, Plasmodium yoelii-infected RBCs were obtained from infected mice, and mature schizont-infected RBCs enriched via Histodenz™ density gradients. Merozoites retaining invasion activity were then isolated by passing the preparations through a filter membrane. RBC-invaded parasites developed to mature stages in vitro in a synchronous manner. Isolated merozoites were evaluated for retention of invasion activity following storage at different temperatures prior to incubation with uninfected mouse RBCs. Isolated merozoites retained their invasion activity 4h after isolation at 10 or 15 °C, whereas their invasion activity reduced to 0-10% within 30 min when incubated on ice or at 37 °C prior to RBC invasion assay. Images of merozoites at successive steps during RBC invasion were captured by light and transmission electron microscopy. Synthetic peptides derived from the amino acid sequence of the P. yoelii invasion protein RON2 efficiently inhibited RBC invasion. The developed method to isolate and keep invasive P. yoelii merozoites for up to 4h is a powerful tool to study the RBC invasion biology of this parasite

  8. Fine mapping and conditional analysis identify a new mutation in the autoimmunity susceptibility gene BLK that leads to reduced half-life of the BLK protein

    PubMed Central

    Delgado-Vega, Angélica M; Dozmorov, Mikhail G; Quirós, Manuel Bernal; Wu, Ying-Yu; Martínez-García, Belén; Kozyrev, Sergey V; Frostegård, Johan; Truedsson, Lennart; de Ramón, Enrique; González-Escribano, María F; Ortego-Centeno, Norberto; Pons-Estel, Bernardo A; D'Alfonso, Sandra; Sebastiani, Gian Domenico; Witte, Torsten; Lauwerys, Bernard R; Endreffy, Emoke; Kovács, László; Vasconcelos, Carlos; da Silva, Berta Martins; Wren, Jonathan D; Martin, Javier; Castillejo-López, Casimiro; Alarcón-Riquelme, Marta E

    2012-01-01

    Objectives To perform fine mapping of the autoimmunity susceptibility gene BLK and identify functional variants involved in systemic lupus erythematosus (SLE). Methods Genotyping of 1163 European SLE patients and 1482 controls and imputation were performed covering the BLK gene with 158 single-nucleotide polymorphisms. Logistic regression analysis was done using PLINK and conditional analyses using GENABEL's test score. Transfections of BLK constructs on HEK293 cells containing the novel mutation or the wild type form were analysed for their effect on protein half-life using a protein stability assay, cycloheximide and western blot. CHiP-qPCR for detection of nuclear factor κ B (NFkB) binding. Results Fine mapping of BLK identified two independent genetic effects with functional consequences: one represented by two tightly linked associated haplotype blocks significantly enriched for NFκB-binding sites and numerous putative regulatory variants whose risk alleles correlated with low BLK mRNA levels. Binding of NFkBp50 and p65 to an associated 1.2 Kb haplotype segment was confirmed. A second independent genetic effect was represented by an Ala71Thr, low-frequency missense substitution with an OR=2.31 (95% CI 1.38 to 3.86). The 71Thr decreased BLK protein half-life. Conclusions These results show that rare and common regulatory variants in BLK are involved in disease susceptibility and both, albeit independently, lead to reduced levels of BLK protein. PMID:22696686

  9. Measurement of the double-beta decay half-life and search for the neutrinoless double-beta decay of 48Ca with the NEMO-3 detector

    NASA Astrophysics Data System (ADS)

    Arnold, R.; Augier, C.; Bakalyarov, A. M.; Baker, J. D.; Barabash, A. S.; Basharina-Freshville, A.; Blondel, S.; Blot, S.; Bongrand, M.; Brudanin, V.; Busto, J.; Caffrey, A. J.; Calvez, S.; Cascella, M.; Cerna, C.; Cesar, J. P.; Chapon, A.; Chauveau, E.; Chopra, A.; Duchesneau, D.; Durand, D.; Egorov, V.; Eurin, G.; Evans, J. J.; Fajt, L.; Filosofov, D.; Flack, R.; Garrido, X.; Gómez, H.; Guillon, B.; Guzowski, P.; Hodák, R.; Huber, A.; Hubert, P.; Hugon, C.; Jullian, S.; Klimenko, A.; Kochetov, O.; Konovalov, S. I.; Kovalenko, V.; Lalanne, D.; Lang, K.; Lebedev, V. I.; Lemière, Y.; Le Noblet, T.; Liptak, Z.; Liu, X. R.; Loaiza, P.; Lutter, G.; Mamedov, F.; Marquet, C.; Mauger, F.; Morgan, B.; Mott, J.; Nemchenok, I.; Nomachi, M.; Nova, F.; Nowacki, F.; Ohsumi, H.; Pahlka, R. B.; Perrot, F.; Piquemal, F.; Povinec, P.; Přidal, P.; Ramachers, Y. A.; Remoto, A.; Reyss, J. L.; Richards, B.; Riddle, C. L.; Rukhadze, E.; Rukhadze, N. I.; Saakyan, R.; Salazar, R.; Sarazin, X.; Shitov, Yu.; Simard, L.; Šimkovic, F.; Smetana, A.; Smolek, K.; Smolnikov, A.; Söldner-Rembold, S.; Soulé, B.; Štekl, I.; Suhonen, J.; Sutton, C. S.; Szklarz, G.; Thomas, J.; Timkin, V.; Torre, S.; Tretyak, Vl. I.; Tretyak, V. I.; Umatov, V. I.; Vanushin, I.; Vilela, C.; Vorobel, V.; Waters, D.; Zhukov, S. V.; Žukauskas, A.; NEMO-3 Collaboration

    2016-06-01

    The NEMO-3 experiment at the Modane Underground Laboratory investigates the double-beta decay of 48Ca. Using 5.25 yr of data recorded with a 6.99 g sample of 48Ca, approximately 150 double-beta decay candidate events are selected with a signal-to-background ratio greater than 3. The half-life for the two-neutrino double-beta decay of 48Ca is measured to be T1/2 2 ν=[6. 4-0.6+0.7(stat)-0.9 +1.2(syst ) ]×1 019 yr . A search for neutrinoless double-beta decay of 48Ca yields a null result, and a corresponding lower limit on the half-life is found to be T1/2 0 ν>2.0 ×1 022 yr at 90% confidence level, translating into an upper limit on the effective Majorana neutrino mass of ⟨mβ β⟩<6.0 - 26 eV , with the range reflecting different nuclear matrix element calculations. Limits are also set on models involving Majoron emission and right-handed currents.

  10. Strategies to Increase Drug Penetration in Solid Tumors

    PubMed Central

    Choi, Il-Kyu; Strauss, Robert; Richter, Maximilian; Yun, Chae-Ok; Lieber, André

    2013-01-01

    Despite significant improvement in modalities for treatment of cancer that led to a longer survival period, the death rate of patients with solid tumors has not changed during the last decades. Emerging studies have identified several physical barriers that limit the therapeutic efficacy of cancer therapeutic agents such as monoclonal antibodies, chemotherapeutic agents, anti-tumor immune cells, and gene therapeutics. Most solid tumors are of epithelial origin and, although malignant cells are de-differentiated, they maintain intercellular junctions, a key feature of epithelial cells, both in the primary tumor as well as in metastatic lesions. Furthermore, nests of malignant epithelial tumor cells are shielded by layers of extracellular matrix (ECM) proteins (e.g., collagen, elastin, fibronectin, laminin) whereby tumor vasculature rarely penetrates into the tumor nests. In this chapter, we will review potential strategies to modulate the ECM and epithelial junctions to enhance the intratumoral diffusion and/or to remove physical masking of target receptors on malignant cells. We will focus on peptides that bind to the junction protein desmoglein 2 and trigger intracellular signaling, resulting in the transient opening of intercellular junctions. Intravenous injection of these junction openers increased the efficacy and safety of therapies with monoclonal antibodies, chemotherapeutics, and T cells in mouse tumor models and was safe in non-human primates. Furthermore, we will summarize approaches to transiently degrade ECM proteins or downregulate their expression. Among these approaches is the intratumoral expression of relaxin or decorin after adenovirus- or stem cell-mediated gene transfer. We will provide examples that relaxin-based approaches increase the anti-tumor efficacy of oncolytic viruses, monoclonal antibodies, and T cells. PMID:23898462

  11. Drug-induced long QT syndrome increases the risk of drowning.

    PubMed

    Vincenzi, Frank F

    2016-02-01

    There is strong evidence linking inherited long QT syndromes with an increased risk of drowning due to fatal arrhythmias in the water. Drug-induced long QT syndrome (DILQTS) is hypothesized to increase the risk of drowning by similar mechanisms. It is suggested that QT prolongation caused by a drug or drugs, when combined with the autonomic conflict associated with the mammalian dive reflex and/or the cold shock reflex, sets up conditions that may result in a sudden fatal arrhythmia while in water - thus an increased risk of drowning related to a drug-induced prolongation of the QT interval. Many widely used drugs prolong the QT interval thus raising a drug safety issue that needs confirmation or refutation.

  12. Targeting the ion channel Kv1.3 with scorpion venom peptides engineered for potency, selectivity, and half-life.

    PubMed

    Edwards, Wilson; Fung-Leung, Wai-Ping; Huang, Chichi; Chi, Ellen; Wu, Nancy; Liu, Yi; Maher, Michael P; Bonesteel, Rachelle; Connor, Judith; Fellows, Ross; Garcia, Elena; Lee, Jerry; Lu, Lu; Ngo, Karen; Scott, Brian; Zhou, Hong; Swanson, Ronald V; Wickenden, Alan D

    2014-08-15

    Ion channels are an attractive class of drug targets, but progress in developing inhibitors for therapeutic use has been limited largely due to challenges in identifying subtype selective small molecules. Animal venoms provide an alternative source of ion channel modulators, and the venoms of several species, such as scorpions, spiders and snails, are known to be rich sources of ion channel modulating peptides. Importantly, these peptides often bind to hyper-variable extracellular loops, creating the potential for subtype selectivity rarely achieved with small molecules. We have engineered scorpion venom peptides and incorporated them in fusion proteins to generate highly potent and selective Kv1.3 inhibitors with long in vivo half-lives. Kv1.3 has been reported to play a role in human T cell activation, and therefore, these Kv1.3 inhibitor fusion proteins may have potential for the treatment of autoimmune diseases. Our results support an emerging approach to generating subtype selective therapeutic ion channel inhibitors.

  13. Biological half-life of radioactive cesium in Japanese rockfish Sebastes cheni contaminated by the Fukushima Daiichi nuclear power plant accident.

    PubMed

    Matsumoto, Akira; Shigeoka, Yu; Arakawa, Hisayuki; Hirakawa, Naoto; Morioka, Yoshiaki; Mizuno, Takuji

    2015-12-01

    Since the Fukushima accident in March 2011 the concentration of radioactive cesium in Japanese rockfish (Sebastes cheni) has been decreasing slower than other fish species. The aim of this study was therefore to investigate the possibility of slow elimination rate (i.e., relatively longer Tb) as one of the reasons for the slow decrease in (137)Cs concentrations in Japanese rockfish (S. cheni). To do this, we reared twenty-three individuals of this species for a period of about 1 year, during which time we measured the (137)Cs concentrations and γ-ray spectra 14 times by using a high-efficiency NaI(Tl) scintillator. We then examined the relationship between the (137)Cs concentrations and the total length of each individual. We estimated the biological half-life (Tb, day) for each individual using the total number of (137)Cs counts in the energy region, and examined the effects of total length and (137)Cs concentration on Tb by generalized linear model (GLM). We also examined the effect of sex, total length, seawater temperature, and the (137)Cs concentration of seawater on temporal changes in the (137)Cs count reduction rate by GLM. There was no clear relationship between the corrected whole-body (137)Cs concentrations and the total length in females, however there was a significant positive correlation between these two variables in males. The difference between males and females may be attributable to variation in the degree of dilution because of variable growth of individuals, and suggests that the (137)Cs concentrations of small individuals may be greatly diluted because of faster growth. However, there was no significant difference in Tb between sexes. The mean Tb (±SD) in all individuals was 269 (±39) days; this Tb value is 2.7-5.4 times longer than past Tb values (marine fish: 50-100 days), and is thought to be one of the reasons for the slower decrease in (137)Cs concentrations in this species than other fish species on the coast of Fukushima. The GLM

  14. Factors Contributing to Increases in Prescription Drug Expenditures Borne by National Health Insurance in South Korea

    PubMed Central

    Jo, Jeong-Sook; Kim, Young-Man; Paek, Kyung Won; Bea, Min Hee

    2016-01-01

    Purpose Rapid growth of prescription drug expenditures is a problem in South Korea. The objective of this study was to assess the contributions of four variables (therapeutic choice, drug-mix, original use, and price changes) to increases in drug expenditures paid by the National Health Insurance (NHI) in Korea. Materials and Methods A retrospective cohort study was conducted between January 1, 2008 and June 30, 2012 utilizing data from the NHI Claims Database of the Health Insurance Review and Assessment Service. The number of target drug types for final analysis was 13959. To analyze the growth rates of drug expenditures, this study used Fisher ideal index and the Laspeyres and Paasche indexes. Results With the exception of 2012, therapeutic choice contributed to about 40–60% of the increase in drug expenditures every year, while drug-mix contributed to another 30–40%. Conclusion The rapid growth in prescription drug expenditure was found to be largely due to drug-mix and therapeutic choice over time. Original use had little impact on drug spending. PMID:27189299

  15. Modulation of Mannose and Asialoglycoprotein Receptor Expression Determines Glycoprotein Hormone Half-life at Critical Points in the Reproductive Cycle*

    PubMed Central

    Mi, Yiling; Lin, Angela; Fiete, Dorothy; Steirer, Lindsay; Baenziger, Jacques U.

    2014-01-01

    The rate at which glycoproteins are cleared from the circulation has a critical impact on their biologic activity in vivo. We have shown that clearance rates for glycoproteins such as luteinizing hormone (LH) that undergo regulated release into the circulation determine their potency. Two highly abundant, carbohydrate-specific, endocytic receptors, the asialoglycoprotein receptor (ASGR) and the mannose receptor (ManR) are expressed in the liver by parenchymal and sinusoidal endothelial cells, respectively. We demonstrate that the ManR mediates the clearance of glycoproteins such as LH that bear N-linked glycans terminating with β1,4-linked GalNAc-4-SO4, as well as glycoproteins bearing glycans that terminate with Man. Steady state levels of mRNA encoding the ASGR and the ManR are regulated by progesterone in pregnant mice, reaching maximal levels on day 12.5 of pregnancy. Protein expression and glycan-specific binding activity also increase in the livers of pregnant mice. In contrast, ManR mRNA, but not ASGR mRNA, decreases in male mice at the time of sexual maturation. We show that levels of ManR and ASGR expression control the clearance rate for glycoproteins bearing recognized glycans. Thus, reduced expression of the ManR at the time of sexual maturation will increase the potency of LH in vivo, whereas increased expression during pregnancy will reduce LH potency until progesterone and receptor levels fall prior to parturition. PMID:24619407

  16. Modulation of mannose and asialoglycoprotein receptor expression determines glycoprotein hormone half-life at critical points in the reproductive cycle.

    PubMed

    Mi, Yiling; Lin, Angela; Fiete, Dorothy; Steirer, Lindsay; Baenziger, Jacques U

    2014-04-25

    The rate at which glycoproteins are cleared from the circulation has a critical impact on their biologic activity in vivo. We have shown that clearance rates for glycoproteins such as luteinizing hormone (LH) that undergo regulated release into the circulation determine their potency. Two highly abundant, carbohydrate-specific, endocytic receptors, the asialoglycoprotein receptor (ASGR) and the mannose receptor (ManR) are expressed in the liver by parenchymal and sinusoidal endothelial cells, respectively. We demonstrate that the ManR mediates the clearance of glycoproteins such as LH that bear N-linked glycans terminating with β1,4-linked GalNAc-4-SO4, as well as glycoproteins bearing glycans that terminate with Man. Steady state levels of mRNA encoding the ASGR and the ManR are regulated by progesterone in pregnant mice, reaching maximal levels on day 12.5 of pregnancy. Protein expression and glycan-specific binding activity also increase in the livers of pregnant mice. In contrast, ManR mRNA, but not ASGR mRNA, decreases in male mice at the time of sexual maturation. We show that levels of ManR and ASGR expression control the clearance rate for glycoproteins bearing recognized glycans. Thus, reduced expression of the ManR at the time of sexual maturation will increase the potency of LH in vivo, whereas increased expression during pregnancy will reduce LH potency until progesterone and receptor levels fall prior to parturition.

  17. Recombinant full-length factor VIII (FVIII) and extended half-life FVIII products in prophylaxis--new insight provided by pharmacokinetic modelling.

    PubMed

    Gringeri, A; Wolfsegger, M; Steinitz, K N; Reininger, A J

    2015-05-01

    The pharmacokinetics (PK) of extended half-life factor VIII (FVIII) products might allow longer dosing intervals in prophylaxis, potentially affecting its efficacy. We used published population PK models of a recombinant full-length FVIII (rAHF-PFM) and a recombinant B-domain-deleted FVIII Fc fusion product (rFVIIIFc) to assess the time spent weekly with FVIII levels below 3 IU dL(-1) or above 10 IU dL(-1) . These FVIII levels were chosen based on the observation that trough levels of 1 IU dL(-1) may not be sufficient in all patients. This approach was applied to a simulated population of 1000 severe haemophilia A subjects with dosing regimens included in the prescribing information or evaluated in clinical trials. FVIII levels remained ≥3 IU dL(-1) in 57% of patients treated with rAHF-PFM 30 IU kg(-1) every 48 h compared with 41.1%, 18.3%, 0.9% and 0% of patients treated with rFVIIIFc 30 IU kg(-1) every 72 h, 50 IU kg(-1) every 96 h or 120 h and 65 IU kg(-1) every 168 h respectively. Patients on rAHF-PFM 30 IU kg(-1) every 48 h spent more time weekly with FVIII levels above 10 IU dL(-1) than those on rFVIIIFc 50 IU kg(-1) every 96 h or 120 h, and 65 IU kg(-1) every 168 h. In conclusion, PK modelling indicates that choice and dosing intervals of standard and extended half-life FVIII products require careful evaluation of individual PK to allow more time at protective levels, especially in patients with active lifestyles.

  18. New Anticancer Drugs Associated With Large Increases In Costs And Life Expectancy.

    PubMed

    Howard, David H; Chernew, Michael E; Abdelgawad, Tamer; Smith, Gregory L; Sollano, Josephine; Grabowski, David C

    2016-09-01

    Spending on anticancer drugs has risen rapidly over the past two decades. A key policy question is whether new anticancer drugs offer value, given their high cost. Using data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we assessed the value of new cancer treatments in routine clinical practice for patients with metastatic breast, lung, or kidney cancer or chronic myeloid leukemia in the periods 1996-2000 and 2007-11. We found that there were large increases in medical costs, but also large gains in life expectancy. For example, among patients with breast cancer who received physician-administered drugs, lifetime costs-including costs for outpatient and inpatient care-increased by $72,000 and life expectancy increased by thirteen months. Changes in life expectancy and costs were much smaller among patients who did not receive these drugs. PMID:27605636

  19. Evaluation of CTX-M steady-state mRNA, mRNA half-life and protein production in various STs of Escherichia coli

    PubMed Central

    Geyer, Chelsie N.; Fowler, Randal C.; Johnson, James R.; Johnston, Brian; Weissman, Scott J.; Hawkey, Peter; Hanson, Nancy D.

    2016-01-01

    Objectives High levels of β-lactamase production can impact treatment with a β-lactam/β-lactamase inhibitor combination. Goals of this study were to: (i) compare the mRNA and protein levels of CTX-M-15- and CTX-M-14-producing Escherichia coli from 18 different STs and 10 different phylotypes; (ii) evaluate the mRNA half-lives and establish a role for chromosomal- and/or plasmid-encoded factors; and (iii) evaluate the zones of inhibition for piperacillin/tazobactam and ceftolozane/tazobactam. Methods Disc diffusion was used to establish zone size. RNA analysis was accomplished using real-time RT–PCR and CTX-M protein levels were evaluated by immunoblotting. Clinical isolates, transformants and transconjugants were used to evaluate mRNA half-lives. Results mRNA levels of CTX-M-15 were up to 165-fold higher compared with CTX-M-14. CTX-M-15 protein levels were 2–48-fold less than their respective transcript levels, while CTX-M-14 protein production was comparable to the observed transcript levels. Nineteen of 25 E. coli (76%) had extended CTX-M-15 mRNA half-lives of 5–15 min and 16 (100%) CTX-M-14 isolates had mRNA half-lives of <2–3 min. Transformants had mRNA half-lives of <2 min for both CTX-M-type transcripts, while transconjugant mRNA half-lives corresponded to the half-life of the donor. Ceftolozane/tazobactam zone sizes were ≥19 mm, while piperacillin/tazobactam zone sizes were ≥17 mm. Conclusions CTX-M-15 mRNA and protein production did not correlate. Neither E. coli ST nor phylotype influenced the variability observed for CTX-M-15 mRNA or protein produced. mRNA half-life is controlled by a plasmid-encoded factor and may influence mRNA transcript levels, but not protein levels. PMID:26612874

  20. Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal: evidence that CYP2E1 possesses a rapid phase half-life of 6 hours or less.

    PubMed

    Roberts, B J; Shoaf, S E; Jeong, K S; Song, B J

    1994-12-15

    Controversy exists as to whether the induction of CYP2E1 by ethanol occurs via increased protein synthesis or protein stabilization. To address these issues in vivo, we chronically administered ethanol to rats and determined levels of immunoreactive CYP2E1 in liver, kidney, brain and upper gastro-intestinal tract (GI). Our data shows that chronic ethanol administration induces hepatic (5-6-fold over pair-fed controls) and extra-hepatic CYP2E1, an effect which is strikingly absent 12 hours after ethanol withdrawal. No changes in CYP2E1 mRNA were observed at any time, suggesting these changes are mainly post-translational at a blood ethanol concentration of 0.15% w/v. Our experimental data indicates that CYP2E1 possesses a half-life of 6 hours or less in the liver and is rapidly degraded following the removal of ethanol. This pattern of CYP2E1 turnover was also observed in other tissues, suggestive of a similar mode of regulation.

  1. BikDDA, a mutant of Bik with longer half-life expression protein, can be a novel therapeutic gene for triple-negative breast cancer.

    PubMed

    Jiao, Shiping; Wu, Minqing; Ye, Feng; Tang, Hailin; Xie, Xinhua; Xie, Xiaoming

    2014-01-01

    Our previous studies showed that BikDD, a constitutively active mutant form of Bik, exhibited powerful antitumor effects in preclinical pancreatic, lung and breast cancer models. Howerver, the antitumor activity of BikDD in triple-negative breast cancer (TNBC) is unknown. Here we show that aberrant expression of p-ERK1/2 was a meaningful molecular phenotype in TNBC patients, and can be an obstacle for treatment because of the converse correlation with Bik. A novel mutant, BikDDA, in which Ser124 was changed to Alanine to block BikDD phosphorylation by p-ERK1/2 prevented subsequent ubiquitin-proteasome degradation. BikDDA showed a prolonged half-life and enhanced pro-apoptotic ability in TNBC cells compared with BikDD. Moreover, aberrant expression of p-ERK1/2 was associated with 5-fluorouracil resistance in breast cancer patients and BikDDA enhanced the therapeutic effects of 5-fluorouracil in vitro.

  2. BikDDA, a Mutant of Bik with Longer Half-Life Expression Protein, Can Be a Novel Therapeutic Gene for Triple-Negative Breast Cancer

    PubMed Central

    Jiao, Shiping; Wu, Minqing; Ye, Feng; Tang, Hailin; Xie, Xinhua; Xie, Xiaoming

    2014-01-01

    Our previous studies showed that BikDD, a constitutively active mutant form of Bik, exhibited powerful antitumor effects in preclinical pancreatic, lung and breast cancer models. Howerver, the antitumor activity of BikDD in triple-negative breast cancer (TNBC) is unknown. Here we show that aberrant expression of p-ERK1/2 was a meaningful molecular phenotype in TNBC patients, and can be an obstacle for treatment because of the converse correlation with Bik. A novel mutant, BikDDA, in which Ser124 was changed to Alanine to block BikDD phosphorylation by p-ERK1/2 prevented subsequent ubiquitin-proteasome degradation. BikDDA showed a prolonged half-life and enhanced pro-apoptotic ability in TNBC cells compared with BikDD. Moreover, aberrant expression of p-ERK1/2 was associated with 5-fluorouracil resistance in breast cancer patients and BikDDA enhanced the therapeutic effects of 5-fluorouracil in vitro. PMID:24637719

  3. Ligand-substitution mode capillary electrophoretic reactor: extending capillary electrophoretic reactor toward measurement of slow dissociation kinetics with a half-life of hours.

    PubMed

    Iki, Nobuhiko; Takahashi, Mariko; Takahashi, Toru; Hoshino, Hitoshi

    2009-09-15

    A method employing capillary electrophoresis (CE) was developed to determine the rate constant of the very slow spontaneous dissociation of a complex species. The method uses a CE reactor (CER) to electrophoretically separate components from a complex zone and, thus, spontaneously dissociate a complex. The dissociation is accelerated by ligand substitution (LS) involving a competing ligand added to the electrophoretic buffer. The LS-CER method is validated using the dissociation of a Ti(IV)-catechin complex and EDTA as a competing ligand. There is good agreement between the spontaneous dissociation rate constant (k(d) = (1.64 +/- 0.63) x 10(-4) s(-1)) and the rate constant obtained by a conventional batchwise LS reaction (k(d) = (1.43 +/- 0.04) x 10(-4) s(-1)). Furthermore, the usefulness of the method is demonstrated using a Ti(IV)-tiron complex, for which k(d) = (0.51 +/- 0.43) x 10(-4) s(-1), corresponding to a half-life (t(1/2)) of 3.8 h. Notably, a single run of LS-CER for the Ti(IV) complex is completed within 40 min, implying that LS-CER requires a considerably shorter measurement time (roughly equal to t(1/2)) than conventional CER. LS-CER can be widely applied to determine the spontaneous dissociation rates of inorganic diagnostic and therapeutic reagents as well as of biomolecular complexes.

  4. Cardiotoxic drugs Herceptin and doxorubicin inhibit cardiac microvascular endothelial cell barrier formation resulting in increased drug permeability

    PubMed Central

    Wilkinson, Emma L.; Sidaway, James E.

    2016-01-01

    ABSTRACT Cardiotoxicity induced by anti-cancer therapeutics is a severe, and potentially fatal, adverse reaction of the heart in response to certain drugs. Current in vitro approaches to assess cardiotoxicity have focused on analysing cardiomyocytes. More recently it has become apparent that non-cardiomyocyte cells of the heart can potentially contribute to cardiotoxicity. Herceptin and doxorubicin are known to induce cardiotoxicity in the clinic. The effect of these drugs on the endothelial tight junction barrier was tested by analysing tight junction formation and zona occludens-1 (ZO-1) levels, revealing that Herceptin and doxorubicin are able to induce barrier perturbment and decrease barrier function in human cardiac microvascular endothelial cells (HCMECs) leading to increased permeability. Herceptin treatment had no effect on the tight junction barrier function in human dermal and human brain microvascular endothelial cells. HCMECs showed detectable levels of HER2 compared with the other endothelial cells suggesting that Herceptin binding to HER2 in these cells may interfere with tight junction formation. Our data suggests that doxorubicin and Herceptin can affect tight junction formation in the cardiac microvasculature leading to increased drug permeability and adverse effects on the cardiac myocytes. PMID:27543060

  5. How Sorbitan Monostearate Can Increase Drug-Loading Capacity of Lipid-Core Polymeric Nanocapsules.

    PubMed

    Poletto, Fernanda S; De Oliveira, Catiúscia P; Wender, Heberton; Regent, Dorothée; Donida, Bruna; Teixeira, Sérgio R; Guterres, Sílvia S; Rossi-Bergmann, Bartira; Pohlmann, Adriana R

    2015-01-01

    Lipid-core polymeric nanocapsules are innovative devices that present distinguished characteristics due to the presence of sorbitan monostearate into the oily-core. This component acted as low-molecular-mass organic gelator for the oil (medium chain triglycerides). The organogel-structured core influenced the polymeric wall characteristics disfavoring the formation of more stable polymer crystallites. This probably occurred due to interpenetration of these pseudo-phases. Sorbitan monostearate dispersed in the oily-core was also able to interact by non-covalent bonding with the drugs increasing the drug loading capacity more than 40 times compared to conventional nanocapsules. We demonstrated that the drug-models quercetin and quercetin pentaacetate stabilized the organogel network probably due to interactions of the drug molecules with the sorbitan monostearate headgroups by hydrogen bonding. PMID:26328447

  6. Incentive learning for morphine-associated stimuli during protracted abstinence increases conditioned drug preference.

    PubMed

    Smith, Rachel J; Aston-Jones, Gary

    2014-01-01

    Previous studies from our laboratory found that rats express increased preference for drug-paired stimuli following 2 or 5 weeks of protracted abstinence from chronic drug exposure as compared with naive animals. Here, we show that this increased morphine place preference depends upon experiencing drug-stimulus pairings specifically in the abstinent state, indicating a critical role for incentive learning. Male Sprague Dawley rats were initially conditioned for morphine place preference (8 mg/kg) and then made dependent on morphine (by subcutaneous morphine pellets) and subjected to forced abstinence. Place preference was tested every 1-2 weeks with no additional drug-cue conditioning. In this paradigm, there was no difference between morphine-pelleted (dependent) and placebo-pelleted (non-dependent) rats in place preference at any time during abstinence (up to 6 weeks). However, these same morphine-pelleted rats expressed significantly increased preference when they were subsequently re-conditioned for morphine place preference during protracted abstinence. Placebo-pelleted rats did not show enhanced preference after re-conditioning. These findings reveal that incentive learning has a key role in increased morphine place preference when drug is experienced during protracted abstinence. This indicates that incentive learning is involved not only in instrumental responding (as previously reported), but also in updating Pavlovian-conditioned responses to morphine-associated stimuli. Therefore, enhanced morphine preference is not a direct consequence of the negative affective state of abstinence, but instead reflects increased acquisition of morphine-stimulus associations during abstinence. These results indicate that, during the development of addiction in humans, drug-associated stimuli acquire increasingly stronger incentive properties each time they are re-experienced.

  7. Modeling the Potential Impact of a Prescription Drug Copayment Increase on the Adult Asthmatic Medicaid Population

    PubMed Central

    Bae, Seung Jin; Paltiel, A. David; Fuhlbrigge, Anne L.; Weiss, Scott T.; Kuntz, Karen M.

    2012-01-01

    Objectives The Commonwealth of Massachusetts increased the copayment for prescription drugs by $1.50 for Medicaid (MassHealth) beneficiaries in 2003. We sought to determine the likely health outcomes and cost shifts attributable to this copayment increase using the example of inhaled corticosteroids (ICS) use among adult asthmatic Medicaid beneficiaries. Method We compared the predicted costs and health outcomes projected over a 1-year time horizon with and without the increase in copayment from the perspective of MassHealth, providers, pharmacies, and MassHealth beneficiaries by employing decision analysis simulation model. Results In a target population of 17,500 adult asthmatics, increased copayments from 50¢ to $2.00 would result in an additional 646 acute events per year, caused by increased drug nonadherence. Annual combined net savings for the state and federal governments would be $2.10 million. Projected MassHealth savings are attributable to both decreased drug utilization and lower pharmacy reimbursement rates; these more than offset the additional costs of more frequent acute exacerbations. Pharmacies would lose $1.98 million in net revenues, MassHealth beneficiaries would pay an additional $0.28 million, and providers would receive additional $0.16 million. Conclusion Over its first year of implementation, increase in the prescription drug copayment is expected to produce more frequent acute exacerbations among asthmatic MassHealth beneficiaries who use ICS and to shift the financial burden from government to other stakeholders. PMID:18237365

  8. Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users.

    PubMed

    Nestor, Liam; Hester, Robert; Garavan, Hugh

    2010-01-01

    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-naive 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.

  9. 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

  10. Alcohol Arrests on Campuses Jumped 10% in 1996; Drug Arrests Increased by 5%.

    ERIC Educational Resources Information Center

    Lively, Kit

    1998-01-01

    Campus police and other college officials believe the 16,237 alcohol arrests and 7,060 drug arrests on college campuses in 1996 reflect tougher enforcement, not increased usage among students. This is particularly true in states such as Michigan, where state law concerning underage drinking has changed, and in communities where enforcement is…

  11. SETDB1 mediated FosB expression increases the cell proliferation rate during anticancer drug therapy

    PubMed Central

    Na, Han-Heom; Noh, Hee-Jung; Cheong, Hyang-Min; Kang, Yoonsung; Kim, Keun-Cheol

    2016-01-01

    The efficacy of anticancer drugs depends on a variety of signaling pathways, which can be positively or negatively regulated. In this study, we show that SETDB1 HMTase is down-regulated at the transcriptional level by several anticancer drugs, due to its inherent instability. Using RNA sequence analysis, we identified FosB as being regulated by SETDB1 during anticancer drug therapy. FosB expression was increased by treatment with doxorubicin, taxol and siSETDB1. Moreover, FosB was associated with an increased rate of proliferation. Combinatory transfection of siFosB and siSETDB1 was slightly increased compared to transfection of siFosB. Furthermore, FosB was regulated by multiple kinase pathways. ChIP analysis showed that SETDB1 and H3K9me3 interact with a specific region of the FosB promoter. These results suggest that SETDB1-mediated FosB expression is a common molecular phenomenon, and might be a novel pathway responsible for the increase in cell proliferation that frequently occurs during anticancer drug therapy. [BMB Reports 2016; 49(4): 238-243] PMID:26949019

  12. The detectability half-life in arthropod predator-prey research: what it is, why we need it, how to measure it, and how to use it.

    PubMed

    Greenstone, Matthew H; Payton, Mark E; Weber, Donald C; Simmons, Alvin M

    2014-08-01

    Molecular gut-content analysis enables detection of arthropod predation with minimal disruption of ecosystem processes. Most assays produce only qualitative results, with each predator testing either positive or negative for target prey remains. Nevertheless, they have yielded important insights into community processes. For example, they have confirmed the long-hypothesized role of generalist predators in retarding early-season build-up of pest populations prior to the arrival of more specialized predators and parasitoids and documented the ubiquity of secondary and intraguild predation. However, raw qualitative gut-content data cannot be used to assess the relative impact of different predator taxa on prey population dynamics: they must first be weighted by the relative detectability periods for molecular prey remains for each predator-prey combination. If this is not carried out, interpretations of predator impact will be biased towards those with the longest detectabilities. We review the challenges in determining detectability half-lives, including unstated assumptions that have often been ignored in the performance of feeding trials. We also show how detectability half-lives can be used to properly weight assay data to rank predators by their importance in prey population suppression, and how sets of half-lives can be used to test hypotheses concerning predator ecology and physiology. We use data from 32 publications, comprising 97 half-lives, to generate and test hypotheses on taxonomic differences in detectability half-lives and discuss the possible role of the detectability half-life in interpreting qPCR and next-generation sequencing data.

  13. Leaching and half-life of the herbicide tebuthiuron on a recharge area of Guarany aquifer in sugarcane fields in Brazil.

    PubMed

    Cerdeira, Antonio L; Desouza, Manoel D; Queiroz, Sonia C N; Ferracini, Vera L; Bolonhezi, Denizart; Gomes, Marco A F; Rosa, Maria A; Balderrama, Otavio; Rampazzo, Paulo; Queiroz, Regina H C; Neto, Carlos F; Matallo, Marcus B

    2007-08-01

    This study was undertaken to evaluate the degradation and mobility of the herbicide tebuthiuron (N-[5-(1,1-dimethylethyl)-1,3,4-thiadiazol-2-yl]-N,N'-dimethylurea) in soil under field conditions, and its potential for leaching and groundwater contamination. A watershed, Espraiado, located over a recharge area in Brazil, was chosen for soil and water studies. At Espraiado, water samples were collected from seven wells at intervals of three months from March 2004 to June 2006 and analyzed for tebuthiuron. Other samples were taken from city wells located outside of the recharge area. To assess the potential movement to the aquifer, tebuthiuron was also applied to trial plots at the recommended label rate of 1.0 kg/ha a.i. in May of 2004, with and without sugarcane coverage, on sandy soil. Soil samples were collected during the years of 2004 and 2005, at depths intervals of 20 cm from soil surface down to 120 cm and analyzed for tebuthiuron at zero, 3, 30, 60, 90, 120, 150, 180, 240, and 300 days after application. There was no clear effect of sugarcane coverage on the tebuthiuron degradation in soils, but it moved faster into the soil where there was no cover. After 180 days there were no measurable residues in the soil, and tebuthiuron was not found below 40 cm depth in any time. Tebuthiuron had a half-life of 20 days under those conditions. No tebuthiuron residue was found in ground water samples at any sampling time.

  14. First measurements on how pressure affects the half-life of 22Na: Comparison to theory and analog to 40K

    NASA Astrophysics Data System (ADS)

    Lee, K. K.; Nelson, R. O.; Rundberg, R.; Steinle-Neumann, G.

