Science.gov

Sample records for increasing drug half-life

  1. Antibody engineering for increased potency, breadth and half-life

    PubMed Central

    Sievers, Stuart A.; Scharf, Louise; West, Anthony P.; Bjorkman, Pamela J.

    2015-01-01

    Purpose of review This review highlights recent developments in HIV-1 antibody engineering and discusses the effects of increased polyreactivity on serum half-lives of engineered antibodies. Recent findings Recent studies have uncovered a wealth of information about the relationship between the sequences and efficacies of anti-HIV-1 antibodies through a combination of bioinformatics, structural characterization and in vivo studies. This knowledge has stimulated efforts to enhance antibody breadth and potency for therapeutic use. Although some engineered antibodies have shown increased polyreactivity and short half-lives, promising efforts are circumventing these problems. Summary Antibodies are desirable as therapeutics due to their ability to recognize targets with both specificity and high affinity. Furthermore, the ability of antibodies to stimulate Fc-mediated effector functions can increase their utility. Thus, mAbs have become central to strategies for the treatment of various diseases. Using both targeted and library-based approaches, antibodies can be engineered to improve their therapeutic properties. This article will discuss recent antibody engineering efforts to improve the breadth and potency of anti-HIV-1 antibodies. The polyreactivity of engineered HIV-1 bNAbs and the effect on serum half-life will be explored along with strategies to overcome problems introduced by engineering antibodies. Finally, advances in creating bispecific anti-HIV-1 reagents are discussed. PMID:25760931

  2. 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

  3. Phosphorylation of calcipressin 1 increases its ability to inhibit calcineurin and decreases calcipressin half-life.

    PubMed Central

    Genescà, Lali; Aubareda, Anna; Fuentes, Juan J; Estivill, Xavier; De La Luna, Susana; Pérez-Riba, Mercè

    2003-01-01

    Calcipressin 1 is an endogenous inhibitor of calcineurin, which is a serine/threonine phosphatase under the control of Ca(2+) and calmodulin. Calcipressin 1 is encoded by DSCR1, a gene on human chromosome 21 with seven exons, exons 1-4 are alternative first exons (isoforms 1-4). We show that calcipressin 1 isoform 1 has an N-terminal coding region longer than that previously described, and this generates a new polypeptide of 252 amino acids. This polypeptide is able to interact with calcineurin A and to inhibit NF-AT-mediated transcriptional activation. We demonstrate for the first time that endogenous calcipressin 1 exists as a complex together with the calcineurin A and B heterodimer. Calcipressin 1 is a phosphoprotein that increases its capacity to inhibit calcineurin when phosphorylated at the FLISPP motif, and this phosphorylation also controls the half-life of calcipressin 1 by accelerating its degradation. Additionally, we have also detected further phosphorylation sites outside the FLISPP motif and these contribute to the complex phosphorylation pattern of calcipressin 1. Taking all these results into consideration we suggest that phosphorylation of calcipressin 1 is involved in the regulation of the phosphatase activity of calcineurin and can therefore act as a modulator of calcineurin-dependent cellular pathways. PMID:12809556

  4. 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.

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

    PubMed

    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 57Co after a tracer dose of [57Co]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 [14C]propionate to 14CO2 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. PMID:2550599

  6. Increased CDA expression/activity in males contributes to decreased cytidine analogue half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy

    PubMed Central

    Mahfouz, Reda Z; Jankowska, Ania; Ebrahem, Quteba; Gu, Xiaorong; Visconte, Valeria; Tabarroki, Ali; Terse, Pramod; Covey, Joseph; Chan, Kenneth; Ling, Yonghua; Engelke, Kory J.; Sekeres, Mikkael A.; Tiu, Ramon; Maciejewski, Jaroslaw; Radivoyevitch, Tomas; Saunthararajah, Yogen

    2013-01-01

    Purpose The cytidine analogues 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application. Design Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated MDS patients (n=90) and cytarabine-treated acute myeloid leukemia (AML) patients (n=76). Results By HPLC, plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females compared to males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass-spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared to high S-phase fraction disease (e.g., MDS versus AML), since in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female MDS patients treated with 5-azacytidine/decitabine. Conclusions Increased CDA expression/activity in males contributes to decreased cytidine analogue half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy. PMID:23287564

  7. 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

  8. Haloperidol half-life after chronic dosing.

    PubMed

    de Leon, Jose; Diaz, Francisco J; Wedlund, Peter; Josiassen, Richard C; Cooper, Thomas B; Simpson, George M

    2004-12-01

    In normal subjects after a single oral dose, haloperidol half-life has been reported to range 14.5-36.7 hours (or up to 1.5 days). After chronic administration, half-lives of up to 21 days have been reported. The objective of this study was to evaluate specific factors that might account for differences in haloperidol half-life in patients taking haloperidol chronically, including gender, age, weight, race, CYP2D6 and CYP3A5 genotypes, comedication, and smoking.Thirty-one patients were administered haloperidol for 4 weeks followed by a 1-week washout before administration of clozapine. Haloperidol plasma levels were measured weekly for at least 2 months after discontinuation. The geometric mean for haloperidol half-life and detectable levels duration were 3.9 and 13.8 days, respectively. Within 31 subjects, 58% (18/31) had half-lives <3 days (1.2-2.3 days) and 42% (13/31) had half-lives > or =3 days. Two of 3 patients with half-lives longer than 30 days (720 hours) and levels detectable >2 months had received haloperidol decanoate. Five patients who received haloperidol decanoate in the prior year were excluded from a comparison between patients with long haloperidol half-lives (> or =3 days, n = 10) and patients with short half-lives (<3 days, n = 16). The only significant difference between the two groups was that African-Americans (n = 4) were all found to have a long haloperidol half-life (P = 0.014). CYP3A5 genotype did not appear to influence haloperidol half-life but the two CYP2D6 poor metabolizer had half-lives > or =3 days. This study suggests that haloperidol half-life following repeated drug administration is substantially more prolonged than what has been observed after acute haloperidol administration. PMID:15538130

  9. 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…

  10. 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. PMID:25900171

  11. 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

  12. 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. PMID:25738396

  13. The uncertainty of the half-life

    NASA Astrophysics Data System (ADS)

    Pommé, S.

    2015-06-01

    Half-life measurements of radionuclides are undeservedly perceived as ‘easy’ and the experimental uncertainties are commonly underestimated. Data evaluators, scanning the literature, are faced with bad documentation, lack of traceability, incomplete uncertainty budgets and discrepant results. Poor control of uncertainties has its implications for the end-user community, varying from limitations to the accuracy and reliability of nuclear-based analytical techniques to the fundamental question whether half-lives are invariable or not. This paper addresses some issues from the viewpoints of the user community and of the decay data provider. It addresses the propagation of the uncertainty of the half-life in activity measurements and discusses different types of half-life measurements, typical parameters influencing their uncertainty, a tool to propagate the uncertainties and suggestions for a more complete reporting style. Problems and solutions are illustrated with striking examples from literature.

  14. 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.

  15. 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

  16. The half-life of infusion fluids

    PubMed Central

    Hahn, Robert G.; Lyons, Gordon

    2016-01-01

    An understanding of the half-life (T1/2) of infused fluids can help prevent iatrogenic problems such as volume overload and postoperative interstitial oedema. Simulations show that a prolongation of the T1/2 for crystalloid fluid increases the plasma volume and promotes accumulation of fluid in the interstitial fluid space. The T1/2 for crystalloids is usually 20 to 40 min in conscious humans but might extend to 80 min or longer in the presence of preoperative stress, dehydration, blood loss of <1 l or pregnancy. The longest T1/2 measured amounts to between 3 and 8 h and occurs during surgery and general anaesthesia with mechanical ventilation. This situation lasts as long as the anaesthesia. The mechanisms for the long T1/2 are only partly understood, but involve adrenergic receptors and increased renin and aldosterone release. In contrast, the T1/2 during the postoperative period is usually short, about 15 to 20 min, at least in response to new fluid. The commonly used colloid fluids have an intravascular persistence T1/2 of 2 to 3 h, which is shortened by inflammation. The fact that the elimination T1/2 of the infused macromolecules is 2 to 6 times longer shows that they also reside outside the bloodstream. With a colloid, fluid volume is eliminated in line with its intravascular persistence, but there is insufficient data to know if this is the same in the clinical setting. PMID:27058509

  17. 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.

  18. Half-life of {sup 66}Ga

    SciTech Connect

    Severin, G. W.; Knutson, L. D.; Voytas, P. A.; George, E. A.

    2010-12-15

    We measured the half-life of {sup 66}Ga by observing positrons from the {beta}{sup +} branch to the ground state of {sup 66}Zn with a superconducting Wu-type beta spectrometer. Our result is t{sub 1/2}=9.304(8)hours, which is the highest-precision measurement to date and disagrees with the Nuclear Data Sheets (NDS) value by over 6{sigma}.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. A recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable manner.

    PubMed

    Schellenberger, Volker; Wang, Chia-Wei; Geething, Nathan C; Spink, Benjamin J; Campbell, Andrew; To, Wayne; Scholle, Michael D; Yin, Yong; Yao, Yi; Bogin, Oren; Cleland, Jeffrey L; Silverman, Joshua; Stemmer, Willem P C

    2009-12-01

    Increasing the in vivo residence times of protein therapeutics could decrease their dosing frequencies. We show that genetic fusion of an unstructured recombinant polypeptide of 864 amino acids, called XTEN, to a peptide or protein provides an apparently generic approach to extend plasma half-life. Allometric scaling suggests that a fusion of XTEN to the exenatide peptide should increase exenatide half-life in humans from 2.4 h to a projected time of 139 h. We confirmed the biological activity of the exenatide-XTEN fusion in mice. As extended stability might exacerbate undesirable side effects in some cases, we show that truncating the XTEN sequence can regulate plasma half-life. XTEN lacks hydrophobic amino acid residues that often contribute to immunogenicity and complicate manufacture. Based on data on XTEN fusions to exenatide, glucagon, GFP and human growth hormone, we expect that XTEN will enable dosing of otherwise rapidly cleared protein drugs at up to monthly intervals in humans. PMID:19915550

  4. Mobility and half-life of bensulide in agricultural soil.

    PubMed

    Antonious, George F

    2010-01-01

    Environmentally and economically viable agriculture requires the use of cultivation practices that maximize agrochemical efficacy while minimizing their off-site movement. Bensulide [O, O-diisopropyl S-2-phenylsulfonylaminoethyl phosphorodithioate] is one of the few herbicides from the organophosphate group used for control of weeds that threaten numerous crops. A field study was conducted on a silty-loam soil of 10% slope at Kentucky State University Research Farm to monitor off-site movement and persistence of bensulide in soil. Eighteen plots of 22 x 3.7 m each were separated using metal borders and the soil in six plots was mixed with sewage sludge and yard waste compost (SS-YW) at 15 t acre(- 1) on dry weight basis, six plots were mixed with sewage sludge (SS) at 15 t acre(- 1), and six unamended plots (NM) were used for comparison purposes. Plots were planted with summer squash, Cucurbita pepo as the test plant. The objectives of this investigation were to: 1) determine the dissipation and half-life (T(1/2)) of bensulide in soil under three management practices; 2) monitor the concentration of bensulide residues in runoff and infiltration water following natural rainfall; and 3) determine the effect of soil amendments on the transport of NO(3), NH(4), and P into surface and subsurface water. Half-life (T(1/2)) values of bensulide in soil were 44.3, 37.6, and 27.1 d in SS-YW, SS, and NM treatments, respectively. Addition of SS-YW and SS to native soil increased water infiltration, lowering runoff water volume and bensulide residues in runoff following natural rainfall events. PMID:20390925

  5. 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

  6. [Animal experimental evidence of the long-lasting efficacy of etofenamate by prolongation of the half-life after intramuscular application].

    PubMed

    Dell, H D; Brons, J; Fiedler, J; Kamp, R; Pelster, B

    1990-03-01

    Animal Experimental Evidence of Long-lasting Liberation of Etofenamate by Half-life Prolongation after Intramuscular Application. The purpose of this investigation was to show in animal experiments that by i.m. injection of etofenamate (active substance of Rheumon i.m.) in oily solution the following effects could be obtained: a fast onset of action (gain of therapeutically relevant drug levels shortly after injection) a long-lasting efficacy (prolonged liberation from the oil depot) and better tolerability as compared to other intramuscularly applicable antiinflammatory drugs (avoidance of high plasma spikes). Etofenamate in rats is liberated with a half-life of 1.29 days from the place of application (cutaneous half-life 8.5 h). Flufenamic acid in muscles is found only in traces. After i.m. administration of etofenamate to dogs maximum plasma levels of etofenamate and flufenamic acid were reached within 2 and 4 h, resp. The mean half-lives of plasma elimination are 14 h for etofenamate and 23.2 h for flufenamic acid formed esterolytically from etofenamate (flufenamic acid oral half-life 2-4 h). Maximum plasma levels after etofenamate are only 6.5-11.8% of the maximum levels after equivalent amounts of flufenamic acid administered orally. According to these data etofenamate i.m. is a drug formulation with fast increasing plasma levels, prolonged half-life and lower maximum plasma levels as compared to orally administered preparations. The results are confirmed in animals (pharmacodynamics, toxicology and tolerability) and man (kinetics, clinical studies). PMID:2346540

  7. Drug combination therapy increases successful drug repositioning.

    PubMed

    Sun, Wei; Sanderson, Philip E; Zheng, Wei

    2016-07-01

    Repositioning of approved drugs has recently gained new momentum for rapid identification and development of new therapeutics for diseases that lack effective drug treatment. Reported repurposing screens have increased dramatically in number in the past five years. However, many newly identified compounds have low potency; this limits their immediate clinical applications because the known, tolerated plasma drug concentrations are lower than the required therapeutic drug concentrations. Drug combinations of two or more compounds with different mechanisms of action are an alternative approach to increase the success rate of drug repositioning. PMID:27240777

  8. 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

  9. 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.