    2007-12-01

    Radioactive decay plays a central role in planetary sciences as appropriate decay schemes are used to date geological and astronomical processes and radioactivity provides an important source of heat in planetary bodies, both in their early history during accretion and differentiation and also over geological times. The most important isotopes that currently heat the Earth are 40K, 232Th, 235U and 238U. As radioactive decay is a nuclear process it is considered to be insensitive to external factors such as pressure or chemical environment. This has been shown to be true for α, β+ and β- processes, however, electron capture decay is dependent on the electron charge density at the nucleus of a compound, which is sensitive to the external environment. Using high-resolution Ge gamma-ray detectors to make relative measurements with 137Cs and the positron decay of 22Na, we measure how pressure affects the half-life of 22Na due to electron-capture decay. Our systematics look favorable for observing this small effect. We will compare our preliminary measurements with complementary ab-initio all-electron computations using the linearized augmented plane wave method (LAPW). Using 22Na as an analog for 40K, our results suggest that the pressure effect for 40K, combined with the opposing effects of high temperatures, will have little, discernible effect on the heat production in the deep Earth as our predicted changes are smaller than the uncertainties in the total decay constant for 40K. This work was supported in part by the Carnegie/DOE Alliance Center (CDAC), through the Stewardship Science Academic Alliances Program of the U.S. Department of Energy. The LANSCE facility is operated, and portions of this work were performed, by Los Alamos National Security, LLC, funded by the U.S. Department of Energy under Contract No. DE-AC52- 06NA25396.

  15. Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant.

    PubMed

    Bernstein, P L; Herrick, D J; Prokipcak, R D; Ross, J

    1992-04-01

    Polysome-associated c-myc mRNA is degraded relatively rapidly in cells and in an in vitro mRNA decay system containing extracts from cultured mammalian cells. Using this system, a competition/screening assay was devised to search for factors that bind to specific regions of polysome-associated c-myc mRNA and thereby alter its half-life. mRNA stability was first assayed in reactions containing exogenous competitor RNAs corresponding to portions of c-myc mRNA itself. The addition of a 182-nucleotide sense strand fragment from the carboxy-terminal portion of the c-myc-coding region destabilized c-myc mRNA by at least eightfold. This RNA fragment had no effect on the stability of other mRNAs tested. Moreover, c-myc mRNA was not destabilized in reactions containing unrelated competitor RNAs or sense strand RNA from the c-myc 5' region. Polysome-associated globin mRNA containing the c-myc-coding region segment in-frame was also destabilized in vitro by the 182-nucleotide RNA. As determined by UV-cross-linking experiments, the 182-nucleotide RNA fragment was recognized by and bound to an approximately 75-kD polysome-associated protein. On the basis of these data plus Northern blotting analyses of c-myc mRNA decay products, we suggest that the approximately 75-kD protein is normally bound to a c-myc-coding region determinant and protects that region of the mRNA from endonuclease attack. Possible links between the protective protein, translation, ribosome pausing, and c-myc mRNA turnover are discussed.

  16. Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter.

    PubMed

    Seebacher, Nicole A; Lane, Darius J R; Jansson, Patric J; Richardson, Des R

    2016-02-19

    Pgp is functional on the plasma membrane and lysosomal membrane. Lysosomal-Pgp can pump substrates into the organelle, thereby trapping certain chemotherapeutics (e.g. doxorubicin; DOX). This mechanism serves as a "safe house" to protect cells against cytotoxic drugs. Interestingly, in contrast to DOX, lysosomal sequestration of the novel anti-tumor agent and P-glycoprotein (Pgp) substrate, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induces lysosomal membrane permeabilization. This mechanism of lysosomal-Pgp utilization enhances cytotoxicity to multidrug-resistant cells. Consequently, Dp44mT has greater anti-tumor activity in drug-resistant relative to non-Pgp-expressing tumors. Interestingly, stressors in the tumor microenvironment trigger endocytosis for cell signaling to assist cell survival. Hence, this investigation examined how glucose variation-induced stress regulated early endosome and lysosome formation via endocytosis of the plasma membrane. Furthermore, the impact of glucose variation-induced stress on resistance to DOX was compared with Dp44mT and its structurally related analogue, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). These studies showed that glucose variation-induced stress-stimulated formation of early endosomes and lysosomes. In fact, through the process of fluid-phase endocytosis, Pgp was redistributed from the plasma membrane to the lysosomal membrane via early endosome formation. This lysosomal-Pgp actively transported the Pgp substrate, DOX, into the lysosome where it became trapped as a result of protonation at pH 5. Due to increased lysosomal DOX trapping, Pgp-expressing cells became more resistant to DOX. In contrast, cytotoxicity of Dp44mT and DpC was potentiated due to more lysosomes containing functional Pgp under glucose-induced stress. These thiosemicarbazones increased lysosomal membrane permeabilization and cell death. This mechanism has critical implications for drug-targeting in

  17. Glucose Modulation Induces Lysosome Formation and Increases Lysosomotropic Drug Sequestration via the P-Glycoprotein Drug Transporter.

    PubMed

    Seebacher, Nicole A; Lane, Darius J R; Jansson, Patric J; Richardson, Des R

    2016-02-19

    Pgp is functional on the plasma membrane and lysosomal membrane. Lysosomal-Pgp can pump substrates into the organelle, thereby trapping certain chemotherapeutics (e.g. doxorubicin; DOX). This mechanism serves as a "safe house" to protect cells against cytotoxic drugs. Interestingly, in contrast to DOX, lysosomal sequestration of the novel anti-tumor agent and P-glycoprotein (Pgp) substrate, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), induces lysosomal membrane permeabilization. This mechanism of lysosomal-Pgp utilization enhances cytotoxicity to multidrug-resistant cells. Consequently, Dp44mT has greater anti-tumor activity in drug-resistant relative to non-Pgp-expressing tumors. Interestingly, stressors in the tumor microenvironment trigger endocytosis for cell signaling to assist cell survival. Hence, this investigation examined how glucose variation-induced stress regulated early endosome and lysosome formation via endocytosis of the plasma membrane. Furthermore, the impact of glucose variation-induced stress on resistance to DOX was compared with Dp44mT and its structurally related analogue, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). These studies showed that glucose variation-induced stress-stimulated formation of early endosomes and lysosomes. In fact, through the process of fluid-phase endocytosis, Pgp was redistributed from the plasma membrane to the lysosomal membrane via early endosome formation. This lysosomal-Pgp actively transported the Pgp substrate, DOX, into the lysosome where it became trapped as a result of protonation at pH 5. Due to increased lysosomal DOX trapping, Pgp-expressing cells became more resistant to DOX. In contrast, cytotoxicity of Dp44mT and DpC was potentiated due to more lysosomes containing functional Pgp under glucose-induced stress. These thiosemicarbazones increased lysosomal membrane permeabilization and cell death. This mechanism has critical implications for drug-targeting in

  18. Increases in Drug and Opioid Overdose Deaths--United States, 2000-2014.

    PubMed

    Rudd, Rose A; Aleshire, Noah; Zibbell, Jon E; Gladden, R Matthew

    2016-01-01

    The United States is experiencing an epidemic of drug overdose (poisoning) deaths. Since 2000, the rate of deaths from drug overdoses has increased 137%, including a 200% increase in the rate of overdose deaths involving opioids (opioid pain relievers and heroin). CDC analyzed recent multiple cause-of-death mortality data to examine current trends and characteristics of drug overdose deaths, including the types of opioids associated with drug overdose deaths. During 2014, a total of 47,055 drug overdose deaths occurred in the United States, representing a 1-year increase of 6.5%, from 13.8 per 100,000 persons in 2013 to 14.7 per 100,000 persons in 2014. The rate of drug overdose deaths increased significantly for both sexes, persons aged 25-44 years and ≥55 years, non-Hispanic whites and non-Hispanic blacks, and in the Northeastern, Midwestern, and Southern regions of the United States. Rates of opioid overdose deaths also increased significantly, from 7.9 per 100,000 in 2013 to 9.0 per 100,000 in 2014, a 14% increase. Historically, CDC has programmatically characterized all opioid pain reliever deaths (natural and semisynthetic opioids, methadone, and other synthetic opioids) as "prescription" opioid overdoses (1). Between 2013 and 2014, the age-adjusted rate of death involving methadone remained unchanged; however, the age-adjusted rate of death involving natural and semisynthetic opioid pain relievers, heroin, and synthetic opioids, other than methadone (e.g., fentanyl) increased 9%, 26%, and 80%, respectively. The sharp increase in deaths involving synthetic opioids, other than methadone, in 2014 coincided with law enforcement reports of increased availability of illicitly manufactured fentanyl, a synthetic opioid; however, illicitly manufactured fentanyl cannot be distinguished from prescription fentanyl in death certificate data. These findings indicate that the opioid overdose epidemic is worsening. There is a need for continued action to prevent opioid

  19. Concomitant intake of alcohol may increase the absorption of poorly soluble drugs.

    PubMed

    Fagerberg, Jonas H; Sjögren, Erik; Bergström, Christel A S

    2015-01-25

    Ethanol can increase the solubility of poorly soluble and hence present a higher drug concentration in the gastrointestinal tract. This may produce a faster and more effective absorption resulting in variable and/or high drug plasma concentrations, both of which can lead to adverse drug reactions. In this work we therefore studied the solubility and absorption effects of nine diverse compounds when ethanol was present. The apparent solubility was measured using the μDiss Profiler Plus (pION, MA) in four media representing gastric conditions with and without ethanol. The solubility results were combined with in-house data on solubility in intestinal fluids (with and without ethanol) and pharmacokinetic parameters extracted from the literature and used as input in compartmental absorption simulations using the software GI-Sim. Apparent solubility increased more than 7-fold for non-ionized compounds in simulated gastric fluid containing 20% ethanol. Compounds with weak base functions (cinnarizine, dipyridamole and terfenadine) were completely ionized at the studied gastric pH and their solubility was therefore unaffected by ethanol. Compounds with low solubility in intestinal media and a pronounced solubility increase due to ethanol in the upper gastric compartments showed an increased absorption in the simulations. The rate of absorption of the acidic compounds indomethacin and indoprofen was slightly increased but the extent of absorption was unaffected as the complete doses were readily absorbed even without ethanol. This was likely due to a high apparent solubility in the intestinal compartment where the weak acids are ionized. The absorption of the studied non-ionizable compounds increased when ethanol was present in the gastric and intestinal media. These results indicate that concomitant intake of alcohol may significantly increase the solubility and hence, the plasma concentration for non-ionizable, lipophilic compounds with the potential of adverse drug

  20. Lung Surfactant Microbubbles Increase Lipophilic Drug Payload for Ultrasound-Targeted Delivery

    PubMed Central

    Sirsi, Shashank R.; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y.; Mountford, Paul A.; Borden, Mark A.

    2013-01-01

    The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta®, Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload. PMID:23781287

  1. Generic Drugs - Decreasing Costs and Room for Increased Number of Kidney Transplantations.

    PubMed

    Spasovski, Goce

    2015-01-01

    Kidney transplantation is the best treatment option in comparison to dialysis, although patients are obliged to receive life-long medical treatment with immunosuppressive drugs (ISDs) for prevention of the graft rejection. Such immunosuppressive treatment may be costly and associated with multiple adverse effects. Since costs are viewed as one of the major constraints for the increasing number of transplantation, the use of generic ISDs may decrease the overall cost of transplantation and raise the possibility for its further development. An ideal ISD should have the security margin between toxic and therapeutic dose, and prevent development of acute or chronic rejection of the transplanted kidney. This is particularly important for drugs with a "narrow therapeutical index" (NTI), where small differences in dose or concentration lead to dose and concentration-dependent, serious therapeutic failures and/or adverse drug reactions. The NTI generic drug is approved if within 90%-112% of the area under the curve of the original product the pharmacokinetics fulfills the strict criteria of pharmaceutical equivalence and bioequivalence. Every generic has to be proven to be bioequivalent to the innovator product, and not to other generic products because of the possible generic "drift". Thus, the generic ISDs may be economically attractive, but theoretically, they may pose a risk to transplant patients. Such risks may be reduced if a long-term clinical studies showing cost-effectiveness of generic ISDs in de novo and prevalent transplant patients for every new generic ISD are performed. In conclusion, the increased number of solid organ transplantation goes in line with the increased health care expenditure for ISDs. The generic immunosuppressants could be a possible solution if safely substituted for innovator products or other generic drug of choice. The substantial cost reduction needs to be redirected into organ donation initiatives so that more patients can benefit

  2. Generic Drugs - Decreasing Costs and Room for Increased Number of Kidney Transplantations.

    PubMed

    Spasovski, Goce

    2015-01-01

    Kidney transplantation is the best treatment option in comparison to dialysis, although patients are obliged to receive life-long medical treatment with immunosuppressive drugs (ISDs) for prevention of the graft rejection. Such immunosuppressive treatment may be costly and associated with multiple adverse effects. Since costs are viewed as one of the major constraints for the increasing number of transplantation, the use of generic ISDs may decrease the overall cost of transplantation and raise the possibility for its further development. An ideal ISD should have the security margin between toxic and therapeutic dose, and prevent development of acute or chronic rejection of the transplanted kidney. This is particularly important for drugs with a "narrow therapeutical index" (NTI), where small differences in dose or concentration lead to dose and concentration-dependent, serious therapeutic failures and/or adverse drug reactions. The NTI generic drug is approved if within 90%-112% of the area under the curve of the original product the pharmacokinetics fulfills the strict criteria of pharmaceutical equivalence and bioequivalence. Every generic has to be proven to be bioequivalent to the innovator product, and not to other generic products because of the possible generic "drift". Thus, the generic ISDs may be economically attractive, but theoretically, they may pose a risk to transplant patients. Such risks may be reduced if a long-term clinical studies showing cost-effectiveness of generic ISDs in de novo and prevalent transplant patients for every new generic ISD are performed. In conclusion, the increased number of solid organ transplantation goes in line with the increased health care expenditure for ISDs. The generic immunosuppressants could be a possible solution if safely substituted for innovator products or other generic drug of choice. The substantial cost reduction needs to be redirected into organ donation initiatives so that more patients can benefit

  3. Increased Expression of Several Collagen Genes is Associated with Drug Resistance in Ovarian Cancer Cell Lines.

    PubMed

    Januchowski, Radosław; Świerczewska, Monika; Sterzyńska, Karolina; Wojtowicz, Karolina; Nowicki, Michał; Zabel, Maciej

    2016-01-01

    Ovarian cancer is the most lethal gynaecological cancer. The main reason for the high mortality among ovarian cancer patients is the development of drug resistance. The expression of collagen genes by cancer cells can increase drug resistance by inhibiting the penetration of the drug into the cancer tissue as well as increase apoptosis resistance. In this study, we present data that shows differential expression levels of collagen genes and proteins in cisplatin- (CIS), paclitaxel- (PAC), doxorubicin- (DOX), topotecan- (TOP), vincristine- (VIN) and methotrexate- (MTX) resistant ovarian cancer cell lines. Quantitative real-time polymerase chain reactions were performed to determine the mRNA levels. Protein expression was detected using Western blot and immunocytochemistry assays. In the drug resistant cell lines, we observed the upregulation of eight collagen genes at the mRNA level and based on these expression levels, we divided the collagen genes into the following three groups: 1. Genes with less than a 50-fold increase in expression: COL1A1, COL5A2, COL12A1 and COL17A1. 2. Genes with greater than a 50-fold increase in expression: COL1A2, COL15A1 and COL21A1. 3. Gene with a very high level of expression: COL3A1. Expression of collagen (COL) proteins from groups 2 and 3 were also confirmed using immunocytochemistry. Western blot analysis showed very high expression levels of COL3A1 protein, and immunocytochemistry analysis showed the presence of extracellular COL3A1 in the W1TR cell line. The cells mainly responsible for the extracellular COL3A1 production are aldehyde dehydrogenase-1A1 (ALDH1A1) positive cells. All correlations between the types of cytostatic drugs and the expression levels of different COL genes were studied, and our results suggest that the expression of fibrillar collagens may be involved in the TOP and PAC resistance of the ovarian cancer cells. The expression pattern of COL genes provide a preliminary view into the role of these proteins in

  4. Increased Expression of Several Collagen Genes is Associated with Drug Resistance in Ovarian Cancer Cell Lines

    PubMed Central

    Januchowski, Radosław; Świerczewska, Monika; Sterzyńska, Karolina; Wojtowicz, Karolina; Nowicki, Michał; Zabel, Maciej

    2016-01-01

    Ovarian cancer is the most lethal gynaecological cancer. The main reason for the high mortality among ovarian cancer patients is the development of drug resistance. The expression of collagen genes by cancer cells can increase drug resistance by inhibiting the penetration of the drug into the cancer tissue as well as increase apoptosis resistance. In this study, we present data that shows differential expression levels of collagen genes and proteins in cisplatin- (CIS), paclitaxel- (PAC), doxorubicin- (DOX), topotecan- (TOP), vincristine- (VIN) and methotrexate- (MTX) resistant ovarian cancer cell lines. Quantitative real-time polymerase chain reactions were performed to determine the mRNA levels. Protein expression was detected using Western blot and immunocytochemistry assays. In the drug resistant cell lines, we observed the upregulation of eight collagen genes at the mRNA level and based on these expression levels, we divided the collagen genes into the following three groups: 1. Genes with less than a 50-fold increase in expression: COL1A1, COL5A2, COL12A1 and COL17A1. 2. Genes with greater than a 50-fold increase in expression: COL1A2, COL15A1 and COL21A1. 3. Gene with a very high level of expression: COL3A1. Expression of collagen (COL) proteins from groups 2 and 3 were also confirmed using immunocytochemistry. Western blot analysis showed very high expression levels of COL3A1 protein, and immunocytochemistry analysis showed the presence of extracellular COL3A1 in the W1TR cell line. The cells mainly responsible for the extracellular COL3A1 production are aldehyde dehydrogenase-1A1 (ALDH1A1) positive cells. All correlations between the types of cytostatic drugs and the expression levels of different COL genes were studied, and our results suggest that the expression of fibrillar collagens may be involved in the TOP and PAC resistance of the ovarian cancer cells. The expression pattern of COL genes provide a preliminary view into the role of these proteins in

  5. Pulsed Intra-Arterial Drug Injection during Diastolic Phase of Cardiac Function Increases Drug Efficacy by Enhancing Pharmacological Exposure of Targeted Tissues.

    PubMed

    Rismanchi, M

    2016-06-01

    Diastolic phase of cardiac function is associated with lower arterial flow and hence higher concentration of intra arterially injected drug is achieved at the site of injection. It is herein postulated that drugs show higher efficacy when injected during the diastolic phase of cardiac function. It is also postulated that this benefit cannot be achieved when the drug is injected with higher rates thus producing the same high concentration at the site of injection. Pulsed intra arterial injection also benefits from the delayed therapeutic effect of the decaying drug before the next shot of injection resaturates the targeted tissue. Altogether, it is estimated that diastolic time-locked pulsed intra arterial injection will increase the drug efficacy up to 1.9 times the efficacy of injected drug with conventional methods. This is significant for drugs with limited dose of administration due to their disastrous side effects like tissue plasminogen activator or chemotherapeutic drugs. PMID:27672631

  6. Pulsed Intra-Arterial Drug Injection during Diastolic Phase of Cardiac Function Increases Drug Efficacy by Enhancing Pharmacological Exposure of Targeted Tissues

    PubMed Central

    Rismanchi, M.

    2016-01-01

    Diastolic phase of cardiac function is associated with lower arterial flow and hence higher concentration of intra arterially injected drug is achieved at the site of injection. It is herein postulated that drugs show higher efficacy when injected during the diastolic phase of cardiac function. It is also postulated that this benefit cannot be achieved when the drug is injected with higher rates thus producing the same high concentration at the site of injection. Pulsed intra arterial injection also benefits from the delayed therapeutic effect of the decaying drug before the next shot of injection resaturates the targeted tissue. Altogether, it is estimated that diastolic time-locked pulsed intra arterial injection will increase the drug efficacy up to 1.9 times the efficacy of injected drug with conventional methods. This is significant for drugs with limited dose of administration due to their disastrous side effects like tissue plasminogen activator or chemotherapeutic drugs. PMID:27672631

  7. Novelty stress increases fecal pellet output in mongolian gerbils: effects of several drugs.

    PubMed

    Okano, Shiho; Nagaya, Hideaki; Inatomi, Nobuhiro

    2005-08-01

    Stress-induced colonic functional changes have been investigated mainly under conditions involving physical stress, like in the restraint stress model. In this study, we established a new stress-induced defecation model involving the placement of Mongolian gerbils in a novel environment (novelty stress) and determined the effects of several drugs on novelty stress-induced fecal pellet output. When animals kept in groups were placed individually in small cages, the fecal pellet output markedly increased, although the upper intestinal transit measured by charcoal method was not changed. The concentration of plasma adrenocorticotropic hormone was moderately but significantly increased by the novelty stress. Drugs reportedly effective for stress-induced defecation, like alosetron hydrochloride, atropine sulfate, and trimebutine maleate, inhibited both the novelty stress-induced increase in fecal pellet output and spontaneous defecation. In contrast, TAK-637, a tachykinin NK1-receptor antagonist, and diazepam inhibited the novelty stress induced defecation but did not inhibit spontaneous defecation. The present study indicated that novelty stress increases fecal pellet output without affecting the upper intestinal transit; this model may be useful for evaluating the effects of drugs on stress-stimulated colonic motility. PMID:16079466

  8. Ethnic hair care products may increase false positives in hair drug testing.

    PubMed

    Kidwell, David A; Smith, Frederick P; Shepherd, Arica R

    2015-12-01

    The question of why different races appear more susceptible to hair contamination by external drugs remains controversial. This research studied susceptibility of head hair to external cocaine and methamphetamine when hair products have been applied. Three different chemical classes of ethnic hair products were applied to Caucasian, Asian, and African hair. Some products increased the methamphetamine and cocaine concentrations in all hair types. A unique finding of this research is that certain ethnic hair products can replace moisture as a diffusion medium, thereby increasing the susceptibility to contamination over 100-fold compared to petroleum-based products. PMID:26338354

  9. Ethnic hair care products may increase false positives in hair drug testing.

    PubMed

    Kidwell, David A; Smith, Frederick P; Shepherd, Arica R

    2015-12-01

    The question of why different races appear more susceptible to hair contamination by external drugs remains controversial. This research studied susceptibility of head hair to external cocaine and methamphetamine when hair products have been applied. Three different chemical classes of ethnic hair products were applied to Caucasian, Asian, and African hair. Some products increased the methamphetamine and cocaine concentrations in all hair types. A unique finding of this research is that certain ethnic hair products can replace moisture as a diffusion medium, thereby increasing the susceptibility to contamination over 100-fold compared to petroleum-based products.

  10. Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart.

    PubMed

    Takeuchi, Ryota; Shinozaki, Kohki; Nakanishi, Takeo; Tamai, Ikumi

    2016-01-01

    Clinical reports indicate that cardiotoxicity due to donepezil can occur after coadministration with cilostazol. We speculated that the concentration of donepezil in heart tissue might be increased as a result of interaction with cilostazol at efflux transporters such as P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), which are expressed in many tissues including the heart, and our study tested this hypothesis. First, donepezil was confirmed to be a substrate of both BCRP and P-glycoprotein in transporter-transfected cells in vitro. Cilostazol inhibited BCRP and P-glycoprotein with half-inhibitory concentrations of 130 nM and 12.7 μM, respectively. Considering the clinically achievable unbound plasma concentration of cilostazol (about 200 nM), it is plausible that BCRP-mediated transport of donepezil would be affected by cilostazol in vivo. Indeed, in an in vivo rat study, we found that coadministration of cilostazol significantly increased the concentrations of donepezil in the heart and brain, where BCRP functions as a part of the blood-tissue barrier, whereas the plasma concentration of donepezil was unaffected. In addition, in vitro accumulation of donepezil in heart tissue slices of rats was significantly increased in the presence of cilostazol. These results indicate that donepezil-cilostazol interaction at BCRP may be clinically relevant in heart and brain tissues. In other words, the tissue distribution of drugs can be influenced by drug-drug interaction (DDI) at efflux transporters in certain tissues (local DDI) without any apparent change in plasma concentration (systemic DDI).

  11. Pharmacokinetic studies of intravenous glycosylated recombinant human granulocyte colony-stimulating factor in various hematological disorders: inverse correlation between the half-life and bone marrow myeloid cell pool.

    PubMed

    Watari, K; Ozawa, K; Takahashi, S; Tojo, A; Tani, K; Kamachi, S; Asano, S

    1997-07-01

    The pharmacokinetics of an intravenous bolus dose of glycosylated recombinant human G-CSF (rhG-CSF) was examined in 15 patients with various hematological disorders and 3 normal volunteers. The elimination half-life of rhG-CSF varied with the disorder. The half-life of an initial dose of rhG-CSF (2 micrograms/weight kg) was significantly prolonged in patients with aplastic anemia (2.7 +/- 0.3 h, n = 3) and myelodysplastic syndrome-refractory anemia (2.0 +/- 0.3 h, n = 3) when compared with those in normal controls (0.9 +/- 0.5 h, n = 3). In contrast, in patients with acute myelogenous leukemia which was overt leukemia from myelodysplastic syndrome-refractory anemia with excess of blasts in transformation, the half-life was shortened after chemotherapy (0.2 +/- 0.1 h, n = 3). The half-life of rhG-CSF in 2 patients with acute lymphoblastic leukemia in complete remission was prolonged (2.0 and 2.7 h) at the time of marrow-suppression after chemotherapy and then shortened (0.5, 1.0 h, respectively) in the recovery phase. The half-life of rhG-CSF was very weakly, inversely correlated with absolute neutrophil count in blood (n = 24, r2 = 0.32, P < 0.01), and was inversely correlated with the absolute count of bone-marrow myeloid cells (nucleated cell count in bone-marrow aspirates x the percentage of myeloid cells/100) of patients with aplastic anemia and myelodysplastic syndrome-refractory anemia (n = 12, r2 = 0.63, P = 0.002). These results suggest that the half-life of intravenously administered rhG-CSF (2 micrograms/kg) reflects the size of the myeloid cell compartment in vivo, and support the hypothesis that receptor-mediated consumption mainly accounts for the clearance of exogenous G-CSF.

  12. Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs.

    PubMed

    Mei, H; Sun, S; Bai, Y; Chen, Y; Chai, R; Li, H

    2015-04-02

    Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors.

  13. Reduced mtDNA copy number increases the sensitivity of tumor cells to chemotherapeutic drugs

    PubMed Central

    Mei, H; Sun, S; Bai, Y; Chen, Y; Chai, R; Li, H

    2015-01-01

    Many cancer drugs are toxic to cells by activating apoptotic pathways. Previous studies have shown that mitochondria have key roles in apoptosis in mammalian cells, but the role of mitochondrial DNA (mtDNA) copy number variation in the pathogenesis of tumor cell apoptosis remains largely unknown. We used the HEp-2, HNE2, and A549 tumor cell lines to explore the relationship between mtDNA copy number variation and cell apoptosis. We first induced apoptosis in three tumor cell lines and one normal adult human skin fibroblast cell line (HSF) with cisplatin (DDP) or doxorubicin (DOX) treatment and found that the mtDNA copy number significantly increased in apoptotic tumor cells, but not in HSF cells. We then downregulated the mtDNA copy number by transfection with shRNA-TFAM plasmids or treatment with ethidium bromide and found that the sensitivity of tumor cells to DDP or DOX was significantly increased. Furthermore, we observed that levels of reactive oxygen species (ROS) increased significantly in tumor cells with lower mtDNA copy numbers, and this might be related to a low level of antioxidant gene expression. Finally, we rescued the increase of ROS in tumor cells with lipoic acid or N-acetyl-L-cysteine and found that the apoptosis rate decreased. Our studies suggest that the increase of mtDNA copy number is a self-protective mechanism of tumor cells to prevent apoptosis and that reduced mtDNA copy number increases ROS levels in tumor cells, increases the tumor cells' sensitivity to chemotherapeutic drugs, and increases the rate of apoptosis. This research provides evidence that mtDNA copy number variation might be a promising new therapeutic target for the clinical treatment of tumors. PMID:25837486

  14. Increasing Access to Subsidized Artemisinin-based Combination Therapy through Accredited Drug Dispensing Outlets in Tanzania

    PubMed Central

    2011-01-01

    Background In Tanzania, many people seek malaria treatment from retail drug sellers. The National Malaria Control Program identified the accredited drug dispensing outlet (ADDO) program as a private sector mechanism to supplement the distribution of subsidized artemisinin-based combination therapies (ACTs) from public facilities and increase access to the first-line antimalarial in rural and underserved areas. The ADDO program strengthens private sector pharmaceutical services by improving regulatory and supervisory support, dispenser training, and record keeping practices. Methods The government's pilot program made subsidized ACTs available through ADDOs in 10 districts in the Morogoro and Ruvuma regions, covering about 2.9 million people. The program established a supply of subsidized ACTs, created a price system with a cost recovery plan, developed a plan to distribute the subsidized products to the ADDOs, trained dispensers, and strengthened the adverse drug reactions reporting system. As part of the evaluation, 448 ADDO dispensers brought their records to central locations for analysis, representing nearly 70% of ADDOs operating in the two regions. ADDO drug register data were available from July 2007-June 2008 for Morogoro and from July 2007-September 2008 for Ruvuma. This intervention was implemented from 2007-2008. Results During the pilot, over 300,000 people received treatment for malaria at the 448 ADDOs. The percentage of ADDOs that dispensed at least one course of ACT rose from 26.2% during July-September 2007 to 72.6% during April-June 2008. The number of malaria patients treated with ACTs gradually increased after the start of the pilot, while the use of non-ACT antimalarials declined; ACTs went from 3% of all antimalarials sold in July 2007 to 26% in June 2008. District-specific data showed substantial variation among the districts in ACT uptake through ADDOs, ranging from ACTs representing 10% of all antimalarial sales in Kilombero to 47% in

  15. Increasing complexity: which drug class to choose for treatment of hypertension in the elderly?

    PubMed Central

    Kaiser, Edelgard Anna; Lotze, Ulrich; Schäfer, Hans Hendrik

    2014-01-01

    Treatment of hypertension in the elderly is expected to become more complex in the coming decades. Based on the current landscape of clinical trials, guideline recommendations remain inconclusive. The present review discusses the latest evidence derived from studies available in 2013 and investigates optimal blood pressure (BP) and preferred treatment substances. Three common archetypes are discussed that hamper the treatment of hypertension in the very elderly. In addition, this paper presents the current recommendations of the NICE 2011, JNC7 2013-update, ESH/ESC 2013, CHEP 2013, JNC8 and ASH/ISH guidelines for elderly patients. Advantages of the six main substance classes, namely diuretics, beta-blockers (BBs), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and direct renin inhibitors (DRIs) are discussed. Medical and economic implications of drug administration in the very elderly are presented. Avoidance of treatment-related adverse effects has become increasingly relevant. Current substance classes are equally effective, with similar effects on cardiovascular outcomes. Selection of substances should therefore also be based on collateral advantages of drugs that extend beyond BP reduction. The combination of ACEIs and diuretics appears to be favorable in managing systolic/diastolic hypertension. Diuretics are a preferred and cheap combination drug, and the combination with CCBs is recommended for patients with isolated systolic hypertension. ACEIs and CCBs are favorable for patients with dementia, while CCBs and ARBs imply substantial cost savings due to high adherence. PMID:24711696

  16. Resident assistant training program for increasing alcohol, other drug, and mental health first-aid efforts.

    PubMed

    Thombs, Dennis L; Gonzalez, Jennifer M Reingle; Osborn, Cynthia J; Rossheim, Matthew E; Suzuki, Sumihiro

    2015-05-01

    In college and university residence halls, resident assistants (RAs) are expected to serve as first-aid providers to students who may have alcohol, other drug, mental health, and academic problems. Despite this responsibility, evidence-based, first-aid programs have not been developed and tested for the RA workforce. The current study examined effects of an investigational first-aid program designed specifically for RAs. The online Peer Hero Training program is a novel approach to RA training in its use of interactive video dramatizations of incidents involving substance-using or distressed residents. A 9-month randomized trial conducted on eight US campuses compared RAs who participated in the Peer Hero Training program to RAs who received training-as-usual. Participation in the Peer Hero Training program significantly increased RA first-aid efforts for residential students who may have had alcohol, other drug, mental health, or academic problems 6 months after baseline. Compared with those in the training-as-usual condition, RAs in the Peer Hero Training program made more than 10 times as many first-aid efforts for possible alcohol problems, almost 14 times the number of first-aid efforts for possible drug use, almost 3 times the number of first-aid efforts for possible mental health problems, and 3 times the number of first-aid efforts for academic problems. There was no evidence that measured RA attitudes mediated the effects of the intervention. Results of this preliminary evaluation trial suggest that online training using interactive video dramatizations is a viable approach to strengthening RAs' ability to provide alcohol, other drugs, and mental health first-aid to undergraduates.

  17. Resident Assistant Training Program for Increasing Alcohol, Other Drug, and Mental Health First-Aid Efforts

    PubMed Central

    Thombs, Dennis L.; Gonzalez, Jennifer M. Reingle; Osborn, Cynthia J.; Rossheim, Matthew E.; Suzuki, Sumihiro

    2014-01-01

    In college and university residence halls, resident assistants (RAs) are expected to serve as first-aid providers to students who may have alcohol, other drug, mental health, and academic problems. Despite this responsibility, evidence-based, first-aid programs have not been developed and tested for the RA workforce. The current study examined effects of an investigational first-aid program designed specifically for RAs. The online Peer Hero Training program is a novel approach to RA training in its use of interactive video dramatizations of incidents involving substance-using or distressed residents. A 9-month randomized trial conducted on 8 U.S. campuses compared RAs who participated in the Peer Hero Training program to RAs who received training-as-usual. Participation in the Peer Hero Training program significantly increased RA first-aid efforts for residential students who may have had alcohol, other drug, mental health, or academic problems six months after baseline. Compared to those in the training-as-usual condition, RAs in the Peer Hero Training program made more than 10 times as many first-aid efforts for possible alcohol problems, almost 14 times the number of first-aid efforts for possible drug use, almost 3 times the number of first-aid efforts for possible mental health problems, and 3 times the number of first-aid efforts for academic problems. There was no evidence that measured RA attitudes mediated the effects of the intervention. Results of this preliminary evaluation trial suggest that online training using interactive video dramatizations is a viable approach to strengthening RAs’ ability to provide alcohol, other drug, and mental health first-aid to undergraduates. PMID:25322950

  18. Chitosan-decorated selenium nanoparticles as protein carriers to improve the in vivo half-life of the peptide therapeutic BAY 55-9837 for type 2 diabetes mellitus

    PubMed Central

    Rao, Lei; Ma, Yi; Zhuang, Manjiao; Luo, Tianjie; Wang, Yayu; Hong, An

    2014-01-01

    Purpose As a potential protein therapeutic for type 2 diabetes mellitus (T2DM), BAY 55-9837 is limited by poor stability and a very short half-life in vivo. The purpose of this study was to construct a novel nanostructured biomaterial by conjugating BAY 55-9837 to chitosan-decorated selenium nanoparticles (CS-SeNPs) to prolong the in vivo half-life of BAY 55-9837 by reducing its renal clearance rate. Materials and methods BAY 55-9837-loaded CS-SeNPs (BAY-CS-SeNPs) were prepared, and their surface morphology, particle size, zeta potential, and structure were characterized. The stability, protein-loading rate, and in vitro release of BAY 55-9837 from CS-SeNPs were also quantified. Additionally, a sensitive high-performance liquid chromatography (HPLC) assay was developed for the quantification of BAY 55-9837 in mouse plasma. Thereafter, mice were injected via the tail vein with either BAY 55-9837 or BAY-CS-SeNPs, and the plasma concentration of BAY 55-9837 was determined via our validated HPLC method at different time intervals postinjection. Relevant in vivo pharmacokinetic parameters (half-life, area under the curve from time 0 to last sampling point, observed clearance) were then calculated and analyzed. Results BAY-CS-SeNPs were successfully synthesized, with diameters of approximately 200 nm. BAY-CS-SeNPs displayed good stability with a high protein-loading rate, and the release process of BAY 55-9837 from the CS-SeNPs lasted for over 70 hours, with the cumulative release reaching 78.9%. Moreover, the conjugation of CS-SeNPs to BAY 55-9837 significantly reduced its renal clearance to a rate of 1.56 mL/h and extended its half-life to 20.81 hours. Conclusion In summary, our work provides a simple method for reducing the renal clearance rate and extending the half-life of BAY 55-9837 in vivo by utilizing CS-SeNPs as nanocarriers. PMID:25378923

  19. Loading of Gemcitabine on chitosan magnetic nanoparticles increases the anti-cancer efficacy of the drug.

    PubMed

    Parsian, Maryam; Unsoy, Gozde; Mutlu, Pelin; Yalcin, Serap; Tezcaner, Aysen; Gunduz, Ufuk

    2016-08-01

    Targeted delivery of anti-cancer drugs increase the efficacy, while decreasing adverse effects. Among various delivery systems, chitosan coated iron oxide nanoparticles (CsMNPs) gained attention with their biocompatibility, biodegradability, low toxicity and targetability under magnetic field. This study aimed to increase the cellular uptake and efficacy of Gemcitabine. CsMNPs were synthesized by in situ co-precipitation and Gemcitabine was loaded onto the nanoparticles. Nanoparticle characterization was performed by TEM, FTIR, XPS, and zeta potential. Gemcitabine release and stability was analyzed. The cellular uptake was shown. Cytotoxicity of free-Gemcitabine and Gem-CsMNPs were examined on SKBR and MCF-7 breast cancer cells by XTT assay. Gemcitabine loading was optimized as 30µM by spectrophotometric analyses. Drug release was highest (65%) at pH 4.2, while it was 8% at pH 7.2. This is a desired release characteristic since pH of tumor-tissue and endosomes are acidic, while the blood-stream and healthy-tissues are neutral. Peaks reflecting the presence of Gemcitabine were observed in FTIR and XPS. At neutral pH, zeta potential increased after Gemcitabine loading. TEM images displayed, Gem-CsMNPs were 4nm with uniform size-distribution and have spherical shape. The cellular uptake and targetability of CsMNPs was studied on MCF-7 breast cancer cell lines. IC50 value of Gem-CsMNPs was 1.4 fold and 2.6 fold lower than free-Gem on SKBR-3 and MCF-7 cell lines respectively, indicating the increased efficacy of Gemcitabine when loaded onto nanoparticles. Targetability by magnetic field, stability, size distribution, cellular uptake and toxicity characteristics of CsMNPs in this study provides a useful targeted delivery system for Gemcitabine in cancer therapy. PMID:27181067

  20. Is there a rational approach for increasing drug specificity? Considerations on CNS target choice and validation.

    PubMed

    Resende, Rodrigo R; Ulrich, Henning; Faria, Marcella

    2007-01-01

    The description of mental illness states brings into light a referential paradox on the absence of grounds for normality. Furthermore, the semiology itself poses a problem throughout the intricate consensual relations between psychiatrists. New molecules with activity on the CNS are ever more specific as to molecular cognitive capabilities, reaching limits of individual genetic variability. Cultural mechanisms of neuronal adaptation also contribute significantly to representations and its correlation with feelings. Neuropeptides increase excitability in various different brain regions, with networks underlying optimal behaviour patterns. Therefore, the sole specification of target molecules yet does not lead directly to specific results, as insights from a systematic approach should conceal. Current validation methods generate insufficient data for discriminating successful treatable candidates. Instead of regarding the heuristics of empirically classified disease models, a new tendency to compromise scientia rationale with technical capabilities should be regarded. Some of the drugs that have obtained patents recently will be discussed in the framework of their rational and actual specificity. The molecular basis underlining function will be contrasted with an alternative approach, namely: how functional organization constrains molecular action. The categories comprising neurogenarative pathologies at one hand and the mood disorders at the other hand will be analysed separately as the procedures guiding drug design in each case seem to be different. PMID:18221216

  1. Tumor-selective peptide-carrier delivery of Paclitaxel increases in vivo activity of the drug

    PubMed Central

    Brunetti, Jlenia; Pillozzi, Serena; Falciani, Chiara; Depau, Lorenzo; Tenori, Eleonora; Scali, Silvia; Lozzi, Luisa; Pini, Alessandro; Arcangeli, Annarosa; Menichetti, Stefano; Bracci, Luisa

    2015-01-01

    Taxanes are highly effective chemotherapeutic drugs against proliferating cancer and an established option in the standard treatment of ovarian and breast cancer. However, treatment with paclitaxel is associated with severe side effects, including sensory axonal neuropathy, and its poor solubility in water complicates its formulation. In this paper we report the in vitro and in vivo activity of a new form of paclitaxel, modified for conjugation with a tumor-selective tetrabranched peptide carrier (NT4). NT4 selectively targets tumor cells by binding to membrane sulfated glycosaminoglycans (GAG) and to endocytic receptors, like LRP1 and LRP6, which are established tumor markers. Biological activity of NT4-paclitaxel was tested in vitro on MDA-MB 231 and SKOV-3 cell lines, representing breast and ovarian cancer, respectively, and in vivo in an orthotopic mouse model of human breast cancer. Using in vivo bioluminescence imaging, we found that conjugation of paclitaxel with the NT4 peptide led to increased therapeutic activity of the drug in vivo. NT4-paclitaxel induced tumor regression, whereas treatment with unconjugated paclitaxel only produced a reduction in tumor growth. Moreover, unlike paclitaxel, NT4-paclitaxel is very hydrophilic, which may improve its pharmacokinetic profile and allow the use of less toxic dilution buffers, further decreasing its general chemotherapic toxicity. PMID:26626158

  2. [Therapeutic drug monitoring of rufinamide].

    PubMed

    Bentué-Ferrer, Danièle; Tribut, Olivier; Verdier, Marie-Clémence

    2012-01-01

    Rufinamide is a third-generation antiepileptic drug, available since early 2010 in France. It is indicated in combination therapy in the Lennox-Gastaut syndrome from the age of 4. It has orphan drug status. The bioavailability of rufinamide is high, but decreases with the dose and increases with food intake. Rufinamide is not metabolized by cytochromes but hydrolyzed by a carboxylesterase in an inactive carboxylic derivative. Elimination is mainly renal. The half-life varies from 6 to 10h. Although established from relatively few studies, exposure efficacy and exposure toxicity relationships are argued. A plasma concentration of 15 mg/L, obtained with a standard regimen, reduces the number of seizures of 25%. Few factors of intrinsic variability are described. There are few clinically significant pharmacokinetic interactions and they concern combinations with other antiepileptic drugs, especially valproate. Although there is no validated therapeutic range, the level of evidence for this therapeutic drug monitoring has been estimated at "possibly useful". PMID:22850104

  3. Increased temperature and entropy production in cancer: the role of anti-inflammatory drugs.

    PubMed

    Pitt, Michael A

    2015-02-01

    Some cancers have been shown to have a higher temperature than surrounding normal tissue. This higher temperature is due to heat generated internally in the cancer. The higher temperature of cancer (compared to surrounding tissue) enables a thermodynamic analysis to be carried out. Here I show that there is increased entropy production in cancer compared with surrounding tissue. This is termed excess entropy production. The excess entropy production is expressed in terms of heat flow from the cancer to surrounding tissue and enzymic reactions in the cancer and surrounding tissue. The excess entropy production in cancer drives it away from the stationary state that is characterised by minimum entropy production. Treatments that reduce inflammation (and therefore temperature) should drive a cancer towards the stationary state. Anti-inflammatory agents, such as aspirin, other non-steroidal anti-inflammatory drugs, corticosteroids and also thyroxine analogues have been shown (using various criteria) to reduce the progress of cancer.

  4. Specialty drug coupons lower out-of-pocket costs and may improve adherence at the risk of increasing premiums.

    PubMed

    Starner, Catherine I; Alexander, G Caleb; Bowen, Kevin; Qiu, Yang; Wickersham, Peter J; Gleason, Patrick P

    2014-10-01

    Expenditures for specialty drugs account for more than 25 percent of total US drug spending and have been increasing at more than 13 percent annually. We examined insurers' role in maintaining the affordability and accessibility of specialty drugs while maximizing their value. We conducted two analyses: one using an administrative claims database with information on more than ten million commercially insured patients and another using the same database combined with the drug prescription records from a specialty pharmacy. First, we examined the prevalence of specialty drug coupons and the degree to which these reduced patients' out-of-pocket costs, focusing on 264,801 prescriptions. Second, we quantified the association between the magnitude of out-of-pocket costs for specialty drugs and patients' abandonment of their new or restarted therapy, focusing on a group of nearly 16,000 patients. We found that drug coupons accounted for $21.2 million of patients' $35.3 million annual out-of-pocket costs. In the vast majority of cases, coupons reduced monthly cost sharing to less than $250, a point at which patients were far less likely to abandon therapy with biologic anti-inflammatory drugs or with drugs for multiple sclerosis. However, by reducing cost sharing, coupons may also circumvent efforts to encourage patients to use the most cost-effective drugs.

  5. OxyContin® as currency: OxyContin® use and increased social capital among rural Appalachian drug users.

    PubMed

    Jonas, Adam B; Young, April M; Oser, Carrie B; Leukefeld, Carl G; Havens, Jennifer R

    2012-05-01

    Studies have shown that position within networks of social relations can have direct implications on the health behaviors of individuals. The present study examines connections between drug use and individual social capital within social networks of drug users (n = 503) from rural Appalachian Kentucky, U.S.A. Respondent driven sampling was used to recruit individuals age 18 and older who had used one of the following drugs to get high: cocaine, crack, heroin, methamphetamine, or prescription opioids. Substance use was measured via self-report and social network analysis of participants' drug use network was used to compute effective size, a measure of social capital. Drug network ties were based on sociometric data on recent (past 6 month) drug co-usage. Multivariate multi-level ordinal regression was used to model the independent effect of socio-demographic and drug use characteristics on social capital. Adjusting for gender, income, and education, daily OxyContin(®) use was found to be significantly associated with greater social capital, and daily marijuana use was associated with less social capital. These results suggest that in regions with marked economic disparities such as rural Appalachia, OxyContin(®) may serve as a form of currency that is associated with increased social capital among drug users. Interventions focusing on increasing alternate pathways to acquiring social capital may be one way in which to alleviate the burden of drug use in this high-risk population.

  6. OxyContin® as Currency: OxyContin® Use and Increased Social Capital among Rural Appalachian Drug Users

    PubMed Central

    Jonas, Adam B.; Young, April M.; Oser, Carrie B.; Leukefeld, Carl G.; Havens, Jennifer R.

    2012-01-01

    Studies have shown that position within networks of social relations can have direct implications on the health behaviors of individuals. The present study examines connections between drug use and individual social capital within social networks of drug users (n=503) from rural Appalachian Kentucky, U.S.A. Respondent driven sampling was used to recruit individuals age 18 and older who had used one of the following drugs to get high: cocaine, crack, heroin, methamphetamine, or prescription opioids. Substance use was measured via self-report and social network analysis of participants’ drug use network was used to compute effective size, a measure of social capital. Drug network ties were based on sociometric data on recent (past 6 month) drug co-usage. Multivariate multi-level ordinal regression was used to model the independent effect of sociodemographic and drug use characteristics on social capital. Adjusting for gender, income, and education, daily OxyContin® use was found to be significantly associated with greater social capital, and daily marijuana use was associated with less social capital. These results suggest that in regions with marked economic disparities such as rural Appalachia, OxyContin® may serve as a form of currency that is associated with increased social capital among drug users. Interventions focusing on increasing alternate pathways to acquiring social capital may be one way in which to alleviate the burden of drug use in this high-risk population. PMID:22465379

  7. OxyContin® as currency: OxyContin® use and increased social capital among rural Appalachian drug users.

    PubMed

    Jonas, Adam B; Young, April M; Oser, Carrie B; Leukefeld, Carl G; Havens, Jennifer R

    2012-05-01

    Studies have shown that position within networks of social relations can have direct implications on the health behaviors of individuals. The present study examines connections between drug use and individual social capital within social networks of drug users (n = 503) from rural Appalachian Kentucky, U.S.A. Respondent driven sampling was used to recruit individuals age 18 and older who had used one of the following drugs to get high: cocaine, crack, heroin, methamphetamine, or prescription opioids. Substance use was measured via self-report and social network analysis of participants' drug use network was used to compute effective size, a measure of social capital. Drug network ties were based on sociometric data on recent (past 6 month) drug co-usage. Multivariate multi-level ordinal regression was used to model the independent effect of socio-demographic and drug use characteristics on social capital. Adjusting for gender, income, and education, daily OxyContin(®) use was found to be significantly associated with greater social capital, and daily marijuana use was associated with less social capital. These results suggest that in regions with marked economic disparities such as rural Appalachia, OxyContin(®) may serve as a form of currency that is associated with increased social capital among drug users. Interventions focusing on increasing alternate pathways to acquiring social capital may be one way in which to alleviate the burden of drug use in this high-risk population. PMID:22465379

  8. [The increase in receptor-mediated endocytosis of drugs in the composition of nanoparticles with the address fragment].

    PubMed

    Kostryukova, L V; Sanzhakov, M A; Ignatov, D V; Prozorovskyi, V N; Druzhilovskaya, O S; Kasatkina, E S; Medvedeva, N V; Ipatova, O M

    2016-03-01

    It is known that disorders in the cell functioning of the organs/tissues is accompanied by increased expression of certain receptors. A modern approach to improve the specificity of the drug accumulation in the affected area is to construct the delivery nanosystems with the address fragments. Active tagged transport may help to reduce the dose of the drug, minimizing the impact on healthy cells and organs (reduced adverse events). This approach is particularly important in oncology because of the high toxicity of the drugs used. In this work we have obtained and characterized the pharmaceutical composition of doxorubicin and chlorine e6 into colloidal nanoparticles with synthesized previously targeted conjugates based on folic acid and biotin. On the cell culture Hep G2 it was shown an increase in the internalization of drugs when they were introduced in the incubation medium in the form of drug compositions with transport nanosystems and targeted fragments. PMID:27420624

  9. Salinomycin sensitizes antimitotic drugs-treated cancer cells by increasing apoptosis via the prevention of G2 arrest

    SciTech Connect

    Kim, Ju-Hwa; Yoo, Hye-In; Kang, Han Sung; Ro, Jungsil; Yoon, Sungpil

    2012-02-03

    Highlights: Black-Right-Pointing-Pointer Sal sensitizes antimitotic drugs-treated cancer cells. Black-Right-Pointing-Pointer Sal sensitizes them by prevention of G2 arrest and reduced cyclin D1 levels. Black-Right-Pointing-Pointer Sal also sensitizes them by increasing DNA damage and reducing p21 level. Black-Right-Pointing-Pointer A low concentration of Sal effectively sensitized the cancer cells to antimitotic drugs. -- Abstract: Here, we investigated whether Sal could sensitize cancer cells to antimitotic drugs. We demonstrated that Sal sensitized paclitaxcel (PAC)-, docetaxcel (DOC)-, vinblastin (VIN)-, or colchicine (COL)-treated cancer cell lines, suggesting that Sal has the ability to sensitize the cells to any form of microtubule-targeting drugs. Sensitization to the antimitotic drugs could be achieved with very low concentrations of Sal, suggesting that there is a possibility to minimize Sal toxicity associated with human cancer patient treatments. Sensitization by Sal increased apoptosis, which was observed by C-PARP production. Sal sensitized the cancer cells to antimitotic drugs by preventing G2 arrest, suggesting that Sal contributes to the induction of mitotic catastrophe. Sal generally reduced cyclin D1 levels in PAC-, DOC-, and VIN-treated cells. In addition, Sal treatment increased pH2AX levels and reduced p21 levels in antimitotic drugs-treated cells. These observations suggest that the mechanisms underlying Sal sensitization to DNA-damaging compounds, radiation, and microtubule-targeting drugs are similar. Our data demonstrated that Sal sensitizes cancer cells to antimitotic drugs by increasing apoptosis through the prevention of G2 arrest via conserved Sal-sensitization mechanisms. These results may contribute to the development of Sal-based chemotherapy for cancer patients treated with antimitotic drugs.

  10. α1-Syntrophin Variant Identified in Drug-Induced Long QT Syndrome Increases Late Sodium Current

    PubMed Central

    Choi, Jong-Il; Wang, Chaojian; Thomas, Matthew J.; Pitt, Geoffrey S.

    2016-01-01

    Drug-induced long-QT syndrome (diLQTS) is often due to drug block of IKr, especially in genetically susceptible patients with subclinical mutations in the IKr-encoding KCHN2. Few variants in the cardiac NaV1.5 Na+ channel complex have been associated with diLQTS. We tested whether a novel SNTA1 (α1-syntrophin) variant (p.E409Q) found in a patient with diLQTS increases late sodium current (INa-L), thereby providing a disease mechanism. Electrophysiological studies were performed in HEK293T cells co-expressing human NaV1.5/nNOS/PMCA4b with either wild type (WT) or SNTA1 variants (A390V-previously reported in congenital LQTS; and E409Q); and in adult rat ventricular cardiomyocytes infected with SNTA1 expressing adenoviruses (WT or one of the two SNTA1 variants). In HEK293T cells and in cardiomyocytes, there was no significant difference in the peak INa densities among the SNTA1 WT and variants. However, both variants increased INa-L (% of peak current) in HEK293T cells (0.58±0.10 in WT vs. 0.90±0.11 in A390V, p = 0.048; vs. 0.88±0.07 in E409Q, p = 0.023). In cardiomyocytes, INa-L was significantly increased by E409Q, but not by A390V compared to WT (0.49±0.14 in WT vs.0.94±0.23 in A390V, p = 0.099; vs. 1.12±0.24 in E409Q, p = 0.019). We demonstrated that a novel SNTA1 variant is likely causative for diLQTS by augmenting INa-L. These data suggest that variants within the NaV1.5-interacting α1-syntrophin are a potential mechanism for diLQTS, thereby expanding the concept that variants within congenital LQTS loci can cause diLQTS. PMID:27028743

  11. Fusion to an albumin-binding domain with a high affinity for albumin extends the circulatory half-life and enhances the in vivo antitumor effects of human TRAIL.

    PubMed

    Li, Rui; Yang, Hao; Jia, Dianlong; Nie, Qianxue; Cai, Huawei; Fan, Qing; Wan, Lin; Li, Lin; Lu, Xiaofeng

    2016-04-28

    Clinical applications of recombinant human tumor necrosis factor-related apoptosis-inducing ligand (hTRAIL) have been limited by their poor pharmacokinetics. Using endogenous albumin as a carrier is an attractive approach for circulatory half-life extension. Here, we produced ABD-hTRAIL and hTRAIL-ABD by fusing the albumin-binding domain (ABD) from protein G to the N- or C-terminus of hTRAIL. We found that ABD-hTRAIL bound human serum albumin (HSA) with a high affinity (0.4 ± 0.18 nM) and formed nanoparticles with an average diameter (~12 nm) above the threshold (~7 nm) of renal filtration. ABD-hTRAIL also bound mouse serum albumin (MSA); thus, its half-life was 40-50-fold greater than that of hTRAIL (14.1 ± 0.87 h vs 0.32 ± 0.14 h). Tumor uptake of ABD-hTRAIL 8-48 h post-injection was 6-16-fold that of hTRAIL. Consequently, the tumor suppression of ABD-hTRAIL in mice bearing subcutaneous xenografts was 3-4 times greater than that of hTRAIL. Additionally, the time period during which ABD-hTRAIL could kill circulating tumor cells was approximately 8 times longer than that of hTRAIL. These results demonstrate that ABD fused to the N-terminus endows hTRAIL with albumin binding ability; once it enters the vasculature, ABD mediates binding with endogenous albumin, thus prolonging the half-life and enhancing the antitumor effect of hTRAIL. However, hTRAIL-ABD did not show a high affinity for albumin and therefore did not display the prolonged circulatory half-life and enhanced antitumor effects. These results demonstrate that N-terminal, but not C-terminal, ABD-fusion is an efficient technique for enhancing the antitumor effects of hTRAIL by using endogenous albumin as a carrier.

  12. ATOX1 gene silencing increases susceptibility to anticancer therapy based on copper ionophores or chelating drugs.

    PubMed

    Barresi, Vincenza; Spampinato, Giorgia; Musso, Nicolò; Trovato Salinaro, Angela; Rizzarelli, Enrico; Condorelli, Daniele Filippo

    2016-03-01

    Copper is a catalytic cofactor required for the normal function of many enzymes involved in fundamental biological processes but highly cytotoxic when in excess. Therefore its homeostasis and distribution is strictly regulated by a network of transporters and intracellular chaperones. ATOX1 (antioxidant protein 1) is a copper chaperone that plays a role in copper homeostasis by binding and transporting cytosolic copper to ATPase proteins in the trans-Golgi network. In the present study the Caco-2 cell line, a colon carcinoma cell line, was used as an in vitro model to evaluate if ATOX1 deficiency could affect sensitivity to experimentally induced copper dyshomeostasis. Silencing of ATOX1 increased toxicity of a short treatment with a high concentration of Cu(2+). Copper ionophores, such as 5-chloro-8-hydroxyquinoline, induced a copper-dependent cell toxicity which was significantly potentiated after ATOX1 silencing. The copper chelator TPEN (N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine) produced a form of cell toxicity that was reversed by the addition of Cu(2+). ATOX1 silencing increased Caco-2 cell sensitivity to TPEN toxicity. Our results suggest the possibility of a therapy with copper-chelating or ionophore drugs in subtypes of tumors showing specific alterations in ATOX1 expression. PMID:26784148

  13. Drug delivery nanoparticles in skin cancers.

    PubMed

    Dianzani, Chiara; Zara, Gian Paolo; Maina, Giovanni; Pettazzoni, Piergiorgio; Pizzimenti, Stefania; Rossi, Federica; Gigliotti, Casimiro Luca; Ciamporcero, Eric Stefano; Daga, Martina; Barrera, Giuseppina

    2014-01-01

    Nanotechnology involves the engineering of functional systems at nanoscale, thus being attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of the nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for prevention, diagnosis, and treatment of diseases, including cancer disease. Over the past two decades, the rapid developments in nanotechnology have allowed the incorporation of multiple therapeutic, sensing, and targeting agents into nanoparticles, for detection, prevention, and treatment of cancer diseases. Nanoparticles offer many advantages as drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported.

  14. Drug Delivery Nanoparticles in Skin Cancers

    PubMed Central

    Dianzani, Chiara; Zara, Gian Paolo; Maina, Giovanni; Pettazzoni, Piergiorgio; Pizzimenti, Stefania; Rossi, Federica; Gigliotti, Casimiro Luca; Ciamporcero, Eric Stefano; Daga, Martina; Barrera, Giuseppina

    2014-01-01

    Nanotechnology involves the engineering of functional systems at nanoscale, thus being attractive for disciplines ranging from materials science to biomedicine. One of the most active research areas of the nanotechnology is nanomedicine, which applies nanotechnology to highly specific medical interventions for prevention, diagnosis, and treatment of diseases, including cancer disease. Over the past two decades, the rapid developments in nanotechnology have allowed the incorporation of multiple therapeutic, sensing, and targeting agents into nanoparticles, for detection, prevention, and treatment of cancer diseases. Nanoparticles offer many advantages as drug carrier systems since they can improve the solubility of poorly water-soluble drugs, modify pharmacokinetics, increase drug half-life by reducing immunogenicity, improve bioavailability, and diminish drug metabolism. They can also enable a tunable release of therapeutic compounds and the simultaneous delivery of two or more drugs for combination therapy. In this review, we discuss the recent advances in the use of different types of nanoparticles for systemic and topical drug delivery in the treatment of skin cancer. In particular, the progress in the treatment with nanocarriers of basal cell carcinoma, squamous cell carcinoma, and melanoma has been reported. PMID:25101298

  15. Total gastrectomy may result in reduced drug effectiveness due to an increase in the expression of the drug-metabolizing enzyme Cytochrome P450, in the liver.

    PubMed

    Ishii, Makoto; Toda, Takahiro; Ikarashi, Nobutomo; Kusunoki, Yoshiki; Kon, Risako; Ochiai, Wataru; Machida, Yoshiaki; Sugiyama, Kiyoshi

    2014-01-23

    In patients with gastrectomy, it is possible that drug effectiveness is reduced compared to healthy subjects due to the increased of the drug-metabolizing enzyme, Cytochrome P450 (CYP). The purpose of this study is to verify this possibility. Gastrectomy model mice were prepared to evaluate the expression level of various CYPs in the liver from 2 to 24 weeks post-operation. No significant differences were observed in the protein expression levels of CYP3A, CYP1A, CYP2C, and CYP2D between the sham operation group and the gastrectomy group up to 4 weeks after the gastrectomy. On the other hand, significant increases in the protein expression levels of any CYPs were observed in the gastrectomy group compared to the sham operation group from 12 weeks after the gastrectomy onward. These increases in expression levels were maintained until 24 weeks after the gastrectomy. The examination of metabolic activity in the liver in the gastrectomy group using triazolam revealed that the metabolic activity at 12 weeks after the gastrectomy was significantly increased in the gastrectomy group. The administration of the anticancer drug imatinib, which is a substrate of CYP3A, to mice at 12weeks after gastrectomy resulted in an increase in the metabolic rate, suggesting a possible decrease in drug effectiveness. It has been revealed that drug effectiveness may be reduced after gastrectomy because the expression levels of various CYPs in the liver were increased over a prolonged period. The results of this study can serve as valuable fundamental knowledge for drug therapy in patients with gastrectomy.

  16. Antibiotic-containing polymers for localized, sustained drug delivery

    PubMed Central

    Stebbins, Nicholas D.; Ouimet, Michelle A.; Uhrich, Kathryn E.

    2014-01-01

    Many currently used antibiotics suffer from issues such as systemic toxicity, short half-life, and increased susceptibility to bacterial resistance. Although most antibiotic classes are administered systemically through oral or intravenous routes, a more efficient delivery system is needed. This review discusses the chemical conjugation of antibiotics to polymers, achieved by forming covalent bonds between antibiotics and a pre-existing polymer or by developing novel antibiotic-containing polymers. Through conjugating antibiotics to polymers, unique polymer properties can be taken advantage of. These polymeric antibiotics display controlled, sustained drug release and vary in antibiotic class type, synthetic method, polymer composition, bond lability, and antibacterial activity. The polymer synthesis, characterization, drug release, and antibacterial activities, if applicable, will be presented to offer a detailed overview of each system. PMID:24751888

  17. Antibiotic-containing polymers for localized, sustained drug delivery.

    PubMed

    Stebbins, Nicholas D; Ouimet, Michelle A; Uhrich, Kathryn E

    2014-11-30

    Many currently used antibiotics suffer from issues such as systemic toxicity, short half-life, and increased susceptibility to bacterial resistance. Although most antibiotic classes are administered systemically through oral or intravenous routes, a more efficient delivery system is needed. This review discusses the chemical conjugation of antibiotics to polymers, achieved by forming covalent bonds between antibiotics and a pre-existing polymer or by developing novel antibiotic-containing polymers. Through conjugating antibiotics to polymers, unique polymer properties can be taken advantage of. These polymeric antibiotics display controlled, sustained drug release and vary in antibiotic class type, synthetic method, polymer composition, bond lability, and antibacterial activity. The polymer synthesis, characterization, drug release, and antibacterial activities, if applicable, will be presented to offer a detailed overview of each system.

  18. Caudate nucleus-dependent navigational strategies are associated with increased use of addictive drugs

    PubMed Central

    Bohbot, Veronique D; Balso, Daniel; Conrad, Kate; Konishi, Kyoko; Leyton, Marco

    2013-01-01

    This study aimed to investigate the relationship between navigational strategies and the use of abused substances in a sample of healthy young adults. Navigational strategies were assessed with the 4-on-8 virtual maze (4/8VM), a task previously shown to dissociate between hippocampal-dependent spatial navigational strategies and caudate nucleus-dependent stimulus-response navigational strategies. Spatial strategies involve learning the spatial relationships between the landmarks in an environment, while response learning strategies involve learning a rigid set of stimulus-response type associations, e.g., see the tree, turn left. We have shown that spatial learners have increased gray matter and fMRI activity in the hippocampus compared with response learners, while response learners have increased gray matter and fMRI activity in the caudate nucleus. We were interested in the prevalence of use of substances of abuse in spatial and response learners because of the evidence that people who score high on traits such as novelty seeking, sensation seeking, reward seeking, and impulsivity, are more cue-responsive and more likely to use substances of abuse. Since response learners show increased activity and gray matter in the caudate nucleus of the striatum, which is a brain area involved in addiction, we hypothesized that response learners would have a greater use of abused substances than spatial learners. Fifty-five young adults were tested on the 4/8VM and completed a time-line follow-back assessment of drug and alcohol use. We found that response learners had smoked a significantly greater number of cigarettes in their lifetime than spatial learners, were more likely to have used cannabis, and had double the lifetime alcohol consumption. We discuss the possible relationship between substance abuse and response strategies as well as the implications for the hippocampus, risks of neurological and psychiatric disorders, and healthy cognition. © 2013 The Authors

  19. A copayment increase for prescription drugs: the long-term and short-term effects on use and expenditures.

    PubMed

    Gibson, Teresa B; McLaughlin, Catherine G; Smith, Dean G

    2005-01-01

    This study estimates the effects of an increase in an outpatient prescription drug copayment using a natural experiment based upon a large firm that implemented such an increase. The findings suggest that the primary effect of a copayment increase is attenuation of the trend in prescription drug utilization. We also find an initial reduction in expenditures, with the effects on spending diminishing. Employees with an existing chronic illness and those without a chronic illness show a similar, inelastic response to a copayment increase; employees with a newly diagnosed chronic illness have a more inelastic response.

  20. 77 FR 5027 - Food and Drug Administration Transparency Initiative: Exploratory Program To Increase Access to...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-01

    ... HUMAN SERVICES Food and Drug Administration Food and Drug Administration Transparency Initiative... and Human Services responding to a January 18, 2011, Presidential Memorandum on Regulatory Compliance, (76 FR 3825, January 21, 2011), FDA recounted the actions it had already implemented, as well as...

  1. Mass spectrometry study of increased breakdown of an anticonvulsivant drug substance

    NASA Astrophysics Data System (ADS)

    Buret, D.; Breton, D.; Clair, P.; Lafosse, M.

    2006-06-01

    The French Military Health Service (SSA) developed a new pharmaceutic speciality as a treatment against neurotoxic organophosphate poisoning (NSP), as a substitute for existing therapeutics. The Armed Forces Central Pharmacy (PCA) is in charge of the development of therapeutic formulation and stability studies. This product includes three drug substances: atropine, pralidoxime and avizafone, an amine prodrug of diazepam, soluble in water. The PCA performed a stability study of this formulation according to the International Conference on Harmonization (ICH) recommendations: it was used to display interaction between the molecules and the plastic of the cartridge (the container turned yellow). Since no degradation product of atropine and pralidoxime was observed, a complementary evaluation of avizafone and its main known degradation products (diazepam, carbostyril and methylaminobenzochlorophenone [MACB]) was initiated. The results were used to determine the degradation products obtained under different conditions and the kind of mechanisms, which may occur as the formulation ages: adsorption or absorption by the bulk and/or increasing degradation products. The analytical methods developed here are a direct sample analysis by mass spectrometry (MS) using different ionization modes and liquid chromatography (LC) with UV detection to confirm the results obtain with MS.

  2. Drug polyconsumption is associated with increased synchronization of brain electrical-activity at rest and in a counting task.

    PubMed

    Coullaut-Valera, R; Arbaiza, I; Bajo, R; Arrúe, R; López, M E; Coullaut-Valera, J; Correas, A; López-Sanz, D; Maestu, F; Papo, D

    2014-02-01

    Drug abusers typically consume not just one but several types of drugs, starting from alcohol and marijuana consumption, and then dramatically lapsing into addiction to harder drugs, such as cocaine, heroin, or amphetamine. The brain of drug abusers presents various structural and neurophysiological abnormalities, some of which may predate drug consumption onset. However, how these changes translate into modifications in functional brain connectivity is still poorly understood. To characterize functional connectivity patterns, we recorded Electroencephalogram (EEG) activity from 21 detoxified drug abusers and 20 age-matched control subjects performing a simple counting task and at rest activity. To evaluate the cortical brain connectivity network we applied the Synchronization Likelihood algorithm. The results showed that drug abusers had higher synchronization levels at low frequencies, mainly in the θ band (4-8 Hz) between frontal and posterior cortical regions. During the counting task, patients showed increased synchronization in the β (14-35 Hz), and γ (35-45 Hz) frequency bands, in fronto-posterior and interhemispheric temporal regions. Taken together 'slow-down' at rest and task-related 'over-exertion' could indicate that the brain of drug abusers is suffering from a premature form of ageing. Future studies will clarify whether this condition can be reversed following prolonged periods of abstinence.

  3. Steady Increase In Prices For Oral Anticancer Drugs After Market Launch Suggests A Lack Of Competitive Pressure.

    PubMed

    Bennette, Caroline S; Richards, Catherine; Sullivan, Sean D; Ramsey, Scott D

    2016-05-01

    The cost of treating cancer has risen to unprecedented heights, putting tremendous financial pressure on patients, payers, and society. Previous studies have documented the rising prices of cancer drugs at launch, but less critical attention has been paid to the cost of these drugs after launch. We used pharmacy claims for commercially insured individuals to examine trends in postlaunch prices over time for orally administered anticancer drugs recently approved by the Food and Drug Administration (FDA). In the period 2007-13, inflation-adjusted per patient monthly drug prices increased 5 percent each year. Certain market changes also played a role, with prices rising an additional 10 percent with each supplemental indication approved by the FDA and declining 2 percent with the FDA's approval of a competitor drug. Our findings suggest that there is currently little competitive pressure in the oral anticancer drug market. Policy makers who wish to reduce the costs of anticancer drugs should consider implementing policies that affect prices not only at launch but also later.

  4. Shiga toxin type 2 (Stx2), a potential agent of bioterrorism, has a short distribution and a long elimination half-life, and induces kidney and thymus lesions in rats.

    PubMed

    Liu, Yue-Nan; Wang, Sheng-Han; Li, Tao; Wang, Qin; Tu, Wei; Cai, Kun; Hou, Xiao-Jun; Tian, Ren-Mao; Gao, Xiang; Liu, Hao; Xiao, Le; Shi, Jing; Cheng, Yuan-Guo; Li, Jian-Chun; Wang, Hui

    2011-09-01

    Shiga toxin type 2, a major virulence factor produced by the Shiga toxin-producing Escherichia coli, is a potential toxin agent of bioterrorism. In this study, iodine-125 (125I) was used as an indicator to describe the in vivo Stx2 biodistribution profile. The rats were injected intravenously (i.v.) with 125I-Stx2 at three doses of 5.1-127.5 μg/kg body weight. Stx2 had a short distribution half-life (t (1/2)α, less than 6 min) and a long elimination half-life in rat. The toxicokinetics of Stx2 in rats was dose dependent and nonlinear. Stx2 concentrations in various tissues were detected at 5-min, 0.5-h, and 72-h postinjection. High radioactivity was found in the lungs, kidneys, nasal turbinates, and sometimes in the eyes, which has never been reported in previous studies. In a preliminary assessment, lesions were found in the kidney and thymus.

  5. Engineering of a bispecific affibody molecule towards HER2 and HER3 by addition of an albumin-binding domain allows for affinity purification and in vivo half-life extension.

    PubMed

    Malm, Magdalena; Bass, Tarek; Gudmundsdotter, Lindvi; Lord, Martin; Frejd, Fredrik Y; Ståhl, Stefan; Löfblom, John

    2014-09-01

    Emerging strategies in cancer biotherapy include the generation and application of bispecific antibodies, targeting two tumor-associated antigens for improved tumor selectivity and potency. Here, an alternative format for bispecific molecules was designed and investigated, in which two Affibody molecules were linked by an albumin-binding domain (ABD). Affibody molecules are small (6 kDa) affinity proteins and this new format allows for engineering of molecules with similar function as full-length bispecific antibodies, but in a dramatically smaller size (around eight-fold smaller). The ABD was intended to function both as a tag for affinity purification as well as for in vivo half-life extension in future preclinical and clinical investigations. Affinity-purified bispecific Affibody molecules, targeting HER2 and HER3, showed simultaneous binding to the three target proteins (HER2, HER3, and albumin) when investigated in biosensor assays. Moreover, simultaneous interactions with the receptors and albumin were demonstrated using flow cytometry on cancer cells. The bispecific Affibody molecules were also able to block ligand-induced phosphorylation of the HER receptors, indicating an anti-proliferative effect. We believe that this compact and flexible format has great potential for developing new potent bispecific affinity proteins in the future, as it combines the benefits of a small size (e.g. improved tissue penetration and reduced cost of goods) with a long circulatory half-life.

  6. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase.

    PubMed

    Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert

    2015-10-01

    Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 µM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl(-) and the decreased HCO3 (-) concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na-K-2Cl electroneutral cotransporter or Cl(-)/HCO3 (-) anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells. PMID:25868554

  7. Thiazolidinedione Drugs Promote Onset, Alter Characteristics, and Increase Mortality of Ischemic Ventricular Fibrillation in Pigs

    PubMed Central

    Sarraf, Mohammad; Lu, Li; Ye, Shuyu; Reiter, Michael J.; Greyson, Clifford R.