  10. Determination of the ^229Th isomer half-life

    NASA Astrophysics Data System (ADS)

    Burke, Jason; Beck, Bret; Becker, John; Haydell, Michael; Norman, Rick; Scielzo, Nicholas; Sheets, Steven; Swanberg, Erik

    2009-10-01

    Recently there has been renewed interest in studying the nuclear properties of the ^229Th isomer. ^229Th has the lowest known isomer at 7.6 eV [1]. Direct laser manipulation of the ground and first excited states could lead to the realization of the world's first nuclear clock. To understand the linewidth of the isomeric state we are conducting experiments to directly observe the half-life of the isomer decay. We use a novel ``hot-atom'' technique in which we catch the recoiling ^229Th nuclei following the alpha decay of ^233U -> ^229Th + α. On average 2% of the ^229Th populate the isomeric 3/2+ state compared to the 5/2+ ground state. Recoils are collected on various catcher plate materials, rotated in vacuum in front of an einzel lense and multi-channel plate detector. The internal conversion electrons are counted as a function of time to determine the half-life. Varying the catcher plate material we can investigate the effect that the materials have on the half-life. Determination of the half-life we will provide valuable guidance to Th trapping research [2]. 1) Beck et al., PRL 98, 142501 (2007) 2) Campbell et al., PRL 102, 233004 (2009) This work performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

  11. Precise measurement of the {sup 19}Ne half-life

    SciTech Connect

    Triambak, S.

    2011-11-30

    We describe a high-precision measurement of the half-life of the T = 1/2 nucleus {sup 19}Ne, performed at TRIUMF, Canada's National Laboratory for Nuclear and Particle Physics, Vancouver, Canada. Some implications of this measurement related to tests of the Standard Model are discussed.

  12. The half-life of infusion fluids: An educational review.

    PubMed

    Hahn, Robert G; Lyons, Gordon

    2016-07-01

    An understanding of the half-life (T1/2) of infused fluids can help prevent iatrogenic problems such as volume overload and postoperative interstitial oedema. Simulations show that a prolongation of the T1/2 for crystalloid fluid increases the plasma volume and promotes accumulation of fluid in the interstitial fluid space. The T1/2 for crystalloids is usually 20 to 40 min in conscious humans but might extend to 80 min or longer in the presence of preoperative stress, dehydration, blood loss of <1 l or pregnancy.The longest T1/2 measured amounts to between 3 and 8 h and occurs during surgery and general anaesthesia with mechanical ventilation. This situation lasts as long as the anaesthesia. The mechanisms for the long T1/2 are only partly understood, but involve adrenergic receptors and increased renin and aldosterone release. In contrast, the T1/2 during the postoperative period is usually short, about 15 to 20 min, at least in response to new fluid.The commonly used colloid fluids have an intravascular persistence T1/2 of 2 to 3 h, which is shortened by inflammation. The fact that the elimination T1/2 of the infused macromolecules is 2 to 6 times longer shows that they also reside outside the bloodstream. With a colloid, fluid volume is eliminated in line with its intravascular persistence, but there is insufficient data to know if this is the same in the clinical setting. PMID:27058509

  13. 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.

  14. 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. PMID:24216249

  15. 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

  16. 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

  17. 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).

  18. 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

  19. 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.

  20. 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

  1. 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

  2. Multivalent Antiviral XTEN–Peptide Conjugates with Long in Vivo Half-Life and Enhanced Solubility

    PubMed Central

    2015-01-01

    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. PMID:24932887

  3. 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. PMID:24932887

  4. 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.

  5. 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.

  6. 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

  7. Measurement of the half-life of {sup 198}Au in a nonmetal: High-precision measurement shows no host-material dependence

    SciTech Connect

    Goodwin, J. R.; Nica, N.; Iacob, V. E.; Dibidad, A.; Hardy, J. C.

    2010-10-15

    We have measured the half-life of the {beta}{sup -} decay of {sup 198}Au to be 2.6948(9) d, with the nuclide sited in an insulating environment. Comparing this result with the half-life we measured previously with a metallic environment, we find the half-lives in both environments to be the same within 0.04%, thus contradicting a prediction that screening from a ''plasma'' of quasifree electrons in a metal increases the half-life by as much as 7%.

  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. PMID:26720263

  9. Extending the Serum Half-Life of G-CSF via Fusion with the Domain III of Human Serum Albumin

    PubMed Central

    Zhao, Shuqiang; Zhang, Yu; Tian, Hong; Chen, Xiaofei; Cai, Di; Yao, Wenbing; Gao, Xiangdong

    2013-01-01

    Protein fusion technology is one of the most commonly used methods to extend the half-life of therapeutic proteins. In this study, in order to prolong the half-life of Granulocyte colony stimulating factor (G-CSF), the domain III of human serum albumin (3DHSA) was genetically fused to the N-terminal of G-CSF. The 3DHSA-G-CSF fusion gene was cloned into pPICZαA along with the open reading frame of the α-factor signal under the control of the AOX1 promoter. The recombinant expression vector was transformed into Pichia pastoris GS115, and the recombinant strains were screened by SDS-PAGE. As expected, the 3DHSA-G-CSF showed high binding affinity with HSA antibody and G-CSF antibody, and the natural N-terminal of 3DHSA was detected by N-terminal sequencing. The bioactivity and pharmacokinetic studies of 3DHSA-G-CSF were respectively determined using neutropenia model mice and human G-CSF ELISA kit. The results demonstrated that 3DHSA-G-CSF has the ability to increase the peripheral white blood cell (WBC) counts of neutropenia model mice, and the half-life of 3DHSA-G-CSF is longer than that of native G-CSF. In conclusion, 3DHSA can be used to extend the half-life of G-CSF. PMID:24151579

  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. PMID:27457423

  11. A Fab-Selective Immunoglobulin-Binding Domain from Streptococcal Protein G with Improved Half-Life Extension Properties

    PubMed Central

    Unverdorben, Felix; Hutt, Meike; Seifert, Oliver; Kontermann, Roland E.

    2015-01-01

    Background Half-life extension strategies have gained increasing interest to improve the pharmacokinetic and pharmacodynamic properties of protein therapeutics. Recently, we established an immunoglobulin-binding domain (IgBD) from streptococcal protein G (SpGC3) as module for half-life extension. SpGC3 is capable of binding to the Fc region as well as the CH1 domain of Fab arms under neutral and acidic conditions. Methodology/Principal Findings Using site-directed mutagenesis, we generated a Fab-selective mutant (SpGC3Fab) to avoid possible interference with the FcRn-mediated recycling process and improved its affinity for mouse and human IgG by site-directed mutagenesis and phage display selections. In mice, this affinity-improved mutant (SpGC3FabRR) conferred prolonged plasma half-lives compared with SpGC3Fab when fused to small recombinant antibody fragments, such as single-chain Fv (scFv) and bispecific single-chain diabody (scDb). Hence, the SpGC3FabRR domain seems to be a suitable fusion partner for the half-life extension of small recombinant therapeutics. Conclusions/Significance The half-life extension properties of SpGC3 can be retained by restricting binding to the Fab fragment of serum immunoglobulins and can be improved by increasing binding activity. The modified SpGC3 module should be suitable to extend the half-life of therapeutic proteins and, thus to improve therapeutic activity. PMID:26430884

  12. 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).

  13. 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

  14. 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

  15. 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.

  16. 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%.

  17. The half-life of ²²⁷Th by direct and indirect measurements.

    PubMed

    Collins, S M; Pommé, S; Jerome, S M; Ferreira, K M; Regan, P H; Pearce, A K

    2015-10-01

    Utilising a chemically purified solution the radioactive half-life of (227)Th has been determined indirectly by observation of the ingrowth of (223)Ra using an ionisation chamber (IC) and for the first time by direct observation of the change in activity with time using a high-purity germanium (HPGe) γ-ray spectrometer. The radioactive decay was observed for ~104 days (~5.6 half-lives) by γ-ray spectrometry and approximately 63 days and 72 days (~3.4 and ~3.9 half-lives) using an ionisation chamber (IC). The resulting half-life values - 18.695 (4) days (IC) and 18.683 (20) days (HPGe) - are consistent and detailed uncertainty budgets are presented for the two measurement techniques. A weighted mean of our results of 18.695 (4) days is inconsistent with the most precise published half-life value of 18.7176 (52) days (Jordan and Blanke, 1967). A critical evaluation of literature data has been performed, indicating a paucity of reliable and independent measurements. Selected independent published values have been used to determine a recommended half-life of 18.697 (7) days. A method has been introduced in the course of this work so that the recommended half-life of (227)Th as determined by ingrowth can be modified if a different (223)Ra half-life has been determined, evaluated and adopted. PMID:26197020

  18. High-Precision Half-Life Measurements for the Superallowed β+ emitter 10C

    NASA Astrophysics Data System (ADS)

    Dunlop, Michelle

    2014-09-01

    High precision measurements of superallowed Fermi beta transitions between 0+ isobaric analogue states allow for stringent tests of the electroweak interaction described by the Standard Model. These transitions provide an experimental probe of the unitary of the Cabibbo-Kobayashi-Maskawa matrix, the Conserved-Vector-Current hypothesis, as well as set limits on the existence of scalar currents in the weak interaction. Half-life measurements for the lightest of the superallowed emitters are of particular interest as the low-Z superallowed decays are most sensitive to a possible scalar current contribution. The half-life of 10C can be measured by directly counting the β particles or measuring the γ-ray activity following β decay. Previous results for the 10C half-life measured via these two methods differ at the 1.5 σ level, motivating further independent measurements of the 10C half-life using both techniques. Recent 10C half-life measurements via both gamma-ray photo-peak and direct beta counting were performed at TRIUMF's Isotope Separator and Accelerator facility. This presentation will highlight the importance of these measurements and preliminary half-life results will be presented.

  19. High-precision half-life measurements for the superallowed β+ emitter 10C

    NASA Astrophysics Data System (ADS)

    Dunlop, Michelle

    2015-10-01

    High precision measurements of the ft values for superallowed Fermi beta transitions between 0+ isobaric analogue states allow for stringent tests of the electroweak interaction described by the Standard Model. These transitions provide an experimental probe of the unitary of the Cabibbo-Kobayashi-Maskawa matrix, the Conserved-Vector-Current hypothesis, as well as set limits on the existence of scalar currents in the weak interaction. Half-life measurements for the lightest of the superallowed emitters are of particular interest as the low-Z superallowed decays are most sensitive to a possible scalar current contribution. The half-life of 10C can be measured by directly counting the β particles or by measuring the γ-ray activity following β decay. Previous results for the 10C half-life measured via these two methods differ at the 1.3 σ level, motivating further measurements of the 10C half-life using both techniques. Recent 10C half-life measurements via both gamma-ray photo-peak and direct beta counting were performed at TRIUMF's Isotope Separator and Accelerator facility. This presentation will highlight the importance of these measurements and half-life results will be presented.

  20. 25(OH)D2 Half-Life Is Shorter Than 25(OH)D3 Half-Life and Is Influenced by DBP Concentration and Genotype

    PubMed Central

    Assar, S.; Harnpanich, D.; Bouillon, R.; Lambrechts, D.; Prentice, A.; Schoenmakers, I.

    2014-01-01

    Context: There is uncertainty over the equivalence of vitamins D2 and D3 to maintain plasma 25-hydroxyvitamin D (25(OH)D). Objective: The objective of the study was to compare the plasma half-lives of 25(OH)D2 and 25(OH)D3 in two distinct populations with different dietary calcium intake and 25(OH)D status. Participants: Healthy men (aged 24 and 39 y), resident in The Gambia (n = 18) or the United Kingdom (n = 18) participated in the study. Interventions: The intervention included an oral tracer dose of deuterated-25(OH)D2 and deuterated-25(OH)D3 (both 40 nmol). Blood samples were collected over 33 days. Main Outcome Measures: 25(OH)D2 and 25(OH)D3 plasma half-lives, concentrations of 25(OH)D, and vitamin D binding protein (DBP) and DBP genotypes were measured. Results: 25(OH)D2 half-life [mean (SD)] [13.9 (2.6) d] was shorter than 25(OH)D3 half-life [15.1 (3.1) d; P = .001] for countries combined, and in Gambians [12.8 (2.3) d vs 14.7 (3.5) d; P < .001], but not in the United Kingdom [15.1 (2.4) d vs 15.6 (2.5) d; P = .3]. 25(OH)D concentration was 69 (13) and 29 (11) nmol/L (P < .0001), and the DBP concentration was 259 (33) and 269 (23) mg/L (P = .4) in The Gambia and United Kingdom, respectively. Half-lives were positively associated with plasma DBP concentration for countries combined [25(OH)D2 half-life: regression coefficient (SE) 0.03 (0.01) d per 1 mg/L DBP, P = .03; 25(OH)D3 half-life: 0.04 (0.02) d, P = .02] and in Gambians [25(OH)D2 half-life: 0.04 (0.01) d; P = .02; 25(OH)D3 half-life: 0.06 (0.02) d, P = .01] but not in UK participants. The DBP concentration × country interactions were not significant. DBP Gc1f/1f homozygotes had shorter 25(OH)D2 half-lives compared with other combined genotypes (P = .007) after correction for country. Conclusions: 25(OH)D2 half-life was shorter than 25(OH)D3 half-life, and half-lives were affected by DBP concentration and genotype. The stable isotope 25(OH)D half-life measurements provide a novel tool to investigate

  1. 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)

  2. 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

  3. 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

  4. 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. PMID:25754016

  5. 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.

  6. 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

  7. 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.

  8. [External radiation exposure and effective half-life in Lu-177-Dota-Tate therapy].

    PubMed

    Fitschen, Jürgen; Knoop, Bernd O; Behrendt, Rüdiger; Knapp, Wolfram H; Geworski, Lilli

    2011-12-01

    The aim of the study was to estimate the external radiation exposure emitted by the patient to his surroundings after discharge. Being in compliance with legal requirements is especially important when doing multiple therapies. To estimate the effective half-life to be used quite realistically, the individual effective half-lives for 41 patients with 52 therapies were calculated. From the resulting histogram the maximum value was determined to be 100 h. Substituting the physical half-life by this maximum effective half-life results in dose estimates, which are lower but still conservative. In addition, the analysis of dose related parameters for patients who underwent multiple therapies demonstrates that the parameters estimated for the first therapy cannot be transferred to the subsequent ones. PMID:21719263

  9. 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.

  10. Half-Life and Magnetic Moment of the First Excited State in ^132I

    NASA Astrophysics Data System (ADS)

    Izumi, S.; Tanigaki, M.; Ouchi, H.; Sasaki, A.; Hoshino, S.; Miyashita, Y.; Sato, N.; Shimada, K.; Wakui, T.; Shinozuka, T.; Ohkubo, Y.

    2009-10-01

    The half-life and the magnetic moment of the first excited state in ^132I are reported. There have been a long time confusion on the half-life measurements of the first excited state in ^132I. Several groups performed the lifetime measurements, but the reported values range from 1 ns to 7 ns. The only reported value of the magnetic moment for this state was measured by Singh, but their result should be treated as unreliable because the time-integral perturbed angular correlation technique (TIPAC), which requires the life time data of this state, was used in their measurement. From this point of view, the half-life and the magnetic moment of this state were measured. ^132I was obtained as the radioactive beam of ^132Te and ^132Sb from the newly developed RF-IGISOL (Radio Frequency IGISOL system) at Tohoku University. The half-life for this state was determined to be 1.120 ± 0.015 ns by a conventional coincidence technique with a pair of BaF2 detectors. The TDPAC measurement for the ^132I implanted kinematically into nickel was performed with the help of a strong hyperfine field at iodine site in nickel, and the magnetic moment of this state was determined to be μ=+ (2.06 ± 0.18)μN. The configuration of this state based on the present results will be discussed.

  11. 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…

  12. 18F Half-life measurement using 2-γ coincidence method

    NASA Astrophysics Data System (ADS)

    Kang, Y. S.; Ahn, J. K.; Kim, S. H.; Byun, J. I.; Han, J. B.; Lee, K. B.

    2015-11-01

    The accuracy of the half-life measurement of short-lived radioisotopes such as positron-emitting 18F (τ1/2 ≈ 100 min) is limited mainly by inaccuracies in the detector counting statistics. Gamma-ray measurement with a high-activity 18F source requires counting-loss corrections to compensate for random summing effects and the detector's dead time. In this study, we measure the half-life of 18F with two 511-keV γ-rays using two high-purity germanium (HPGe) detectors. The counting-loss corrections are performed via two approaches to address the problems of random coincidence summing and dead time: a half-life measurement with a 22Na source and a Geant4 simulation of the detector response. Variations in the full-width at half maximum (FWHM) of the 511-keV peak are found to show good correlation with the random summing effect. The half-life of 18F is estimated as 109.73 ± 0.14 min.

  13. Half-life of the superallowed {beta}{sup +} emitter {sup 18}Ne

    SciTech Connect

    Grinyer, G. F.; Andreoiu, C.; Finlay, P.; Hyland, B.; Phillips, A. A.; Schumaker, M. A.; Svensson, C. E.; Valiente-Dobon, J. J.; Smith, M. B.; Andreyev, A. N.; Ball, G. C.; Bricault, P.; Chakrawarthy, R. S.; Hackman, G.; Morton, A. C.; Pearson, C. J.; Williams, S. J.; Daoud, J. J.; Garrett, P. E.; Leslie, J. R.

    2007-08-15

    The half-life of {sup 18}Ne has been determined by detecting 1042-keV {gamma} rays in the daughter {sup 18}F following the superallowed-Fermi {beta}{sup +} decay of samples implanted at the center of the 8{pi}{gamma}-ray spectrometer, a spherical array of 20 HPGe detectors. Radioactive {sup 18}Ne beams were produced on-line, mass-separated, and ionized using an electron-cyclotron-resonance ionization source at the ISAC facility at TRIUMF in Vancouver, Canada. This is the first high-precision half-life measurement of a superallowed Fermi {beta} decay to utilize both a large-scale HPGe spectrometer and the isotope separation on-line technique. The half-life of {sup 18}Ne, 1.6656 {+-} 0.0019 s, deduced following a 1.4{sigma} correction for detector pulse pile-up, is four times more precise than the previous world average. As part of an investigation into potential systematic effects, the half-life of the heavier isotope {sup 23}Ne was determined to be 37.11 {+-} 0.06 s, a factor of 2 improvement over the previous precision.

  14. 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

  15. 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. PMID:24532089

  16. 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. PMID:24268817

  17. 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. PMID:27103110

  18. 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. PMID:26149020

  19. 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.

  20. 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.

  1. Precise half-life measurement of the superallowed {beta}{sup +} emitter {sup 10}C

    SciTech Connect

    Iacob, V. E.; Hardy, J. C.; Golovko, V.; Goodwin, J.; Nica, N.; Park, H. I.; Trache, L.; Tribble, R. E.

    2008-04-15

    The half-life of {sup 10}C has been measured to be 19.310(4) s, a result with 0.02% precision, which is a factor of three improvement over the best previous result. Since {sup 10}C is the lightest superallowed 0{sup +}{yields}0{sup +} {beta}{sup +} emitter, its ft value has the greatest weight in setting an upper limit on the possible presence of scalar currents.

  2. 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.

  3. Regulation of the mRNA half-life in breast cancer.

    PubMed

    Griseri, Paola; Pagès, Gilles

    2014-08-10

    The control of the half-life of mRNA plays a central role in normal development and in disease progression. Several pathological conditions, such as breast cancer, correlate with deregulation of the half-life of mRNA encoding growth factors, oncogenes, cell cycle regulators and inflammatory cytokines that participate in cancer. Substantial stability means that a mRNA will be available for translation for a longer time, resulting in high levels of protein gene products, which may lead to prolonged responses that subsequently result in over-production of cellular mediators that participate in cancer. The stability of these mRNA is regulated at the 3'UTR level by different mechanisms involving mRNA binding proteins, micro-RNA, long non-coding RNA and alternative polyadenylation. All these events are tightly inter-connected to each other and lead to steady state levels of target mRNAs. Compelling evidence also suggests that both mRNA binding proteins and regulatory RNAs which participate to mRNA half-life regulation may be useful prognostic markers in breast cancers, pointing to a potential therapeutic approach to treatment of patients with these tumors. In this review, we summarize the main mechanisms involved in the regulation of mRNA decay and discuss the possibility of its implication in breast cancer aggressiveness and the efficacy of targeted therapy. PMID:25114848

  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. Regulation of the mRNA half-life in breast cancer

    PubMed Central

    Griseri, Paola; Pagès, Gilles

    2014-01-01

    The control of the half-life of mRNA plays a central role in normal development and in disease progression. Several pathological conditions, such as breast cancer, correlate with deregulation of the half-life of mRNA encoding growth factors, oncogenes, cell cycle regulators and inflammatory cytokines that participate in cancer. Substantial stability means that a mRNA will be available for translation for a longer time, resulting in high levels of protein gene products, which may lead to prolonged responses that subsequently result in over-production of cellular mediators that participate in cancer. The stability of these mRNA is regulated at the 3’UTR level by different mechanisms involving mRNA binding proteins, micro-RNA, long non-coding RNA and alternative polyadenylation. All these events are tightly inter-connected to each other and lead to steady state levels of target mRNAs. Compelling evidence also suggests that both mRNA binding proteins and regulatory RNAs which participate to mRNA half-life regulation may be useful prognostic markers in breast cancers, pointing to a potential therapeutic approach to treatment of patients with these tumors. In this review, we summarize the main mechanisms involved in the regulation of mRNA decay and discuss the possibility of its implication in breast cancer aggressiveness and the efficacy of targeted therapy. PMID:25114848

  6. 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.

  7. 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.

  8. Computational tools and resources for metabolism-related property predictions. 2. Application to prediction of half-life time in human liver microsomes

    PubMed Central

    Zakharov, Alexey V; Peach, Megan L; Sitzmann, Markus; Filippov, Igor V; McCartney, Heather J; Smith, Layton H; Pugliese, Angelo; Nicklaus, Marc C

    2014-01-01

    Background The most important factor affecting metabolic excretion of compounds from the body is their half-life time. This provides an indication of compound stability of, for example, drug molecules. We report on our efforts to develop QSAR models for metabolic stability of compounds, based on in vitro half-life assay data measured in human liver microsomes. Method A variety of QSAR models generated using different statistical methods and descriptor sets implemented in both open-source and commercial programs (KNIME, GUSAR and StarDrop) were analyzed. The models obtained were compared using four different external validation sets from public and commercial data sources, including two smaller sets of in vivo half-life data in humans. Conclusion In many cases, the accuracy of prediction achieved on one external test set did not correspond to the results achieved with another test set. The most predictive models were used for predicting the metabolic stability of compounds from the open NCI database, the results of which are publicly available on the NCI/CADD Group web server (http://cactus.nci.nih.gov). PMID:23088274

  9. 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.

  10. 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

  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. 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

  13. 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.

  14. 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.

  15. 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.

  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. PMID:25679883

  17. 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

  18. Precise half-life measurement of the superallowed {beta}{sup +} emitter {sup 26}Si

    SciTech Connect

    Iacob, V. E.; Hardy, J. C.; Banu, A.; Chen, L.; Golovko, V. V.; Goodwin, J.; Horvat, V.; Nica, N.; Park, H. I.; Trache, L.; Tribble, R. E.

    2010-09-15

    We measured the half-life of the superallowed 0{sup +{yields}}0{sup +} {beta}{sup +} emitter {sup 26}Si to be 2245.3(7) ms. We used pure sources of {sup 26}Si and employed a high-efficiency gas counter, which was sensitive to positrons from both this nuclide and its daughter {sup 26}Al{sup m}. The data were analyzed as a linked parent-daughter decay. To contribute meaningfully to any test of the unitarity of the Cabibbo-Kobayashi-Maskawa (CKM) matrix, the ft value of a superallowed transition must be determined to a precision of 0.1% or better. With a precision of 0.03%, the present result is more than sufficient to be compatible with that requirement. Only the branching ratio now remains to be measured precisely before a {+-}0.1% ft value can be obtained for the superallowed transition from {sup 26}Si.

  19. Q value and half-life of double-electron capture in 184Os

    NASA Astrophysics Data System (ADS)

    Smorra, C.; Rodríguez, T. R.; Beyer, T.; Blaum, K.; Block, M.; Düllmann, Ch. E.; Eberhardt, K.; Eibach, M.; Eliseev, S.; Langanke, K.; Martínez-Pinedo, G.; Nagy, Sz.; Nörtershäuser, W.; Renisch, D.; Shabaev, V. M.; Tupitsyn, I. I.; Zubova, N. A.

    2012-10-01

    184Os has been excluded as a promising candidate for the search of neutrinoless double-electron capture. High-precision mass measurements with the Penning-trap mass spectrometer TRIGA-TRAP result in a marginal resonant enhancement with Δ=-8.89(58) keV excess energy to the 1322.152(22) keV 0+ excited state in 184W. State-of-the-art energy density functional calculations are applied for the evaluation of the nuclear matrix elements to the excited states predicting a strong suppression due to the large deformation of mother and daughter states. The half-life of the transition exceeds T1/2(184Os)≥1.3×1029 yr for an effective neutrino mass of 1 eV.

  20. {beta}{sup +} Decay Partial Half-Life of {sup 54}Mn and Cosmic Ray Chronometry

    SciTech Connect

    Wuosmaa, A.H.; Ahmad, I.; Fischer, S.M.; Greene, J.P.; Hackman, G.; Nanal, V.; Savard, G.; Schiffer, J.P.; Wilt, P.; Austin, S.M.; Brown, B.A.; Freedman, S.J.; Connell, J.J.

    1998-03-01

    The weak {beta}{sup +} decay of the astrophysically significant radioisotope {sup 54}Mn has been observed. The energies of positrons from a chemically purified {sup 54}Mn source were measured using the APEX spectrometer at Argonne National Laboratory. We deduce a {beta}{sup +} decay branch of (1.20{plus_minus}0.26){times}10{sup {minus}9} , corresponding to a partial half-life of (7.1{plus_minus}1.5){times}10{sup 8} yr . The implications of this value for cosmic-ray confinement times are discussed in light of recent satellite measurements of the cosmic-ray abundance of {sup 54}Mn . {copyright} {ital 1998} {ital The American Physical Society}

  1. {beta}{sup +} decay and cosmic-ray half-life of {sup 54}Mn

    SciTech Connect

    da Cruz, M.T.F.; Norman, E.B.; Chan, Y.D.; Garcia, A.; Larimer, R.M.; Lesko, K.T.; Stokstad, R.G.; Wietfeldt, F.E. |; Hindi, M.M.; Zlimen, I.

    1993-03-29

    We performed a search for the {beta}{sup +} branch of {sup 54}Mn decay. As a cosmic ray, {sup 54}Mn, deprived of its atomic electrons, can decay only via {beta}{sup +} and {beta}{sup {minus}} decay, with a half-life of the order of 10{sup 6} yr. This turns {sup 54} Mn into a suitable cosmic chronometer for the study of cosmic-ray confinement times. We searched for coincident back-to-back 511-keV {gamma}-rays using two germanium detectors inside a Nal(Tl) annulus. An upper limit of 2{times}10{sup {minus}8} was found for the {beta}{sup +} decay branch, corresponding to a lower limit of 13.7 for the log ft value.

  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. 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.

  4. The antitumor agent 3-bromopyruvate has a short half-life at physiological conditions.

    PubMed

    Glick, Matthew; Biddle, Perry; Jantzi, Josh; Weaver, Samantha; Schirch, Doug

    2014-09-12

    Clinical research is currently exploring the validity of the anti-tumor candidate 3-bromopyruvate (3-BP) as a novel treatment for several types of cancer. However, recent publications have overlooked rarely-cited earlier work about the instability of 3-BP and its decay to 3-hydroxypyruvate (3-HP) which have obvious implications for its mechanism of action against tumors, how it is administered, and for precautions when preparing solutions of 3-BP. This study found the first-order decay rate of 3-BP at physiological temperature and pH has a half-life of only 77 min. Lower buffer pH decreases the decay rate, while choice of buffer and concentration do not affect it. A method for preparing more stable solutions is also reported. PMID:25152397

  5. ORIGEN-S Decay Data Library and Half-Life Uncertainties

    SciTech Connect

    Hermann, O.W.