    2016-01-01

    Purpose Despite favorable metabolic and vascular effects, thiazolidinedione (TZD) drugs have not convincingly reduced cardiovascular mortality in clinical trials, raising the possibility of countervailing, off-target effects. We previously showed that TZDs block cardiac ATP-sensitive potassium (KATP) channels in pigs. In this study, we investigated whether TZDs affect onset, spectral characteristics, and mortality of ischemic ventricular fibrillation (VF) and whether such effects are recapitulated by a non-selective KATP blocker (glyburide) or a mitochondrial KATP blocker (5-hydroxydecanoate). Methods A total of 121 anesthetized pigs were pre-treated with TZD (pioglitazone or rosiglitazone, 1 mg/kg IV, resulting in clinically relevant plasma concentrations), glyburide (1 mg/kg IV), 5-hydroxydecanoate (5 mg/kg IV) or inert vehicle. Ischemia was produced by occlusion of the left anterior descending coronary artery. In a subset of pigs treated with rosiglitazone or vehicle, ischemic preconditioning was performed. Results VF developed in all but 6 pigs. In non-preconditioned pigs, onset of VF occurred sooner with pioglitazone (11± 3 min, p<0.05) or rosiglitazone (14±3 min, p=0.06) than with vehicle (20±2 min). Defibrillation of VF was successful in 44% of pigs treated with vehicle, compared with 0% with pioglitazone (p=0.057) and 33% with rosiglitazone (NS). After ischemic preconditioning, defibrillation was successful in 62% of pigs treated with vehicle, compared with 26% treated with rosiglitazone (p=0.03). TZDs attenuated slowing of conduction due to ischemia and shifted ECG power spectra during VF toward higher frequencies. All effects of TZDs were recapitulated by glyburide, but not by 5-hydroxydecanoate, supporting an interaction of TZDs with the sarcolemmal KATP channel. Conclusion In a porcine model, TZDs promote onset and increase mortality of ischemic VF, associated with alterations of conduction and VF spectral characteristics. Similar effects in a

  8. Sphaeropsidin A shows promising activity against drug-resistant cancer cells by targeting regulatory volume increase

    PubMed Central

    Mathieu, Véronique; Chantôme, Aurélie; Lefranc, Florence; Cimmino, Alessio; Miklos, Walter; Paulitschke, Verena; Mohr, Thomas; Maddau, Lucia; Kornienko, Alexander; Berger, Walter; Vandier, Christophe; Evidente, Antonio; Delpire, Eric; Kiss, Robert

    2016-01-01

    Despite the recent advances in the treatment of tumors with intrinsic chemotherapy resistance, such as melanoma and renal cancers, their prognosis remains poor and new chemical agents with promising activity against these cancers are urgently needed. Sphaeropsidin A, a fungal metabolite whose anticancer potential had previously received little attention, was isolated from Diplodia cupressi and found to display specific anticancer activity in vitro against melanoma and kidney cancer subpanels in the National Cancer Institute (NCI) 60-cell line screen. The NCI data revealed a mean LC50 of ca. 10 μM and a cellular sensitivity profile that did not match that of any other agent in the 765,000 compound database. Subsequent mechanistic studies in melanoma and other multidrug-resistant in vitro cancer models showed that sphaeropsidin A can overcome apoptosis as well as multidrug resistance by inducing a marked and rapid cellular shrinkage related to the loss of intracellular Cl− and the decreased HCO3− concentration in the culture supernatant. These changes in ion homeostasis and the absence of effects on the plasma membrane potential were attributed to the sphaeropsidin A-induced impairment of regulatory volume increase (RVI). Preliminary results also indicate that depending on the type of cancer, the sphaeropsidin A effects on RVI could be related to Na–K–2Cl electroneutral cotransporter or Cl−/HCO3− anion exchanger(s) targeting. This study underscores the modulation of ion-transporter activity as a promising therapeutic strategy to combat drug-resistant cancers and identifies the fungal metabolite, sphaeropsidin A, as a lead to develop anticancer agents targeting RVI in cancer cells. PMID:25868554

  9. Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi.

    PubMed

    van Oosterhout, J J; Dzinjalamala, F K; Dimba, A; Waterhouse, D; Davies, G; Zijlstra, E E; Molyneux, M E; Molyneux, E M; Ward, S

    2015-10-01

    pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the Cmax and AUC0-24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.

  10. Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi

    PubMed Central

    Dzinjalamala, F. K.; Dimba, A.; Waterhouse, D.; Davies, G.; Zijlstra, E. E.; Molyneux, M. E.; Molyneux, E. M.; Ward, S.

    2015-01-01

    pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the Cmax and AUC0–24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further. PMID:26248378

  11. Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi.

    PubMed

    van Oosterhout, J J; Dzinjalamala, F K; Dimba, A; Waterhouse, D; Davies, G; Zijlstra, E E; Molyneux, M E; Molyneux, E M; Ward, S

    2015-10-01

    pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the Cmax and AUC0-24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further. PMID:26248378

  12. Use of Aspirin or Nonsteroidal Anti-inflammatory Drugs Increases Risk for Diverticulitis and Diverticular Bleeding

    PubMed Central

    Strate, Lisa L.; Liu, Yan L.; Huang, Edward S.; Giovannucci, Edward L.; Chan, Andrew T.

    2011-01-01

    BACKGROUND & AIMS Nonsteroidal Anti-inflammatory Drugs (NSAIDs), including aspirin, have been implicated in diverticular complications. We examined the influence of aspirin and NSAID use on risk of diverticulitis and diverticular bleeding in a large prospective cohort. METHODS We studied 47,210 US men in the Health Professionals Follow-up Study cohort who were 40–75 years old at baseline, in 1986. We assessed use of aspirin, non-aspirin NSAIDs, and other risk factors biennially. We identified men with diverticulitis or diverticular bleeding based on responses to biennial and supplemental questionnaires. RESULTS We documented 939 cases of diverticulitis and 256 cases of diverticular bleeding during a 22-year period of follow-up. After adjustment for risk factors, men who used aspirin regularly (≥2 times per week) had a multivariable relative risk (RR) of 1.25 (95% confidence interval [CI], 1.05–1.47) for diverticulitis and RR of 1.70 (95% CI, 1.21–2.39) for diverticular bleeding, compared with non-users of aspirin and NSAIDs. Use of aspirin at intermediate doses (2–5.9 standard, 325 mg, tablets per week) and frequency (4–6 days per week) were associated with the highest risk of bleeding (multivariable RR=2.32; 95% CI, 1.34–4.02, and multivariable RR=3.13; 95% CI, 1.82–5.38, respectively). Regular users of non-aspirin NSAIDs also had an increased risk of diverticulitis (multivariable RR=1.72; 95% CI, 1.40–2.11) and diverticular bleeding (multivariable RR=1.74; 95% CI, 1.15–2.64), compared with men who denied use of these medications. CONCLUSIONS Regular use of aspirin or NSAIDs is associated with an increased risk for diverticulitis and diverticular bleeding. Patients at risk of diverticular complications should carefully consider the potential risks and benefits of using these medications. PMID:21320500

  13. Increased Risk of Autism Development in Children Whose Mothers Experienced Birth Complications or Received Labor and Delivery Drugs

    PubMed Central

    Smallwood, Melissa; Sareen, Ashley; Baker, Emma; Hannusch, Rachel; Kwessi, Eddy

    2016-01-01

    Autism spectrum disorder (ASD) is a perplexing and pervasive developmental disorder characterized by social difficulties, communicative deficits, and repetitive behavior. The increased rate of ASD diagnosis has raised questions concerning the genetic and environmental factors contributing to the development of this disorder; meanwhile, the cause of ASD remains unknown. This study surveyed mothers of ASD and non-ASD children to determine possible effects of labor and delivery (L&D) drugs on the development of ASD. The survey was administered to mothers; however, the results were analyzed by child, as the study focused on the development of autism. Furthermore, an independent ASD dataset from the Southwest Autism Research and Resource Center was analyzed and compared. Indeed, L&D drugs are associated with ASD (p = .039). Moreover, the Southwest Autism Research and Resource Center dataset shows that the labor induction drug, Pitocin, is significantly associated with ASD (p = .004). We also observed a synergistic effect between administrations of L&D drugs and experiencing a birth complication, in which both obstetrics factors occurring together increased the likelihood of the fetus developing ASD later in life (p = .0003). The present study shows the possible effects of L&D drugs, such as Pitocin labor-inducing and analgesic drugs, on children and ASD. PMID:27511908

  14. Increased Risk of Autism Development in Children Whose Mothers Experienced Birth Complications or Received Labor and Delivery Drugs.

    PubMed

    Smallwood, Melissa; Sareen, Ashley; Baker, Emma; Hannusch, Rachel; Kwessi, Eddy; Williams, Tyisha

    2016-08-01

    Autism spectrum disorder (ASD) is a perplexing and pervasive developmental disorder characterized by social difficulties, communicative deficits, and repetitive behavior. The increased rate of ASD diagnosis has raised questions concerning the genetic and environmental factors contributing to the development of this disorder; meanwhile, the cause of ASD remains unknown. This study surveyed mothers of ASD and non-ASD children to determine possible effects of labor and delivery (L&D) drugs on the development of ASD. The survey was administered to mothers; however, the results were analyzed by child, as the study focused on the development of autism. Furthermore, an independent ASD dataset from the Southwest Autism Research and Resource Center was analyzed and compared. Indeed, L&D drugs are associated with ASD (p = .039). Moreover, the Southwest Autism Research and Resource Center dataset shows that the labor induction drug, Pitocin, is significantly associated with ASD (p = .004). We also observed a synergistic effect between administrations of L&D drugs and experiencing a birth complication, in which both obstetrics factors occurring together increased the likelihood of the fetus developing ASD later in life (p = .0003). The present study shows the possible effects of L&D drugs, such as Pitocin labor-inducing and analgesic drugs, on children and ASD. PMID:27511908

  15. Therapeutic drug monitoring of voriconazole: a case report of multiple drug interactions in a patient with an increased CYP2C19 activity

    PubMed Central

    2014-01-01

    Background Voriconazole is metabolized by cytochrome P450 (CYP) 2C19 and CYP 3A4. Drug-drug interactions and genetic polymorphisms modulate their activities. Case presentation A 35-year old African female patient with resistant HIV and a cerebral mass of unknown origin was treated with voriconazole for a suspicion of disseminated Aspergillosis infection. Voriconazole trough concentrations (C0) were within target range while the patient was under esomeprazole, a CYP2C19 inhibitor. Phenotyping showed decreased CYP2C19 activity, whereas genotyping showed a variant allele associated with increased enzyme activity. The patient was switched to ranitidine because of the introduction of atazanavir. CYP3A4 inhibition by atazanavir combined with uninhibited CYP2C19 activity resulted in subtherapeutic voriconazole C0. The reintroduction of esomeprazole allowed restoring voriconazole C0 back to target range. Conclusion The integration of drug-drug interactions and pharmacogenetics data is crucial to interpret drug concentrations correctly, thus preventing suboptimal exposure to voriconazole. PMID:25120580

  16. Short-term Efficacy of a Brief Intervention to Reduce Drug Misuse and Increase Drug Treatment Utilization Among Adult Emergency Department Patients

    PubMed Central

    Merchant, Roland C.; Baird, Janette R.; Liu, Tao

    2016-01-01

    Objectives Although brief interventions (BIs) have shown some success for smoking cessation and alcohol misuse, it is not known if they can be applied in the emergency department (ED) to drug use and misuse. The objectives of this investigation were to assess the 3-month efficacy of a BI to reduce drug use and misuse, increase drug treatment services utilization among adult ED patients, and identify subgroups more likely to benefit from the BI. Methods This randomized, controlled trial enrolled 18- to 64-year-old English- or Spanish-speaking patients from two urban, academic EDs whose responses to the Alcohol, Smoking, and Substance Involvement Screening Test indicated a need for a brief or intensive intervention. Treatment participants received a tailored BI, while control participants only completed the study questionnaires. At the 3-month follow-up, each participant’s past 3-month drug use and misuse and treatment utilization were compared to his or her baseline enrollment data. Regression modeling was used to identify subgroups of patients (per demographic and clinical factors) more likely to stop or reduce their drug use or misuse or engage in drug treatment by the 3-month follow-up assessment. Results Of the 1,030 participants, the median age was 30 years (interquartile range = 24 to 42 years), and 46% were female; 57% were white/non-Hispanic, 24.9% were black/non-Hispanic, and 15% were Hispanic. The most commonly misused drugs were marijuana, prescription opioids, cocaine/crack, and benzodiazepines. Although at follow-up the proportions of participants reporting any past 3-month drug misuse had decreased in both study arms (control 84% vs. treatment 78%), the decreases were similar between the two study arms (Δ−6.3%; 95% confidence interval [CI] = −13.0% to 0.0). In addition, at follow-up there were no differences between study arms in those who were currently receiving drug treatment (Δ1.8; 95% CI = −3.5 to 6.8), who had received treatment during

  17. Improved measurement of the half-life of the Jπ = 8- nuclear isomer 152m2 Eu

    SciTech Connect

    Humby, Peter; Simon, Anna; Beausang, C. W.; Ross, T. J.; Hughes, R. O.; Burke, J. T.; Casperson, R. J.; Koglin, J.; Ota, S.; Allmond, James M.; McCleskey, M.; McCleskey, E.; Saastamoinen, A.; Chyzh, R.; Dag, M.; Gell, K.; Tarlow, T.; Vyas, G.

    2015-02-23

    The standard γ-ray energy calibration source 152Eu is well known based on the 13.5 y decay of its ground state. Nevertheless, in addition to this decay 152Eu also has two relatively long-lived isomeric states: a 9 h Jπ=0- state at E*=46 keV and a 96 min Jπ=8- state at E*=148 keV. Here we report a new measurement of the half-lives of both of these isomeric states. Excited states in 152Eu were populated following the 154Sm (p,3n) reaction using a 25 MeV proton beam from the K-150 cyclotron at the Cyclotron Institute of Texas A&M University. Post irradiation, γ rays from the de-excitation of the long lived isomeric states were measured using the six BGO shielded high-purity germanium (HPGe) clover detectors that are part of the STARLiTeR array. The half-life of the Jπ=8- isomer 152m2Eu was obtained by measuring the decrease in intensity of the 90 keV γ ray from the cascade to the ground state. The half-life of this state was measured to be 95.8(4) min which is in agreement with and significantly more precise than the previously measured value of 96(1) min. In a manner similar to the ground state the second long-lived isomer 151m1Eu, the Jπ=0- state at 46 keV, β decays to excited states in 152Gd and 152Sm. Also, the half-life of this state was measured to be 9.39(7) h using five γ-ray transitions.

  18. Emergency slaughter of casualty cattle increases the prevalence of anthelmintic drug residues in muscle.

    PubMed

    Cooper, K M; Whyte, M; Danaher, M; Kennedy, D G

    2012-08-01

    The ProSafeBeef project studied the prevalence of residues of anthelmintic drugs used to control parasitic worms and fluke in beef cattle in Ireland. Injured (casualty) cattle may enter the human food chain under certain conditions, verified by an attending veterinarian and the livestock keeper. An analytical survey was conducted to determine if muscle from casualty cattle contained a higher prevalence of anthelmintic drug residues than healthy (full slaughter weight) cattle as a result of possible non-observance of complete drug withdrawal periods. A validated analytical method based on matrix solid-phase dispersive extraction (QuEChERS) and ultra-performance liquid chromatography-tandem mass spectrometry was used to quantify 37 anthelmintic drugs and metabolites in muscle (assay decision limits, CCα, 0.15-10.2 µg kg⁻¹). Of 199 control samples of beef purchased in Irish shops, 7% contained detectable anthelmintic drug residues but all were compliant with European Union Maximum Residue Limits (MRL). Of 305 muscle samples from injured cattle submitted to abattoirs in Northern Ireland, 17% contained detectable residues and 2% were non-compliant (containing either residues at concentrations above the MRL or residues of a compound unlicensed for use in cattle). Closantel and ivermectin were the most common residues, but a wider range of drugs was detected in muscle of casualty cattle than in retail beef. These data suggest that specific targeting of casualty cattle for testing for anthelmintic residues may be warranted in a manner similar to the targeted testing for antimicrobial compounds often applied in European National Residues Surveillance Schemes. PMID:22632575

  19. The cost offsets and cost-effectiveness associated with pegylated drugs: a review of the literature.

    PubMed

    Becker, Russell; Dembek, Carole; White, Leigh Ann; Garrison, Louis P

    2012-12-01

    Pegylation (PEG) is used as both a drug-delivery and a drug-modification technology in ten drugs approved by the US FDA. Benefits of PEG drugs can include increased plasma half-life, longer absorption, improved tumor targeting and less antigenicity and immunogenicity. Clinical benefits of PEG drugs over non-PEG drugs may include reduced administration, improved efficacy, improved tolerability, and decreased severity and incidence of adverse events. This study reviews 37 economic literature publications featuring PEG drugs versus non-PEG versions. PEG drugs showed some reductions in overall costs resulting from various offsets including fewer administrations, lower adverse event treatment costs, reduced disease complication costs or reduced inpatient/outpatient costs. Of the 18 cost-effectiveness studies reviewed, 17 of them found PEG drugs to be cost effective versus the non-PEG drugs. Cost offsets and cost-effectiveness of PEG drugs have been demonstrated in multiple studies across various therapies, indications and country settings, and the results have been found to be stable when key parameters were varied in analyses. Further studies are needed to assess the potential for cost savings and cost-effectiveness for new PEG therapies in development.

  20. The use of thermodynamic and kinetic data in drug discovery: decisive insight or increasing the puzzlement?

    PubMed

    Klebe, Gerhard

    2015-02-01

    The prime property to rate the success of hit-to-lead-to-drug optimization in drug discovery is binding affinity. Rational approaches try to relate this property with structure. Affinity can be linked to the thermodynamic property, Gibbs free energy of binding, which itself factorizes into enthalpy and entropy. With respect to kinetic properties, affinity can be associated with the ratio of koff and kon of complex formation. Do these features help to obtain better insight into affinity? The present viewpoint assesses our current understanding of thermodynamics- or kinetics-structure relationships and questions the accuracy of data collected to learn about the thermodynamic and kinetic basis to comprehend affinity.

  1. Targeting the chromatin remodeling enzyme BRG1 increases the efficacy of chemotherapy drugs in breast cancer cells

    PubMed Central

    Wu, Qiong; Sharma, Soni; Cui, Hang; LeBlanc, Scott E.; Zhang, Hong; Muthuswami, Rohini; Nickerson, Jeffrey A.; Imbalzano, Anthony N.

    2016-01-01

    Brahma related gene product 1 (BRG1) is an ATPase that drives the catalytic activity of a subset of the mammalian SWI/SNF chromatin remodeling enzymes. BRG1 is overexpressed in most human breast cancer tumors without evidence of mutation and is required for breast cancer cell proliferation. We demonstrate that knockdown of BRG1 sensitized triple negative breast cancer cells to chemotherapeutic drugs used to treat breast cancer. An inhibitor of the BRG1 bromodomain had no effect on breast cancer cell viability, but an inhibitory molecule that targets the BRG1 ATPase activity recapitulated the increased drug efficacy observed in the presence of BRG1 knockdown. We further demonstrate that inhibition of BRG1 ATPase activity blocks the induction of ABC transporter genes by these chemotherapeutic drugs and that BRG1 binds to ABC transporter gene promoters. This inhibition increased intracellular concentrations of the drugs, providing a likely mechanism for the increased chemosensitivity. Since ABC transporters and their induction by chemotherapy drugs are a major cause of chemoresistance and treatment failure, these results support the idea that targeting the enzymatic activity of BRG1 would be an effective adjuvant therapy for breast cancer. PMID:27029062

  2. 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

  3. p53 Pulses Diversify Target Gene Expression Dynamics in an mRNA Half-Life-Dependent Manner and Delineate Co-regulated Target Gene Subnetworks.

    PubMed

    Porter, Joshua R; Fisher, Brian E; Batchelor, Eric

    2016-04-27

    The transcription factor p53 responds to DNA double-strand breaks by increasing in concentration in a series of pulses of fixed amplitude, duration, and period. How p53 pulses influence the dynamics of p53 target gene expression is not understood. Here, we show that, in bulk cell populations, patterns of p53 target gene expression cluster into groups with stereotyped temporal behaviors, including pulsing and rising dynamics. These behaviors correlate statistically with the mRNA decay rates of target genes: short mRNA half-lives produce pulses of gene expression. This relationship can be recapitulated by mathematical models of p53-dependent gene expression in single cells and cell populations. Single-cell transcriptional profiling demonstrates that expression of a subset of p53 target genes is coordinated across time within single cells; p53 pulsing attenuates this coordination. These results help delineate how p53 orchestrates the complex DNA damage response and give insight into the function of pulsatile signaling pathways.

  4. Solvent Free Fabrication of Micro and Nanostructured Drug Coatings by Thermal Evaporation for Controlled Release and Increased Effects

    PubMed Central

    Zarie, Eman S.; Kaidas, Viktor; Gedamu, Dawit; Mishra, Yogendra K.; Adelung, Rainer; Furkert, Franz H.; Scherließ, Regina; Steckel, Hartwig; Groessner-Schreiber, Birte

    2012-01-01

    Nanostructuring of drug delivery systems offers many promising applications like precise control of dissolution and release kinetics, enhanced activities, flexibility in terms of surface coatings, integration into implants, designing the appropriate scaffolds or even integrating into microelectronic chips etc. for different desired applications. In general such kind of structuring is difficult due to unintentional mixing of chemical solvents used during drug formulations. We demonstrate here the successful solvent-free fabrication of micro-nanostructured pharmaceutical molecules by simple thermal evaporation (TE). The evaporation of drug molecules and their emission to a specific surface under vacuum led to controlled assembling of the molecules from vapour phase to solid phase. The most important aspects of thermal evaporation technique are: solvent-free, precise control of size, possibility of fabricating multilayer/hybrid, and free choice of substrates. This could be shown for twenty eight pharmaceutical substances of different chemical structures which were evaporated on surfaces of titanium and glass discs. Structural investigations of different TE fabricated drugs were performed by atomic force microscopy, scanning electron microscopy and Raman spectroscopy which revealed that these drug substances preserve their structurality after evaporation. Titanium discs coated with antimicrobial substances by thermal evaporation were subjected to tests for antibacterial or antifungal activities, respectively. A significant increase in their antimicrobial activity was observed in zones of inhibition tests compared to controls of the diluted substances on the discs made of paper for filtration. With thermal evaporation, we have successfully synthesized solvent-free nanostructured drug delivery systems in form of multilayer structures and in hybrid drug complexes respectively. Analyses of these substances consolidated that thermal evaporation opens up the possibility to

  5. Solvent free fabrication of micro and nanostructured drug coatings by thermal evaporation for controlled release and increased effects.

    PubMed

    Zarie, Eman S; Kaidas, Viktor; Gedamu, Dawit; Mishra, Yogendra K; Adelung, Rainer; Furkert, Franz H; Scherließ, Regina; Steckel, Hartwig; Groessner-Schreiber, Birte

    2012-01-01

    Nanostructuring of drug delivery systems offers many promising applications like precise control of dissolution and release kinetics, enhanced activities, flexibility in terms of surface coatings, integration into implants, designing the appropriate scaffolds or even integrating into microelectronic chips etc. for different desired applications. In general such kind of structuring is difficult due to unintentional mixing of chemical solvents used during drug formulations. We demonstrate here the successful solvent-free fabrication of micro-nanostructured pharmaceutical molecules by simple thermal evaporation (TE). The evaporation of drug molecules and their emission to a specific surface under vacuum led to controlled assembling of the molecules from vapour phase to solid phase. The most important aspects of thermal evaporation technique are: solvent-free, precise control of size, possibility of fabricating multilayer/hybrid, and free choice of substrates. This could be shown for twenty eight pharmaceutical substances of different chemical structures which were evaporated on surfaces of titanium and glass discs. Structural investigations of different TE fabricated drugs were performed by atomic force microscopy, scanning electron microscopy and Raman spectroscopy which revealed that these drug substances preserve their structurality after evaporation. Titanium discs coated with antimicrobial substances by thermal evaporation were subjected to tests for antibacterial or antifungal activities, respectively. A significant increase in their antimicrobial activity was observed in zones of inhibition tests compared to controls of the diluted substances on the discs made of paper for filtration. With thermal evaporation, we have successfully synthesized solvent-free nanostructured drug delivery systems in form of multilayer structures and in hybrid drug complexes respectively. Analyses of these substances consolidated that thermal evaporation opens up the possibility to

  6. Hydrocortisone and dexamethasone in very deformable drug carriers have increased biological potency, prolonged effect, and reduced therapeutic dosage.

    PubMed

    Cevc, Gregor; Blume, Gabriele

    2004-05-27

    We characterised biological properties of novel formulations of two low-potency glucocorticosteroids, dexamethasone and hydrocortisone, which have an equivalent dose ratio of 1:50 in vasoconstriction tests. The rate of such carrier-mediated, mainly non-diffusive glucocorticosteroids transport with very deformable lipid vesicles (Transfersomes) through the skin, and the corresponding cutaneous drug biodistribution data, were complemented with the drug bio-efficacy studies. The minimum effective drug dose that reduces arachidonic acid-induced murine ear oedema by 50% was used as one bioactivity indicator. The minimum drug amount ensuring such an effect in mouse skin decreases appreciably when a corticosteroid is applied epicutaneously with very deformable vesicles rather than a lotion or a crème. Specifically, the minimum effective dose for hydrocortisone in very deformable carriers is 2-3 microg cm(-2) whereas for the crème- or lotion-like preparations at least 10 microg cm(-2) is required. Such three- to fivefold relative increase of hydrocortisone potency is accompanied by at least 13%, and more often >20%, absolute drug potency enhancement. The delivery of hydrocortisone with very deformable carriers moreover prolongs the suppression of the drug-induced oedema nearly 2-fold (to approximately 24 h per application). The effective dose of dexamethasone delivered with very deformable vesicles into murine skin is reduced >10 times compared with the crème- or lotion-based products. Specifically, less than 0.1 microg cm(-2) dexamethasone in very deformable vesicles suppresses the arachidonic acid-induced murine ear oedema >50%, on the average. Dexamethasone use on the skin in such vesicles extends the duration of drug action fourfold, compared with a commercial crème, i.e. to >48 h per application. Epicutaneous use of glucocorticosteroids in very deformable vesicles also diminishes such drug's abrasion sensitivity and may increase the general robustness of drug

  7. Increased Drug Use and STI Risk with Injection Drug Use Among HIV-Seronegative Heterosexual Methamphetamine Users†

    PubMed Central

    Cheng, W. Susan; Garfein, Richard S.; Semple, Shirley J.; Strathdee, Steffanie A.; Zians, James K.; Patterson, Thomas L.

    2010-01-01

    Methamphetamine (MA) use has been found to be associated with increased risk of HIV and sexually transmitted infections (STI) among men having sex with men, but it is unknown whether those who inject MA are at greater risk for these infections than those who administer MA by other routes. Furthermore, comparable data from heterosexual MA users are lacking. We investigated whether the HIV and STI risks of male and female heterosexual MA users who inject MA differ from those of comparable users who do not inject. Between 2001 and 2005, we interviewed 452 HIV-negative men and women aged 18 and older who had recently used MA and engaged in unprotected sex. Their mean age was 36.6 years; 68% were male; ethnicity was 49.4% Caucasian, 26.8% African-American, and 12.8% Hispanic. Logistic regression identified factors associated with injecting MA. Compared to non-IDU, IDU were more likely to: be Caucasian; be homeless; have used MA for a longer period and used more grams of MA in the last 30 days; have a history of felony conviction; and report a recent STI. HIV and STI prevention interventions should be tailored according to MA users’ method of administration. PMID:20464802

  8. Increased Clearance of Antipyrine and d-Propranolol after Phenobarbital Treatment in the Monkey

    PubMed Central

    Branch, Robert A.; Shand, David G.; Wilkinson, Grant R.; Nies, Alan S.

    1974-01-01

    The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179±15 to 239±27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value. PMID:4205524

  9. 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.…

  10. Direct-to-Consumer Drug Advertisements Can Paradoxically Increase Intentions to Adopt Lifestyle Changes

    PubMed Central

    Mathur, Maya B.; Gould, Michael; Khazeni, Nayer

    2016-01-01

    Background: Direct-to-consumer (DTC) prescription drug advertisements are thought to induce “boomerang effects,” meaning they reduce the perceived effectiveness of a potential alternative option: non-pharmaceutical treatment via lifestyle change. Past research has observed such effects using artificially created, text-only advertisements that may not adequate capture the complex, conflicting portrayal of lifestyle change in real television advertisements. In other risk domains, individual “problem status” often moderates boomerang effects, such that subjects who currently engage in the risky behavior exhibit the strongest boomerang effects. Objectives: We aimed to assess whether priming with real DTC television advertisements elicited boomerang effects on perceptions of lifestyle change and whether these effects, if present, were moderated by individual problem status. Methods: We assembled a sample of real, previously aired DTC television advertisements in order to naturalistically capture the portrayal of lifestyle change in real advertisements. We randomized 819 adults in the United States recruited via Amazon Mechanical Turk to view or not view an advertisement for a prescription drug. We further randomized subjects to judge either lifestyle change or drugs on three measures: general effectiveness, disease severity for a hypothetical patient, and personal intention to use the intervention if diagnosed with the target health condition. Results: Advertisement exposure induced a statistically significant, but weak, boomerang effect on general effectiveness (p = 0.01, partial R2 = 0.007) and did not affect disease severity score (p = 0.32, partial R2 = 0.0009). Advertisement exposure elicited a reverse boomerang effect of similar effect size on personal intentions, such that advertisement-exposed subjects reported comparatively higher intentions to use lifestyle change relative to drugs (p = 0.006, partial R2 = 0.008). Individual problem status did not

  11. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment.

    PubMed

    Tannergren, Christer; Bergendal, Anna; Lennernäs, Hans; Abrahamsson, Bertil

    2009-01-01

    The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) < 50%). There was a clear correlation between in vitro Caco-2 permeability and Frel(colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

  12. Convection-enhanced drug delivery of interleukin-4 Pseudomonas exotoxin (PRX321): increased distribution and magnetic resonance monitoring.

    PubMed

    Mardor, Y; Last, D; Daniels, D; Shneor, R; Maier, S E; Nass, D; Ram, Z

    2009-08-01

    Convection-enhanced drug delivery (CED) enables achieving a drug concentration within brain tissue and brain tumors that is orders of magnitude higher than by systemic administration. Previous phase I/II clinical trials using intratumoral convection of interleukin-4 Pseudomonas exotoxin (PRX321) have demonstrated an acceptable safety and toxicity profile with promising signs of therapeutic activity. The present study was designed to assess the distribution efficiency and toxicity of this PRX321 using magnetic resonance imaging (MRI) and to test whether reformulation with increased viscosity could enhance drug distribution. Convection of low- [0.02% human serum albumin (HSA)] and high-viscosity (3% HSA) infusates mixed with gadolinium-diethylenetriamine pentaacetic acid and PRX321 were compared with low- and high-viscosity infusates without the drug, in normal rat brains. MRI was used for assessment of drug distribution and detection of early and late toxicity. Representative brain samples were subjected to histological examination. Distribution volumes calculated from the magnetic resonance images showed that the average distribution of 0.02% HSA was larger than that of 0.02% HSA with PRX321 by a factor of 1.98 (p < 0.02). CED of 3.0% HSA, with or without PRX321, tripled the volume of distribution compared with 0.02% HSA with PRX321 (p < 0.015). No drug-related toxicity was detected. These results suggest that the impeded convection of the PRX321 infusate used in previous clinical trials can be reversed by increasing infusate viscosity and lead to tripling of the volume of distribution. This effect was not associated with any detectable toxicity. A similar capability to reverse impeded convection was also demonstrated in a CED model using acetic acid. These results will be implemented in an upcoming phase IIb PRX321 CED trial with a high-viscosity infusate.

  13. Pharmacokinetic Interactions for Drugs with a Long Half-Life—Evidence for the Need of Model-Based Analysis.

    PubMed

    Svensson, Elin M; Acharya, Chayan; Clauson, Björn; Dooley, Kelly E; Karlsson, Mats O

    2016-01-01

    Pharmacokinetic drug-drug interactions (DDIs) can lead to undesired drug exposure, resulting in insufficient efficacy or aggravated toxicity. Accurate quantification of DDIs is therefore crucial but may be difficult when full concentration-time profiles are problematic to obtain. We have compared non-compartmental analysis (NCA) and model-based predictions of DDIs for long half-life drugs by conducting simulation studies and reviewing published trials, using antituberculosis drug bedaquiline (BDQ) as a model compound. Furthermore, different DDI study designs were evaluated. A sequential design mimicking conducted trials and a population pharmacokinetic (PK) model of BDQ and the M2 metabolite were utilized in the simulations where five interaction scenarios from strong inhibition (clearance fivefold decreased) to strong induction (clearance fivefold increased) were evaluated. In trial simulations, NCA systematically under-predicted the DDIs’ impact. The bias in average exposure was 29–96% for BDQ and 20–677% for M2. The model-based analysis generated unbiased predictions, and simultaneous fitting of metabolite data increased precision in DDI predictions. The discrepancy between the methods was also apparent for conducted trials, e.g., lopinavir/ritonavir was predicted to increased BDQ exposure 22% by NCA and 188% by model-based methods. In the design evaluation, studies with parallel designs were considered and shown to generally be inferior to sequential/cross-over designs. However, in the case of low inter-individual variability and no informative metabolite data, a prolonged parallel design could be favored. Model-based analysis for DDI assessments is preferable over NCA for victim drugs with a long half-life and should always be used when incomplete concentration-time profiles are part of the analysis.

  14. Brief intermittent cocaine self-administration and abstinence sensitizes cocaine effects on the dopamine transporter and increases drug seeking.

    PubMed

    Calipari, Erin S; Siciliano, Cody A; Zimmer, Benjamin A; Jones, Sara R

    2015-02-01

    Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of 1 or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction. PMID:25212486

  15. Brief Intermittent Cocaine Self-Administration and Abstinence Sensitizes Cocaine Effects on the Dopamine Transporter and Increases Drug Seeking

    PubMed Central

    Calipari, Erin S; Siciliano, Cody A; Zimmer, Benjamin A; Jones, Sara R

    2015-01-01

    Although traditional sensitization paradigms, which result in an augmentation of cocaine-induced locomotor behavior and dopamine (DA) overflow following repeated experimenter-delivered cocaine injections, are often used as a model to study drug addiction, similar effects have been difficult to demonstrate following cocaine self-administration. We have recently shown that intermittent access (IntA) to cocaine can result in increased cocaine potency at the DA transporter (DAT); however, traditional sensitization paradigms often show enhanced effects following withdrawal/abstinence periods. Therefore, we determined a time course of IntA-induced sensitization by examining the effects of 1 or 3 days of IntA, as well as a 7-day abstinence period on DA function, cocaine potency, and reinforcement. Here we show that cocaine potency is increased following as little as 3 days of IntA and further augmented following an abstinence period. In addition, IntA plus abstinence produced greater evoked DA release in the presence of cocaine as compared with all other groups, demonstrating that following abstinence, both cocaine's ability to increase DA release and inhibit uptake at the DAT, two separate mechanisms for increasing DA levels, are enhanced. Finally, we found that IntA-induced sensitization of the DA system resulted in an increased reinforcing efficacy of cocaine, an effect that was augmented after the 7-day abstinence period. These results suggest that sensitization of the DA system may have an important role in the early stages of drug abuse and may drive the increased drug seeking and taking that characterize the transition to uncontrolled drug use. Human data suggest that intermittency, sensitization, and periods of abstinence have an integral role in the process of addiction, highlighting the importance of utilizing pre-clinical models that integrate these phenomena, and suggesting that IntA paradigms may serve as novel models of human addiction. PMID:25212486

  16. Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS

    PubMed Central

    Garrison, Kimberly L.; Sahin, Selma; Benet, Leslie Z.

    2015-01-01

    Purpose To determine the number of drugs exhibiting flip-flop pharmacokinetics following oral dosing from immediate release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. Method The literature was searched for drugs displaying flip-flop kinetics (i.e. absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Results Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (9 drugs), monkey (3 drugs), horse (2 drugs), and/or rabbit (2 drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse however it would not exhibit flip-flop kinetics in humans where the oral dosing terminal half-life is 1.4 hr. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. Conclusion The few drugs displaying oral flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters. PMID:26010239

  17. Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS.

    PubMed

    Garrison, Kimberly L; Sahin, Selma; Benet, Leslie Z

    2015-09-01

    This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters.

  18. Incorporating Stage-Specific Drug Action into Pharmacological Modeling of Antimalarial Drug Treatment

    PubMed Central

    2016-01-01

    Pharmacological modeling of antiparasitic treatment based on a drug's pharmacokinetic and pharmacodynamic properties plays an increasingly important role in identifying optimal drug dosing regimens and predicting their potential impact on control and elimination programs. Conventional modeling of treatment relies on methods that do not distinguish between parasites at different developmental stages. This is problematic for malaria parasites, as their sensitivity to drugs varies substantially during their 48-h developmental cycle. We investigated four drug types (short or long half-lives with or without stage-specific killing) to quantify the accuracy of the standard methodology. The treatment dynamics of three drug types were well characterized with standard modeling. The exception were short-half-life drugs with stage-specific killing (i.e., artemisinins) because, depending on time of treatment, parasites might be in highly drug-sensitive stages or in much less sensitive stages. We describe how to bring such drugs into pharmacological modeling by including additional variation into the drug's maximal killing rate. Finally, we show that artemisinin kill rates may have been substantially overestimated in previous modeling studies because (i) the parasite reduction ratio (PRR) (generally estimated to be 104) is based on observed changes in circulating parasite numbers, which generally overestimate the “true” PRR, which should include both circulating and sequestered parasites, and (ii) the third dose of artemisinin at 48 h targets exactly those stages initially hit at time zero, so it is incorrect to extrapolate the PRR measured over 48 h to predict the impact of doses at 48 h and later. PMID:26902760

  19. A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells.

    PubMed

    Hu, Yi; Stephen, Andrew G; Cao, Jin; Tanzer, Lee R; Slapak, Christopher A; Harrison, Steadman D; Devanarayan, Viswanath; Dantzig, Anne H; Starling, James J; Rome, Leonard H; Moore, Robert E

    2002-01-10

    U-937 human leukemia cells were selected for resistance to doxorubicin in the presence or absence of a specific drug modulator that inhibits the activity of P-glycoprotein (Pgp), encoded by the multidrug-resistance gene (MDR1). Parental cells expressed low basal levels of the multidrug-resistance-associated gene (MRP1) and major vault protein (MVP) mRNAs and no MDR1 mRNA. Two doxorubicin-resistant cell lines were selected. Both drug-resistant cell lines upregulated the MVP mRNA level 1.5-fold within 1 cell passage. The MVP mRNA level continued to increase over time as the doxorubicin selection pressure was increased. MVP protein levels generally paralleled the mRNA levels. The 2 high molecular weight vault protein mRNAs were always expressed at constitutive levels. Fully formed vault particles consisting of the MVP, the 2 high molecular weight proteins and the vault RNA assembled and accumulated to increased levels in drug-selected cells. MVP induction is therefore the rate-limiting step for vault particle formation in U-937 cells. By passage 25 and thereafter, the selected cells were resistant to doxorubicin, etoposide, mitoxantrone and 5-fluorouracil by a pathway that was independent of MDR1, MRP1, MRP2 and breast cancer resistance protein. In summary, U-937 doxorubicin-selected cells are programmed to rapidly upregulate MVP mRNA levels, to accumulate vault particles and to become multidrug resistant.