    1998-01-01

    The results of an extensive update of the decay data of the ORIGEN-S library are presented in this report. The updated decay data were provided for both the ORIGEN-S and ORIGEN2 libraries in the same project. A complete edit of the decay data plus the available half-life uncertainties are included in Appendix A. A detailed description of the types of data contained in the library, the format of the library, and the data sources are also presented. Approximately 24% of the library nuclides are stable, 66% were updated from ENDF/B-VI, about 8% were updated from ENSDF, and the remaining 2% were not updated. Appendix B presents a listing of percentage changes in decay heat from the old to the updated library for all nuclides containing a difference exceeding 1% in any parameter.

  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. European pharmacovigilance: increasingly outsourced to drug companies.

    PubMed

    2014-12-01

    New regulations reorganising pharmacovigilance at the European level were adopted in late 2010, then revised in 2012 in the wake of the Mediator (benfluorex) disaster. The European Commission's original proposals, released in 2008, would have represented a major step backwards in the protection afforded to European citizens, in particular by facilitating earlier marketing authorisations. Thanks to the mobilisation of civil society, the Members of the European Parliament have improved these proposals, supported by EU health ministers. The role of the new European Pharmacovigilance Risk Assessment Committee (PRAC) has been strengthened. Patients in every Member State have the right to report adverse drug effects directly to health authorities. EU drug regulatory agencies are required to provide greater transparency, and public access to information about adverse effects has been improved. However, one major regression persists: the central role given to pharmaceutical companies in the collection and interpretation of reports of adverse drug effects, despite their conflicts of interest. Drug companies are asked to record the adverse effect reports of which they are aware in a vast European centralised database, Eudravigilance, without going through drug regulatory agencies. Pharmaceutical companies remain responsible for producing "a scientific evaluation of the risk-benefit balance" of their drug, as part of the periodic benefit-risk assessment reports they are required to submit to drug regulatory agencies. These reports are analysed for the entire EU by two Member States (one rapporteur and one co-rapporteur), so that harmonised decisions can be taken. But these decisions are based on data preanalysed by the drug companies. In addition, the independence of the European Medicines Agency is undermined by its financial reliance on the fees paid by pharmaceutical companies in exchange for these assessments. In 2012, following France's Mediator disaster, several modest

  8. 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.

  9. 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

  10. Collagen VII Half-Life at the Dermal-Epidermal Junction Zone: Implications for Mechanisms and Therapy of Genodermatoses.

    PubMed

    Kühl, Tobias; Mezger, Markus; Hausser, Ingrid; Guey, Lin T; Handgretinger, Rupert; Bruckner-Tuderman, Leena; Nyström, Alexander

    2016-06-01

    The tissue half-life of proteins largely determines treatment frequency of non-gene-editing-based therapies targeting the cause of genodermatoses. Surprisingly, such knowledge is missing for a vast number of proteins involved in pathologies. The dermal-epidermal junction zone is believed to be a rather static structure, but to our knowledge no detailed analysis of the stability of proteins within this zone has been performed. Here, we addressed the in vivo half-life of collagen type VII using genetic ablation of its expression and therapeutic introduction of exogenous collagen VII in a preclinical model. A similar in vivo stability of collagen VII was observed in the skin, tongue, and esophagus, with a half-life of about 1 month. Collagen VII expressed by intradermally injected mesenchymal stromal cells also exhibited a similar half-life. Our study provides key information needed for the development of protein replacement or cell-based therapies for dystrophic epidermolysis bullosa caused by genetic deficiency of collagen VII. Moreover, by showing what we define as an intermediate half-life of collagen VII, our study challenges the view of the dermal-epidermal junction zone as a static structure with very slow turnover. PMID:26899947

  11. A novel long-acting human growth hormone fusion protein (VRS-317): enhanced in vivo potency and half-life.

    PubMed

    Cleland, Jeffrey L; Geething, Nathan C; Moore, Jerome A; Rogers, Brian C; Spink, Benjamin J; Wang, Chai-Wei; Alters, Susan E; Stemmer, Willem P C; Schellenberger, Volker

    2012-08-01

    A novel recombinant human growth hormone (rhGH) fusion protein (VRS-317) was designed to minimize receptor-mediated clearance through a reduction in receptor binding without mutations to rhGH by genetically fusing with XTEN amino acid sequences to the N-terminus and the C-terminus of the native hGH sequence. Although in vitro potency of VRS-317 was reduced approximately 12-fold compared with rhGH, in vivo potency was increased because of the greatly prolonged exposure to the target tissues and organs. VRS-317 was threefold more potent than daily rhGH in hypophysectomized rats and fivefold more potent than daily rhGH in juvenile monkeys. In juvenile monkeys, a monthly dose of 1.4 mg/kg VRS-317 (equivalent to 0.26 mg/kg rhGH) caused a sustained pharmacodynamic response for 1 month equivalent to 0.05 mg/kg/day rhGH (1.4 mg/kg rhGH total over 28 days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110 h, was rapidly and near-completely absorbed, and was well tolerated with no observed adverse effects after every alternate week subcutaneous dosing for 14 weeks. VRS-317 also did not cause lipoatrophy in pig and monkey studies. VRS-317 is currently being studied in GH-deficient patients to confirm the observations in these animal studies. PMID:22678811

  12. 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.

  13. Measurement of the 135Cs half-life with accelerator mass spectrometry and inductively coupled plasma mass spectrometry

    NASA Astrophysics Data System (ADS)

    MacDonald, C. M.; Cornett, R. J.; Charles, C. R. J.; Zhao, X. L.; Kieser, W. E.

    2016-01-01

    The isotope 135Cs is quoted as having a half-life of 2.3 Myr. However, there are three published values ranging from 1.8 to 3 Myr. This research reviews previous measurements and reports a new measurement of the half-life using newly developed accelerator mass spectrometry (AMS) and inductively coupled plasma mass spectrometry (ICPMS) techniques along with β and γ radiometric analysis. The half-life was determined to be (1.6 ±0.6 ) ×106 yr by AMS and (1.3 ±0.2 ) ×106 yr by ICPMS with 95% confidence. The two values agree with each other but differ from the accepted value by ˜40 % .

  14. Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life

    PubMed Central

    Boesch, Austin W.; Alter, Galit; Ackerman, Margaret E.

    2015-01-01

    Purpose of review A wealth of recent animal model data suggests that as exciting possibilities for the use of antibodies in passive immunotherapy strategies continue to develop, it will be important to broadly consider how antibodies achieve anti-HIV-1 effect in vivo. Recent findings Beyond neutralization breadth and potency, substantial evidence from natural infection, vaccination, and studies in animal models points to a critical role for antibody Fc receptor (FcR) engagement in reducing risk of infection, decreasing postinfection viremia, and delaying viral rebound. Supporting these findings in the setting of HIV, the clinical maturation of recombinant antibody therapeutics has reinforced the importance of Fc-driven activity in vivo across many disease settings, as well as opportunely resulted in the development and exploration of a number of engineered Fc sequence and glycosylation variants that possess differential binding to FcRs. Exploiting these variants as tools, the individual and concerted effects of antibody effector functions such as antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated virus inhibition, phagocytosis, complement-dependent cytotoxicity, antibody half-life, and compartmentalization are now being explored. As exciting molecular therapies are advanced, these studies promise to provide insight into optimal in-vivo antibody activity profiles. Summary Careful consideration of recent progress in understanding protective antibody activities in vivo can point toward how tailoring antibody activity via Fc domain modification may enable optimization of HIV prevention and eradication strategies. PMID:25700208

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

    PubMed Central

    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

    2012-01-01

    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 (R2 = 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. PMID:23055061

  16. Conversion of experimental half-life to effective electron neutrino mass in 0nubetabeta decay

    SciTech Connect

    Smolnikov, Anatoly; Grabmayr, Peter

    2010-02-15

    The Germanium Detector Array (GERDA) collaboration will be searching for neutrinoless double beta decay of {sup 76}Ge. As a result it will measure the half-life T{sub 1/2} of this rare process; or at least a new value for the lower limit for T{sub 1/2} will be derived. The sensitivity of the GERDA experiment on the effective electron neutrino mass depends on the theoretical value for the nuclear matrix element M and the kinematical phase space factor G.In this Brief Report we focus on existing difficulties in applying the dimensionless values of M calculated by various theoretical groups, which use different methods and parametrizations. The implicit radius dependencies in M and G are discussed. Resulting values of the neutrino mass are tabulated for various representative half-lives T{sub 1/2} representing the sensitivity of the various phases of the GERDA experiment.

  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. 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. PMID:21041026

  19. Measurement of the ββ decay half-life of 130Te with the NEMO-3 detector.

    PubMed

    Arnold, R; Augier, C; Baker, J; Barabash, A S; Basharina-Freshville, A; Blondel, S; Bongrand, M; Broudin-Bay, G; Brudanin, V; Caffrey, A J; Chapon, A; Chauveau, E; Durand, D; Egorov, V; Flack, R; Garrido, X; Grozier, J; Guillon, B; Hubert, Ph; Hugon, C; Jackson, C M; Jullian, S; Kauer, M; Klimenko, A; Kochetov, O; Konovalov, S I; Kovalenko, V; Lalanne, D; Lamhamdi, T; Lang, K; Liptak, Z; Lutter, G; Mamedov, F; Marquet, Ch; Martin-Albo, J; Mauger, F; Mott, J; Nachab, A; Nemchenok, I; Nguyen, C H; Nova, F; Novella, P; Ohsumi, H; Pahlka, R B; Perrot, F; Piquemal, F; Reyss, J L; Richards, B; Ricol, J S; Saakyan, R; Sarazin, X; Simard, L; Simkovic, F; Shitov, Yu; Smolnikov, A; Söldner-Rembold, S; Stekl, I; Suhonen, J; Sutton, C S; Szklarz, G; Thomas, J; Timkin, V; Torre, S; Tretyak, V I; Umatov, V; Vála, L; Vanyushin, I; Vasiliev, V; Vorobel, V; Vylov, Ts; Zukauskas, A

    2011-08-01

    We report results from the NEMO-3 experiment based on an exposure of 1275 days with 661 g of (130)Te in the form of enriched and natural tellurium foils. The ββ decay rate of (130)Te is found to be greater than zero with a significance of 7.7 standard deviations and the half-life is measured to be T(½)(2ν) = [7.0 ± 0.9(stat) ± 1.1(syst)] × 10(20) yr. This represents the most precise measurement of this half-life yet published and the first real-time observation of this decay. PMID:21902318

  20. Measurement of the ββ Decay Half-Life of Te130 with the NEMO-3 Detector

    NASA Astrophysics Data System (ADS)

    Arnold, R.; Augier, C.; Baker, J.; Barabash, A. S.; Basharina-Freshville, A.; Blondel, S.; Bongrand, M.; Broudin-Bay, G.; Brudanin, V.; Caffrey, A. J.; Chapon, A.; Chauveau, E.; Durand, D.; Egorov, V.; Flack, R.; Garrido, X.; Grozier, J.; Guillon, B.; Hubert, Ph.; Hugon, C.; Jackson, C. M.; Jullian, S.; Kauer, M.; Klimenko, A.; Kochetov, O.; Konovalov, S. I.; Kovalenko, V.; Lalanne, D.; Lamhamdi, T.; Lang, K.; Liptak, Z.; Lutter, G.; Mamedov, F.; Marquet, Ch.; Martin-Albo, J.; Mauger, F.; Mott, J.; Nachab, A.; Nemchenok, I.; Nguyen, C. H.; Nova, F.; Novella, P.; Ohsumi, H.; Pahlka, R. B.; Perrot, F.; Piquemal, F.; Reyss, J. L.; Richards, B.; Ricol, J. S.; Saakyan, R.; Sarazin, X.; Simard, L.; Šimkovic, F.; Shitov, Yu.; Smolnikov, A.; Söldner-Rembold, S.; Štekl, I.; Suhonen, J.; Sutton, C. S.; Szklarz, G.; Thomas, J.; Timkin, V.; Torre, S.; Tretyak, V. I.; Umatov, V.; Vála, L.; Vanyushin, I.; Vasiliev, V.; Vorobel, V.; Vylov, Ts.; Zukauskas, A.

    2011-08-01

    We report results from the NEMO-3 experiment based on an exposure of 1275 days with 661 g of Te130 in the form of enriched and natural tellurium foils. The ββ decay rate of Te130 is found to be greater than zero with a significance of 7.7 standard deviations and the half-life is measured to be T1/22ν=[7.0±0.9(stat)±1.1(syst)]×1020yr. This represents the most precise measurement of this half-life yet published and the first real-time observation of this decay.

  1. 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.

  2. 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

  3. Comparison of isotope dilution and excretion methods for determining the half-life of ascorbic acid in the guinea pig

    SciTech Connect

    Kipp, D.E.; Rivers, J.M.

    1984-08-01

    The half-life of ascorbic acid (AA) in guinea pigs was investigated by the isotope dilution and excretion methods. The dilution method measures (1-14C)AA disappearance from the plasma, whereas the excretion method measures the elimination of (1-14C)AA and the metabolites from the body. Two groups of animals underwent both isotope studies in reverse order. Animals were conditioned to the experimental procedures and fed 2.5 mg AA/100 g body weight orally to maintain a daily intake of the vitamin independent of food consumption. The two isotope procedures imposed similar stress on the animals, as determined by plasma cortisol levels and body weight changes. The AA half-life calculations of the rapidly exchangeable pool by the isotope dilution method yielded values of 1.23 and 0.34 hours for the two groups, respectively. The half-life of the slowly exchangeable pool for the two groups was 60.2 and 65.8 hours, respectively. The half-life of AA in the rapidly exchangeable pool, as measured by the excretion studies, was 4.57-8.75 hours. For the slowly exchangeable pool, it was 146-149 hours. The longer half-life of both pools obtained with the excretion method indicates that the isotope is disappearing from the plasma more rapidly than it is being excreted. This suggests that a portion of the (1-14C)AA leaving the plasma is removed to a body pool that is not sampled by the isotope excretion method.

  4. The functional half-life of an mRNA depends on the ribosome spacing in an early coding region.

    PubMed

    Pedersen, Margit; Nissen, Søren; Mitarai, Namiko; Lo Svenningsen, Sine; Sneppen, Kim; Pedersen, Steen

    2011-03-18

    Bacterial mRNAs are translated by closely spaced ribosomes and degraded from the 5'-end, with half-lives of around 2 min at 37 °C in most cases. Ribosome-free or "naked" mRNA is known to be readily degraded, but the initial event that inactivates the mRNA functionally has not been fully described. Here, we characterize a determinant of the functional stability of an mRNA, which is located in the early coding region. Using literature values for the mRNA half-lives of variant lacZ mRNAs in Escherichia coli, we modeled how the ribosome spacing is affected by the translation rate of the individual codons. When comparing the ribosome spacing at various segments of the mRNA to its functional half-life, we found a clear correlation between the functional mRNA half-life and the ribosome spacing in the mRNA region approximately between codon 20 and codon 45. From this finding, we predicted that inserts of slowly translated codons before codon 20 or after codon 45 should shorten or prolong, respectively, the functional mRNA half-life by altering the ribosome density in the important region. These predictions were tested on eight new lacZ variants, and their experimentally determined mRNA half-lives all supported the model. We thus suggest that translation-rate-mediated differences in the spacing between ribosomes in this early coding region is a parameter that determines the mRNAs functional half-life. We present a model that is in accordance with many earlier observations and that allows a prediction of the functional half-life of a given mRNA sequence. PMID:21255584

  5. High-precision half-life measurements of the T =1 /2 mirror β decays 17F and 33Cl

    NASA Astrophysics Data System (ADS)

    Grinyer, J.; Grinyer, G. F.; Babo, M.; Bouzomita, H.; Chauveau, P.; Delahaye, P.; Dubois, M.; Frigot, R.; Jardin, P.; Leboucher, C.; Maunoury, L.; Seiffert, C.; Thomas, J. C.; Traykov, E.

    2015-10-01

    Background: Measurements of the f t values for T =1 /2 mirror β+ decays offer a method to test the conserved vector current hypothesis and to determine Vud, the up-down matrix element of the Cabibbo-Kobayashi-Maskawa matrix. In most mirror decays used for these tests, uncertainties in the f t values are dominated by the uncertainties in the half-lives. Purpose: Two precision half-life measurements were performed for the T =1 /2 β+ emitters, 17F and 33Cl, in order to eliminate the half-life as the leading source of uncertainty in their f t values. Method: Half-lives of 17F and 33Cl were determined using β counting of implanted radioactive ion beam samples on a moving tape transport system at the Système de Production d'Ions Radioactifs Accélérés en Ligne low-energy identification station at the Grand Accélérateur National d'Ions Lourds. Results: The 17F half-life result, 64.347 (35) s, precise to ±0.05 % , is a factor of 5 times more precise than the previous world average. The half-life of 33Cl was determined to be 2.5038 (22) s. The current precision of ±0.09 % is nearly 2 times more precise compared to the previous world average. Conclusions: The precision achieved during the present measurements implies that the half-life no longer dominates the uncertainty of the f t values for both T =1 /2 mirror decays 17F and 33Cl.

  6. Colleges Report Increases in Arrests for Drug and Alcohol Violations.

    ERIC Educational Resources Information Center

    Nicklin, Julie L.

    1999-01-01

    Arrests for violations of drug/alcohol laws at colleges and universities rose 7.2 and 3.6%, respectively, from 1996 to 1997. Campus police attribute the increases not to increased drug and alcohol use but to more aggressive enforcement. However, some health researchers feel usage has risen. Campus weapons violations and forcible rape arrests have…

  7. A Novel Long-Acting Human Growth Hormone Fusion Protein (VRS-317): Enhanced In Vivo Potency and Half-Life

    PubMed Central

    Cleland, Jeffrey L; Geething, Nathan C; Moore, Jerome A; Rogers, Brian C; Spink, Benjamin J; Wang, Chai-Wei; Alters, Susan E; Stemmer, Willem P C; Schellenberger, Volker

    2012-01-01

    A novel recombinant human growth hormone (rhGH) fusion protein (VRS-317) was designed to minimize receptor-mediated clearance through a reduction in receptor binding without mutations to rhGH by genetically fusing with XTEN amino acid sequences to the N-terminus and the C-terminus of the native hGH sequence. Although in vitro potency of VRS-317 was reduced approximately 12-fold compared with rhGH, in vivo potency was increased because of the greatly prolonged exposure to the target tissues and organs. VRS-317 was threefold more potent than daily rhGH in hypophysectomized rats and fivefold more potent than daily rhGH in juvenile monkeys. In juvenile monkeys, a monthly dose of 1.4 mg/kg VRS-317 (equivalent to 0.26 mg/kg rhGH) caused a sustained pharmacodynamic response for 1 month equivalent to 0.05 mg/kg/day rhGH (1.4 mg/kg rhGH total over 28 days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110 h, was rapidly and near-completely absorbed, and was well tolerated with no observed adverse effects after every alternate week subcutaneous dosing for 14 weeks. VRS-317 also did not cause lipoatrophy in pig and monkey studies. VRS-317 is currently being studied in GH-deficient patients to confirm the observations in these animal studies. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2744–2754, 2012 PMID:22678811

  8. 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

  9. Measurement of the Double-Beta Decay Half-life of {sup 136}Xe in KamLAND-Zen

    SciTech Connect

    KamLAND-Zen Collaboration; 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.

    2012-01-23

    We present results from the KamLAND-Zen double-beta decay experiment based on an exposure of 77.6 days with 129 kg of {sup 136}Xe. The measured two-neutrino double-beta decay half-life of {sup 136}Xe is T{sup 2{nu}}{sub 1/2} = 2:38 {+-} 0:02(stat) {+-}0.14(syst) x10{sup 21} yr, consistent with a recent measurement by EXO-200. We also obtain a lower limit for the neutrinoless double-beta decay half-life, T{sup 0{nu}}{sub 1/2} > 5.7 x 10{sup 24} yr at 90% C.L.

  10. Measurement of the double-β decay half-life of 136Xe with the KamLAND-Zen experiment

    NASA Astrophysics Data System (ADS)

    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.

    2012-04-01

    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 T1/22ν=2.38±0.02(stat)±0.14(syst)×1021 yr, consistent with a recent measurement by EXO-200. We also obtain a lower limit for the neutrinoless double-beta decay half-life, T1/20ν>5.7×1024 yr at 90% confidence level (C. L.), which corresponds to almost a fivefold improvement over previous limits.

  11. High-Precision Half-Life Measurement for the Superallowed {beta}{sup +} Emitter {sup 26}Al{sup m}

    SciTech Connect

    Finlay, P.; Svensson, C. E.; Green, K. L.; Leach, K. G.; Phillips, A. A.; Sumithrarachchi, C. S.; Ettenauer, S.; Ball, G. C.; Bandyopadhyay, D.; Djongolov, M.; Hackman, G.; Pearson, C. J.; Williams, S. J; Leslie, J. R.; Andreoiu, C.; Cross, D. S.; Austin, R. A. E.; Demand, G.; Garrett, P. E.; Triambak, S.

    2011-01-21

    A high-precision half-life measurement for the superallowed {beta}{sup +} emitter {sup 26}Al{sup m} was performed at the TRIUMF-ISAC radioactive ion beam facility yielding T{sub 1/2}=6346.54{+-}0.46{sub stat{+-}}0.60{sub syst} ms, consistent with, but 2.5 times more precise than, the previous world average. The {sup 26}Al{sup m} half-life and ft value, 3037.53(61) s, are now the most precisely determined for any superallowed {beta} decay. Combined with recent theoretical corrections for isospin-symmetry-breaking and radiative effects, the corrected Ft value for {sup 26}Al{sup m}, 3073.0(12) s, sets a new benchmark for the high-precision superallowed Fermi {beta}-decay studies used to test the conserved vector current hypothesis and determine the V{sub ud} element of the Cabibbo-Kobayashi-Maskawa quark mixing matrix.

  12. 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.

  13. Tafazzins from Drosophila and mammalian cells assemble in large protein complexes with a short half-life.

    PubMed

    Xu, Yang; Malhotra, Ashim; Claypool, Steven M; Ren, Mindong; Schlame, Michael

    2015-03-01

    Tafazzin is a transacylase that affects cardiolipin fatty acid composition and mitochondrial function. Mutations in human tafazzin cause Barth syndrome yet the enzyme has mostly been characterized in yeast. To study tafazzin in higher organisms, we isolated mitochondria from Drosophila and mammalian cell cultures. Our data indicate that tafazzin binds to multiple protein complexes in these organisms, and that the interactions of tafazzin lack strong specificity. Very large tafazzin complexes could only be detected in the presence of cardiolipin, but smaller complexes remained intact even upon treatment with phospholipase A2. In mammalian cells, tafazzin had a half-life of only 3-6h, which was much shorter than the half-life of other mitochondrial proteins. The data suggest that tafazzin is a transient resident of multiple protein complexes. PMID:25598000

  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. Precise half-life measurements for the superallowed {beta}{sup +} emitters {sup 34}Ar and {sup 34}Cl

    SciTech Connect

    Iacob, V. E.; Hardy, J. C.; Brinkley, J. F.; Gagliardi, C. A.; Mayes, V. E.; Nica, N.; Sanchez-Vega, M.; Tabacaru, G.; Trache, L.; Tribble, R. E.

    2006-11-15

    To contribute meaningfully to any test of the unitarity of the Cabibbo-Kobayashi-Maskawa (CKM) matrix, the measured ft value of a superallowed 0{sup +}{yields}0{sup +} {beta}{sup +} transition must be obtained to a precision of 0.1% or better. We have determined the half-life of the superallowed emitter {sup 34}Ar to be 843.8(4)ms; the quoted precision, 0.05%, is a factor of five improvement on the best previous measurement and meets this demanding requirement. Our measurement employed a high-efficiency gas counter, which was sensitive to positrons from both {sup 34}Ar and its daughter {sup 34}Cl. We achieved the required precision on {sup 34}Ar by analyzing the parent-daughter composite decay with a new fitting technique. We also obtained an improved half-life for {sup 34}Cl of 1.5268(5) s, which has 0.03% precision and is a factor of two improvement on previous results. As a by-product of these measurements, we determined the half-life of {sup 35}Ar to be 1.7754(11) s.

  16. 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. PMID:24133142

  17. GLP2-2G-XTEN: A Pharmaceutical Protein with Improved Serum Half-Life and Efficacy in a Rat Crohn’s Disease Model

    PubMed Central

    Alters, Susan E.; McLaughlin, Bryant; Spink, Benjamin; Lachinyan, Tigran; Wang, Chia-wei; Podust, Vladimir; Schellenberger, Volker; Stemmer, Willem P. C.

    2012-01-01

    Objectives Glucagon-like peptide 2 (GLP2) is an intestinal growth factor that has been shown to stimulate intestinal growth and reduce disease severity in preclinical models of short bowel syndrome and inflammatory bowel disease. Teduglutide, a recombinant human GLP2 variant (GLP2-2G), has increased half-life and stability as compared to the native GLP2 peptide, but still requires twice daily dosing in preclinical models and daily dosing in the clinic. The goal of this study was to produce and characterize the preclinical pharmacokinetic and therapeutic properties of GLP2-2G-XTEN, a novel, long-acting form of GLP2-2G. Methodology and Results A GLP2-2G-XTEN fusion protein with extended exposure profile was produced by genetic fusion of GLP2-2G peptide to XTEN, a long, unstructured, non-repetitive, hydrophilic sequence of amino acids. The serum half-life of GLP2-2G-XTEN in mice, rats and monkeys was 34, 38 and 120 hours, respectively. Intestinotrophic effects were demonstrated in normal rats, where GLP2-2G-XTEN administration resulted in a significant increase in both small intestine weight and length. Efficacy of the GLP2-2G-XTEN protein was compared to that of GLP2-2G peptide in a rat Crohn’s disease model, indomethacin-induced inflammation. Prophylactic administration of GLP2-2G-XTEN significantly increased the length, reduced the number of trans-ulcerations and adhesions, and reduced the TNFα content of the small intestine. GLP2-2G-XTEN demonstrated greater in vivo potency as compared to GLP2-2G peptide, and improvement in histopathology supported the GLP2-2G-XTEN treatment effects. Conclusions and Significance GLP2-2G-XTEN is intestinotrophic and demonstrates efficacy in a rat Crohn’s disease model requiring a lower molar dose and less frequent dosing relative to GLP2-2G peptide. Allometric scaling based on pharmacokinetics from mouse, rat and monkey projects a human half-life of 240 hours. These improvements in preclinical pharmacokinetics and dosing

  18. 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.

  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

    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. 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.

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

    DOE PAGESBeta

    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

  3. 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

  4. 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

  5. Phase-space factors and half-life predictions for Majoron-emitting β-β- decay

    NASA Astrophysics Data System (ADS)

    Kotila, J.; Barea, J.; Iachello, F.

    2015-06-01

    A complete calculation of phase space factors (PSFs) for Majoron-emitting 0 ν β-β- decay modes is presented. The calculation makes use of exact Dirac wave functions with finite nuclear size and electron screening and includes lifetimes, single-electron spectra, summed electron spectra, and angular electron correlations. Combining these results with recent microscopic interacting boson model nuclear matrix elements (NMEs) we make half-life predictions for the ordinary Majoron decay (spectral index n =1 ). Furthermore, comparing theoretical predictions with the obtained experimental lower bounds for this decay mode we are able to set limits on the effective Majoron-neutrino coupling constant .

  6. 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

  7. 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.

  8. Application of a sealed tube neutron generator to the characterization of very short half-life isomeric states

    NASA Astrophysics Data System (ADS)

    Antonot, B.; Cluzeau, S.; Le Tourneur, P.; Bergamo, F.

    1995-05-01

    A SODERN sealed tube neutron generator producing 14 MeV neutrons has been used for detecting radionuclides with a half-life from about 20 μs to 1 s. An interesting feature of this kind of sealed tube neutron generator is the pulsed operation at adjustable pulse width from 5 μs to 10 ms or more, and at frequencies from continuous mode to 10 kHz. This capability allows the study of very short-lived isotopes down to a few microseconds with the cyclic activation method. A semiconductor γ ray detector Ge(HP) and ORTEC electronics were used for spectrometric measurements. The half-life measurement of short-lived activation products is performed with a fast multiscaler. Seven isomeric states have been successfully studied, characterized and their activation cross sections evaluated by the cyclic activation method: 114In ∗, 181Ta ∗, 181W ∗, 205Pb ∗, 206Pb ∗, 207Pb ∗, and 208Bi ∗.