  20. Stabilisation of amorphous furosemide increases the oral drug bioavailability in rats.

    PubMed

    Nielsen, Line Hagner; Rades, Thomas; Müllertz, Anette

    2015-07-25

    A glass solution of the amorphous sodium salt of furosemide (ASSF) and polyvinylpyrrolidone (PVP) (80:20 w/w%) was prepared by spray drying. It was investigated if PVP was able to stabilise ASSF during storage and dissolution and whether this influenced the in vivo performance of the glass solution after oral dosing to rats. The glass solution had a glass transition temperature of 121.3 ± 0.5°C, which was significantly higher than that of the pure drug (101.2°C). ASSF in the glass solution was stable for at least 168 days when stored at 20°C and 0% relative humidity. The glass solution exhibited fast dissolution in simulated intestinal medium, pH 6.5; the intrinsic dissolution rate was found to be 10.1 ± 0.6 mg/cm(2)/min, which was significantly faster than the pure ASSF. When investigating the stability during dissolution in stimulated intestinal medium at pH 6.5, the ASSF in the glass solution showed signs of crystallinity after 1 min of dissolution, but crystallised to a lesser extent than pure ASSF. The stabilising effect of PVP on ASSF, led to improved relative oral bioavailability in rats of 263%, when compared to the pure ASSF. PMID:26026252

  1. Localized increase of tissue oxygen tension by magnetic targeted drug delivery

    NASA Astrophysics Data System (ADS)

    Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

    2014-07-01

    Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to

  2. Dosimetric evaluation of 153Sm-EDTMP, 177Lu-EDTMP and 166Ho-EDTMP for systemic radiation therapy: Influence of type and energy of radiation and half-life of radionuclides

    NASA Astrophysics Data System (ADS)

    Ranjbar, Hassan; Ghannadi-Maragheh, Mohammad; Bahrami-Samani, Ali; Beiki, Davood

    2015-03-01

    In radiopharmaceutical therapy, delivered doses to critical organs must be below a certain threshold therefore internal radiation dosimetry of radiopharmaceuticals is essential. Advantages and disadvantages of radionuclides with different characteristics were evaluated for selection of appropriate radionuclide. The Monte Carlo MCNPX simulation program was used to obtain radial dose and cumulative dose of 153Sm, 177Lu and 166Ho used in radiotherapy of bone metastases. A cylindrical geometry with constant density materials was supposed for simulation of femur bone. The radius of bone marrow, bone, and surrounding soft tissue was considered 0.6 cm, 1.3 cm and 4 cm, respectively. It was assumed that the radionuclides were uniformly distributed throughout the tumor. "continuous energy spectrum" of beta particle was used instead of mean beta energy. Our simulations show that absorbed dose in target organ (bone) is greater than other organs and 166Ho gives a higher dose to the critical organ of bone marrow than either 153Sm or 177Lu. Absorbed dose versus time demonstrate faster dose delivery for the short half-life radionuclides (153Sm and 166Ho). These results are in good agreement with clinical observations which show a pain relief within 1 week after intravenous administration of 153Sm-EDTMP, whereas it occurs within 2 week in the case of 177Lu-EDTMP. According to the results, combination of different radionuclides with different characteristics such as 153Sm-EDTMP and 177Lu-EDTMP could be more advantageous to patients with painful bone metastasis.

  3. Target-specific cytotoxic effects on HER2-expressing cells by the tripartite fusion toxin ZHER2:2891-ABD-PE38X8, including a targeting affibody molecule and a half-life extension domain.

    PubMed

    Liu, Hao; Seijsing, Johan; Frejd, Fredrik Y; Tolmachev, Vladimir; Gräslund, Torbjörn

    2015-08-01

    Development of cancer treatment regimens including immunotoxins is partly hampered by their immunogenicity. Recently, deimmunized versions of toxins have been described, potentially being better suited for translation to the clinic. In this study, a recombinant tripartite fusion toxin consisting of a deimmunized version of exotoxin A from Pseudomonas aeruginosa (PE38) genetically fused to an affibody molecule specifically interacting with the human epidermal growth factor receptor 2 (HER2), and also an albumin binding domain (ABD) for half-life extension, has been produced and characterized in terms of functionality of the three moieties. Biosensor based assays showed that the fusion toxin was able to interact with human and mouse serum albumin, but not with bovine serum albumin and that it interacted with HER2 (KD=5 nM). Interestingly, a complex of the fusion toxin and human serum albumin also interacted with HER2 but with a somewhat weaker affinity (KD=12 nM). The IC50-values of the fusion toxin ranged from 6 to 300 pM on SKOV-3, SKBR-3 and A549 cells and was lower for cells with higher surface densities of HER2. The fusion toxin was found specific for HER2 as shown by blocking available HER2 receptors with free affibody molecule before subjecting the cells to the toxin. Analysis of contact time showed that 10 min was sufficient to kill 50% of the cells. In conclusion, all three regions of the fusion toxin were found to be functional.

  4. Measurement of the 2 νβ β decay half-life of 150Nd and a search for 0 νβ β decay processes with the full exposure from the NEMO-3 detector

    NASA Astrophysics Data System (ADS)

    Arnold, R.; Augier, C.; Baker, J. D.; Barabash, A. S.; Basharina-Freshville, A.; Blondel, S.; Blot, S.; Bongrand, M.; Brudanin, V.; Busto, J.; Caffrey, A. J.; Calvez, S.; Cascella, M.; Cerna, C.; Cesar, J. P.; Chapon, A.; Chauveau, E.; Chopra, A.; Duchesneau, D.; Durand, D.; Egorov, V.; Eurin, G.; Evans, J. J.; Fajt, L.; Filosofov, D.; Flack, R.; Garrido, X.; Gómez, H.; Guillon, B.; Guzowski, P.; Hodák, R.; Huber, A.; Hubert, P.; Hugon, C.; Jullian, S.; Klimenko, A.; Kochetov, O.; Konovalov, S. I.; Kovalenko, V.; Lalanne, D.; Lang, K.; Lemière, Y.; Le Noblet, T.; Liptak, Z.; Liu, X. R.; Loaiza, P.; Lutter, G.; Mamedov, F.; Marquet, C.; Mauger, F.; Morgan, B.; Mott, J.; Nemchenok, I.; Nomachi, M.; Nova, F.; Nowacki, F.; Ohsumi, H.; Pahlka, R. B.; Perrot, F.; Piquemal, F.; Povinec, P.; Přidal, P.; Ramachers, Y. A.; Remoto, A.; Reyss, J. L.; Richards, B.; Riddle, C. L.; Rukhadze, E.; Saakyan, R.; Salazar, R.; Sarazin, X.; Shitov, Yu.; Simard, L.; Šimkovic, F.; Smetana, A.; Smolek, K.; Smolnikov, A.; Söldner-Rembold, S.; Soulé, B.; Štekl, I.; Suhonen, J.; Sutton, C. S.; Szklarz, G.; Thomas, J.; Timkin, V.; Torre, S.; Tretyak, Vl. I.; Tretyak, V. I.; Umatov, V. I.; Vanushin, I.; Vilela, C.; Vorobel, V.; Waters, D.; Žukauskas, A.; NEMO-3 Collaboration

    2016-10-01

    We present results from a search for neutrinoless double-β (0 νβ β ) decay using 36.6 g of the isotope 150Nd with data corresponding to a live time of 5.25 y recorded with the NEMO-3 detector. We construct a complete background model for this isotope, including a measurement of the two-neutrino double-β decay half-life of T1/2 2 ν=[9.34 ±0.22 (stat)-0.60+0.62 (syst)]×1018 y for the ground state transition, which represents the most precise result to date for this isotope. We perform a multivariate analysis to search for 0 νβ β decays in order to improve the sensitivity and, in the case of observation, disentangle the possible underlying decay mechanisms. As no evidence for 0 νβ β decay is observed, we derive lower limits on half-lives for several mechanisms involving physics beyond the standard model. The observed lower limit, assuming light Majorana neutrino exchange mediates the decay, is T1/2 0 ν>2.0 ×1 022 y at the 90% C.L., corresponding to an upper limit on the effective neutrino mass of ⟨mν⟩<1.6 - 5.3 eV .

  5. Development of a novel osmotically driven drug delivery system for weakly basic drugs.

    PubMed

    Guthmann, C; Lipp, R; Wagner, T; Kranz, H

    2008-06-01

    The drug substance SAG/ZK has a short biological half-life and because of its weakly basic nature a strong pH-dependent solubility was observed. The aim of this study was to develop a controlled release (cr) multiple unit pellet formulation for SAG/ZK with pH-independent drug release. Pellets with a drug load of 60% were prepared by extrusion/spheronization followed by cr-film coating with an extended release polyvinyl acetate/polyvinyl pyrrolidone dispersion (Kollidon SR 30 D). To overcome the problem of pH-dependent drug release the pellets were then coated with a second layer of an enteric methacrylic acid and ethyl acrylate copolymer (Kollicoat MAE 30 DP). To increase the drug release rates from the double layered cr-pellets different osmotically active ionic (sodium and potassium chloride) and nonionic (sucrose) additives were incorporated into the pellet core. Drug release studies were performed in media of different osmotic pressure to clarify the main release mechanism. Extended release coated pellets of SAG/ZK demonstrated pH-dependent drug release. Applying a second enteric coat on top of the extended release film coat failed in order to achieve pH-independent drug release. Already low enteric polymer levels on top of the extended release coated pellets decreased drug release rates at pH 1 drastically, thus resulting in a reversal of the pH-dependency (faster release at pH 6.8 than in 0.1N HCl). The addition of osmotically active ingredients (sodium and potassium chloride, and sucrose) increased the imbibing of aqueous fluids into the pellet cores thus providing a saturated drug solution inside the beads and increasing drug concentration gradients. In addition, for these pellets increased formation of pores and cracks in the polymer coating was observed. Hence drug release rates from double layered beads increased significantly. Therefore, pH-independent osmotically driven SAG/ZK release was achieved from pellets containing osmotically active ingredients

  6. Nanomedicine for therapeutic drug therapy: Approaches to increase the efficacy of drug therapy with nanoemulsion delivery and reduce the toxicity of quantum dots

    NASA Astrophysics Data System (ADS)

    Kambalapally, Swetha Reddy

    The advancement of nanotechnology has paved the way for novel nanoscale materials for use in a wide range of applications. The use of these nanomaterials in biomedicine facilitates the improvement of existing technologies for disease prevention and treatment through diagnostics, tumor detection, drug delivery, medical imaging and vaccine development. Nanotechnology delivery systems for therapeutic uses includes the formulation of nanoparticles in emulsions. These novel delivery systems can improve drug efficacy by their ability to enhance bioavailability, minimize drug side effects, decrease drug toxicity, provide targeted site delivery and increase circulation of the drug in the blood. Additionally, these delivery systems also improve the drug stability and encapsulation efficiency. In the Introduction, this thesis will describe a novel technique for the preparation of nanoemulsions which was utilized in drug delivery and diagnostic applications. This novel Phase Inversion Temperature (PIT) method is a solvent and polymer-free and low energy requiring emulsification method, typically utilizing oils stabilized by nonionic surfactants to prepare water in oil (W/O) emulsions. The correlation between the particle size, zeta potential and the emulsion stability is described. The use of this nanoemulsion delivery system for pharmaceuticals and nutraceuticals by utilizing in vitro systems was investigated. Using the PIT method, a self assembling nanoemulsion (SANE) of gamma Tocotrienols (gammaT3), a component of Vitamin E family has been demonstrated to reduce cholesterol accumulation in HepG-2 cells. The nanoemulsion is stable and the particle size is around 20 nm with a polydispersity index (PDI) of 0.065. The effect of the nano gammaT3 on the metabolism of cholesterol, HMG-CoA activity and Apo-B levels were evaluated in an in vitro system utilizing HepG2 cells. A new class of nanoparticles, Quantum dots (QDs) has shown immense potential as novel nanomaterials used as

  7. Drug-drug Interaction between Pravastatin and Gemfibrozil (Antihyperlipidemic) with Gliclazide (Antidiabetic) in Rats.

    PubMed

    Sultanpur, Cm; Satyanarayana, S; Reddy, Ns; Kumar, Ke; Kumar, S

    2010-04-01

    Diabetes mellitus is a condition of increased blood glucose level in the body. Antihyperlipidemic drugs like statins and fibrates are widely used for prophylactic treatment in dyslipideamia and atherosclerosis. Diabetic dislipidemia exists with increased triglycerides, low HDL and high LDL levels. Hence, with oral hypoglycemic drugs, the addition of a lipid-lowering drug is necessary for controlling dislipidemia. In such a situation, there may be chances of drug-drug interactions between antidiabetic and antihyperlipidemic drugs. The present study is planned to evaluate the safety of gliclazide (antidiabetic) in the presence of pravastatin and gemfibrozil (antihyperlpidemic) in rats. Studies in normal and alloxan-induced diabetic rats were conducted with oral doses of gliclazide and their combination with pravastatin and gemfibrozil, with an adequate washout period in between the treatments. Blood samples were collected in rats by retroorbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. All the blood samples were analyzed for glucose by GOD -POD. Gliclazide (½ TD) produced hypoglycemic activity in normal and diabetic rats, with peak activity at 2 and 8 h. Pravastatin (TD) + gemfibrozil (TD) combination treatment increased the hypoglycemic effect of gliclazide in normal rats or diabetic rats when administered together. The interaction observed due to inhibition of both the enzymes (CYP 450 2C9 and CYP 450 3A4) responsible for the metabolism of gliclazide showed increased half-life, which was seen in the present study. Because concomitant administration of gliclazide with provastatin and gemfibrozil in diabetes is associated with atherosclerosis, it should be contraindicated or used with caution.

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

    PubMed

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

    1998-04-15

    In an attempt to examine the cellular changes associated with cisplatin resistance, we selected a cisplatin-resistant (A43 1/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellular defence systems and other cellular factors probably involved in dealing with cisplatin-induced DNA damage. Resistant cells exhibited decreased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. Analysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G2M arrest in sensitive and resistant cells. Interestingly, a slowdown in S-phase transit was found in A431/Pt cells. A comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to tolerate higher levels of cisplatin-induced DNA damage than their parental counterparts. Analysis of the expression of proteins involved in DNA mismatch repair showed a decreased level of MSH2 in resistant cells. Since MSH2 seems to be involved in recognition of drug-induced DNA damage, this change may account for the increased tolerance to DNA damage observed in the resistant subline. In conclusion, the involvement of accumulation defects and the increased tolerance to cisplatin-induced DNA damage in these cisplatin-resistant cells support the notion that multiple changes contribute to confer a low level of cisplatin resistance. PMID:9719480

  9. Role of the increased noradrenergic neurotransmission in drug self-administration.

    PubMed

    Wee, Sunmee; Wang, Zhixia; He, Rong; Zhou, Jia; Kozikowski, Alan P; Woolverton, William L

    2006-04-28

    Psychostimulants increase extracellular monoamine concentrations in the CNS. While the contributions of dopamine (DA) and serotonin (5-HT) to the reinforcing effect of psychostimulants have been examined, less is known about the involvement of norepinephrine (NE). In the present study, cocaine, desipramine (DMI) and JZ-III-84 were made available to rhesus monkeys (n=4) responding under a progressive-ratio (PR) schedule. These compounds vary in their in vitro selectivities for blocking NE uptake relative to DA from high (DMI) to modest (JZ-III-84) to non-selective (cocaine). Additionally, cocaine mixed with DMI in mg/kg dose-ratios of 1:1 to 1:3 was made available for self-administration. NE uptake inhibition by the mixture of cocaine and DMI at a ratio of 1:3 was evaluated in an ex vivo uptake assay. Cocaine (0.01-0.1 mg/(kg injection)) and JZ-III-84 (0.001-0.1 mg/(kg injection)) functioned as positive reinforcers with sigmoidal or biphasic dose-response functions, whereas DMI failed to do so. The addition of DMI to cocaine did not systemically alter self-administration of cocaine. In the ex vivo uptake assay, the addition of DMI to cocaine significantly increased the NE uptake inhibition compared to cocaine. These results support the conclusion that CNS NE is not involved in the reinforcing mechanism of psychostimulants. PMID:16213110

  10. Immunoassays in monitoring biotechnological drugs.

    PubMed

    Gygax, D; Botta, L; Ehrat, M; Graf, P; Lefèvre, G; Oroszlan, P; Pfister, C

    1996-08-01

    For the evaluation and interpretation of pharmacokinetic data reliable quantitative determinations are a requirement that can only be met by well-characterized and fully validated analytical methods. To cope with these requirements a method is being established that is based on an integrated and automated fiber-optic biospecific interaction analysis system (FOBIA) for immunoassays. Performance characteristics of this system used in monitoring of recombinant hirudin (CGP 39 393) are presented. Recombinant hirudin is a highly potent and selective inhibitor of human thrombin. Owing to its size and charge, recombinant hirudin is mainly eliminated by glomerular filtration. But only a fraction of the hirudin dose seems to be reabsorbed at the proximal tubule by luminal endocytosis and hydrolyzed by lysosomal enzymes, leaving approximately 50% of the dose to be extracted in the urine. Thus, renal clearance of recombinant hirudin in the absence of renal insufficiency appears to depend primarily on the glomerular filtration rate. During a 3-month i.v. tolerability study in dogs, some of the dogs developed antibodies against recombinant hirudin. The hirudin-antibody complex accumulated in plasma and apparent hirudin plasma concentrations were therefore much higher than expected from single-dose kinetics. Hirudin captured by antibodies showed an extended half-life and the hirudin-antibody complex is still pharmacologically active, as demonstrated by the observed increase in thrombin time. In conclusion, only appropriate analytical methods allow adequate monitoring and pharmacokinetic characterization of biotechnology drugs in biological materials. PMID:8857560

  11. Oral coadministration of β-glucuronidase to increase exposure of extensively glucuronidated drugs that undergo enterohepatic recirculation.

    PubMed

    Eichenbaum, Gary; Hsu, C-P; Subrahmanyam, Vangala; Chen, Jing; Scicinski, Jan; Galemmo, Robert A; Tuman, Robert W; Johnson, Dana L

    2012-07-01

    Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme β-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with β-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.005) in the mean area under the plasma concentration versus time curve (AUC; approx. threefold) and maximum plasma concentration (C(max); approx. twofold) of JNJ-10198409. The AUC and C(max) were 60 ± 18 ng h/mL and 76 ± 29 ng/mL, respectively, with no enzyme and 177 ± 55 ng h/mL and 129 ± 41 ng/mL, respectively, with β-glucuronidase coadministered. Moreover, the AUC of the primary glucuronide metabolite increased approximately sevenfold from 1173 ± 361 (ng h)/mL with no enzyme coadministered to 8723 ± 2133 ng h/mL with coadministered enzyme. These pharmacokinetic data support the hypothesis that when the primary glucuronide is secreted into the duodenum via the bile duct, the glucuronide is converted by β-glucuronidase back to the parent compound. The parent compound is then reabsorbed and reconjugated, resulting in elevated systemic exposures to both parent and glucuronide. Potential clinical and preclinical applications and considerations for this approach are discussed.

  12. Prolonged administration of antidepressant drugs leads to increased binding of [(3)H]MPEP to mGlu5 receptors.

    PubMed

    Nowak, Gabriel; Pomierny-Chamioło, Lucyna; Siwek, Agata; Niedzielska, Ewa; Pomierny, Bartosz; Pałucha-Poniewiera, Agnieszka; Pilc, Andrzej

    2014-09-01

    Metabotropic glutamate 5 (mGlu5) receptors are functionally connected with NMDA receptors. The antidepressant activity of the NMDA receptor antagonist ketamine in both preclinical and clinical studies, along with the antidepressant-like activities of negative allosteric modulators (NAMs) of mGlu5, led us to investigate if prolonged administration of various antidepressant drugs or the mGlu5 NAM, MTEP, causes changes in mGlu5 receptor availability or protein expression or in expression of Homer proteins in the rat brain. Our results clearly show that prolonged treatment with antidepressants with various mechanisms of action (such as escitalopram, reboxetine, milnacipran, moclobemide and imipramine) or with MTEP led to significant increases in [(3)H]MPEP binding in homogenates of the hippocampus and/or cerebral cortex. Increases in mGlu5 expression were also observed, though they did not always parallel the increase in binding. The results indicate that adaptive up-regulation of mGlu5 receptors may be a common change induced by antidepressant drugs. PMID:24796254

  13. Nanostructured lipid carriers (NLCs) for drug delivery and targeting.

    PubMed

    Fang, Chia-Lang; Al-Suwayeh, Saleh A; Fang, Jia-You

    2013-01-01

    Nanostructured lipid carriers (NLCs) are drug-delivery systems composed of both solid and liquid lipids as a core matrix. It was shown that NLCs reveal some advantages for drug therapy over conventional carriers, including increased solubility, the ability to enhance storage stability, improved permeability and bioavailability, reduced adverse effect, prolonged half-life, and tissue-targeted delivery. NLCs have attracted increasing attention in recent years. This review describes recent developments in drug delivery using NLCs strategies. The structures, preparation techniques, and physicochemical characterization of NLCs are systematically elucidated in this review. The potential of NLCs to be used for different administration routes is highlighted. Special attention is paid to parenteral injection and topical delivery since these are the most common routes for investigating NLCs. Relevant issues for the introduction of NLCs to market, including pharmaceutical and cosmetic applications, are discussed. The related patents of NLCs for drug delivery are also reviewed. Finally, the future development and current obstacles needing to be resolved are elucidated. PMID:22946628

  14. BMX Negatively Regulates BAK Function, Thereby Increasing Apoptotic Resistance to Chemotherapeutic Drugs.

    PubMed

    Fox, Joanna L; Storey, Alan

    2015-04-01

    The ability of chemotherapeutic agents to induce apoptosis, predominantly via the mitochondrial (intrinsic) apoptotic pathway, is thought to be a major determinant of the sensitivity of a given cancer to treatment. Intrinsic apoptosis, regulated by the BCL2 family, integrates diverse apoptotic signals to determine cell death commitment and then activates the nodal effector protein BAK to initiate the apoptotic cascade. In this study, we identified the tyrosine kinase BMX as a direct negative regulator of BAK function. BMX associates with BAK in viable cells and is the first kinase to phosphorylate the key tyrosine residue needed to maintain BAK in an inactive conformation. Importantly, elevated BMX expression prevents BAK activation in tumor cells treated with chemotherapeutic agents and is associated with increased resistance to apoptosis and decreased patient survival. Accordingly, BMX expression was elevated in prostate, breast, and colon cancers compared with normal tissue, including in aggressive triple-negative breast cancers where BMX overexpression may be a novel biomarker. Furthermore, BMX silencing potentiated BAK activation, rendering tumor cells hypersensitive to otherwise sublethal doses of clinically relevant chemotherapeutic agents. Our finding that BMX directly inhibits a core component of the intrinsic apoptosis machinery opens opportunities to improve the efficacy of existing chemotherapy by potentiating BAK-driven cell death in cancer cells. PMID:25649765

  15. No increase in drug dispensing for acute gastroenteritis after Storm Klaus, France 2009.

    PubMed

    Pirard, P; Goria, S; Nguengang Wakap, S; Galey, C; Motreff, Y; Guillet, A; Le Tertre, A; Corso, M; Beaudeau, P

    2015-09-01

    During the night of 23-24 January 2009, Storm Klaus hit south-western France and caused power outages affecting 1,700,000 homes and stopping numerous pumping and drinking water disinfection systems. In France, medicalized acute gastroenteritis (MAGE) outbreaks are monitored by analysing the daily amount of reimbursements of medical prescriptions, registered in the French National Health Insurance database, at the 'commune' administrative level. As AGE is suspected to be associated with perturbations to water supply systems as well as power outages, Storm Klaus provided an opportunity to test its influence on the incidence of MAGE in the communes of three affected French departments (administrative areas larger than communes). The geographical exposure indicator was built by using the mapping of the water distribution zones, the reported distribution/production stoppages and their duration. Irrespective of exposure class, a relative risk of MAGE of 0.86 (95% confidence 0.84-0.88) was estimated compared with the 'unexposed' reference level. Although these results must be considered with caution because of a potential marked decrease in global medical consultation probably due to impassable roads, they do not suggest a major public health impact of Klaus in terms of increased MAGE incidence. PMID:26322759

  16. No increase in drug dispensing for acute gastroenteritis after Storm Klaus, France 2009.

    PubMed

    Pirard, P; Goria, S; Nguengang Wakap, S; Galey, C; Motreff, Y; Guillet, A; Le Tertre, A; Corso, M; Beaudeau, P

    2015-09-01

    During the night of 23-24 January 2009, Storm Klaus hit south-western France and caused power outages affecting 1,700,000 homes and stopping numerous pumping and drinking water disinfection systems. In France, medicalized acute gastroenteritis (MAGE) outbreaks are monitored by analysing the daily amount of reimbursements of medical prescriptions, registered in the French National Health Insurance database, at the 'commune' administrative level. As AGE is suspected to be associated with perturbations to water supply systems as well as power outages, Storm Klaus provided an opportunity to test its influence on the incidence of MAGE in the communes of three affected French departments (administrative areas larger than communes). The geographical exposure indicator was built by using the mapping of the water distribution zones, the reported distribution/production stoppages and their duration. Irrespective of exposure class, a relative risk of MAGE of 0.86 (95% confidence 0.84-0.88) was estimated compared with the 'unexposed' reference level. Although these results must be considered with caution because of a potential marked decrease in global medical consultation probably due to impassable roads, they do not suggest a major public health impact of Klaus in terms of increased MAGE incidence.

  17. A role for cytochrome b5 in the in vivo disposition of anti-cancer and cytochrome P450 probe drugs in mice

    PubMed Central

    Henderson, Colin J.; McLaughlin, Lesley A.; Finn, Robert D.; Ronseaux, Sebastien; Kapelyukh, Yury; Wolf, C. Roland

    2014-01-01

    The role of microsomal cytochrome b5 (Cyb5) in defining the rate of drug metabolism and disposition has been intensely debated for several decades. Recently we described mouse models involving the hepatic or global deletion of Cyb5, demonstrating its central role in in vivo drug disposition. We have now used the cytochrome b5 complete null (BCN) model to determine the role of Cyb5 in the metabolism of ten pharmaceuticals metabolised by a range of cytochrome P450s, including five anti-cancer drugs, in vivo and in vitro. The extent to which metabolism was significantly affected by the absence of Cyb5 was substrate-dependent, with AUC increased (75-245%), and clearance decreased (35-72%), for phenacetin, metoprolol and chlorzoxazone. Tolbutamide disposition was not significantly altered by Cyb5 deletion, while for midazolam clearance was decreased by 66%. The absence of Cyb5 had no effect on gefitinib and paclitaxel disposition, while significant changes in the in vivo pharmacokinetics of cyclophosphamide were measured (Cmax and terminal half-life increased 55% and 40%, respectively), tamoxifen (AUClast and Cmax increased 370% and 233%, respectively) and anastrozole (AUC and terminal half-life increased 125% and 62%, respectively; clearance down 80%). These data from provide strong evidence that both hepatic and extra-hepatic Cyb5 levels are an important determinant of in vivo drug disposition catalysed by a range of cytochrome P450s, including currently-prescribed anti-cancer agents, and that individuality in Cyb5 expression could be a significant determinant in rates of drug disposition in man. PMID:24115751

  18. Novel Dosing Strategies Increase Exposures of the Potent Antituberculosis Drug Rifapentine but Are Poorly Tolerated in Healthy Volunteers

    PubMed Central

    Savic, Radojka M.; Park, Jeong-Gun; Cramer, Yoninah; Hafner, Richard; Hogg, Evelyn; Janik, Jennifer; Marzinke, Mark A.; Patterson, Kristine; Benson, Constance A.; Hovind, Laura; Dorman, Susan E.; Haas, David W.

    2015-01-01

    Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase rifapentine exposures: dividing the dose or giving the drug with a high-fat meal. In arm 1, rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC0–24ss) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC0–24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration

  19. [The microencapsulated genetic engineering cells: a new platform on treatment of cancer instead of genetic engineering drugs].

    PubMed

    Pan, Yuelong; Zheng, Shu

    2003-06-01

    The microencapsulated genetic cells may be a new platform instead of genetic engineering drugs, as they can overcome the genetic engineering drugs' shortages such as short half-life in vivo, low activity, and incomplete elimination of organic solvent. This article reviews and summarizes the advantages, possible problems and solution and the feasibility of using microencapsulated genetic engineering cells in the treatment of cancer.

  20. Brief Intervention to Increase Emergency Department Uptake of Combined Rapid HIV and Hepatitis C Screening Among a Drug Misusing Population

    PubMed Central

    Merchant, Roland C.; Baird, Janette R.; Liu, Tao; Taylor, Lynn E.; Montague, Brian T.; Nirenberg, Ted D.

    2014-01-01

    Objectives In this study, Increasing Viral Testing in the Emergency Department (InVITED), the authors investigated if a brief intervention about human immunodeficiency virus (HIV) and hepatitis C virus (HCV) risk-taking behaviors and drug use and misuse in addition to a self-administered risk assessment, as compared to a self-administered risk assessment alone, increased uptake of combined screening for HIV and HCV, self-perception of HIV/HCV risk, and beliefs and opinions on HIV/HCV screening. Methods InVITED was a randomized, controlled trial conducted at two urban emergency departments (EDs) from February 2011 to March 2012. ED patients who self-reported drug use within the past three months were invited to enroll. Drug misuse severity and need for a brief or more intensive intervention was assessed using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Participants were randomly assigned to one of two study arms: a self-administered HIV/HCV risk assessment alone (control arm), or the assessment plus a brief intervention about their drug misuse and screening for HIV/HCV (intervention arm). Beliefs on the value of combined HIV/HCV screening, self-perception of HIV/HCV risk, and opinions on HIV/HCV screening in the ED were measured in both study arms before the HIV/HCV risk assessment (pre), after the assessment in the control arm, and after the brief intervention in the intervention arm (post). Participants in both study arms were offered free combined rapid HIV/HCV screening. Uptake of screening was compared by study arm. Multivariable logistic regression models were used to evaluate factors related to uptake of screening. Results Of the 395 participants in the study, the median age was 28 years (IQR 23 to 38 years), 44.8% were female, 82.3% had ever been tested for HIV, and 67.3% had ever been tested for HCV. Uptake of combined rapid HIV/HCV screening was nearly identical by study arm (64.5% vs. 65.2%; Δ = −0.7%; 95% CI = −10.1% to 8

  1. Increased Hb A2 values in an HIV-1-infected patient receiving antiretroviral drugs: a pitfall for thalassemia antenatal diagnosis.

    PubMed

    Pornprasert, Sakorn; Sukunthamala, Kanyakan; Leechanachai, Pranee; Sanguansermsri, Torpong

    2009-01-01

    We report a human immunodeficiency virus-1 (HIV-1)-infected couple, where the woman in the 11th week of gestation, carried a Hb E trait. She and her spouse were referred to the hemoglobinopathy counselors. Her spouse's blood was subsequently tested and showed an increased Hb A(2) value. However, his red cell indices and osmotic fragility test were different from those found in beta-thalassemia (beta-thal) carriers. The beta-thal genes were investigated further and no mutations were observed. Therefore, it is unlikely that he is a beta-thal carrier and the increased Hb A(2) value is a result of receiving antiretroviral drugs. As antenatal thalassemia screening becomes more widespread, measuring the Hb A(2) values should be taken in all HIV-1-infected couples before the initiation of antiretroviral drugs to rule out misdiagnosis of beta-thal. However, if these tests are not available, the results of the red cell indices and osmotic fragility test should be considered as they may provide great value for beta-thal investigations.

  2. Cyclooxygenase-2 inhibitors and most traditional nonsteroidal anti-inflammatory drugs cause similar moderately increased risks of cardiovascular disease.

    PubMed

    Hennekens, Charles H; Borzak, Steven

    2008-03-01

    Cyclooxygenase-2 inhibitors relieve pain from inflammatory conditions by decreasing the gastrointestinal side effects from traditional nonsteroidal anti-inflammatory drugs. Basic research provided plausible mechanisms and some observational epidemiological studies, case-control and cohort, indicated that patients prescribed with cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory drugs had increased risks for myocardial infarction and stroke. Because patients prescribed with cyclooxygenase-2 inhibitors were systematically different, uncontrolled and uncontrollable confounding by indication was as large as the observed risks. Thus, epidemiological studies or their meta-analyses could not discern whether, and if so, how much, the risks were real. A comprehensive meta-analysis of randomized trials indicated that cyclooxygenase-2 inhibitors increased the risk of vascular events by 42%, almost exclusively myocardial infarction, as did high-dose regimens of ibuprofen and diclofenac, but not naproxen. Individual clinical judgments and policy decisions should include cardiovascular disease and noncardiovascular disease risks including gastrointestinal side effects and clinical benefits including improved quality of life from less pain and disability.

  3. Development and characterization of chronomodulated drug delivery system of captopril

    PubMed Central

    Patil, Archana S; Dandagi, Panchaxari M; Masthiholimath, Vinayak S; Gadad, Anand P; Najwade, Basavaraj K

    2011-01-01

    Background: Hypertension shows circadian rhythm that there is a rise in pressure from the time of waking or before (about 4 to 8 a.m.), in most people. Conventional drug delivery system of captopril is inappropriate for the delivery of drug, as they cannot be administered just before the symptoms are worsened, because during this time the patients are asleep, bedtime dosing of captopril will not provide a therapeutic plasma drug concentration at the early hours of morning because of poor pharmacokinetic profile and shorter half-life of 1.9 hours. Thus, this study attempts to design and evaluate a chronomodulated pulsatile drug delivery system of captopril which was aimed to release the drug after a lag time of 6 hours. Materials and Methods: Present delivery system was prepared by rupturable coating method. The core containing captopril as a bioactive compound were prepared by direct compression method and then coated sequentially with an inner swelling layer containing hydrocolloid HPMC E5 and an outer rupturable layer consisted of Eudragit RL/RS (1 : 1). Total 12 formulations with different levels of inner swelling layer and outer polymeric layer were prepared and subjected to various processing and formulative parameters like the effect of core composition, level of swelling layer, and rupturable coating on lag time was investigated. In vitro drug release and rupture tests were performed using United States Pharmacopoeia paddle method at 50 rpm in 0.1N HCl and phosphate buffer of pH 6.8. Results: The results showed that as the amount of inner swelling layer increases, the lag time decreases and as the Eudragit coating level increases, the lag time increases and percent water uptake of time-dependent pulsatile release system decreases. The presence of an osmotic agent and effervescent agent helped in shortening of lag time. Conclusion: The system was found to be satisfactory in terms of release of the drug after the lag time of 6 hours. PMID:23071948

  4. Drug-drug interactions between moxifloxacin and rifampicin based on pharmacokinetics in vivo in rats.

    PubMed

    Huang, Lifei; Liu, Jiajun; Yu, Xin; Shi, Lei; Liu, Jian; Xiao, Heping; Huang, Yi

    2016-10-01

    Moxifloxacin and rifampicin are all the first-line options for the treatment of active tuberculosis, which are often combined for the treatment of multidrug resistance pulmonary tuberculosis in clinic. However, the potential drug-drug interactions between moxifloxacin and rifampicin were unknown. The aim of this study was to investigate the drug-drug interactions between moxifloxacin and rifampicin based on their pharmacokinetics in vivo after oral administration of the single drug and both drugs, and reveal their mutual effects on their pharmacokinetics. Eighteen male Sprague-Dawley rats were randomly assigned to three groups: moxifloxacin group, rifampicin group and moxifloxacin + rifampicin group. Plasma concentrations of moxifloxacin and rifampicin were determined using LC-MS at the designated time points after drug administration, and the main pharmacokinetic parameters were calculated. In addition, effects of moxifloxacin and rifampicin on their metabolic rate and absorption were investigated using rat liver microsome incubation systems and Caco-2 cell transwell model. The main pharmacokinetic parameters of moxifloxacin including Tmax , Cmax , t1/2 and AUC(0-t) increased more in the moxifloxacin + rifampicin group than in the moxifloxacin group, but the difference was not significant (p > 0.05). However, the pharmacokinetic parameters of rifampicin, including peak concentration, area under the concentration-time curve, half-life and the area under the first moment plasma concentration-time curve, increased significantly (p < 0.05) compared with the rifampicin group, and the time to peak concentration decreased significantly (p < 0.05). The mean residence time of rifampicin also increased in moxifloxacin + rifampicin group compared with the rifampicin group, but the difference was not significant (p > 0.05). The rat liver microsome incubation experiment indicated that moxifloxacin could increase the metabolic rate of rifampicin from 23.7 to 38.7 min. However

  5. Drug-facilitated sexual assault and analytical toxicology: the role of LC-MS/MS A case involving zolpidem.

    PubMed

    Kintz, Pascal; Villain, Marion; Dumestre-Toulet, Véronique; Ludes, Bertrand

    2005-02-01

    The use of a drug to modify a person's behavior for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm in the general public. Drugs involved can be pharmaceuticals, such as benzodiazepines (flunitrazepam, lorazepam, etc.), hypnotics (zopiclone, zolpidem), sedatives (neuroleptics, some histamine H1-antagonists) or anaesthetics (gamma-hydroxybutyrate, ketamine), drugs of abuse, such as cannabis, ecstasy or lysergide, or more often ethanol. Drugs said to be used to facilitate sexual assaults can be difficult to detect (active products at low dosages, chemical instability), possess amnesic properties and can be rapidly cleared from the body (short half-life). We present here a case involving a 23-year old girl that declared a sexual assault 6 days after the event was said to have occurred. To the Police, the victim claimed a total amnesia of the offense associated with intense sedation. Toxicological analyses for unknown sedative drugs achieved by LC-MS/MS revealed the presence of zolpidem (Stilnox), a non-benzodiazepine hypnotic. Concentrations after 6 days were 16 and 32 pg/mL in blood and urine, respectively. The drug tested also positive in the corresponding hair segment at 0.75 pg/mg. The requested extraordinary sensitivity of LC-MS/MS appears as a pre-requisite to document any case involving drug-facilitated sexual assault. PMID:15763689

  6. Increasing use of 'party drugs' in people living with HIV on antiretrovirals: a concern for patient safety.

    PubMed

    Bracchi, Margherita; Stuart, David; Castles, Richard; Khoo, Saye; Back, David; Boffito, Marta

    2015-08-24

    Use of 'party drugs', a particular set of recreational drugs used in the context of 'ChemSex', is frequent among MSM living with HIV. A recently published observational study showed that more than half of HIV-infected MSM interviewed reported use of illicit substances in the previous 3 months, with frequent concomitant use of three or more drugs. These substances are a combination of 'club drugs' (methylenedioxymethamphetamine, gamma-hydroxybutyrate, ketamine, benzodiazepine) and drugs that are more specifically used in a sexualized context (methamphetamine, mephedrone, poppers and erectile dysfunction agents). Although formal data on pharmacokinetic or pharmacodynamic interactions between recreational drugs and antiretroviral agents are lacking, information regarding potentially toxic interactions can be theorized or sometimes conclusions may be drawn from case studies and cohort observational studies. However, the risk of coadministering party drugs and antiretrovirals should not be overestimated. The major risk for a drug-drug interaction is when using ritonavir-boosting or cobicistat-boosting agents, and maybe some nonnucleoside reverse transcriptase inhibitors. Knowledge of the metabolic pathways of 'party drugs' may help in advising patients on which illicit substances have a high potential for drug-drug interactions, as this is not the case for all. PMID:26372268

  7. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP

    SciTech Connect

    Yun, C.H.; Mengwasser, K.E.; Toms, A.V.; Woo, M.S.; Greulich, H.; Wong, K.K.; Meyerson, M.; Eck, M.J.