  9. Does Physician Dispensing Increase Drug Expenditures? Empirical Evidence from Switzerland.

    PubMed

    Kaiser, Boris; Schmid, Christian

    2016-01-01

    This paper analyzes whether the opportunity for physicians to dispense drugs increases healthcare expenditures. We study the case of Switzerland, where dispensing physicians face financial incentives to overprescribe and sell more expensive pharmaceuticals. Using comprehensive physician-level data, we exploit the regional variation in the dispensing regime to estimate causal effects. The empirical strategy consists of a doubly-robust estimation that combines inverse probability weighting with regression. Our main finding suggests that dispensing leads to higher drug costs on the order of 34% per patient. PMID:25393362

  10. Increasing the structural coverage of tuberculosis drug targets

    DOE PAGESBeta

    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

  11. 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.

  12. Increasing the structural coverage of tuberculosis drug targets.

    PubMed

    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

    2015-03-01

    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 <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. PMID:25613812

  13. 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 Central

    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

    2015-01-01

    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. PMID:25762629

  14. 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

  15. Dynamic palmitoylation of lymphoma proprotein convertase prolongs its half-life, but is not essential for trans-Golgi network localization.

    PubMed Central

    van de Loo, J W; Teuchert, M; Pauli, I; Plets, E; Van de Ven, W J; Creemers, J W

    2000-01-01

    Proprotein convertases are responsible for the endoproteolytic activation of proproteins in the secretory pathway. The most recently discovered member of this family, lymphoma proprotein convertase (LPC), is a type-I transmembrane protein. Previously, we have demonstrated that its cytoplasmic tail is palmitoylated. In this study, we have identified the two most proximal cysteine residues in the cytoplasmic tail as palmitoylation sites. Substitution of either cysteine residue by alanine interfered with palmitoylation of the other. Palmitoylation of LPC was found to be sensitive to the protein palmitoyltransferase inhibitor tunicamycin but not cerulenin. It was also insensitive to the drugs brefeldin A, monensin and cycloheximide, indicating that the modification occurs in a late exocytic or endocytic compartment. Turnover of palmitoylated LPC is significantly faster (t(1/2) approximately 50 min) than that of the LPC polypeptide backbone (t(1/2) approximately 3 h), suggesting that palmitoylation is reversible. Abrogation of palmitoylation reduced the half-life of the LPC protein, but did not affect steady-state localization of LPC in the trans-Golgi network. Finally, LPC could not be detected in detergent-resistant membrane rafts. Taken together, these results suggest that dynamic palmitoylation of LPC is important for stability, but does not function as a dominant trafficking signal. PMID:11104692

  16. Effect of deformation and vibration on the α decay half-life

    NASA Astrophysics Data System (ADS)

    Ghodsi, O. N.; Gholami, E.

    2016-05-01

    In this work, we expand upon our previous study of the effect of surface vibrations (low-lying vibrational states) on the calculation of penetration probability in α decay of spherical isotopes [Phys. Rev. C 91, 034611 (2015), 10.1103/PhysRevC.91.034611]. For this pupose, the Coulomb and proximity potential model, taking into account the ground state deformations of the involved nuclei along with the surface vibrations in the daughter nucleus, is used to evaluate the α decay probability. The results are compared with those obtained with a spherical potential barrier, which shows the dramatic effect of employing the ground state deformations in case of deformed nuclei. As well, inclusion of surface vibrations gives rise to an increase in the value of tunneling probability in better agreement with experimental data.

  17. High-precision β decay half-life measurements of proton-rich nuclei for testing the CVC hypothesis

    NASA Astrophysics Data System (ADS)

    Kurtukian-Nieto, T.

    2011-11-01

    The experimental study of super-allowed nuclear β decays serves as a sensitive probe of the conservation of the weak vector current (CVC) and allows tight limits to be set on the presence of scalar or right-handed currents. Once CVC is verified, it is possible to determine the Vud element of the CKM quark-mixing matrix. Similarly, the study of nuclear mirror β decays allows to arrive at the same final quantity Vud. Whereas dedicated studies of 0+ → 0+ decays are performed for several decades now, the potential of mirror transitions was only rediscovered recently. Therefore, it can be expected that important progress is possible with high-precision studies of different mirror β decays. In the present piece of work the half-life measurements performed by the CENBG group of the proton-rich nuclei 42Ti, 38-39Ca, 30-31S and 29P are summarised.

  18. 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

  19. The influence of irradiation on the biological half-life of prostacyclin in plasma of patients with gastrointestinal cancer.

    PubMed Central

    Polterauer, P.; Sinzinger, H.; Peskar, B. A.

    1987-01-01

    In seven patients suffering from inoperable pancreatic cancer and in 14 patients with inoperable colonic cancer the half-life (T/2) of prostaglandin (PG)I2 in plasma in vitro has been determined before and at various intervals after irradiation. No significant difference of PGI2-T/2 could be observed either before irradiation, at the end of the irradiation period or 3 and 6 weeks after the last irradiation. Thus irradiation does not appear to interfere with the degradation of PGI2-T/2 in plasma. In patients with inoperable pancreatic and colonic cancer the PGI2-T/2 was not significantly different to that of the PGI2-T/2 of controls. Thus, a shortening of PGI2-T/2 is not a common feature in tumour patients. Hyperaggregation promoting seeding of metastases is not influenced by irradiation via the particular parameter of the PG-system. PMID:3318903

  20. 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…

  1. Declining Drug Use in Relation to Increased Drug Education: A Trend Study 1979-1991.

    ERIC Educational Resources Information Center

    Smart, Reginald G.; And Others

    1993-01-01

    Examined data from repeated cross-sectional probability surveys of alcohol/drug use conducted biennially since 1979 in Ontario schools to determine relationships between classroom alcohol, tobacco, and cannabis education and student use of these substances. Found strong inverse association between increases in exposure to alcohol and drug…

  2. 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. PMID:26187320

  3. 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.

  4. Increasing Use of Drugs by Our Youth. Remarks.

    ERIC Educational Resources Information Center

    Dolins, Robert

    A general look at the drug abuse problem comprises the first part of the paper. The author views drug abuse in terms of dependence rather than addiction, and as being either physiological or psychological. He briefly discusses which drugs are used, by whom, and for what purposes. Drug abuse is seen as an old problem with contemporary…

  5. 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

  6. 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. PMID:26121420

  7. 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

  8. 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

  9. 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. PMID:26310188

  10. Recombinant thyrotropin containing a beta-subunit chimera with the human chorionic gonadotropin-beta carboxy-terminus is biologically active, with a prolonged plasma half-life: role of carbohydrate in bioactivity and metabolic clearance.

    PubMed

    Joshi, L; Murata, Y; Wondisford, F E; Szkudlinski, M W; Desai, R; Weintraub, B D

    1995-09-01

    Recombinant TSH is now successfully being used in clinical studies of thyroid cancer. Because of its therapeutic potential, we have constructed a longer acting analog of TSH by fusing the carboxy-terminal extension peptide (CTEP) of hCG beta onto TSH beta. When coexpressed either with alpha-subunit complementary DNA or alpha minigene in African green monkey (COS-7) and human embryonic kidney (293) cells, the chimera was fully bioactive in vitro and exhibited enhanced in vivo potency associated with a prolonged plasma half-life. The addition of 25 amino acids with 4 O-linked oligosaccharide chains did not affect the assembly and secretion of chimeric TSH. Wild-type (WT) and chimeric TSH secreted by COS-7 and 293 cells displayed wide differences in their plasma half-lives, presumably due to the presence of terminal sialic acid and SO4 on their oligosaccharide chains, respectively. Chimeric and WT TSH secreted by both cell lines demonstrated similar bioactivity in cAMP production, with some differences in [3H]thymidine incorporation. Chimeric TSH appears to be more effective in COS-7 cells than in 293 cells, as judged by growth assay. COS-7-produced chimeric TSH showed the maximum increase in half-life, indicating the importance of sialic acid in prolonging half-life and in vivo potency. Sulfation of both subunits, predominantly beta and to a lesser extent alpha, appears to be responsible at least in part for the increased metabolic clearance of WT and chimeric TSH secreted by 293 cells. Apart from its therapeutic potential, chimeric TSH produced in various cell lines can be used as a tool to delineate the roles of sulfate and sialic acid in the in vivo clearance and, thereby, the in vivo bioactivity. PMID:7544273

  11. 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

  12. Plasminogen activator inhibitor with very long half-life (VLHL PAI-1) can reduce bleeding in PAI-1-deficient patients.

    PubMed

    Jankun, Jerzy; Skrzypczak-Jankun, Ewa

    2013-08-01

    This review summarizes our current knowledge of plasminogen activator inhibitor (PAI-1) deficiency and proposes some novel treatments for this condition. PAI-1 is a fast acting inhibitor of tissue and urokinase plasminogen activators (tPA and uPA). PAI-1 controls/slows clot lysis triggered by tPA activated plasminogen. PAI-1 deficiency was once considered to be an extremely rare disorder characterized by frequent and prolonged bleeding episodes. PAI-1 deficiency is now thought to be more frequent than initially reported and is known to be caused by mutations in the PAI-1 gene that produce a dysfunctional PAI-1 protein or slow the secretion of PAI-1 into the circulation. PAI-1 deficiency is characterized by hyperfibrinolysis that results in frequent bleeding episodes. Patients with this condition form normal blood clots that are quickly lysed by unopposed tPA-activated plasmin. Spontaneous bleeding is rare in PAI-1 deficient patients, but moderate hemorrhaging of the knees, elbows, nose, and gums can be triggered by mild trauma. Additionally, prolonged bleeding after surgery is common and menstrual bleeding may be severe. Moderate PAI-1 deficiency is associated with a lifelong bleeding tendency, but severe deficiencies can be life-threatening. The diagnosis of this disorder remains challenging due to the lack of a clear definition of PAI-1 deficiency as well as a lack of standardized tests. Patients with mild PAI-1 deficiency may be treated with antifibrinolytic agents (ε-aminocaproic acid or tranexamic acid); however, not all patients respond well to these treatments. These patients may be treated with wild-type PAI-1; however, this molecule quickly converts into its inactive form. We propose to use PAI-1 with an extended half-life to treat these patients. PMID:23988002

  13. 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. PMID:11194159

  14. 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.

  15. 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. PMID:26303025

  16. 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…

  17. 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

  18. Newly formed mRNA lacking polyadenylic acid enters the cytoplasm and the polyribosomes but has a shorter half-life in the absence of polyadenylic acid

    SciTech Connect

    Zeevi, M.; Nevins, J.R.; Darnell, J.E. Jr.

    1982-05-01

    Labeled adenovirus type 2 nuclear RNA molecules from cells treated with 3'-deoxyadenosine (3'dA) were earlier reported to lack polyadenylic acid (poly(A)), but to be correctly spliced in the nucleus. The authors found that the shortened mRNA molecules, lacking poly(A), can also be found in the cytoplasm of 3'dA-treated cells in association with the polyribosomes. In addition, the accumulation of labeled, nuclear adenovirus-specific RNA complementary to early regions 1a, 1b, and 2 of the adenovirus genome was approximately equal in 3'dA-treated and control cells. At the initial appearance of newly labeled adenovirus type 2 RNA (10 min) in the cytoplasm, there was one-half as much labeled RNA in 3'dA-treated as in the control. However, control cells accumulated additional mRNA in the cytoplasm very rapidly in the first 40 min of labeling, whereas the 3'dA-treated cells did not. Therefore, it appears that the correctly spliced, poly(A)/sup -/ mRNa molecules that are labeled in the presence of 3'dA can be transported from the nucleus with nearly the same frequency and the same exit time as in control cells and can be translated in the cytoplasm but have a much shorter half-life than the poly(A)/sup +/ mRNa molecules from control infected cells. From these results it is suggested that the role of poly(A) may be entirely to increase the longevity of cytoplasmic mRNA.

  19. Measurement of the half-life of the two-neutrino double beta decay of 76Ge with the GERDA experiment

    NASA Astrophysics Data System (ADS)

    The GERDA Collaboration; Agostini, M.; Allardt, M.; Andreotti, E.; Bakalyarov, A. M.; Balata, M.; Barabanov, I.; Barnabé Heider, M.; Barros, N.; Baudis, L.; Bauer, C.; Becerici-Schmidt, N.; Bellotti, E.; Belogurov, S.; Belyaev, S. T.; Benato, G.; Bettini, A.; Bezrukov, L.; Bode, T.; Brudanin, V.; Brugnera, R.; Budjáš, D.; Caldwell, A.; Cattadori, C.; Chernogorov, A.; Cossavella, F.; Demidova, E. V.; Denisov, A.; Domula, A.; Egorov, V.; Falkenstein, R.; Ferella, A. D.; Freund, K.; Froborg, F.; Frodyma, N.; Gangapshev, A.; Garfagnini, A.; Gazzana, S.; Grabmayr, P.; Gurentsov, V.; Gusev, K.; Guthikonda, K. K.; Hampel, W.; Hegai, A.; Heisel, M.; Hemmer, S.; Heusser, G.; Hofmann, W.; Hult, M.; Inzhechik, L. V.; Ioannucci, L.; Janicskó Csáthy, J.; Jochum, J.; Junker, M.; Kianovsky, S.; Kirpichnikov, I. V.; Kirsch, A.; Klimenko, A.; Knöpfle, K. T.; Kochetov, O.; Kornoukhov, V. N.; Kuzminov, V.; Laubenstein, M.; Lazzaro, A.; Lebedev, V. I.; Lehnert, B.; Liao, H. Y.; Lindner, M.; Lippi, I.; Liu, X.; Lubashevskiy, A.; Lubsandorzhiev, B.; Lutter, G.; Machado, A. A.; Majorovits, B.; Maneschg, W.; Nemchenok, I.; Nisi, S.; O'Shaughnessy, C.; Pandola, L.; Pelczar, K.; Peraro, L.; Pullia, A.; Riboldi, S.; Ritter, F.; Sada, C.; Salathe, M.; Schmitt, C.; Schönert, S.; Schreiner, J.; Schulz, O.; Schwingenheuer, B.; Shevchik, E.; Shirchenko, M.; Simgen, H.; Smolnikov, A.; Stanco, L.; Strecker, H.; Tarka, M.; Ur, C. A.; Vasenko, A. A.; Volynets, O.; von Sturm, K.; Walter, M.; Wegmann, A.; Wojcik, M.; Yanovich, E.; Zavarise, P.; Zhitnikov, I.; Zhukov, S. V.; Zinatulina, D.; Zuber, K.; Zuzel, G.