    2008-07-15

    Lung cancers caused by activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to small molecule tyrosine kinase inhibitors (TKIs), but the efficacy of these agents is often limited because of the emergence of drug resistance conferred by a second mutation, T790M. Threonine 790 is the 'gatekeeper' residue, an important determinant of inhibitor specificity in the ATP binding pocket. The T790M mutation has been thought to cause resistance by sterically blocking binding of TKIs such as gefitinib and erlotinib, but this explanation is difficult to reconcile with the fact that it remains sensitive to structurally similar irreversible inhibitors. Here, we show by using a direct binding assay that T790M mutants retain low-nanomolar affinity for gefitinib. Furthermore, we show that the T790M mutation activates WT EGFR and that introduction of the T790M mutation increases the ATP affinity of the oncogenic L858R mutant by more than an order of magnitude. The increased ATP affinity is the primary mechanism by which the T790M mutation confers drug resistance. Crystallographic analysis of the T790M mutant shows how it can adapt to accommodate tight binding of diverse inhibitors, including the irreversible inhibitor HKI-272, and also suggests a structural mechanism for catalytic activation. We conclude that the T790M mutation is a 'generic' resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.

  8. The Result of Multiple I-131 Treatments on the Effective Half-Life of Retained Radioactivity in Patients Ablated for Differentiated Thyroid Cancer: Possible Evidence for Thyroid Remnant Function Impairment.

    PubMed

    Okkalides, Demetrios

    2016-03-01

    The ablation of differentiated thyroid cancer by ingested I-131 depends on the activity absorbed by the remnant. This depends on the function of the thyroid cells and on the rate that radioactivity is excreted from the blood. The reduction of radioiodine is described by the effective half-life (EHL), which is the time taken to half the retained radioactivity. If the tumor recurs, more treatments are prescribed, often with escalating activities. Patients may receive several treatments during the evolution of the disease, and the total radioactivity administered (TRA) is the sum of all such activities. The patients' archived information permitted the calculation of EHL and TRA. The patient cohort processed here comprised 274 females and 101 males treated during 1997 to 2015. The TRA to the patients ranged between 1.1 and 129.5 GBq (average = 7.93 ± 9.9 GBq) and the EHL varied between 5.06 and 43.87 hours (average = 14.13 ± 5.7 hours). The data were processed as follows: (a) the EHL corresponding to the last treatment of each patient was plotted against TRA to patients who were treated once and to those treated several times for comparison and (b) using a small subgroup of 16 patients who were treated at least 5 times, the EHL and TRA corresponding to each treatment of each patient were plotted. A function of the form y = p-k·ln(x) was fitted on the data in all graphs and k was calculated. For patients treated once, EHL was independent of TRA. A decrease was seen in (a) multitreated patients, with the gradient (k) ranging between -0.541 and -13.880 and (b) 13 out of 16 patients, with the gradient (k) ranging between -5.55 and -31.17, both indicating an impairment of the remnant function, perhaps identified as "stunning." Since this is not avoidable, the uptake may be boosted by splitting the prescribed activity into low radioactivity fractions, which will also reduce patient hospitalization.

  9. Sucrose esters increase drug penetration, but do not inhibit p-glycoprotein in caco-2 intestinal epithelial cells.

    PubMed

    Kiss, Lóránd; Hellinger, Éva; Pilbat, Ana-Maria; Kittel, Ágnes; Török, Zsolt; Füredi, András; Szakács, Gergely; Veszelka, Szilvia; Sipos, Péter; Ózsvári, Béla; Puskás, László G; Vastag, Monika; Szabó-Révész, Piroska; Deli, Mária A

    2014-10-01

    Sucrose fatty acid esters are increasingly used as excipients in pharmaceutical products, but few data are available on their toxicity profile, mode of action, and efficacy on intestinal epithelial models. Three water-soluble sucrose esters, palmitate (P-1695), myristate (M-1695), laurate (D-1216), and two reference absorption enhancers, Tween 80 and Cremophor RH40, were tested on Caco-2 cells. Caco-2 monolayers formed a good barrier as reflected by high transepithelial resistance and positive immunostaining for junctional proteins claudin-1, ZO-1, and β-catenin. Sucrose esters in nontoxic concentrations significantly reduced resistance and impedance, and increased permeability for atenolol, fluorescein, vinblastine, and rhodamine 123 in Caco-2 monolayers. No visible opening of the tight junctions was induced by sucrose esters assessed by immunohistochemistry and electron microscopy, but some alterations were seen in the structure of filamentous actin microfilaments. Sucrose esters fluidized the plasma membrane and enhanced the accumulation of efflux transporter ligands rhodamine 123 and calcein AM in epithelial cells, but did not inhibit the P-glycoprotein (P-gp)-mediated calcein AM accumulation in MES-SA/Dx5 cell line. These data indicate that in addition to their dissolution-increasing properties sucrose esters can enhance drug permeability through both the transcellular and paracellular routes without inhibiting P-gp.

  10. Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells.

    PubMed

    Chakravarty, Geetika; Mathur, Aditi; Mallade, Pallavi; Gerlach, Samantha; Willis, Joniece; Datta, Amrita; Srivastav, Sudesh; Abdel-Mageed, Asim B; Mondal, Debasis

    2016-05-01

    Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemosensitizers. Well known MDR mechanisms include: (i) upregulation of drug-efflux; (ii) increased signaling via AKT; and (iii) decreased apoptosis. Therefore, chemosensitizers should target multiple resistance mechanisms. We investigated the efficacy of nelfinavir (NFV), a clinically approved anti-HIV drug, in increasing doxorubicin (DOX) toxicity in a MDR breast cancer cell line, MCF-7/Dox. As compared to parental MCF-7 cells, the MCF-7/Dox were 15-20 fold more resistant to DOX-induced cytotoxicity at 48 h post-exposure (DOX IC50 = 1.8 μM vs. 32.4 μM). Coexposures to NFV could significantly (p < 0.05) decrease DOX-IC50 in MCF-7/Dox cells. Multiple exposures to physiologic concentrations of NFV (2.25 μM or 6.75 μM) decreased DOX-IC50 by 21-fold and 50-fold, respectively. Interestingly, although single exposure to NFV transiently induced P-glycoprotein (P-gp) levels, multiple treatments with NFV inhibited both P-gp expression and efflux function, which increased intracellular DOX concentrations. Single exposure to NFV augmented the markers of cell-survival (AKT) and autophagy (LC3-II), whereas multiple exposures enabled suppression of both total AKT (t-AKT) and insulin like growth factor-1 (IGF-1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xenografts, intraperitoneal (i.p.) injection of NFV (20 mg/kg/day) and DOX (2 mg/kg/twice/wk) decreased tumor growth more significantly (p < 0.01) than either agent alone. Immunohistochemical (IHC) analysis revealed decreased p-AKT and Ki-67 levels. Thus

  11. The politics behind the implementation of the WTO Paragraph 6 Decision in Canada to increase global drug access

    PubMed Central

    2012-01-01

    accounted for by experience in implementing the legislation and hence a greater representation of the interests of potential beneficiary country governments. Conclusions The Canadian Government designed CAMR as a last resort measure. Increased input from the developing country beneficiaries and shifting to institutions where the right to health gets prioritized may lead to policies that better achieves affordable drug access. PMID:22472291

  12. 3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

    SciTech Connect

    Lagerloef, Jakob H.; Kindblom, Jon; Bernhardt, Peter

    2011-08-15

    Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2

  13. Increasing Coverage in Mass Drug Administration for Lymphatic Filariasis Elimination in an Urban Setting: a Study of Malindi Town, Kenya

    PubMed Central

    Njomo, Doris W.; Mukoko, Dunstan A.; Nyamongo, Nipher K.; Karanja, Joan

    2014-01-01

    Introduction Implementation of Mass Drug Administration (MDA) in urban settings is an obstacle to Lymphatic Filariasis (LF) elimination. No urban-specific guidelines on MDA in urban areas exist. Malindi district urban area had received 4 MDA rounds by the time the current study was implemented. Programme data showed average treatment coverage of 28.4% (2011 MDA), far below recommended minimum of 65–80%. Methods To identify, design and test strategies for increased treatment coverage in urban areas, a quasi-experimental study was conducted in Malindi urban area. Three sub-locations with lowest treatment coverage in 2011 MDA were purposively selected. In the pre-test phase, 947 household heads sampled using systematic random method were interviewed for quantitative data. For qualitative data, 12 Focus Group Discussions (FGDs) with single sex adult and youth male and female groups and 3 with community drug distributors (CDDs) were conducted. Forty in-depth interviews with opinion leaders and self-administered questionnaires with District Public Health officers purposively selected were carried out. The quantitative data were analyzed using SPSS version 16 and statistical significance assessed by χ2 test.The qualitative data were analyzed manually according to study's themes. Results and Discussion The identified strategies were implemented prior to and during 2012 MDA in two sub-locations (experimental) while in the third (control), usual MDA strategies were applied. In the post-test phase, 2012 MDA coverage in experimental and control sub-locations was comparatively assessed for effect of the newly designed strategies on urban MDA. Results indicated improved treatment coverage in experimental sub-locations, 77.1% in Shella and 66.0% in Barani. Central (control) sub-location also attained high coverage, 70.4% indicating average treatment coverage of 71%. Conclusion The identified strategies contributed to increased treatment coverage in experimental sites and

  14. Preparation and evaluation of multi particulates drug delivery system using natural polymers.

    PubMed

    Baig, Tariq; Sheikh, Hammad; Srivastava, Ankur; Tripathi, Pushpendra K; Tripathi, Shalini

    2015-01-01

    Simvastatin potassium is a hypolipidemic drug used with exercise, diet, and weight-loss to control elevated cholesterol, or hypercholesterolemia. It is a member of the statin class of pharmaceuticals. Okra mucilage is used to reduce the cholesterol level since microspheres has formulated by using okra mucilage to developed a synergistic effect. Calcium chloride act as a cross linking agent, when react with sodium alginate form a calcium alginate, since develope a gel like microbeads (microspheres). The half life of simvastatin is 2h for simvastatin acid. Simvastatin microspheres were prepared by using sodium alginate in combination with Abelmoschus esculentus (Okra), as drug release modifiers in various proportions to overcome the drug related adverse effects. The drug entrapment efficiency increased progressively with increasing concentration of both sodium alginate and okra mucilage resulting in the formation of larger microspheres entrapping greater amounts of the drug. The prepared microspheres were subjected to various evaluation and in vitro release studies. The particle sizes of the prepared microspheres were determined by optical microscopy and Scanning Electron Microscopy (SEM) analysis. The prepared microspheres had good spherical geometry with smooth surface as evidence by SEM. Study the capability of the formulation to withstand the physiological environment of the stomach and small intestine.

  15. Preparation and evaluation of multi particulates drug delivery system using natural polymers.

    PubMed

    Baig, Tariq; Sheikh, Hammad; Srivastava, Ankur; Tripathi, Pushpendra K; Tripathi, Shalini

    2015-01-01

    Simvastatin potassium is a hypolipidemic drug used with exercise, diet, and weight-loss to control elevated cholesterol, or hypercholesterolemia. It is a member of the statin class of pharmaceuticals. Okra mucilage is used to reduce the cholesterol level since microspheres has formulated by using okra mucilage to developed a synergistic effect. Calcium chloride act as a cross linking agent, when react with sodium alginate form a calcium alginate, since develope a gel like microbeads (microspheres). The half life of simvastatin is 2h for simvastatin acid. Simvastatin microspheres were prepared by using sodium alginate in combination with Abelmoschus esculentus (Okra), as drug release modifiers in various proportions to overcome the drug related adverse effects. The drug entrapment efficiency increased progressively with increasing concentration of both sodium alginate and okra mucilage resulting in the formation of larger microspheres entrapping greater amounts of the drug. The prepared microspheres were subjected to various evaluation and in vitro release studies. The particle sizes of the prepared microspheres were determined by optical microscopy and Scanning Electron Microscopy (SEM) analysis. The prepared microspheres had good spherical geometry with smooth surface as evidence by SEM. Study the capability of the formulation to withstand the physiological environment of the stomach and small intestine. PMID:25488418

  16. Usual care and management of fall risk increasing drugs in older dizzy patients in Dutch general practice

    PubMed Central

    Stam, Hanneke; Harting, Thomas; van der Sluijs, Marjolijn; van Marum, Rob; van der Horst, Henriëtte; van der Wouden, Johannes C.; Maarsingh, Otto R.

    2016-01-01

    Objective For general practitioners (GPs) dizziness is a challenging condition to deal with. Data on the management of dizziness in older patients are mostly lacking. Furthermore, it is unknown whether GPs attempt to decrease Fall Risk Increasing Drugs (FRIDs) use in the management of dizziness in older patients. The aim of this study is to gain more insight into GP’s management of dizziness in older patients, including FRID evaluation and adjustment. Design Data were derived from electronic medical records, obtained over a 12-month period in 2013. Setting Forty-six Dutch general practices. Patients The study sample comprised of 2812 older dizzy patients of 65 years and over. Patients were identified using International Classification of Primary Care codes and free text. Main outcome measures Usual care was categorized into wait-and-see strategy (no treatment initiated); education and advice; additional testing; medication adjustment; and referral. Results Frequently applied treatments included a wait-and-see strategy (28.4%) and education and advice (28.0%). Additional testing was performed in 26.8%; 19.0% of the patients were referred. Of the patients 87.2% had at least one FRID prescription. During the observation period, GPs adjusted the use of one or more FRIDs for 11.7% of the patients. Conclusion This study revealed a wide variety in management strategies for dizziness in older adults. The referral rate for dizziness was high compared to prior research. Although many older dizzy patients use at least one FRID, FRID evaluation and adjustment is scarce. We expect that more FRID adjustments may reduce dizziness and dizziness-related impairment. Key PointsIt is important to know how general practitioners manage dizziness in older patients in order to assess potential cues for improvement.This study revealed a wide variety in management strategies for dizziness in older patients.There was a scarcity in Fall Risk Increasing Drug (FRID) evaluation and adjustment

  17. Veterinary Medicine Needs New Green Antimicrobial Drugs

    PubMed Central

    Toutain, Pierre-Louis; Ferran, Aude A.; Bousquet-Melou, Alain; Pelligand, Ludovic; Lees, Peter

    2016-01-01

    Given that: (1) the worldwide consumption of antimicrobial drugs (AMDs) used in food-producing animals will increase over the coming decades; (2) the prudent use of AMDs will not suffice to stem the rise in human antimicrobial resistance (AMR) of animal origin; (3) alternatives to AMD use are not available or not implementable, there is an urgent need to develop novel AMDs for food-producing animals. This is not for animal health reasons, but to break the link between human and animal resistomes. In this review we establish the feasibility of developing for veterinary medicine new AMDs, termed “green antibiotics,” having minimal ecological impact on the animal commensal and environmental microbiomes. We first explain why animal and human commensal microbiota comprise a “turnstile” exchange, between the human and animal resistomes. We then outline the ideal physico-chemical, pharmacokinetic, and pharmacodynamic properties of a veterinary green antibiotic and conclude that they can be developed through a rational screening of currently used AMD classes. The ideal drug will be hydrophilic, of relatively low potency, slow clearance and small volume of distribution. It should be eliminated principally by the kidney as inactive metabolite(s). For oral administration, bioavailability can be enhanced by developing lipophilic pro-drugs. For parenteral administration, slow-release formulations of existing eco-friendly AMDs with a short elimination half-life can be developed. These new eco-friendly veterinary AMDs can be developed from currently used drug classes to provide alternative agents to those currently used in veterinary medicine and mitigate animal contributions to the human AMR problem. PMID:27536285

  18. Veterinary Medicine Needs New Green Antimicrobial Drugs.

    PubMed

    Toutain, Pierre-Louis; Ferran, Aude A; Bousquet-Melou, Alain; Pelligand, Ludovic; Lees, Peter

    2016-01-01

    Given that: (1) the worldwide consumption of antimicrobial drugs (AMDs) used in food-producing animals will increase over the coming decades; (2) the prudent use of AMDs will not suffice to stem the rise in human antimicrobial resistance (AMR) of animal origin; (3) alternatives to AMD use are not available or not implementable, there is an urgent need to develop novel AMDs for food-producing animals. This is not for animal health reasons, but to break the link between human and animal resistomes. In this review we establish the feasibility of developing for veterinary medicine new AMDs, termed "green antibiotics," having minimal ecological impact on the animal commensal and environmental microbiomes. We first explain why animal and human commensal microbiota comprise a "turnstile" exchange, between the human and animal resistomes. We then outline the ideal physico-chemical, pharmacokinetic, and pharmacodynamic properties of a veterinary green antibiotic and conclude that they can be developed through a rational screening of currently used AMD classes. The ideal drug will be hydrophilic, of relatively low potency, slow clearance and small volume of distribution. It should be eliminated principally by the kidney as inactive metabolite(s). For oral administration, bioavailability can be enhanced by developing lipophilic pro-drugs. For parenteral administration, slow-release formulations of existing eco-friendly AMDs with a short elimination half-life can be developed. These new eco-friendly veterinary AMDs can be developed from currently used drug classes to provide alternative agents to those currently used in veterinary medicine and mitigate animal contributions to the human AMR problem. PMID:27536285

  19. Veterinary Medicine Needs New Green Antimicrobial Drugs.

    PubMed

    Toutain, Pierre-Louis; Ferran, Aude A; Bousquet-Melou, Alain; Pelligand, Ludovic; Lees, Peter

    2016-01-01

    Given that: (1) the worldwide consumption of antimicrobial drugs (AMDs) used in food-producing animals will increase over the coming decades; (2) the prudent use of AMDs will not suffice to stem the rise in human antimicrobial resistance (AMR) of animal origin; (3) alternatives to AMD use are not available or not implementable, there is an urgent need to develop novel AMDs for food-producing animals. This is not for animal health reasons, but to break the link between human and animal resistomes. In this review we establish the feasibility of developing for veterinary medicine new AMDs, termed "green antibiotics," having minimal ecological impact on the animal commensal and environmental microbiomes. We first explain why animal and human commensal microbiota comprise a "turnstile" exchange, between the human and animal resistomes. We then outline the ideal physico-chemical, pharmacokinetic, and pharmacodynamic properties of a veterinary green antibiotic and conclude that they can be developed through a rational screening of currently used AMD classes. The ideal drug will be hydrophilic, of relatively low potency, slow clearance and small volume of distribution. It should be eliminated principally by the kidney as inactive metabolite(s). For oral administration, bioavailability can be enhanced by developing lipophilic pro-drugs. For parenteral administration, slow-release formulations of existing eco-friendly AMDs with a short elimination half-life can be developed. These new eco-friendly veterinary AMDs can be developed from currently used drug classes to provide alternative agents to those currently used in veterinary medicine and mitigate animal contributions to the human AMR problem.

  20. Inhibition of Lysyl Oxidases Improves Drug Diffusion and Increases Efficacy of Cytotoxic Treatment in 3D Tumor Models

    PubMed Central

    Schütze, Friedrich; Röhrig, Florian; Vorlová, Sandra; Gätzner, Sabine; Kuhn, Anja; Ergün, Süleyman; Henke, Erik

    2015-01-01

    Tumors are characterized by a rigid, highly cross-linked extracellular matrix (ECM), which impedes homogeneous drug distribution and potentially protects malignant cells from exposure to therapeutics. Lysyl oxidases are major contributors to tissue stiffness and the elevated expression of these enzymes observed in most cancers might influence drug distribution and efficacy. We examined the effect of lysyl oxidases on drug distribution and efficacy in 3D in vitro assay systems. In our experiments elevated lysyl oxidase activity was responsible for reduced drug diffusion under hypoxic conditions and consequently impaired cytotoxicity of various chemotherapeutics. This effect was only observed in 3D settings but not in 2D-cell culture, confirming that lysyl oxidases affect drug efficacy by modification of the ECM and do not confer a direct desensitizing effect. Both drug diffusion and efficacy were strongly enhanced by inhibition of lysyl oxidases. The results from the in vitro experiments correlated with tumor drug distribution in vivo, and predicted response to therapeutics in murine tumor models. Our results demonstrate that lysyl oxidase activity modulates the physical barrier function of ECM for small molecule drugs influencing their therapeutic efficacy. Targeting this process has the potential to significantly enhance therapeutic efficacy in the treatment of malignant diseases. PMID:26620400

  1. Measurement of the double- β decay half-life of 136Xe with the KamLAND-Zen experiment

    SciTech Connect

    Gando, A.; Gando, Y.; Hanakago, H.; Ikeda, H.; Inoue, K.; Kato, R.; Koga, M.; Matsuda, S.; Mitsui, T.; Nakada, T.; Nakamura, K.; Obata, A.; Oki, A.; Ono, Y.; Shimizu, I.; Shirai, J.; Suzuki, A.; Takemoto, Y.; Tamae, K.; Ueshima, K.; Watanabe, H.; Xu, B. D.; Yamada, S.; Yoshida, H.; Kozlov, A.; Yoshida, S.; Banks, T. I.; Detwiler, J. A.; Freedman, S. J.; Fujikawa, B. K.; Han, K.; O’Donnell, T.; Berger, B. E.; Efremenko, Y.; Karwowski, H. J.; Markoff, D. M.; Tornow, W.; Enomoto, S.; Decowski, M. P.

    2012-04-19

    We present results from the KamLAND-Zen double-beta decay experiment based on an exposure of 77.6 days with 129 kg of 136Xe. The measured two-neutrino double-beta decay half-life of 136Xe is T$2ν\\atop{1/2}$ = 2.38 ± 0.02(stat) ± 0.14(syst) x1021 yr, consistent with a recent measurement by EXO-200. We also obtain a lower limit for the neutrinoless double-beta decay half-life, T$0ν\\atop{1/2}$ > 5.7 x 1024 yr at 90% C.L.

  2. Increasing pharmacological knowledge about human neurological and psychiatric disorders through functional neuroimaging and its application in drug discovery.

    PubMed

    Nathan, Pradeep J; Phan, K Luan; Harmer, Catherine J; Mehta, Mitul A; Bullmore, Edward T

    2014-02-01

    Functional imaging methods such as fMRI have been widely used to gain greater understanding of brain circuitry abnormalities in CNS disorders and their underlying neurochemical basis. Findings suggest that: (1) drugs with known clinical efficacy have consistent effects on disease relevant brain circuitry, (2) brain activation changes at baseline or early drug effects on brain activity can predict long-term efficacy; and (3) fMRI together with pharmacological challenges could serve as experimental models of disease phenotypes and be used for screening novel drugs. Together, these observations suggest that drug related modulation of disease relevant brain circuitry may serve as a promising biomarker/method for use in drug discovery to demonstrate target engagement, differential efficacy, dose-response relationships, and prediction of clinically relevant changes.

  3. Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models.

    PubMed

    Apte, Anjali; Koren, Erez; Koshkaryev, Alexander; Torchilin, Vladimir P

    2014-01-01

    Multidrug resistance (MDR) is a hallmark of cancer cells and a crucial factor in chemotherapy failure, cancer reappearance, and patient deterioration. We have previously described the physicochemical characteristics and the in vitro anticancer properties of a multifunctional doxorubicin-loaded liposomal formulation. Lipodox(®), a commercially available PEGylated liposomal doxorubicin, was made multifunctional by surface-decorating with a cell-penetrating peptide, TATp, conjugated to PEG 1000-PE, to enhance liposomal cell uptake. A pH-sensitive polymer, PEG 2000-Hz-PE, with a pH-sensitive hydrazone (Hz) bond to shield the peptide in the body and expose it only at the acidic tumor cell surface, was used as well. In addition, an anti-nucleosome monoclonal antibody 2C5 attached to a long-chain polymer to target nucleosomes overexpressed on the tumor cell surface was also present. Here, we report the in vitro cell uptake and cytotoxicity of the modified multifunctional immunoliposomes as well as the in vivo studies on tumor xenografts developed subcutaneously in nude mice with MDR and drug-sensitive human ovarian cancer cells (SKOV-3). Our results show the ability of multifunctional immunoliposomes to overcome MDR by enhancing cytotoxicity in drug-resistant cells, compared with non-modified liposomes. Furthermore, in comparison with the non-modified liposomes, upon intravenous injection of these multifunctional immunoliposomes into mice with tumor xenografts, a significant reduction in tumor growth and enhanced therapeutic efficacy of the drug in both drug-resistant and drug-sensitive mice was obtained. The use of "smart" multifunctional delivery systems may provide the basis for an effective strategy to develop, improve, and overcome MDR cancers in the future. PMID:24145298

  4. Doxorubicin in TAT peptide-modified multifunctional immunoliposomes demonstrates increased activity against both drug-sensitive and drug-resistant ovarian cancer models

    PubMed Central

    Apte, Anjali; Koren, Erez; Koshkaryev, Alexander; Torchilin, Vladimir P

    2014-01-01

    Multidrug resistance (MDR) is a hallmark of cancer cells and a crucial factor in chemotherapy failure, cancer reappearance, and patient deterioration. We have previously described the physicochemical characteristics and the in vitro anticancer properties of a multifunctional doxorubicin-loaded liposomal formulation. Lipodox®, a commercially available PEGylated liposomal doxorubicin, was made multifunctional by surface-decorating with a cell-penetrating peptide, TATp, conjugated to PEG1000-PE, to enhance liposomal cell uptake. A pH-sensitive polymer, PEG2000-Hz-PE, with a pH-sensitive hydrazone (Hz) bond to shield the peptide in the body and expose it only at the acidic tumor cell surface, was used as well. In addition, an anti-nucleosome monoclonal antibody 2C5 attached to a long-chain polymer to target nucleosomes overexpressed on the tumor cell surface was also present. Here, we report the in vitro cell uptake and cytotoxicity of the modified multifunctional immunoliposomes as well as the in vivo studies on tumor xenografts developed subcutaneously in nude mice with MDR and drug-sensitive human ovarian cancer cells (SKOV-3). Our results show the ability of multifunctional immunoliposomes to overcome MDR by enhancing cytotoxicity in drug-resistant cells, compared with non-modified liposomes. Furthermore, in comparison with the non-modified liposomes, upon intravenous injection of these multifunctional immunoliposomes into mice with tumor xenografts, a significant reduction in tumor growth and enhanced therapeutic efficacy of the drug in both drug-resistant and drug-sensitive mice was obtained. The use of “smart” multifunctional delivery systems may provide the basis for an effective strategy to develop, improve, and overcome MDR cancers in the future. PMID:24145298

  5. Survey of intensive care units and availability of drug assays in Australasia.

    PubMed

    Morris, R G; Kennedy, M; Kiloh, N

    2001-06-01

    The availability of drug assays, toxicologic screens, or both can play a significant role in the clinical decision-making processes affecting comatose patients with brain injury, including the decision to continue life support. However, with the widespread trend to reduce such comprehensive laboratory services down to core routine drugs, many clinical staff are finding it increasingly difficult to obtain such assay results in a time-frame relevant to the clinical needs of their patients and families. The authors have surveyed the intensive care units in Australasia to assess their perspectives in this area. The results from 53% of units responding showed there was insufficient clinical pharmacologic support available. Whereas the majority of centers had ready access to the standard immunoassays and urine drug screens, few had access to more complex assays, especially in the time-frame that was required. Interestingly, there was wide variability between centers as to the time to terminate life support in the absence of other indices (e.g., 4-vessel angiography). The use of basic pharmacokinetic principles including drug half-life was practiced in some centers, albeit probably inappropriately in this patient subpopulation. There is generally insufficient availability of specialized drug assay laboratories to meet clinical demands, primarily because of reduction in services and financial constraints in the public hospital system. PMID:11360041

  6. Relationship of pharmacokinetics and drug distribution in tissue to increased safety of amphotericin B colloidal dispersion in dogs.

    PubMed Central

    Fielding, R M; Singer, A W; Wang, L H; Babbar, S; Guo, L S

    1992-01-01

    The safety, pharmacokinetics, and distribution in tissue of an amphotericin B (AmB)-cholesteryl sulfate colloidal dispersion (ABCD) were compared with those of micellar amphotericin B-deoxycholate (m-AmB). Dogs received 14 daily injections of ABCD (0.6 to 10 mg/kg of body weight per day) or m-AmB (0.6 mg/kg/day). Safety was evaluated by monitoring body weight, hematology, clinical chemistry, and urinalysis during the study and by microscopic examination of tissues at the time of necropsy (day 16). AmB concentrations in plasma were measured in some groups on days 1, 7, and 14 and in necropsy tissue samples. ABCD produced a spectrum of toxic effects in the kidneys, gut, and liver similar to those of m-AmB, but ABCD was eightfold safer than m-AmB. The highest tolerated dose of ABCD (5.0 mg/kg/day) produced effects similar to those of m-AmB (0.6 mg/kg/day). ABCD produced lower concentrations in plasma than an equal dose of m-AmB did. Clearances on days 7 and 14 were higher for ABCD (304 and 295 ml/h.kg) than they were for m-AmB (67 and 53 ml/h.kg). Concentrations in plasma reached steady state after ABCD administration, but they increased after repeated dosing with m-AmB. Diurnal fluctuations in AmB concentrations in plasma were observed 4 to 8 h after the time of dosing. ABCD resulted in lower AmB concentrations in tissue than m-AmB did, except in the reticuloendothelial system. Up to 90% of AmB administered as ABCD was recovered from the liver and spleen on day 16. Reduced drug levels in the kidneys and gut correlated with reduced indications of toxicity in these organs after ABCD administration. Although ABCD increased concentrations of AmB in the reticuloendothelial system, increased toxicity was not observed in these organs. Images PMID:1605595

  7. Ketorolac: a parenteral nonsteroidal antiinflammatory drug.

    PubMed

    Resman-Targoff, B H

    1990-11-01

    Ketorolac tromethamine is a pyrrolo-pyrrole nonsteroidal antiinflammatory drug (NSAID) with potent analgesic effects when administered intramuscularly for the treatment of acute pain. Ketorolac is well absorbed and has a rapid onset of action. Maximum plasma concentrations are achieved in 45-50 minutes and peak analgesic effects in about one to two hours following intramuscular injection. Ketorolac is more than 99 percent bound to plasma proteins and has a mean apparent volume of distribution of 0.11-0.25 L/kg. About 91 percent of a dose is excreted in urine, mostly as inactive metabolites, and approximately 6 percent is eliminated in feces. The elimination half-life, approximately four to six hours, increases in elderly patients and those with renal impairment. Its analgesic effectiveness was similar or superior to that of morphine, meperidine, or pentazocine in single-dose studies of patients with postoperative pain or renal colic and greater than that of placebo in patients with chronic cancer pain. The adverse effects are generally mild to moderate, self-limiting, and similar to those seen with other prostaglandin inhibitors. Ketorolac has a reversible inhibitory effect on platelet aggregation. It can cause dose-related gastric ulcerations, even when administered parenterally. Ketorolac is a promising parenteral alternative to oral NSAIDs and a nonnarcotic alternative to opioid analgesics. Additional multiple-dose studies are needed to more clearly define its place in therapy.

  8. Challenges and Opportunities for Increasing the Knowledge Base Related to Drug Biotransformation and Pharmacokinetics during Growth and Development.

    PubMed

    Leeder, J Steven; Meibohm, Bernd

    2016-07-01

    It is generally acknowledged that there is a need and role for informative pharmacokinetic models to improve predictions and simulation as well as individualization of drug therapy in pediatric populations of different ages and developmental stages. This special issue contains more than 20 papers responding to the challenge of providing new information on scaling factors, ontogeny functions for drug metabolizing enzymes and transporters, the mechanisms underlying the observed developmental trajectories for these gene products, age-dependent changes in physiologic processes affecting drug disposition in children, as well as in vitro and in vivo studies describing the relative contribution of ontogeny and genetic factors as sources of variability in drug disposition in children. Considered together, these contributions serve to illustrate some of the current limitations regarding sample availability, number, and quality, but also provide a framework that allows for the potential value of the results of a given study to be interpreted within the context of these limitations. Among the challenges for the future are improving our understanding of the mechanisms regulating age-dependent changes in factors influencing drug disposition and response, thereby facilitating generalization to systems lacking detailed data, better integrating age-dependent changes in pharmacokinetics with age-dependent changes in pharmacodynamics, and allowing better predictability and individualization of drug disposition and response across the pediatric age spectrum. PMID:27302933

  9. CONDITIONS THAT INCREASE DRUG MARKET INVOLVEMENT: THE INVITATIONAL EDGE AND THE CASE OF MEXICANS IN SOUTH TEXAS

    PubMed Central

    Valdez, Avelardo; Kaplan, Charles

    2010-01-01

    Research on drug trafficking has not been able to discern the exact nature of illegal drug markets and the relationship between their individual and group participants. This article delineates the role of Mexican immigrants and Mexican-American participants involved in the stratified drug market of South Texas. This article synthesizes ethnographic materials drawn from two previous National Institute on Drug Abuse (NIDA) studies in order identify the different types of drug distribution behaviors that occur within the groups, the differentiated roles of individuals, the organizational framework, and most significantly, the processes that link market participants to others outside of the drug market. This illegal behavior can be interpreted as an adaptive mechanism that is a direct response to the marginal economic status imposed by macro socio-economical background factors. As well, we conclude that the specific foreground factors of the opportunities offered by the context, culture, and proximity of the U.S./Mexico border and invitational edges explain this behavior. There are both parallels and particular differences between the South Texas case and the structuring and functioning of informal legal and illegal markets that are characteristic of other economically disadvantaged communities. PMID:21218142

  10. Estimated GFR reporting is associated with decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function

    PubMed Central

    Wei, Li; MacDonald, Thomas M; Jennings, Claudine; Sheng, Xia; Flynn, Robert W; Murphy, Michael J

    2013-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used; however, they are also nephrotoxic with both acute and chronic effects on kidney function. Here we determined NSAID prescribing before and after estimated GFR (eGFR) reporting and evaluate renal function in patients who used NSAIDs but stopped these after their first eGFR report. A population-based longitudinal analysis using a record-linkage database was conducted with the GFR estimated using the four-variable equation from the MDRD study and analyzed by trend test, paired t-test, and logistic regression modeling. Prescriptions for NSAIDs significantly decreased from 39,459 to 35,415 after implementation of eGFR reporting from the second quarter of 2005 compared with the first quarter of 2007. Reporting eGFR was associated with reduced NSAID prescriptions (adjusted odds ratio, 0.78). NSAID prescription rates in the 6 months before April 2006 were 18.8, 15.4, and 7.0% in patients with CKD stages 3, 4, and 5 and 15.5, 10.7, and 6.3%, respectively, after eGFR reporting commenced. In patients who stopped NSAID treatment, eGFR significantly increased from 45.9 to 46.9, 23.9 to 27.1, and 12.4 to 26.4 ml/min per 1.73 m2 in 1340 stage 3 patients, 162 stage 4 patients, and 9 stage 5 patients, respectively. Thus, NSAID prescribing decreased after the implementation of eGFR reporting, and there were significant improvements in estimated renal function in patients who stopped taking NSAIDs. Hence, eGFR reporting may result in safer prescribing. PMID:23486517

  11. 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

    Background Due to the global occurrence of multi-drug-resistant malarial parasites (Plasmodium falciparum), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood (Artemisia annua). However, artemisinin is in short supply and unaffordable to most malaria patients. Artemisinin can be semi-synthesized from its precursor artemisinic acid, which can be synthesized from simple sugars using microorganisms genetically engineered with genes from A. annua. In order to develop an industrially competent yeast strain, detailed analyses of microbial physiology and development of gene expression strategies are required. Results Three plant genes coding for amorphadiene synthase, amorphadiene oxidase (AMO or CYP71AV1), and cytochrome P450 reductase, which in concert divert carbon flux from farnesyl diphosphate to artemisinic acid, were expressed from a single plasmid. The artemisinic acid production in the engineered yeast reached 250 μg mL-1 in shake-flask cultures and 1 g L-1 in bio-reactors with the use of Leu2d selection marker and appropriate medium formulation. When plasmid stability was measured, the yeast strain synthesizing amorphadiene alone maintained the plasmid in 84% of the cells, whereas the yeast strain synthesizing artemisinic acid showed poor plasmid stability. Inactivation of AMO by a point-mutation restored the high plasmid stability, indicating that the low plasmid stability is not caused by production of the AMO protein but by artemisinic acid synthesis or accumulation. Semi-quantitative reverse-transcriptase (RT)-PCR and quantitative real time-PCR consistently showed that pleiotropic drug resistance (PDR) genes, belonging to the family of ATP-Binding Cassette (ABC) transporter, were massively induced in the yeast strain producing artemisinic acid, relative to the yeast strain producing the hydrocarbon amorphadiene alone. Global transcriptional analysis by

  12. Hot topic: Early postpartum treatment of commercial dairy cows with nonsteroidal antiinflammatory drugs increases whole-lactation milk yield.