    2013-03-01

    The primary goal of the GERmanium Detector Array (GERDA) experiment at the Laboratori Nazionali del Gran Sasso of INFN is the search for the neutrinoless double beta decay of 76Ge. High-purity germanium detectors made from material enriched in 76Ge are operated directly immersed in liquid argon, allowing for a substantial reduction of the background with respect to predecessor experiments. The first 5.04 kg yr of data collected in Phase I of the experiment have been analyzed to measure the half-life of the neutrino-accompanied double beta decay of 76Ge. The observed spectrum in the energy range between 600 and 1800 keV is dominated by the double beta decay of 76Ge. The half-life extracted from GERDA data is T2ν1/2 = (1.84+0.14-0.10) × 1021 yr.

  20. 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.

  1. 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

  2. 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

  3. First half-life measurement of 60Fe using the direct decay of 60mCo and Acceleratory Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Ostdiek, Karen; Anderson, Tyler; Bauder, William; Bowers, Matthew; Collon, Philippe; Lu, Wenting; Robertson, Daniel; Skulski, Michael; Dressler, Rugard; Schumann, Dorothea; Greene, John; Kutschera, Walter; Paul, Michael; Wallner, Anton

    2016-03-01

    Radioisotopes, produced in stars and ejected through core collapse supernovae (SNe), are important for constraining stellar and early Solar System (ESS) models. The presence of these isotopes, specifically 60Fe , can identify progenitors of SN types, give evidence for nearby SN, and can be a chronometer for ESS events. The 60Fe half-life, which has been in dispute, can have an impact on calculations for the timing for ESS events, the distance to nearby SN, and the brightness of 60Fe gamma ray sources in the Galaxy. To measure such a long half life, one needs to simultaneously determine the number of atoms in and the activity of an 60Fe sample. We have undertaken a half-life measurement at Notre Dame and have successfully measured the activity of our 60Fe sample using the isomeric decay in 60Co rather than the traditional 60Co grow-in decay. This will then be coupled with the results of the 60Fe concentration measurement of our sample using Accelerator Mass Spectrometry (AMS). The most recent results of both will be presented.

  4. Pharmacokinetics of Repeated Sodium Salicylate Administration to Laying Hens: Evidence for Time Dependent Increase in Drug Elimination from Plasma and Eggs

    PubMed Central

    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

  5. 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

  6. Serum half-life and tumor localization of a chimeric antibody deleted of the C sub H 2 domain and directed against the disialoganglioside GD2

    SciTech Connect

    Mueller, B.M.; Reisfeld, R.A. ); Gillies, S.D. )

    1990-08-01

    Recombinant techniques allow one to engineer an antibody molecule and, in this way, manipulate its properties and functions. The authors engineered a chimeric human/mouse antibody to the tumor-associated antigen ganglioside GD2, with the aim of decreasing its serum half-life, maintaining its full antigen-binding capacity, and deleting its effector functions, thus making it a potentially useful reagent for the radioimaging of tumors. To this end, the constant region of the human {gamma}1 chain was mutated by deleting the second domain (C{sub H}2). Here the authors show that the C{sub H}2-deleted antibody (ch14.18-{Delta}CH2) was cleared from the blood of athymic (nu/nu) mice bearing human melanoma tumors with the same kinetics as human IgG F(ab{prime}){sub 2}. At a {beta} t{sub 1/2} of 12 hr, 0.9% of the injected dose of {sup 125}I-labeled ch14.18-{Delta}CH2 was found per milliliter of blood 24 hr after i.v. injection. In biodistribution experiments, {sup 125}I-labeled ch14.18-{Delta}CH2 targeted specifically to melanoma xenografts, achieving optimal tumor-to-tissue ratios 12-16 hr after i.v. injection. ch14.18-{Delta}CH2 was localized to the melanoma tumors more rapidly and with better localization ratios than the intact chimeric antibody ch14.18. Sixteen hours after i.v. injection, the tumor-to-blood and tumor-to-liver ratios of ch14.18-{Delta}CH2 were 5 and 12, respectively, while optimal localization ratios obtained for ch14.18 were 1 and 5, respectively, but 96 hr after injection. A reagent such as ch14.18-{Delta}CH2 should be useful for radioimmunodetection of human tumors because of reduced immunogenicity, increased targeting specificity, and rapid clearance from circulation.

  7. 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

  8. Measurement of the Half-Life of the T =1/2 Mirror Decay of Ne19 and its Implication on Physics Beyond the Standard Model

    NASA Astrophysics Data System (ADS)

    Broussard, L. J.; Back, H. O.; Boswell, M. S.; Crowell, A. S.; Dendooven, P.; Giri, G. S.; Howell, C. R.; Kidd, M. F.; Jungmann, K.; Kruithof, W. L.; Mol, A.; Onderwater, C. J. G.; Pattie, R. W.; Shidling, P. D.; Sohani, M.; van der Hoek, D. J.; Rogachevskiy, A.; Traykov, E.; Versolato, O. O.; Willmann, L.; Wilschut, H. W.; Young, A. R.

    2014-05-01

    The 1/2+→1/2+ superallowed mixed mirror decay of Ne19 to F19 is excellently suited for high precision studies of the weak interaction. However, there is some disagreement on the value of the half-life. In a new measurement we have determined this quantity to be T1/2=17.2832±0.0051(stat)±0.0066(syst) s, which differs from the previous world average by 3 standard deviations. The impact of this measurement on limits for physics beyond the standard model such as the presence of tensor currents is discussed.

  9. {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.

  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. PMID:26826633

  12. Pain, Epilepsy Drug Lyrica May Increase Birth Defects Risk, Study Suggests

    MedlinePlus

    ... 158906.html Pain, Epilepsy Drug Lyrica May Increase Birth Defects Risk, Study Suggests Expectant mothers should probably ... pregabalin (Lyrica) may slightly increase the risk for birth defects, a new study suggests. In a small ...

  13. 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

  14. Interaction with the Bardet-Biedl gene product TRIM32/BBS11 modifies the half-life and localization of Glis2/NPHP7.

    PubMed

    Ramachandran, Haribaskar; Schäfer, Tobias; Kim, Yunhee; Herfurth, Konstantin; Hoff, Sylvia; Lienkamp, Soeren S; Kramer-Zucker, Albrecht; Walz, Gerd

    2014-03-21

    Although the two ciliopathies Bardet-Biedl syndrome and nephronophthisis share multiple clinical manifestations, the molecular basis for this overlap remains largely unknown. Both BBS11 and NPHP7 are unusual members of their respective gene families. Although BBS11/TRIM32 represents a RING finger E3 ubiquitin ligase also involved in hereditary forms of muscular dystrophy, NPHP7/Glis2 is a Gli-like transcriptional repressor that localizes to the nucleus, deviating from the ciliary localization of most other ciliopathy-associated gene products. We found that BBS11/TRIM32 and NPHP7/Glis2 can physically interact with each other, suggesting that both proteins form a functionally relevant protein complex in vivo. This hypothesis was further supported by the genetic interaction and synergist cyst formation in the zebrafish pronephros model. However, contrary to our expectation, the E3 ubiquitin ligase BBS11/TRIM32 was not responsible for the short half-life of NPHP7/Glis2 but instead promoted the accumulation of mixed Lys(48)/Lys(63)-polyubiquitylated NPHP7/Glis2 species. This modification not only prolonged the half-life of NPHP7/Glis2, but also altered the subnuclear localization and the transcriptional activity of NPHP7/Glis2. Thus, physical and functional interactions between NPHP and Bardet-Biedl syndrome gene products, demonstrated for Glis2 and TRIM32, may help to explain the phenotypic similarities between these two syndromes. PMID:24500717

  15. 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.

  16. Synthesis and bioimaging of positron-emitting 15O-labeled 2-deoxy-D-glucose of two-minute half-life.

    PubMed

    Yorimitsu, Hideki; Murakami, Yoshihiro; Takamatsu, Hiroyuki; Nishimura, Shintaro; Nakamura, Eiichi

    2007-01-01

    In positron emission tomography (PET), which exploits the affinity of a radiopharmaceutical for the target organ, a systematic repertoire of oxygen-15-labeled PET tracers is expected to be useful for bioimaging owing to the ubiquity of oxygen atoms in organic compounds. However, because of the 2-min half-life of 15O, the synthesis of complex biologically active 15O-labeled organic molecules has not yet been achieved. A state-of-the-art synthesis now makes available an 15O-labeled complex organic molecule, 6-[15O]-2-deoxy-D-glucose. Ultrarapid radical hydroxylation of 2,6-dideoxy-6-iodo-D-glucose with molecular oxygen labeled with 15O of two-minute half-life provided the target 15O-labeled molecule. The labeling reaction with 15O was complete in 1.3 min, and the entire operation time starting from the generation of 15O-containing dioxygen by a cyclotron to the purification of the labeled sugar was 7 min. The labeled sugar accumulated in the metabolically active organs as well as in the bladder of mice and rats. 15O-labeling offers the possibility of repetitive scanning and the use of multiple PET tracers in the same body within a short time, and hence should significantly expand the scope of PET studies of small animals. PMID:17441139

  17. Targeting the Ion Channel Kv1.3 with Scorpion Venom Peptides Engineered for Potency, Selectivity, and Half-life

    PubMed Central

    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.

    2014-01-01

    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. PMID:24939846

  18. 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

  19. 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

  20. Numerical Model to Characterize the Size Increase of Combination Drug and Hygroscopic Excipient Nanoparticle Aerosols

    PubMed Central

    Longest, P. Worth; Hindle, Michael

    2011-01-01

    Enhanced excipient growth is a newly proposed respiratory delivery strategy in which submicrometer or nanometer particles composed of a drug and hygroscopic excipient are delivered to the airways in order to minimize extrathoracic depositional losses and maximize lung retention. The objective of this study was to develop a validated mathematical model of aerosol size increase for hygroscopic excipients and combination excipient-drug particles and to apply this model to characterize growth under typical respiratory conditions. Compared with in vitro experiments, the droplet growth model accurately predicted the size increase of single component and combination drug and excipient particles. For typical respiratory drug delivery conditions, the model showed that droplet size increase could be effectively correlated with the product of a newly defined hygroscopic parameter and initial volume fractions of the drug and excipient in the particle. A series of growth correlations was then developed that successively included the effects of initial drug and excipient mass loadings, initial aerosol size, and aerosol number concentration. Considering EEG delivery, large diameter growth ratios (2.1–4.6) were observed for a range of hygroscopic excipients combined with both hygroscopic and non-hygroscopic drugs. These diameter growth ratios were achieved at excipient mass loadings of 50% and below and at realistic aerosol number concentrations. The developed correlations were then used for specifying the appropriate initial mass loadings of engineered insulin nanoparticles in order to achieve a predetermined size increase while maximizing drug payload and minimizing the amount of hygroscopic excipient. PMID:21804683

  1. Pain, Epilepsy Drug Lyrica May Increase Birth Defects Risk, Study Suggests

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_158906.html Pain, Epilepsy Drug Lyrica May Increase Birth Defects Risk, Study ... prescribed for a range of health problems, including epilepsy, fibromyalgia and anxiety. The new study findings should ...

  2. Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution.

    PubMed

    Girard, A E; Girard, D; English, A R; Gootz, T D; Cimochowski, C R; Faiella, J A; Haskell, S L; Retsema, J A

    1987-12-01

    Azithromycin (CP-62,993), a new acid-stable 15-membered-ring macrolide, was well absorbed following oral administration in mice, rats, dogs, and cynomolgus monkeys. This compound exhibited a uniformly long elimination half-life and was distributed exceptionally well into all tissues. This extravascular penetration of azithromycin was demonstrated by tissue/plasma area-under-the-curve ratios ranging from 13.6 to 137 compared with ratios for erythromycin of 3.1 to 11.6. The significance of these pharmacokinetic advantages of azithromycin over erythromycin was shown through efficacy in a series of animal infection models. Azithromycin was orally effective in treating middle ear infections induced in gerbils by transbulla challenges with amoxicillin-resistant Haemophilus influenzae or susceptible Streptococcus pneumoniae; erythromycin failed and cefaclor was only marginally active against the H. influenzae challenge. Azithromycin was equivalent to cefaclor and erythromycin against Streptococcus pneumoniae. In mouse models, the new macrolide was 10-fold more potent than erythromycin and four other antibiotics against an anaerobic infection produced by Fusobacterium necrophorum. Similarly, azithromycin was effective against established tissue infections induced by Salmonella enteritidis (liver and spleen) and Staphylococcus aureus (thigh muscle); erythromycin failed against both infections. The oral and subcutaneous activities of azithromycin, erythromycin, and cefaclor were similar against acute systemic infections produced by Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, or S. aureus, whereas azithromycin was more potent than erythromycin and cefaclor against the intracellular pathogen Listeria monocytogenes. The pharmacokinetic advantage of azithromycin over erythromycin in half-life was clearly demonstrated in prophylactic treatment of an acute mouse model of S. aureus infection. These properties of azithromycin strongly support the

  3. GSK3β-Dependent Phosphorylation Alters DNA Binding, Transactivity and Half-Life of the Transcription Factor USF2

    PubMed Central

    Horbach, Tina; Chi, Tabughang Franklin; Götz, Claudia; Sharma, Satyan; Juffer, André H.; Dimova, Elitsa Y.; Kietzmann, Thomas

    2014-01-01

    The upstream stimulatory factor 2 (USF2) is a regulator of important cellular processes and is supposed to have also a role during tumor development. However, the knowledge about the mechanisms that control the function of USF2 is limited. The data of the current study show that USF2 function is regulated by phosphorylation and identified GSK3β as an USF2-phosphorylating kinase. The phosphorylation sites within USF2 could be mapped to serine 155 and threonine 230. In silico analyses of the 3-dimensional structure revealed that phosphorylation of USF2 by GSK3β converts it to a more open conformation which may influence transactivity, DNA binding and target gene expression. Indeed, experiments with GSK-3β-deficient cells revealed that USF2 transactivity, DNA binding and target gene expression were reduced upon lack of GSK3β. Further, experiments with USF2 variants mimicking GSK3β phosphorylated USF2 in GSK3β-deficient cells showed that phosphorylation of USF2 by GSK3β did not affect cell proliferation but increased cell migration. Together, this study reports a new mechanism by which USF2 may contribute to cancerogenesis. PMID:25238393

  4. An Increasing Trend of Illicit Drug use among Romanian University Students from 1999 to 2011

    PubMed Central

    LOTREAN, Lucia Maria; SANTILLAN, Edna Arillo; THRASHER, James; LAZA, Valeria

    2016-01-01

    Aim The present study investigates the evolution of illicit drug use among Romanian university students from 1999 to 2011. Methods The study was performed in Cluj-Napoca, Romania, in three phases: in 1999 (T1), in 2003 (T2) and in 2011 (T3). The study was carried out by means of anonymous questionnaires among university students aged 19–24. Results The results show that among girls the lifetime illicit drugs use increased statistically significantly from 2.5% in 1999 to 7.5% in 2003 and to 15% in 2011. Among boys the trend was also increasing, the prevalence of illicit drug use was 14.2% at T1, 18.1% at T2, and it increased dramatically to 30.6% at T3. The percentage of students reporting cannabis use was almost identical with the total prevalence of illicit drug use. Ecstasy was the second most frequent drug used by the students; its consumption had also an increasing trend during the examined periods (from 0 to 5.6% among girls and from 0.8% to 11.2% among boys). The results of the bivariate correlation analyses show that lifetime illicit drug use was associated with having friends who experimented with illicit drugs both among boys and girls. Moreover, girls who declared stress management problems and depressive episodes were more likely to try illicit drugs, while among boys illicit drug use was associated with poorer academic performance. Conclusions The data pointed out by our study call for comprehensive actions regarding the prevention of illicit drug use among Romanian young people.