    PubMed

    Carpenter, A J; Ylioja, C M; Vargas, C F; Mamedova, L K; Mendonça, L G; Coetzee, J F; Hollis, L C; Gehring, R; Bradford, B J

    2016-01-01

    Previous research has shown that postpartum administration of the nonsteroidal antiinflammatory drug (NSAID) sodium salicylate can increase 305-d milk yield in older dairy cattle (parity 3 and greater). However, in this prior work, sodium salicylate was delivered to cows via the drinking water, a method that does not align well with current grouping strategies on commercial dairy farms. The objective of the current study was to replicate these results on a commercial dairy farm with a simplified treatment protocol and to compare sodium salicylate with another NSAID, meloxicam. Dairy cattle in their second lactation and greater (n=51/treatment) were alternately assigned to 1 of 3 treatments at parturition, with treatments lasting for 3d. Experimental treatments began 12 to 36 h after parturition and were (1) 1 placebo bolus on the first day and 3 consecutive daily drenches of sodium salicylate (125 g/cow per day; SAL); (2) 1 bolus of meloxicam (675 mg/cow) and 3 drenches of an equal volume of water (MEL); or (3) 1 placebo bolus and 3 drenches of water (CON). Blood samples were collected on the first day of treatment, immediately following the last day of treatment, and 7d after the last day of treatment; plasma was analyzed for glucose, β-hydroxybutyrate (BHB), free fatty acids, haptoglobin, and paraoxonase. Milk production, body condition score, reproductive status, and retention in the herd were monitored for 365 d posttreatment, and effects of treatment, parity, days in milk, and interactions were evaluated in mixed effects models. Significance was declared at P<0.05. Whole-lactation milk and protein yields were greater in NSAID-treated cows, although 305-d fat production was not affected. There was a significant interaction of treatment and parity for plasma glucose concentration; MEL increased plasma glucose concentrations compared with CON and SAL in older cows. Sodium salicylate decreased plasma BHB concentration compared with MEL at 7d posttreatment

  13. Polymer combination increased both physical stability and oral absorption of solid dispersions containing a low glass transition temperature drug: physicochemical characterization and in vivo study.

    PubMed

    Sakurai, Atsushi; Sakai, Toshiro; Sako, Kazuhiro; Maitani, Yoshie

    2012-01-01

    The purpose of this study was establishing a solid dispersion formulation containing a low glass transition temperature (T(g)) and poorly water-soluble drug. Drug/polymer blends with differing physicochemical stabilities and oral absorption were prepared from copolyvidone (PVP-VA), polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) by a hot melt extrusion. HPMC drastically increased the drug oral absorption property, while PVP-VA or PVP stabilized solid dispersions during storage by increasing the T(g) in proportion to polymer concentration. Experimental T(g) values corresponded closely with theoretical T(g) values; indeed, the T(g) values of solid dispersion with HPMC did not increase significantly compared to the T(g) value for the drug alone. A solid dispersion formulation incorporating two different polymers-HPMC and either PVP-VA or PVP-maintained increased T(g), physicochemical stability, solubility, and bioavailability of the solid dispresions owing to each polymer. These findings suggested that both oral absorption and physicochemical stability of low-T(g) drug will be improved using less amount of solid dispersion of combined two polymers than polymer alone.

  14. [Neonatal risks of drugs exposure at the end of pregnancy].

    PubMed

    Autret-Leca, Elisabeth; Cissoko, Hawaré; Jonville-Béra, Annie Pierre

    2011-01-01

    Foetal drugs exposure consequences depend according to the drug involved and to the length of the exposure which in the sum of length of treatment and of drug elimination (5 half life). Decisions are based upon risk evaluation and are a compromise between a risk banalisation and an excess of carefully. We described risks management for drugs used for a disease due to the pregnancy (glucocorticoïdes, antibiotics) then for drugs used for a chronic disease often preceding the pregnancy (non steroidal anti-inflammatory, serotonin recapture inhibitors, benzodiazepines, antiepileptics, conversion enzyme inhibitors/renine angiotensine antagonists, betabloquants). We also present the elements to take in account for the best drug choice at the end of pregnancy and/or for an adapted advice if the drug has been already taken: the drug itself (pharmacological effects, kinetics in neonate, toxicity marker, risk detection tool), drug amount possibly received by the neonate and literature data about neonatal manifestations due to the drug.

  15. The Synergistic (MARATHON) Effect of Combined Methamphetamine with Sexual Stimulant Drugs on Increasing the Likelihood of High-Risk Sexual Behaviors

    PubMed Central

    Hosseinifard, Seyed Mehdi; Ahmadian, Alireza; Smaeelifar, Neda

    2014-01-01

    Background Chronic drug abuse and sexual dysfunction specifically erectile dysfunction may lead drug abusers to seek over-the-counter or non-prescription medications, out of which Sildenafil citrate, sold as the trade name of Viagra® can be considered as a prime and important treatment. Therefore, the research purpose was to draw a comparison and review the role of methamphetamine abuse and sildenafil use in increasing the likelihood of high-risk sexual behaviors (both concomitant and non-concomitant use). Methods Hence, a total of 40 patients diagnosed with methamphetamine abuse were recruited through the administration of structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition), through purposive sampling and subsequent to being qualified in accordance with the selection criteria by psychologists and general practitioners. All the 40 drug abusers (20 methamphetamine abusers with concomitant use of Aphrodisiac drugs (sexual stimulant pills) and 20 methamphetamine abusers) described their sexual risk behaviors subsequent to the drug use. Findings Supported the between-group difference that is to say that, the group with concomitant methamphetamine abuse differed significantly in all the items when compared with the control group. However, this group scored lower on the item of sexual intercourse with drug addicted prostitutes using condom and both groups demonstrated high pick on this item. Conclusion Overall, the concomitant methamphetamine chronic abuse with sexual stimulant drugs generates Aphrodisiac drugs impulses and is found to be related to higher frequencies of sexual risk behaviors and sexual intercourse with addicted prostitutes. PMID:25984278

  16. Zinc cross-linked hydroxamated alginates for pulsed drug release

    PubMed Central

    Raut, Neha S; Deshmukh, Prasad R; Umekar, Milind J; Kotagale, Nandkishor R

    2013-01-01

    Introduction: Alginates can be tailored chemically to improve solubility, physicochemical, and biological properties and its complexation with metal ion is useful for controlling the drug release. Materials And Methods: Synthesized N,O-dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were subsequently complexed with zinc to form beads. Hydroxamation of sodium alginate was confirmed by Fourier transform infra-red spectroscopy (FTIR) and differential scanning calorimetry (DSC). Results: The synthesized polymeric material exhibited reduced aqueous, HCl and NaOH solubility. The hydroxamated derivatives demonstrated pulsed release where change in pH of the dissolution medium stimulated the atenolol release. Conclusion: Atenolol loaded Zn cross-linked polymeric beads demonstrated the sustained the plasma drug levels with increased half-life. Although the synthesized derivatives greatly altered the aqueous solubility of sodium alginate, no significant differences in in vitro and in vivo atenolol release behavior amongst the N,O-dimethyl, N-methyl, or N-Benzyl hydroxylamine derivatives of sodium alginate were observed. PMID:24350039

  17. Engineered nanoparticles for drug delivery in cancer therapy.

    PubMed

    Sun, Tianmeng; Zhang, Yu Shrike; Pang, Bo; Hyun, Dong Choon; Yang, Miaoxin; Xia, Younan

    2014-11-10

    In medicine, nanotechnology has sparked a rapidly growing interest as it promises to solve a number of issues associated with conventional therapeutic agents, including their poor water solubility (at least, for most anticancer drugs), lack of targeting capability, nonspecific distribution, systemic toxicity, and low therapeutic index. Over the past several decades, remarkable progress has been made in the development and application of engineered nanoparticles to treat cancer more effectively. For example, therapeutic agents have been integrated with nanoparticles engineered with optimal sizes, shapes, and surface properties to increase their solubility, prolong their circulation half-life, improve their biodistribution, and reduce their immunogenicity. Nanoparticles and their payloads have also been favorably delivered into tumors by taking advantage of the pathophysiological conditions, such as the enhanced permeability and retention effect, and the spatial variations in the pH value. Additionally, targeting ligands (e.g., small organic molecules, peptides, antibodies, and nucleic acids) have been added to the surface of nanoparticles to specifically target cancerous cells through selective binding to the receptors overexpressed on their surface. Furthermore, it has been demonstrated that multiple types of therapeutic drugs and/or diagnostic agents (e.g., contrast agents) could be delivered through the same carrier to enable combination therapy with a potential to overcome multidrug resistance, and real-time readout on the treatment efficacy. It is anticipated that precisely engineered nanoparticles will emerge as the next-generation platform for cancer therapy and many other biomedical applications.

  18. Electrosprayed nanocomposites based on hyaluronic acid derivative and Soluplus for tumor-targeted drug delivery.

    PubMed

    Lee, Song Yi; Lee, Jeong-Jun; Park, Ju-Hwan; Lee, Jae-Young; Ko, Seung-Hak; Shim, Jae-Seong; Lee, Jongkook; Heo, Moon Young; Kim, Dae-Duk; Cho, Hyun-Jong

    2016-09-01

    Nanocomposite (NC) based on hyaluronic acid-ceramide (HACE) and Soluplus (SP) was fabricated by electrospraying for the tumor-targeted delivery of resveratrol (RSV). Amphiphilic property of both HACE and SP has been used to entrap RSV in the internal cavity of NC. Electrospraying with established experimental conditions produced HACE/SP/RSV NC with 230nm mean diameter, narrow size distribution, negative zeta potential, and >80% drug entrapment efficiency. Sustained and pH-dependent drug release profiles were observed in drug release test. Cellular uptake efficiency of HACE/SP NC was higher than that of SP NC, mainly based on HA-CD44 receptor interaction, in MDA-MB-231 (CD44 receptor-positive human breast cancer) cells. Selective tumor targetability of HACE/SP NC, compared to SP NC, was also confirmed in MDA-MB-231 tumor-xenograted mouse model using a near-infrared fluorescence (NIRF) imaging. According to the results of pharmacokinetic study in rats, decreased in vivo clearance and increased half-life of RSV in NC group, compared to drug solution group, were shown. Given that these experimental results, developed HACE/SP NC can be a promising theranostic nanosystem for CD44 receptor-expressed cancers. PMID:27208440

  19. Increasing HIV-1 Drug Resistance Between 2010 and 2012 in Adults Participating in Population-Based HIV Surveillance in Rural KwaZulu-Natal, South Africa

    PubMed Central

    Danaviah, Siva; Lessells, Richard; Elshareef, Muna; Tanser, Frank; Wilkinson, Eduan; Pillay, Sureshnee; Mthiyane, Hloniphile; Mwambi, Henry; Pillay, Deenan; de Oliveira, Tulio

    2016-01-01

    Abstract As more human immunodeficiency virus (HIV)–infected patients access combination antiretroviral therapy (cART), higher proportions of newly infected patients may be infected with drug-resistant viruses. Regular surveillance of transmitted drug resistance (TDR) is required in southern Africa where high rates of transmission persist despite rapid expansion of ART. Dried blood spot samples from cART-naive participants from two rounds of an annual population-based HIV surveillance program in rural KwaZulu-Natal were tested for HIV RNA, and samples with HIV RNA >10,000 copies/ml were genotyped for drug resistance. The 2009 surveillance of drug resistance mutation (SDRM) list was used for drug resistance interpretation. The data were added to previously published data from the same program, and the χ2 test for trend was used to test for trend in estimated prevalence of any TDR. Seven hundred and one participants' data were analyzed: 67 (2010), 381 (2011), and 253 (2012). No TDR was detected in 2010. Years 2011 and 2012 had 18 participants with SDRMs 4.7% and 7.1%, respectively (p = .02, χ2 test for trend). The nonnucleoside reverse transcriptase inhibitor mutation, K103N, was the most common mutation, occurring in 27 (3.8%) of the participants, while nucleoside reverse transcriptase inhibitor (NRTI) SDRMs were detected in 10 (1.4%) of the participants, of whom eight had only a single NRTI SDRM. The increase in levels of drug resistance observed in this population could be a signal of increasing transmission of drug-resistant HIV. Thus, continued surveillance is critical to inform public health policies around HIV treatment and prevention. PMID:27002368

  20. Increasing HIV-1 Drug Resistance Between 2010 and 2012 in Adults Participating in Population-Based HIV Surveillance in Rural KwaZulu-Natal, South Africa.

    PubMed

    Manasa, Justen; Danaviah, Siva; Lessells, Richard; Elshareef, Muna; Tanser, Frank; Wilkinson, Eduan; Pillay, Sureshnee; Mthiyane, Hloniphile; Mwambi, Henry; Pillay, Deenan; de Oliveira, Tulio

    2016-08-01

    As more human immunodeficiency virus (HIV)-infected patients access combination antiretroviral therapy (cART), higher proportions of newly infected patients may be infected with drug-resistant viruses. Regular surveillance of transmitted drug resistance (TDR) is required in southern Africa where high rates of transmission persist despite rapid expansion of ART. Dried blood spot samples from cART-naive participants from two rounds of an annual population-based HIV surveillance program in rural KwaZulu-Natal were tested for HIV RNA, and samples with HIV RNA >10,000 copies/ml were genotyped for drug resistance. The 2009 surveillance of drug resistance mutation (SDRM) list was used for drug resistance interpretation. The data were added to previously published data from the same program, and the χ(2) test for trend was used to test for trend in estimated prevalence of any TDR. Seven hundred and one participants' data were analyzed: 67 (2010), 381 (2011), and 253 (2012). No TDR was detected in 2010. Years 2011 and 2012 had 18 participants with SDRMs 4.7% and 7.1%, respectively (p = .02, χ(2) test for trend). The nonnucleoside reverse transcriptase inhibitor mutation, K103N, was the most common mutation, occurring in 27 (3.8%) of the participants, while nucleoside reverse transcriptase inhibitor (NRTI) SDRMs were detected in 10 (1.4%) of the participants, of whom eight had only a single NRTI SDRM. The increase in levels of drug resistance observed in this population could be a signal of increasing transmission of drug-resistant HIV. Thus, continued surveillance is critical to inform public health policies around HIV treatment and prevention. PMID:27002368

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

    PubMed

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

    2016-09-25

    Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. PMID:27473280

  2. Blood concentrations of everolimus are markedly increased by ketoconazole.

    PubMed

    Kovarik, J M; Beyer, D; Bizot, M N; Jiang, Q; Shenouda, M; Schmouder, R L

    2005-05-01

    The authors sought to quantify the influence of the CYP3A and P-glycoprotein inhibitor ketoconazole on the pharmacokinetics of everolimus in healthy subjects. This was a 2-period, single-sequence, crossover study in 12 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of everolimus. In period 2, they received the test treatment of ketoconazole 200 mg twice daily for a total of 8 days and a single dose of everolimus coadministered on the fourth day of ketoconazole therapy. The test/reference ratio and 90% confidence interval were derived for everolimus maximum concentration and area under the curve. During ketoconazole coadministration, everolimus maximum concentration increased 3.9-fold (90% confidence interval, 3.4-4.6) from 15 +/- 4 ng/mL to 59 +/- 13 ng/mL. Everolimus area under the curve increased 15.0-fold (90% confidence interval, 13.6-16.6) from 90 +/- 23 ng*h/mL to 1324 +/- 232 ng*h/mL. Everolimus half-life was prolonged by 1.9-fold from 30 +/- 4 hours to 56 +/- 5 hours. Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in everolimus-treated patients. PMID:15831774

  3. Increases in hepatitis C virus infection related to injection drug use among persons aged ≤30 years - Kentucky, Tennessee, Virginia, and West Virginia, 2006-2012.

    PubMed

    Zibbell, Jon E; Iqbal, Kashif; Patel, Rajiv C; Suryaprasad, Anil; Sanders, Kathy J; Moore-Moravian, Loretta; Serrecchia, Jamie; Blankenship, Steven; Ward, John W; Holtzman, Deborah

    2015-05-01

    Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with approximately three million persons living with current infection. Percutaneous exposure to contaminated blood is the most efficient mode of transmission, and in the United States, injection drug use (IDU) is the primary risk factor for infection. State surveillance reports from the period 2006-2012 reveal a nationwide increase in reported cases of acute HCV infection, with the largest increases occurring east of the Mississippi River, particularly among states in central Appalachia. Demographic and behavioral data accompanying these reports show young persons (aged ≤30 years) from nonurban areas contributed to the majority of cases, with about 73% citing IDU as a principal risk factor. To better understand the increase in acute cases of HCV infection and its correlation to IDU, CDC examined surveillance data for acute case reports in conjunction with analyzing drug treatment admissions data from the Treatment Episode Data Set-Admissions (TEDS-A) among persons aged ≤30 years in four states (Kentucky, Tennessee, Virginia, and West Virginia) for the period 2006-2012. During this period, significant increases in cases of acute HCV infection were found among persons in both urban and nonurban areas, with a substantially higher incidence observed each year among persons residing in nonurban areas. During the same period, the proportion of treatment admissions for opioid dependency increased 21.1% in the four states, with a significant increase in the proportion of persons admitted who identified injecting as their main route of drug administration (an increase of 12.6%). Taken together, these increases indicate a geographic intersection among opioid abuse, drug injecting, and HCV infection in central Appalachia and underscore the need for integrated health services in substance abuse treatment settings to prevent HCV infection and ensure that those who are infected

  4. Increasing HIV-1 pretreatment drug resistance among antiretroviral-naïve adults initiating treatment between 2006 and 2014 in Nairobi, Kenya.

    PubMed

    Chung, Michael H; Silverman, Rachel; Beck, Ingrid A; Yatich, Nelly; Dross, Sandra; McKernan-Mullin, Jennifer; Bii, Stephen; Tapia, Kenneth; Stern, Joshua; Chohan, Bhavna; Sakr, Samah R; Kiarie, James N; Frenkel, Lisa M

    2016-06-19

    Antiretroviral-naïve adults initiating antiretroviral therapy in Nairobi, Kenya were tested for HIV-1 drug resistance at codons K103N, Y181C, G190A, M184V, and K65R using an oligonucleotide ligation assay. Prevalence of pretreatment drug resistance increased from 3.89% in 2006 to 10.93% in 2014 (P < 0.001), and 95% of those with resistance had at least one nonnucleoside reverse transcriptase inhibitor mutation. Resistance to tenofovir (K65R) was found in 2014 but not in 2006. PMID:27058353

  5. Clotrimazole Drug Resistance in Candida glabrata Clinical Isolates Correlates with Increased Expression of the Drug:H(+) Antiporters CgAqr1, CgTpo1_1, CgTpo3, and CgQdr2.

    PubMed

    Costa, Catarina; Ribeiro, Jonathan; Miranda, Isabel M; Silva-Dias, Ana; Cavalheiro, Mafalda; Costa-de-Oliveira, Sofia; Rodrigues, Acácio G; Teixeira, Miguel C

    2016-01-01

    For years, antifungal drug resistance in Candida species has been associated to the expression of ATP-Binding Cassette (ABC) multidrug transporters. More recently, a few drug efflux pumps from the Drug:H(+) Antiporter (DHA) family have also been shown to play a role in this process, although to date only the Candida albicans Mdr1 transporter has been demonstrated to be relevant in the clinical acquisition of antifungal drug resistance. This work provides evidence to suggest the involvement of the C. glabrata DHA transporters CgAqr1, CgQdr2, CgTpo1_1, and CgTpo3 in the clinical acquisition of clotrimazole drug resistance. A screening for azole drug resistance in 138 C. glabrata clinical isolates, from patients attending two major Hospitals in Portugal, was performed. Based on this screening, 10 clotrimazole susceptible and 10 clotrimazole resistant isolates were selected for further analysis. The transcript levels of CgAQR1, CgQDR2, CgTPO1_1, and CgTPO3 were found to be significantly up-regulated in resistant isolates when compared to the susceptible ones, with a level of correlation that was found to be similar to that of CgCDR2, an ABC gene known to be involved in the clinical acquisition of resistance. As a proof-of-concept experiment, the CgTPO3 gene was deleted in an azole resistant C. glabrata isolate, exhibiting high levels of expression of this gene. The deletion of CgTPO3 in this isolate was found to lead to decreased resistance to clotrimazole and fluconazole, and increased accumulation of azole drugs, thus suggesting the involvement of this transporter in the manifestation of azole resistance.

  6. Clotrimazole Drug Resistance in Candida glabrata Clinical Isolates Correlates with Increased Expression of the Drug:H+ Antiporters CgAqr1, CgTpo1_1, CgTpo3, and CgQdr2

    PubMed Central

    Costa, Catarina; Ribeiro, Jonathan; Miranda, Isabel M.; Silva-Dias, Ana; Cavalheiro, Mafalda; Costa-de-Oliveira, Sofia; Rodrigues, Acácio G.; Teixeira, Miguel C.

    2016-01-01

    For years, antifungal drug resistance in Candida species has been associated to the expression of ATP-Binding Cassette (ABC) multidrug transporters. More recently, a few drug efflux pumps from the Drug:H+ Antiporter (DHA) family have also been shown to play a role in this process, although to date only the Candida albicans Mdr1 transporter has been demonstrated to be relevant in the clinical acquisition of antifungal drug resistance. This work provides evidence to suggest the involvement of the C. glabrata DHA transporters CgAqr1, CgQdr2, CgTpo1_1, and CgTpo3 in the clinical acquisition of clotrimazole drug resistance. A screening for azole drug resistance in 138 C. glabrata clinical isolates, from patients attending two major Hospitals in Portugal, was performed. Based on this screening, 10 clotrimazole susceptible and 10 clotrimazole resistant isolates were selected for further analysis. The transcript levels of CgAQR1, CgQDR2, CgTPO1_1, and CgTPO3 were found to be significantly up-regulated in resistant isolates when compared to the susceptible ones, with a level of correlation that was found to be similar to that of CgCDR2, an ABC gene known to be involved in the clinical acquisition of resistance. As a proof-of-concept experiment, the CgTPO3 gene was deleted in an azole resistant C. glabrata isolate, exhibiting high levels of expression of this gene. The deletion of CgTPO3 in this isolate was found to lead to decreased resistance to clotrimazole and fluconazole, and increased accumulation of azole drugs, thus suggesting the involvement of this transporter in the manifestation of azole resistance. PMID:27148215

  7. Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design.

    PubMed

    Massey, Andrew J; Stokes, Stephen; Browne, Helen; Foloppe, Nicolas; Fiumana, Andreá; Scrace, Simon; Fallowfield, Mandy; Bedford, Simon; Webb, Paul; Baker, Lisa; Christie, Mark; Drysdale, Martin J; Wood, Mike

    2015-11-01

    Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation. PMID:26437226

  8. Identification of novel, in vivo active Chk1 inhibitors utilizing structure guided drug design

    PubMed Central

    Massey, Andrew J.; Stokes, Stephen; Browne, Helen; Foloppe, Nicolas; Fiumana, Andreá; Scrace, Simon; Fallowfield, Mandy; Bedford, Simon; Webb, Paul; Baker, Lisa; Christie, Mark; Drysdale, Martin J.; Wood, Mike

    2015-01-01

    Chk1 kinase is a critical component of the DNA damage response checkpoint especially in cancer cells and targeting Chk1 is a potential therapeutic opportunity for potentiating the anti-tumor activity of DNA damaging chemotherapy drugs. Fragment elaboration by structure guided design was utilized to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases. V158411 abrogated gemcitabine and camptothecin induced cell cycle checkpoints, resulting in the expected modulation of cell cycle proteins and increased cell death in cancer cells. V158411 potentiated the cytotoxicity of gemcitabine, cisplatin, SN38 and camptothecin in a variety of p53 deficient human tumor cell lines in vitro, p53 proficient cells were unaffected. In nude mice, V158411 showed minimal toxicity as a single agent and in combination with irinotecan. In tumor bearing animals, V158411 was detected at high levels in the tumor with a long elimination half-life; no pharmacologically significant in vivo drug-drug interactions with irinotecan were identified through analysis of the pharmacokinetic profiles. V158411 potentiated the anti-tumor activity of irinotecan in a variety of human colon tumor xenograft models without additional systemic toxicity. These results demonstrate the opportunity for combining V158411 with standard of care chemotherapeutic agents to potentiate the therapeutic efficacy of these agents without increasing their toxicity to normal cells. Thus, V158411 would warrant further clinical evaluation. PMID:26437226

  9. Do fall-risk-increasing drugs have an impact on mortality in older hip fracture patients? A population-based cohort study

    PubMed Central

    Kragh Ekstam, Annika; Elmståhl, Sölve

    2016-01-01

    Objective The aim of this study was to assess the mortality in hip fracture patients with regard to use of fall-risk-increasing drugs (FRIDs), by comparing survival in exposed and nonexposed individuals. Design This was a general population-based cohort study. Settings Data on hip fracture patients were retrieved from three national databases. Participants All hip fracture patients aged 60 years or older in a Swedish county in 2006 participated in this study. Measurements We studied the mortality in hip fracture patients by comparing those exposed to FRIDs, combinations of FRIDs, and polypharmacy to nonexposed patients, adjusting for age and sex. For survival estimates in patients using four or more FRIDs, a Cox regression analysis was used, adjusting for age, sex, and use of any four or more drugs. Results First-year all-cause mortality was 24.6% (N=503) in 2,043 hip fracture patients aged 60 years or older, including 170 males (33.8%) and 333 females (66.2%). Patients prescribed four or more FRIDs, five or more drugs (polypharmacy), psychotropic drugs, and cardiovascular drugs showed significantly increased first-year mortality. Exposure to four or more FRIDs (518 patients, 25.4%) was associated with an increased mortality at 30 days with odds ratios (ORs) 2.01 (95% confidence interval [CI] 1.44–2.79), 90 days with OR 1.56 (95% CI 1.19–2.04), 180 days with OR 1.54 (95% CI 1.20–1.97), and 365 days with OR 1.43 (95% CI 1.13–1.80). Cox regression analyses adjusted for age, sex, and use of any four or more drugs showed a significantly higher mortality in patients treated with four or more FRIDs at 90 days (P=0.015) and 180 days (P=0.012) compared to patients treated with three or less FRIDs. Conclusion First-year all-cause mortality was significantly higher in older hip fracture patients exposed before the fracture to FRIDs, in particular to four or more FRIDs, polypharmacy, psychotropic, and cardiovascular drugs. Interventions aiming to optimize both safety

  10. Pretreatment with VEGF(R)-inhibitors reduces interstitial fluid pressure, increases intraperitoneal chemotherapy drug penetration, and impedes tumor growth in a mouse colorectal carcinomatosis model

    PubMed Central

    Gremonprez, Félix; Descamps, Benedicte; Izmer, Andrei; Vanhove, Christian; Vanhaecke, Frank; De Wever, Olivier; Ceelen, Wim

    2015-01-01

    Cytoreductive surgery combined with intraperitoneal chemotherapy (IPC) is currently the standard treatment for selected patients with peritoneal carcinomatosis of colorectal cancer. However, especially after incomplete cytoreduction, disease progression is common and this is likely due to limited tissue penetration and efficacy of intraperitoneal cytotoxic drugs. Tumor microenvironment-targeting drugs, such as VEGF(R) and PDGFR inhibitors, can lower the heightened interstitial fluid pressure in tumors, a barrier to drug delivery. Here, we investigated whether tumor microenvironment-targeting drugs enhance the effectiveness of intraperitoneal chemotherapy. A mouse xenograft model with two large peritoneal implants of colorectal cancer cells was developed to study drug distribution and tumor physiology during intraperitoneal Oxaliplatin perfusion. Mice were treated for six days with either Placebo, Imatinib (anti-PDGFR, daily), Bevacizumab (anti-VEGF, twice) or Pazopanib (anti-PDGFR, -VEGFR; daily) followed by intraperitoneal oxaliplatin chemotherapy. Bevacizumab and Pazopanib significantly lowered interstitial fluid pressure, increased Oxaliplatin penetration (assessed by laser ablation inductively coupled plasma mass spectrometry) and delayed tumor growth of peritoneal implants (assessed by MRI). Our findings suggest that VEGF(R)-inhibition may improve the efficacy of IPC, particularly for patients for whom a complete cytoreduction might not be feasible. PMID:26375674

  11. Use of small incentives for increasing participation and reducing dropout in a family drug-use prevention program in a Spanish sample.

    PubMed

    Díaz, Susana Al-Halabí; Pérez, José Manuel Errasti

    2009-01-01

    Poor participation rates represent one of the most serious problems facing family-based drug-use prevention programs. Strategies involving incentives have been used to increase recruitment and retention of the target population of such interventions, but in Spain, such strategies for modifying behavior are unusual. The goal of the research was to study the use of small financial incentives (euro10 voucher) as a strategy to increase attendance and reduce dropout in a family drug-prevention program applied in the school context. Participants were 211 pupils (aged 12-13) and their parents. The results show that small financial incentives can be useful to increase the attendance of families in prevention programs and to reduce dropout. PMID:20001690

  12. Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

    PubMed Central

    Guo, Jin; Guiguemde, Armand W.; Bentura-Marciano, Annael; Clark, Julie; Haynes, Richard K.; Chan, Wing-Chi; Wong, Ho-Ning; Hunt, Nicholas H.; Guy, R. Kiplin

    2012-01-01

    This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM. PMID:22006004

  13. Toxicity of Carboxylic Acid-Containing Drugs: The Role of Acyl Migration and CoA Conjugation Investigated.

    PubMed

    Lassila, Toni; Hokkanen, Juho; Aatsinki, Sanna-Mari; Mattila, Sampo; Turpeinen, Miia; Tolonen, Ari

    2015-12-21

    Many carboxylic acid-containing drugs are associated with idiosyncratic drug toxicity (IDT), which may be caused by reactive acyl glucuronide metabolites. The rate of acyl migration has been earlier suggested as a predictor of acyl glucuronide reactivity. Additionally, acyl Coenzyme A (CoA) conjugates are known to be reactive. Here, 13 drugs with a carboxylic acid moiety were incubated with human liver microsomes to produce acyl glucuronide conjugates for the determination of acyl glucuronide half-lives by acyl migration and with HepaRG cells to monitor the formation of acyl CoA conjugates, their further conjugate metabolites, and trans-acylation products with glutathione. Additionally, in vitro cytotoxicity and mitochondrial toxicity experiments were performed with HepaRG cells to compare the predictability of toxicity. Clearly, longer acyl glucuronide half-lives were observed for safe drugs compared to drugs that can cause IDT. Correlation between half-lives and toxicity classification increased when "relative half-lives," taking into account the formation of isomeric AG-forms due to acyl migration and eliminating the effect of hydrolysis, were used instead of plain disappearance of the initial 1-O-β-AG-form. Correlation was improved further when a daily dose of the drug was taken into account. CoA and related conjugates were detected primarily for the drugs that have the capability to cause IDT, although some exceptions to this were observed. Cytotoxicity and mitochondrial toxicity did not correlate to drug safety. On the basis of the results, the short relative half-life of the acyl glucuronide (high acyl migration rate), high daily dose and detection of acyl CoA conjugates, or further metabolites derived from acyl CoA together seem to indicate that carboxylic acid-containing drugs have a higher probability to cause drug-induced liver injury (DILI). PMID:26558897

  14. Towards increased selectivity of drug delivery to cancer cells: development of a LDL-based nanodelivery system for hydrophobic photosensitizers

    NASA Astrophysics Data System (ADS)

    Buzova, Diana; Huntosova, Veronika; Kasak, Peter; Petrovajova, Dana; Joniova, Jaroslava; Dzurova, Lenka; Nadova, Zuzana; Sureau, Franck; Midkovsky, Pavol; Jancura, Daniel

    2012-10-01

    Low-density lipoproteins (LDL), a natural in vivo carrier of cholesterol in the vascular system, play a key role in the delivery of hydrophobic photosensitizers (pts) to tumor cells in photodynamic therapy (PDT) of cancer. To make this delivery system even more efficient, we have constructed a nano-delivery system by coating of LDL surface by polyethylene glycol (PEG) and dextran. Fluorescence spectroscopy and confocal fluorescence imaging were used to characterize redistribution of hypericin (Hyp), a natural potent pts, loaded in LDL/PEG and LDL/dextran complexes to free LDL molecules as well as to monitor cellular uptake of Hyp by U87-MG cells. It was shown than the redistribution process of Hyp between LDL molecules is significantly suppressed by dextran coating of LDL surface. On the other hand, PEG does not significantly influence this process. The modification of LDL molecules by the polymers does not inhibit their recognition by cellular LDL receptors. U-87 MG cellular uptake of Hyp loaded in LDL/PEG and LDL/dextran complexes appears to be similar to that one observed for Hyp transported by unmodified LDL particles. It is proposed that by polymers modified LDL molecules could be used as a basis for construction of a drug transport system for targeted delivery of hydrophobic drugs to cancer cells expressing high level of LDL receptors.

  15. A Novel Model of Chronic Sleep Restriction Reveals an Increase in the Perceived Incentive Reward Value of Cocaine in High Drug-Taking Rats

    PubMed Central

    Puhl, Matthew D.; Boisvert, Matthew; Guan, Zhiwei; Fang, Jidong; Grigson, Patricia S.

    2013-01-01

    Substance abuse and sleep deprivation are major problems in our society. Clinical studies suggest that measures of poor sleep quality effectively predict relapse to substance abuse. Previously, our laboratory has shown that acute sleep deprivation increases the rate and efficiency (i.e., the goal-directed nature of responding) of cocaine self-administration using a progressive ratio (PR) schedule of reinforcement. However, the problem of sleep deprivation in our nation is largely one of chronicity. Therefore, the current study used a rodent model of chronic sleep restriction more akin to that experienced by humans (approximately 40% reduction in baseline sleep over the course of 8 days) to assess the impact of chronic sleep deprivation on cocaine-seeking and cocaine-taking behaviors in rats early during acquisition of self-administration. While low drug-taking rats were unaffected by chronic sleep restriction, high drug-takers in the chronic sleep restriction (CSR) group exhibited enhanced fixed ratio (FR) responding by the fourth day of FR training and significantly higher PR breakpoints than their non-sleep restriction (NSR) counterparts. This study is the first to directly assess the impact of chronic sleep deprivation on drug self-administration. These results show that chronic sleep deprivation early during acquisition of self-administration has a significant effect on the perceived incentive reward value of cocaine in high drug-takers, as indicated by both increased FR responding and an increased willingness to work for drug. Thus, it is important to be mindful of such factors in clinical settings designed for treatment of addiction and relapse prevention. PMID:23603033

  16. β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

    PubMed

    Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

    2015-11-01

    β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency

  17. National Income Inequality and Declining GDP Growth Rates Are Associated with Increases in HIV Diagnoses among People Who Inject Drugs in Europe: A Panel Data Analysis

    PubMed Central

    Nikolopoulos, Georgios K.; Fotiou, Anastasios; Kanavou, Eleftheria; Richardson, Clive; Detsis, Marios; Pharris, Anastasia; Suk, Jonathan E.; Semenza, Jan C.; Costa-Storti, Claudia; Paraskevis, Dimitrios; Sypsa, Vana; Malliori, Melpomeni-Minerva; Friedman, Samuel R.; Hatzakis, Angelos

    2015-01-01

    Background There is sparse evidence that demonstrates the association between macro-environmental processes and drug-related HIV epidemics. The present study explores the relationship between economic, socio-economic, policy and structural indicators, and increases in reported HIV infections among people who inject drugs (PWID) in the European Economic Area (EEA). Methods We used panel data (2003–2012) for 30 EEA countries. Statistical analyses included logistic regression models. The dependent variable was taking value 1 if there was an outbreak (significant increase in the national rate of HIV diagnoses in PWID) and 0 otherwise. Explanatory variables included the growth rate of Gross Domestic Product (GDP), the share of the population that is at risk for poverty, the unemployment rate, the Eurostat S80/S20 ratio, the Gini coefficient, the per capita government expenditure on health and social protection, and variables on drug control policy and drug-using population sizes. Lags of one to three years were investigated. Findings In multivariable analyses, using two-year lagged values, we found that a 1% increase of GDP was associated with approximately 30% reduction in the odds of an HIV outbreak. In GDP-adjusted analyses with three-year lagged values, the effect of the national income inequality on the likelihood of an HIV outbreak was significant [S80/S20 Odds Ratio (OR) = 3.89; 95% Confidence Interval (CI): 1.15 to 13.13]. Generally, the multivariable analyses produced similar results across three time lags tested. Interpretation Given the limitations of ecological research, we found that declining economic growth and increasing national income inequality were associated with an elevated probability of a large increase in the number of HIV diagnoses among PWID in EEA countries during the last decade. HIV prevention may be more effective if developed within national and European-level policy contexts that promote income equality, especially among vulnerable

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

    PubMed

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

    2012-09-29

    We describe a rapid screening methodology for performing pharmacokinetic (PK) studies in mice called Fast PK. In this Fast PK method, two mice were used per compound and four blood samples were collected from each mouse. The sampling times were staggered (sparse sampling) between the two mice, thus yielding complete PK profile in singlicate across eight time points. The plasma PK parameters from Fast PK were comparable to that obtained from conventional PK methods. This method has been used to rapidly screen compounds in the early stages of drug discovery and about 600 compounds have been profiled in the last 3 years, which has resulted in reduction in the usage of mice by 800 per year in compliance with the 3R principles of animal ethics. In addition, this Fast PK method can also help in evaluating the PK parameters from the same set of animals used in safety/toxicology/efficacy studies without the need for satellite groups. PMID:22789493

  19. Cyclization of a cell-penetrating peptide via click-chemistry increases proteolytic resistance and improves drug delivery.

    PubMed

    Reichart, Florian; Horn, Mareike; Neundorf, Ines

    2016-06-01

    In this work we report synthesis and biological evaluation of a cell-penetrating peptide (CPP), that is partly cyclized via a triazole bridge. Recently, beneficious properties have been reported for cyclized peptides concerning their metabolic stability and intracellular uptake. A CPP based on human calcitonin was used in this study, and side chain cyclization was achieved via copper catalyzed alkyne-azide click reaction. Cell viability studies in several cell-lines revealed no cytotoxic effects. Furthermore, efficient uptake in breast cancer MCF-7 cells could be determined. Moreover, preliminary studies using this novel peptide as drug transporter for daunorubicin were performed. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. PMID:27197760

  20. miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity.

    PubMed

    O'Brien, Keith; Lowry, Michelle C; Corcoran, Claire; Martinez, Vanesa G; Daly, Melissa; Rani, Sweta; Gallagher, William M; Radomski, Marek W; MacLeod, Roderick A F; O'Driscoll, Lorraine

    2015-10-20

    Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer. PMID:26416415

  1. miR-134 in extracellular vesicles reduces triple-negative breast cancer aggression and increases drug sensitivity.

    PubMed

    O'Brien, Keith; Lowry, Michelle C; Corcoran, Claire; Martinez, Vanesa G; Daly, Melissa; Rani, Sweta; Gallagher, William M; Radomski, Marek W; MacLeod, Roderick A F; O'Driscoll, Lorraine

    2015-10-20

    Exosomes (EVs) have relevance in cell-to-cell communication carrying pro-tumorigenic factors that participate in oncogenesis and drug resistance and are proposed to have potential as self-delivery systems. Advancing on our studies of EVs in triple-negative breast cancer, here we more comprehensively analysed isogenic cell line variants and their EV populations, tissues cell line variants and their EV populations, as well as breast tumour and normal tissues. Profiling 384 miRNAs showed EV miRNA content to be highly representative of their cells of origin. miRNAs most substantially down-regulated in aggressive cells and their EVs originated from 14q32. Analysis of miR-134, the most substantially down-regulated miRNA, supported its clinical relevance in breast tumours compared to matched normal breast tissue. Functional studies indicated that miR-134 controls STAT5B which, in turn, controls Hsp90. miR-134 delivered by direct transfection into Hs578Ts(i)8 cells (in which it was greatly down-regulated) reduced STAT5B, Hsp90, and Bcl-2 levels, reduced cellular proliferation, and enhanced cisplatin-induced apoptosis. Delivery via miR-134-enriched EVs also reduced STAT5B and Hsp90, reduced cellular migration and invasion, and enhanced sensitivity to anti-Hsp90 drugs. While the differing effects achieved by transfection or EV delivery are likely to be, at least partly, due to specific amounts of miR-134 delivered by these routes, these EV-based studies identified miRNA-134 as a potential biomarker and therapeutic for breast cancer.

  2. Doxorubicin encapsulated in stealth liposomes conferred with light-triggered drug release.

    PubMed

    Luo, Dandan; Carter, Kevin A; Razi, Aida; Geng, Jumin; Shao, Shuai; Giraldo, Daniel; Sunar, Ulas; Ortega, Joaquin; Lovell, Jonathan F

    2016-01-01

    Stealth liposomes can be used to extend the blood circulation time of encapsulated therapeutics. Inclusion of 2 molar % porphyrin-phospholipid (PoP) imparted optimal near infrared (NIR) light-triggered release of doxorubicin (Dox) from conventional sterically stabilized stealth liposomes. The type and amount of PoP affected drug loading, serum stability and drug release induced by NIR light. Cholesterol and PEGylation were required for Dox loading, but slowed light-triggered release. Dox in stealth PoP liposomes had a long circulation half-life in mice of 21.9 h and was stable in storage for months. Following intravenous injection and NIR irradiation, Dox deposition increased ∼ 7 fold in treated subcutaneous human pancreatic xenografts. Phototreatment induced mild tumor heating and complex tumor hemodynamics. A single chemophototherapy treatment with Dox-loaded stealth PoP liposomes (at 5-7 mg/kg Dox) eradicated tumors while corresponding chemo- or photodynamic therapies were ineffective. A low dose 3 mg/kg Dox phototreatment with stealth PoP liposomes was more effective than a maximum tolerated dose of free (7 mg/kg) or conventional long-circulating liposomal Dox (21 mg/kg). To our knowledge, Dox-loaded stealth PoP liposomes represent the first reported long-circulating nanoparticle capable of light-triggered drug release.

  3. Quitting drugs: quantitative and qualitative features.

    PubMed

    Heyman, Gene M

    2013-01-01

    According to the idea that addiction is a chronic relapsing disease, remission is at most a temporary state. Either addicts never stop using drugs, or if they do stop, remission is short lived. However, research on remission reveals a more complex picture. In national epidemiological surveys that recruited representative drug users, remission rates varied widely and were markedly different for legal and illegal drugs and for different racial/ethnic groups. For instance, the half-life for cocaine dependence was four years, but for alcohol dependence it was 16 years, and although most dependent cocaine users remitted before age 30, about 5% remained heavy cocaine users well into their forties. Although varied, the remission results were orderly. An exponential growth curve closely approximated the cumulative frequency of remitting for different drugs and different ethnic/racial groups. Thus, each year a constant proportion of those still addicted remitted, independent of the number of years since the onset of dependence. PMID:23330937

  4. Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle.

    PubMed

    Meisel, Christian; Schulze-Bonhage, Andreas; Freestone, Dean; Cook, Mark James; Achermann, Peter; Plenz, Dietmar

    2015-11-24

    Pathological changes in excitability of cortical tissue commonly underlie the initiation and spread of seizure activity in patients suffering from epilepsy. Accordingly, monitoring excitability and controlling its degree using antiepileptic drugs (AEDs) is of prime importance for clinical care and treatment. To date, adequate measures of excitability and action of AEDs have been difficult to identify. Recent insights into ongoing cortical activity have identified global levels of phase synchronization as measures that characterize normal levels of excitability and quantify any deviation therefrom. Here, we explore the usefulness of these intrinsic measures to quantify cortical excitability in humans. First, we observe a correlation of such markers with stimulation-evoked responses suggesting them to be viable excitability measures based on ongoing activity. Second, we report a significant covariation with the level of AED load and a wake-dependent modulation. Our results indicate that excitability in epileptic networks is effectively reduced by AEDs and suggest the proposed markers as useful candidates to quantify excitability in routine clinical conditions overcoming the limitations of electrical or magnetic stimulation. The wake-dependent time course of these metrics suggests a homeostatic role of sleep, to rebalance cortical excitability.

  5. 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.

  6. Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

    PubMed Central

    2010-01-01

    Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise

  7. Effect of psychotropic drugs on gastric ulcers induced by immobilization: Increased protective effect of amitriptyline caused by chlordiazepoxide

    NASA Technical Reports Server (NTRS)

    Blum, J. E.; Huerlimann, A.

    1980-01-01

    Amitriptyline, but not chlordiazepoxide, protects rats from the occurrence of gastric erosions and ulcers following immobilization. When, however, chlordiazepoxide is given together with amitriptyline the protective effect of the latter is markedly increased.

  8. Herb-Drug Pharmacokinetic Interaction of a Traditional Chinese Medicine Jia-Wei-Xiao-Yao-San with 5-Fluorouracil in the Blood and Brain of Rat Using Microdialysis

    PubMed Central

    Chiang, Meng-Hsuan; Chang, Li-Wen; Wang, Ju-Wen; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-01-01

    According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS. PMID:25861367

  9. Acylation of SC4 dodecapeptide increases bactericidal potency against Gram-positive bacteria, including drug-resistant strains.

    PubMed Central

    Lockwood, Nathan A; Haseman, Judith R; Tirrell, Matthew V; Mayo, Kevin H

    2004-01-01

    We have conjugated dodecyl and octadecyl fatty acids to the N-terminus of SC4, a potently bactericidal, helix-forming peptide 12-mer (KLFKRHLKWKII), and examined the bactericidal activities of the resultant SC4 'peptide-amphiphile' molecules. SC4 peptide-amphiphiles showed up to a 30-fold increase in bactericidal activity against Gram-positive strains (Staphylococcus aureus, Streptococcus pyogenes and Bacillus anthracis), including S. aureus strains resistant to conventional antibiotics, but little or no increase in bactericidal activity against Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa). Fatty acid conjugation improved endotoxin (lipopolysaccharide) neutralization by 3- to 6-fold. Although acylation somewhat increased lysis of human erythrocytes, it did not increase lysis of endothelial cells, and the haemolytic effects occurred at concentrations 10- to 100-fold higher than those required for bacterial cell lysis. For insight into the mechanism of action of SC4 peptide-amphiphiles, CD, NMR and fluorescence spectroscopy studies were performed in micelle and liposome models of eukaryotic and bacterial cell membranes. CD indicated that SC4 peptide-amphiphiles had the strongest helical tendencies in liposomes mimicking bacterial membranes, and strong membrane integration of the SC4 peptide-amphiphiles was observed using tryptophan fluorescence spectroscopy under these conditions; results that correlated with the increased bactericidal activities of SC4 peptide-amphiphiles. NMR structural analysis in micelles demonstrated that the two-thirds of the peptide closest to the fatty acid tail exhibited a helical conformation, with the positively-charged side of the amphipathic helix interacting more with the model membrane surface. These results indicate that conjugation of a fatty acid chain to the SC4 peptide enhances membrane interactions, stabilizes helical structure in the membrane-bound state and increases bactericidal potency. PMID:14609430

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

    PubMed Central

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

    2015-01-01

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

  11. Ferritins as Nanoplatforms for Imaging and Drug Delivery

    PubMed Central

    Zhen, Zipeng; Tang, Wei; Todd, Trever; Xie, Jin

    2015-01-01

    Introduction Due to unique architecture and surface properties, ferritin has emerged as an important class of biomaterial. Many studies suggest that ferritin and its derivatives hold great potential in a wide range of bio-applications. Areas covered In this review, we summarize recent progress on employing ferritins as a platform to construct functional nanoparticles for applications in magnetic resonance imaging (MRI), optical imaging, cell tracking, and drug delivery. Expert opinion As a natural polymer, ferritins afford advantages such as high biocompatibility, good biodegradability, and a relatively long plasma half-life. These attributes put ferritins ahead of conventional materials in clinical translation for imaging and drug delivery purposes. PMID:25070839

  12. An Efficient Targeted Drug Delivery through Apotransferrin Loaded Nanoparticles

    PubMed Central

    Kishore, Golla; Kondapi, Anand Kumar

    2009-01-01

    Background Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. Methodology/Principal Findings Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano) have diameters of 25–50 ηm, which increase to 60–80 ηm upon direct loading of drug (direct-nano), and showed further increase in dimension (75–95 ηm) in conjugated nanoparticles (conj-nano). The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a) localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus) (b) pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c) the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in regression

  13. Albumin-deficient mouse models for studying metabolism of human albumin and pharmacokinetics of albumin-based drugs

    PubMed Central

    Roopenian, Derry C; Low, Benjamin E; Christianson, Gregory J; Proetzel, Gabriele; Sproule, Thomas J; Wiles, Michael V

    2015-01-01

    Serum albumin is the major determinant of blood colloidal osmotic pressure acting as a depot and distributor of compounds including drugs. In humans, serum albumin exhibits an unusually long half-life mainly due to protection from catabolism by neonatal Fc receptor (FcRn)-mediated recycling. These properties make albumin an attractive courier of therapeutically-active compounds. However, pharmaceutical research and development of albumin-based therapeutics has been hampered by the lack of appropriate preclinical animal models. To overcome this, we developed and describe the first mouse with a genetic deficiency in albumin and its incorporation into an existing humanized FcRn mouse model, B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ (Tg32). Albumin-deficient strains (Alb-/-) were created by TALEN-mediated disruption of the albumin (Alb) gene directly in fertilized oocytes derived from Tg32 mice and its non-transgenic background control, C57BL/6J (B6). The resulting Alb-/- strains are analbuminemic but healthy. Intravenous administration of human albumin to Tg32-Alb-/- mFcRn-/- hFcRnTg/Tg) mice results in a remarkably extended human albumin serum half-life of ∼24 days, comparable to that found in humans, and in contrast to half-lives of 2.6–5.8 d observed in B6, B6-Alb-/- and Tg32 strains. This striking increase can be explained by the absence of competing endogenous mouse albumin and the presence of an active human FcRn. These novel albumin-deficient models provide unique tools for investigating the biology and pathobiology of serum albumin and are a more appropriate rodent surrogates for evaluating human serum albumin pharmacokinetics and albumin-based compounds. PMID:25654695

  14. Patients with first-episode, drug-naive schizophrenia and subjects at ultra-high risk of psychosis shared increased cerebellar-default mode network connectivity at rest

    PubMed Central

    Wang, Houliang; Guo, Wenbin; Liu, Feng; Wang, Guodong; Lyu, Hailong; Wu, Renrong; Chen, Jindong; Wang, Shuai; Li, Lehua; Zhao, Jingping

    2016-01-01

    Increased cerebellar-default mode network (DMN) connectivity has been observed in first-episode, drug-naive patients with schizophrenia. However, it remains unclear whether increased cerebellar-DMN connectivity starts earlier than disease onset. Thirty-four ultra-high risk (UHR) subjects, 31 first-episode, drug-naive patients with schizophrenia and 37 healthy controls were enrolled for a resting-state scan. The imaging data were analyzed using the seed-based functional connectivity (FC) method. Compared with the controls, UHR subjects and patients with schizophrenia shared increased connectivity between the right Crus I and bilateral posterior cingulate cortex/precuneus and between Lobule IX and the left superior medial prefrontal cortex. There are positive correlations between the right Crus I-bilateral precuneus connectivity and clinical variables (Structured Interview for Prodromal Syndromes/Positive and Negative Symptom Scale negative symptoms/total scores) in the UHR subjects. Increased cerebellar-DMN connectivity shared by the UHR subjects and the patients not only highlights the importance of the DMN in the pathophysiology of psychosis but also may be a trait alteration for psychosis. PMID:27188233

  15. Role of Nanotechnology in Delivery of Protein and Peptide Drugs.

    PubMed

    Patil, Sushilkumar; Vhora, Imran; Amrutiya, Jitendra; Lalani, Rohan; Misra, Ambikanandan

    2015-01-01

    The advent of recombinant DNA technology and computational designing has fueled the emergence of proteins and peptides as a new class of modern therapeutics such as vaccines, antigens, antibodies and hormones. Demand for such therapeutics has increased recently due to their distinct pharmacodynamic characteristics of specificity of action and high potency. However, their potential clinical applications are often hindered by involvement of factors which impact their therapeutic potential negatively. Large size, low permeability, conformational fragility, immunogenicity, metabolic degradation and short half-life results in poor bioavailability and inferior efficacy. These challenges have encouraged researchers to devise strategies for effective delivery of proteins and peptides. Recent advances made in nanotechnology are being sought to overcome aforesaid problems and to offer advantages such as higher drug loading, improved stability, sustained release, amenability for non-parenteral administration and targeting through surface modifications. This review focuses on elaborating the role of nanotechnology based formulations and associated challenges in protein and peptide delivery, their clinical outlook and future perspective. PMID:26323432

  16. Role of Nanotechnology in Delivery of Protein and Peptide Drugs.

    PubMed

    Patil, Sushilkumar; Vhora, Imran; Amrutiya, Jitendra; Lalani, Rohan; Misra, Ambikanandan

    2015-01-01

    The advent of recombinant DNA technology and computational designing has fueled the emergence of proteins and peptides as a new class of modern therapeutics such as vaccines, antigens, antibodies and hormones. Demand for such therapeutics has increased recently due to their distinct pharmacodynamic characteristics of specificity of action and high potency. However, their potential clinical applications are often hindered by involvement of factors which impact their therapeutic potential negatively. Large size, low permeability, conformational fragility, immunogenicity, metabolic degradation and short half-life results in poor bioavailability and inferior efficacy. These challenges have encouraged researchers to devise strategies for effective delivery of proteins and peptides. Recent advances made in nanotechnology are being sought to overcome aforesaid problems and to offer advantages such as higher drug loading, improved stability, sustained release, amenability for non-parenteral administration and targeting through surface modifications. This review focuses on elaborating the role of nanotechnology based formulations and associated challenges in protein and peptide delivery, their clinical outlook and future perspective.

  17. Time Varying Apparent Volume of Distribution and Drug Half-Lives Following Intravenous Bolus Injections.

    PubMed

    Wesolowski, Carl A; Wesolowski, Michal J; Babyn, Paul S; Wanasundara, Surajith N

    2016-01-01

    We present a model that generalizes the apparent volume of distribution and half-life as functions of time following intravenous bolus injection. This generalized model defines a time varying apparent volume of drug distribution. The half-lives of drug remaining in the body vary in time and become longer as time elapses, eventually converging to the terminal half-life. Two example fit models were substituted into the general model: biexponential models from the least relative concentration error, and gamma variate models using adaptive regularization for least relative error of clearance. Using adult population parameters from 41 studies of the renal glomerular filtration marker 169Yb-DTPA, simulations of extracellular fluid volumes of 5, 10, 15 and 20 litres and plasma clearances of 40 and 100 ml/min were obtained. Of these models, the adaptively obtained gamma variate models had longer times to 95% of terminal volume and longer half-lives.

  18. Time Varying Apparent Volume of Distribution and Drug Half-Lives Following Intravenous Bolus Injections

    PubMed Central

    Wesolowski, Carl A.; Wesolowski, Michal J.; Babyn, Paul S.

    2016-01-01

    We present a model that generalizes the apparent volume of distribution and half-life as functions of time following intravenous bolus injection. This generalized model defines a time varying apparent volume of drug distribution. The half-lives of drug remaining in the body vary in time and become longer as time elapses, eventually converging to the terminal half-life. Two example fit models were substituted into the general model: biexponential models from the least relative concentration error, and gamma variate models using adaptive regularization for least relative error of clearance. Using adult population parameters from 41 studies of the renal glomerular filtration marker 169Yb-DTPA, simulations of extracellular fluid volumes of 5, 10, 15 and 20 litres and plasma clearances of 40 and 100 ml/min were obtained. Of these models, the adaptively obtained gamma variate models had longer times to 95% of terminal volume and longer half-lives. PMID:27403663

  19. Time Varying Apparent Volume of Distribution and Drug Half-Lives Following Intravenous Bolus Injections.

    PubMed

    Wesolowski, Carl A; Wesolowski, Michal J; Babyn, Paul S; Wanasundara, Surajith N

    2016-01-01

    We present a model that generalizes the apparent volume of distribution and half-life as functions of time following intravenous bolus injection. This generalized model defines a time varying apparent volume of drug distribution. The half-lives of drug remaining in the body vary in time and become longer as time elapses, eventually converging to the terminal half-life. Two example fit models were substituted into the general model: biexponential models from the least relative concentration error, and gamma variate models using adaptive regularization for least relative error of clearance. Using adult population parameters from 41 studies of the renal glomerular filtration marker 169Yb-DTPA, simulations of extracellular fluid volumes of 5, 10, 15 and 20 litres and plasma clearances of 40 and 100 ml/min were obtained. Of these models, the adaptively obtained gamma variate models had longer times to 95% of terminal volume and longer half-lives. PMID:27403663

  20. Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery.

    PubMed

    Ferrara, Katherine W; Borden, Mark A; Zhang, Hua

    2009-07-21

    Ultrasound pressure waves can map the location of lipid-stabilized gas micro-bubbles after their intravenous administration in the body, facilitating an estimate of vascular density and microvascular flow rate. Microbubbles are currently approved by the Food and Drug Administration as ultrasound contrast agents for visualizing opacification of the left ventricle in echocardiography. However, the interaction of ultrasound waves with intravenously-injected lipid-shelled particles, including both liposomes and microbubbles, is a far richer field. Particles can be designed for molecular imaging and loaded with drugs or genes; the mechanical and thermal properties of ultrasound can then effect localized drug release. In this Account, we provide an overview of the engineering of lipid-shelled microbubbles (typical diameter 1000-10 000 nm) and liposomes (typical diameter 65-120 nm) for ultrasound-based applications in molecular imaging and drug delivery. The chemistries of the shell and core can be optimized to enhance stability, circulation persistence, drug loading and release, targeting to and fusion with the cell membrane, and therapeutic biological effects. To assess the biodistribution and pharmacokinetics of these particles, we incorporated positron emission tomography (PET) radioisotopes on the shell. The radionuclide (18)F (half-life approximately 2 h) was covalently coupled to a dipalmitoyl lipid, followed by integration of the labeled lipid into the shell, facilitating short-term analysis of particle pharmacokinetics and metabolism of the lipid molecule. Alternately, labeling a formed particle with (64)Cu (half-life 12.7 h), after prior covalent incorporation of a copper-chelating moiety onto the lipid shell, permits pharmacokinetic study of particles over several days. Stability and persistence in circulation of both liposomes and microbubbles are enhanced by long acyl chains and a poly(ethylene glycol) coating. Vascular targeting has been demonstrated with

  1. Knockdown of PARP-1 Inhibits Proliferation and ERK Signals, Increasing Drug Sensitivity in Osteosarcoma U2OS Cells.

    PubMed

    Li, Sheng; Cui, Zhengli; Meng, Xianfeng

    2016-01-01

    Poly(ADP-ribose) polymerase 1 (PARP-1) is reported to be involved in DNA repair and is now recognized as a key regulator in carcinogenesis. However, the potential role and the molecular mechanism underlying the effect of PARP-1 on osteosarcoma (OS) cells have not been elucidated. In this study, the results showed that knockdown of PARP-1 resulted in decreased cell proliferation, increased cell apoptosis, and G0/G1 phase arrest in U2OS cells. In addition, increased expression of active caspase 3 and Bax, but reduced Bcl-2, cyclin D1, and phosphorylated extracellular signal regulated kinase 1/2 (pERK1/2) were observed in PARP-1 knockdown in U2OS cells. Moreover, knockdown of PARP-1 correlated with elevated chemosensitivity of U2OS cells to cisplatin through inactivation of the ERK1/2 signaling pathway. In conclusion, our findings demonstrated that PARP-1 plays an important role in regulating OS growth, combining PARP-1 gene therapy with traditional chemotherapy, and may serve as a promising approach to OS therapy. PMID:27656839

  2. On the absorption of drugs using chronic dog ileal loop method.

    PubMed

    Kukan, M; Bezek, S; Trnovec, T; Gabauer, I; Styk, J

    1994-01-01

    The absorption rate of three model drugs, i.e., pentacaine (highly lipophilic), stobadine (moderately lipophilic) and acetylsalicylic acid (hydrophilic), was studied using the chronic dog ileal loop method. The drugs were dissolved either in 0.9% unbuffered solution of NaCl or in antacid mixture. When using 0.9% NaCl, the half-lives of absorption (t1/2 (dis)) of pentacaine and stobadine were (mean +/- SD) 23.2 +/- 7.8 min and 20.8 +/- 7.2 min, respectively. For stobadine a good agreement was found between its t1/2 (dis) from the ileum and its absorption half-life determined from blood concentrations after oral administration to dogs. The absorption of acetylsalicylic acid accounted for only 10-20% of the dose introduced into the loop over 45 min; thus, a reliable value of t1/2 (dis) could not be determined. The administration of unbuffered solution of NaCl into the loop was accompanied by rapid increase of pH from acidic to basic value. The antacid mixture failed to affect the absorption rate of the drugs studied. Sampling from the ileum was limited to 35-55 min due to rapid absorption of water. These results suggest that: 1) measurement of the absorption rate of some drugs, e.g., stobadine, by using the chronic dog ileal loop method may adequately predict their absorption rate after peroral administration to the dog, 2) interactions of antacids with drug absorption in the ileum may not play a significant role because of the strong buffering capacity of the ileum, and 3) rapid absorption of water from the ileum does not allow to reliably determine the value of t1/2 (dis) for slowly absorbed drugs. PMID:7837833

  3. The antimetastatic drug NAMI-A potentiates the phenylephrine-induced contraction of aortic smooth muscle cells and induces a transient increase in systolic blood pressure.

    PubMed

    Vadori, M; Florio, C; Groppo, B; Cocchietto, M; Pacor, S; Zorzet, S; Candussio, L; Sava, G

    2015-07-01

    The ruthenium-based drug imidazolium trans-imidazoledimethylsulphoxidetetrachlorido ruthenate (NAMI-A) is a novel antitumour drug under clinical evaluation. In this study, NAMI-A is tested on aortic rings in vitro and on the systolic blood pressure in vivo with the aim of evaluating its effects on smooth muscle cells and, more in general, on the vascular system. Pre-incubation of aortic rings with 10 µM NAMI-A for 10 min potentiates the contraction induced by phenylephrine (PE). The reduction of the B max value of [(3)H]-prazosin bound to NAMI-A-treated aortic rings and the ability of NAMI-A to displace [(3)H]-prazosin and [(3)H]-IP3 binding by 25 and 42%, respectively, suggest the involvement of α1-adrenoceptor in mediating the effects on smooth muscle cells. NAMI-A also decreases the number of maximal sites of [(3)H]-prazosin bound to kidney membrane preparation from 34 to 24 fmol/mg proteins. A single i.p. dose (105 mg/kg) or a repeated treatment for 6 consecutive days (17 mg/kg/day) in Wistar rats increases the systolic blood pressure, respectively, 1 h and 3 days after treatment, and the responsiveness of rat aortic rings to PE. Atomic absorption spectroscopy confirms the presence of ruthenium in the aortic rings excised from the treated rats. These findings suggest monitoring the cardiovascular parameters when the drug is used in humans for treating cancer patients, particularly if the drug is associated with chemicals that are potentially active at the cardiovascular level.

  4. In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity.

    PubMed

    Lucchi, Naomi W; Komino, Franklin; Okoth, Sheila Akinyi; Goldman, Ira; Onyona, Philip; Wiegand, Ryan E; Juma, Elizabeth; Shi, Ya Ping; Barnwell, John W; Udhayakumar, Venkatachalam; Kariuki, Simon

    2015-12-01

    Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya.

  5. In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity

    PubMed Central

    Komino, Franklin; Okoth, Sheila Akinyi; Goldman, Ira; Onyona, Philip; Wiegand, Ryan E.; Juma, Elizabeth; Shi, Ya Ping; Barnwell, John W.; Udhayakumar, Venkatachalam; Kariuki, Simon

    2015-01-01

    Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya. PMID:26392510

  6. In Vitro and Molecular Surveillance for Antimalarial Drug Resistance in Plasmodium falciparum Parasites in Western Kenya Reveals Sustained Artemisinin Sensitivity and Increased Chloroquine Sensitivity.

    PubMed

    Lucchi, Naomi W; Komino, Franklin; Okoth, Sheila Akinyi; Goldman, Ira; Onyona, Philip; Wiegand, Ryan E; Juma, Elizabeth; Shi, Ya Ping; Barnwell, John W; Udhayakumar, Venkatachalam; Kariuki, Simon

    2015-12-01

    Malaria control is hindered by the evolution and spread of resistance to antimalarials, necessitating multiple changes to drug policies over time. A comprehensive antimalarial drug resistance surveillance program is vital for detecting the potential emergence of resistance to antimalarials, including current artemisinin-based combination therapies. An antimalarial drug resistance surveillance study involving 203 Plasmodium falciparum malaria-positive children was conducted in western Kenya between 2010 and 2013. Specimens from enrolled children were analyzed in vitro for sensitivity to chloroquine (CQ), amodiaquine (AQ), mefloquine (MQ), lumefantrine, and artemisinin derivatives (artesunate and dihydroartemisinin) and for drug resistance allele polymorphisms in P. falciparum crt (Pfcrt), Pfmdr-1, and the K13 propeller domain (K13). We observed a significant increase in the proportion of samples with the Pfcrt wild-type (CVMNK) genotype, from 61.2% in 2010 to 93.0% in 2013 (P < 0.0001), and higher proportions of parasites with elevated sensitivity to CQ in vitro. The majority of isolates harbored the wild-type N allele in Pfmdr-1 codon 86 (93.5%), with only 7 (3.50%) samples with the N86Y mutant allele (the mutant nucleotide is underlined). Likewise, most isolates harbored the wild-type Pfmdr-1 D1246 allele (79.8%), with only 12 (6.38%) specimens with the D1246Y mutant allele and 26 (13.8%) with mixed alleles. All the samples had a single copy of the Pfmdr-1 gene (mean of 0.907 ± 0.141 copies). None of the sequenced parasites had mutations in K13. Our results suggest that artemisinin is likely to remain highly efficacious and that CQ sensitivity appears to be on the rise in western Kenya. PMID:26392510

  7. Quantum yields of decomposition and homo-dimerization of solid L-alanine induced by 7.2 eV Vacuum ultraviolet light irradiation: an estimate of the half-life of L-alanine on the surface of space objects.

    PubMed

    Izumi, Yudai; Nakagawa, Kazumichi

    2011-08-01

    One of the leading hypotheses regarding the origin of prebiotic molecules on primitive Earth is that they formed from inorganic molecules in extraterrestrial environments and were delivered by meteorites, space dust and comets. To evaluate the availability of extraterrestrial amino acids, it is necessary to examine their decomposition and oligomerization rates as induced by extraterrestrial energy sources, such as vacuum ultraviolet (VUV) and X-ray photons and high energy particles. This paper reports the quantum yields of decomposition ((8.2 ± 0.7) × 10(-2) photon(-1)) and homo-dimerization ((1.2 ± 0.3) × 10(-3) photon(-1)) and decomposition of the dimer (0.24 ± 0.06 photon(-1)) of solid L-alanine (Ala) induced by VUV light with an energy of 7.2 eV. Using these quantum yields, the half-life of L-Ala on the surface of a space object in the present earth orbit was estimated to be about 52 days, even when only photons with an energy of 7.2 eV emitted from the present Sun were considered. The actual half-life of solid L-Ala on the surface of a space object orbit around the present day Earth would certainly be much shorter than our estimate, because of the added effect of photons and particles of other energies. Thus, we propose that L-Ala needs to be shielded from solar VUV in protected environments, such as the interior of a meteorite, within a time scale of days after synthesis to ensure its arrival on the primitive Earth.

  8. Sex, Drugs (Methamphetamines), and the Internet: Increasing Syphilis Among Men Who Have Sex With Men in California, 2004–2008

    PubMed Central

    Samuel, Michael C.; Lo, Terrence; Bernstein, Kyle T.; Aynalem, Getahun; Klausner, Jeffrey D.; Bolan, Gail

    2013-01-01

    Objectives. We examined primary and secondary syphilis cases among men who have sex with men (MSM) in California, and the association of methamphetamine use and Internet use to meet sex partners (Internet use) with number of sex partners. Methods. We analyzed California surveillance data for MSM who were diagnosed with syphilis between 2004 and 2008, to assess differences in the mean number of sex partners by methamphetamine use and mutually exclusive groups of patients reporting Internet use (Internet users). Results. Large proportions of patients reported methamphetamine use (19.2%) and Internet use (36.4%). From 2006 through 2008, Adam4Adam was the most frequently reported Web site statewide, despite temporal and regional differences in Web site usage. Methamphetamine users reported more sex partners (mean = 11.7) than nonmethamphetamine users (mean = 5.6; P < .001). Internet users reported more sex partners (mean = 9.8) than non-Internet users (mean = 5.0; P < .001). Multivariable analysis of variance confirmed an independent association of methamphetamine and Internet use with increased numbers of sex partners. Conclusions. Higher numbers of partners among MSM syphilis patients were associated with methamphetamine and Internet use. Collaboration between currently stand-alone interventions targeting methamphetamine users and Internet users may offer potential advances in sexually transmitted disease control efforts. PMID:23153138

  9. Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk.

    PubMed

    Moeckel, Douglas; Jeong, Soon Soeg; Sun, Xiaofeng; Broekman, M Johan; Nguyen, Annie; Drosopoulos, Joan H F; Marcus, Aaron J; Robson, Simon C; Chen, Ridong; Abendschein, Dana

    2014-08-01

    In patients with acute myocardial infarction undergoing reperfusion therapy to restore blood flow through blocked arteries, simultaneous inhibition of platelet P2Y12 receptors with the current standard of care neither completely prevents recurrent thrombosis nor provides satisfactory protection against reperfusion injury. Additionally, these antiplatelet drugs increase the risk of bleeding. To devise a different strategy, we engineered and optimized the apyrase activity of human nucleoside triphosphate diphosphohydrolase-3 (CD39L3) to enhance scavenging of extracellular adenosine diphosphate, a predominant ligand of P2Y12 receptors. The resulting recombinant protein, APT102, exhibited greater than four times higher adenosine diphosphatase activity and a 50 times longer plasma half-life than did native apyrase. Treatment with APT102 before coronary fibrinolysis with intravenous recombinant human tissue-type plasminogen activator in conscious dogs completely prevented thrombotic reocclusion and significantly decreased infarction size by 81% without increasing bleeding time. In contrast, clopidogrel did not prevent coronary reocclusion and increased bleeding time. In a murine model of myocardial reperfusion injury caused by transient coronary artery occlusion, APT102 also decreased infarct size by 51%, whereas clopidogrel was not effective. These preclinical data suggest that APT102 should be tested for its ability to safely and effectively maximize the benefits of myocardial reperfusion therapy in patients with arterial thrombosis.

  10. Challenges and solutions for the delivery of biotech drugs--a review of drug nanocrystal technology and lipid nanoparticles.

    PubMed

    Muller, Rainer H; Keck, Cornelia M

    2004-09-30

    Biotechnology allows tailor-made production of biopharmaceuticals and biotechnological drugs; however, many of them require special formulation technologies to overcome drug-associated problems. Such potential challenges to solve are: poor solubility, limited chemical stability in vitro and in vivo after administration (i.e. short half-life), poor bioavailability and potentially strong side effects requiring drug enrichment at the site of action (targeting). This review describes the use of nanoparticulate carriers, developed in our research group, as one solution to overcome such delivery problems, i.e. drug nanocrystals, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and lipid-drug conjugate (LDC) nanoparticles, examples of drugs are given. As a recently developed targeting principle, the concept of differential protein adsorption is described (PathFinder Technology) using as example delivery to the brain. PMID:15380654

  11. An increase in sensitivity of rat cingulate cortical neurones to substance P occurs following withdrawal of chronic administration of antidepressant drugs.

    PubMed Central

    Jones, R. S.; Olpe, H. R.