  5. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    PubMed Central

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  6. 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

  7. Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs.

    PubMed

    Zhao, Ying; Wu, Chao; Zhao, Zongzhe; Hao, Yanna; Xu, Jie; Yu, Tong; Qiu, Yang; Jiang, Jie

    2016-09-01

    Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs. PMID:26166407

  8. 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

  9. Cross-reactive HIV-1-neutralizing activity of serum IgG from a rabbit immunized with gp41 fused to IgG1 Fc: Possible role of the prolonged half-life of the immunogen

    PubMed Central

    Zhang, Mei-Yun; Wang, Yanping; Mankowski, Marie K.; Ptak, Roger G.; Dimitrov, Dimiter S.

    2012-01-01

    The elicitation of broadly cross-reactive HIV-1 neutralizing antibodies in humans remains a major challenge in developing a viable AIDS vaccine. We hypothesized that prolonged exposure to candidate vaccine immunogens could enhance the elicitation of such antibodies. In an attempt to develop HIV-1 vaccine immunogens with prolonged half-lives and increased stability, we constructed a fusion protein, gp41Fc, in which a truncated HIV-1 gp4189.6 was fused to a human IgG1 Fc. Gp41Fc is stable in solution, retains its antigenic structure and is highly immunogenic in rabbits. The serum titers reached 1:102,400 for the gp41Fc and 1:5,120 for gp14089.6. Rabbit IgG neutralized diverse HIV-1 isolates and HIV-2, and the neutralization activity was attributed to gp41-specific IgG. The concentration of the gp41Fc in the serum correlated with the neutralization activity of rabbit IgG which recognized mostly conformation-independent epitopes on gp41 and predominantly bound to peptides derived from the gp41 immunodominant loop region. These results suggest that the prolonged half-life of gp41Fc in the serum may enhance the generation of cross-reactive neutralizing antibodies. Further research is needed to confirm and extend these results which may have implications for the development of vaccine immunogens with enhanced capability to elicit cross-reactive HIV-1-neutralizing antibodies. PMID:19084043

  10. Multiple drug cost containment policies in Michigan's Medicaid program saved money overall, although some increased costs.

    PubMed

    Kibicho, Jennifer; Pinkerton, Steven D

    2012-04-01

    Michigan's Medicaid program implemented four cost containment policies--preferred drug lists, joint and multistate purchasing arrangements, and maximum allowable cost--during 2002-04. The goal was to control growth of drug spending for beneficiaries who were enrolled in both Medicaid and Medicare and taking antihypertensive or antihyperlipidemic prescription drugs. We analyzed the impact of each policy while holding the effect of all other policies constant. Preferred drug lists increased both preferred and generic drugs' market share and reduced daily cost--the cost per day for each prescription provided to a beneficiary. In contrast, the maximum allowable cost policy increased daily cost and was the only policy that did not generate cost savings. The joint and multistate arrangements did not affect daily cost. Despite these policy trade-offs, the cumulative effect was a 10 percent decrease in daily cost and a total cost savings of $46,195 per year. Our findings suggest that policy makers need to evaluate the impact of multiple policies aimed at restraining drug spending, and further evaluate the policy trade-offs, to ensure that scarce public dollars achieve the greatest return for money spent. PMID:22492899

  11. Incentive Learning for Morphine-Associated Stimuli During Protracted Abstinence Increases Conditioned Drug Preference

    PubMed Central

    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. PMID:23942418

  12. 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. PMID:24637719

  13. The Crystal Structure of Thrombin-activable Fibrinolysis Inhibitor (TAFI) Provides the Structural Basis for Its Intrinsic Activity and the Short Half-life of TAFIa*♦

    PubMed Central

    Anand, Kanchan; Pallares, Irantzu; Valnickova, Zuzana; Christensen, Trine; Vendrell, Josep; Wendt, K. Ulrich; Schreuder, Herman A.; Enghild, Jan J.; Avilés, Francesc X.

    2008-01-01

    Mature thrombin-activable fibrinolysis inhibitor (TAFIa) is a highly unstable metallocarboxypeptidase that stabilizes blood clots by clipping C-terminal lysine residues from partially degraded fibrin. In accordance with its in vitro antifibrinolytic activity, animal studies have reported that inhibition of mature TAFI aids in the prevention of thrombosis. The level of TAFI activity is stringently regulated through (i) controlled proteolytic truncation of the zymogen (TAFI), generating the mature enzyme, TAFIa, and (ii) the short half-life of TAFIa. TAFI itself exhibits an intrinsic enzymatic activity, which is likely required to provide a baseline level of antifibrinolytic activity. The novel crystal structure presented here reveals that the active site of TAFI is accessible, providing the structural explanation for the its intrinsic activity. It also supports the notion that an “instability region” exists, in agreement with site-directed mutagenesis studies. Sulfate ions, bound to this region, point toward a potential heparin-binding site and could explain how heparin stabilizes TAFIa. PMID:18669641

  14. Analytical expression for the {alpha}-decay half-life and understanding the data including very long life-times and superheavy nuclei

    SciTech Connect

    Sahu, Basudeb

    2008-10-15

    An analytically solvable composite potential that can closely reproduce the combined potential of an {alpha}+nucleus system consisting of attractive nuclear and repulsive electrostatic potentials is developed. The exact s-wave solution of the Schroedinger equation with this potential in the interior region and the outside Coulomb wave function are used to give a heuristic expression for the width or half-life of the quasibound state at the accurately determined resonance energy, called the Q value of the decaying system. By using the fact that for a relatively low resonance energy, the quasibound state wave function is quite similar to the bound state wave function where the amplitude of the wave function in the interaction region is very large as compared to the amplitude outside, the resonance energy could easily be calculated from the variation of relative probability densities of inside and outside waves as a function of energy. By considering recent {alpha}-decay systems, the applicability of the model is demonstrated with excellent explanations being found for the experimental data of Q values and half-lives of a vast range of masses including superheavy nuclei and nuclei with very long lifetimes (of order 10{sup 22} s). Throughout the application, by simply varying the value of a single potential parameter describing the flatness of the barrier, we obtain successful results in cases with as many as 70 pairs of {alpha}+daughter nucleus systems.

  15. TAT-HSA-α-MSH fusion protein with extended half-life inhibits tumor necrosis factor-α in brain inflammation of mice.

    PubMed

    Wang, Meizhu; Zhi, Dejuan; Wang, Haiqing; Ru, Yi; Ren, Hui; Wang, Na; Liu, Yiyao; Li, Yang; Li, Hongyu

    2016-06-01

    Neuroinflammation constitutes a principal process involved in the progression of various central nervous system (CNS) disorders, including Parkinson's disease, Alzheimer's disease, ischemic stroke, and traumatic brain injury. The safety and efficacy of potential neuroprotective therapeutic agents is controversial and limited. Alpha-melanocyte-stimulating hormone (α-MSH) as a tridecapeptide derived from pro-opiomelanocortin displays potent anti-inflammatory and protective effects with a wide therapeutic window in brain damage. However, it is difficult to deliver effective concentrations of α-MSH into brain tissue via nondirect application. Besides, the half-life of the tridecapeptide is only a few minutes. In the present study, we generated a novel TAT-HSA-α-MSH by genetically fusing α-MSH with N-terminus 11-amino acid protein transduction domain of the human immunodeficiency virus Tat protein (TAT) and human serum albumin (HSA), which showed favorable pharmacokinetic properties and can effectively cross the blood brain barrier (BBB). The findings showed that TAT-HSA-α-MSH significantly inhibits NF-κB activation in human glioma cells A172 and tumor necrosis factor-α (TNF-α) production in experimental brain inflammation. These results indicate that TAT-HSA-α-MSH may be a potential therapeutic agent for treating neuroinflammation which plays a fundamental role in CNS disorders. PMID:26816094

  16. 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

  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. Volume of Distribution in Drug Design.

    PubMed

    Smith, Dennis A; Beaumont, Kevin; Maurer, Tristan S; Di, Li

    2015-08-13

    Volume of distribution is one of the most important pharmacokinetic properties of a drug candidate. It is a major determinant of half-life and dosing frequency of a drug. For a similar log P, a basic molecule will tend to exhibit higher volume of distribution than a neutral molecule. Acids often exhibit low volumes of distribution. Although a design strategy against volume of distribution can be advantageous in achieving desirable dosing regimen, it must be well-directed in order to avoid detrimental effects to other important properties. Strategies to increase volume of distribution include adding lipophilicity and introducing basic functional groups in a way that does not increase metabolic clearance. PMID:25799158

  20. Distribution of ascorbate-2-sulfate and distribution, half-life and turnover rates of (1-/sup 14/C)ascorbic acid in rainbow trout

    SciTech Connect

    Tucker, B.W.; Halver, J.E.

    1984-06-01

    Rainbow trout (250 g) were maintained at 15 degrees C for 3 months on a low ascorbic acid diet, given (1-/sup 14/C)ascorbic acid by gavage, then fed the NAS/NRC requirement 12 times per week. Total urine, fecal water and branchial water were collected daily from five fish placed in metabolism chambers for four successive 5-day periods. Tissue samples were analyzed for /sup 14/C, ascorbic acid (C1) and ascorbate-2-sulfate (C2). Excretion analysis indicated t1/2 . 42 days. After 20 days, the feeding schedule was changed to 3 times per week. Fish fed /sup 14/C were sampled after 1, 2, 3 and 4 months. The half-life in each organ except brain was inversely proportional to the dietary level of ascorbate. Concentrations of C1 and C2 in the various tissues reflected dietary intake of vitamin C. Total C (CT . C1 + C2) levels were maintained in the liver even with the low vitamin C diet. Estimates of body pool for C1 are 27-29 mg/kg. At the higher ascorbate intake CT was 92-114 mg/kg, but decreased by 34% at the lower feeding rate to 51-62 mg/kg. Data indicate that there are two or more body pools that include a store of C2, which is readily interconverted in metabolizing tissues to and from C1. Since air and water stable C2 is antiscorbutic for fish, it is the preferred form of ascorbate for fish feeds.

  1. 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.

  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. 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

  4. Factors influencing prescribing of fall-risk-increasing drugs to the elderly: A qualitative study

    PubMed Central

    Steinsbekk, Aslak; Granas, Anne Gerd

    2015-01-01

    Objective. Explore the situations in which GPs associate drug use with falls among their elderly patients, and the factors influencing the prescribing and cessation of fall-risk-increasing drugs (FRIDs). Design. A qualitative study with 13 GPs who participated in two semi-structured focus groups in Central Norway. Participants were encouraged to share overall thoughts on the use of FRIDs among elderly patients and stories related to prescribing and cessation of FRIDs in their own practice. Results. The main finding was that GPs did not immediately perceive the use of FRIDs to be a prominent factor regarding falls in elderly patients, exceptions being when the patient presented with dizziness, reported a fall, or when prescribing FRIDs for the first time. It was reported as common to renew prescriptions without performing a drug review. Factors influencing the prescribing and cessation of FRIDs were categorized into GPs’ clinical work conditions, uncertainty about outcome of changing prescriptions, patients’ prescribing demands, and lack of patient information. Conclusions. The results from this study indicate that GPs need to be reminded that there is a connection between FRID use and falls among elderly patients of enough clinical relevance to remember to assess the patient's drug list and perform regular drug reviews. PMID:25965505

  5. Decreased dromotropic response to verapamil despite pronounced increased drug concentration in rheumatoid arthritis

    PubMed Central

    Mayo, Patrick R; Skeith, Kenneth; Russell, Anthony S; Jamali, Fakhreddin

    2000-01-01

    Aims Inflammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil. Methods Eight RA patients were age- and sex-matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin-6 (IL-6) and nitrite (NO2−) were measured in predose samples. Results IL-6 and NO2− concentrations were significantly increased in parallel with disease severity. Oral clearance of both S- and R-verapamil was significantly decreased by RA. While the unbound fraction of S- and R-verapamil decreased by 5 and 7-fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S-verapamil. AUC of norverapamil enantiomers was increased 2–3-fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR-interval was significantly reduced by one fold and the effect on the heart rate and blood pressure did not increase. Conclusions RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood flow. A significant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro-inflammatory cytokines and/or NO. PMID:11136300

  6. Improvements in 230Th dating, 230Th and 234U half-life values, and U-Th isotopic measurements by multi-collector inductively coupled plasma mass spectrometry

    NASA Astrophysics Data System (ADS)

    Cheng, Hai; Lawrence Edwards, R.; Shen, Chuan-Chou; Polyak, Victor J.; Asmerom, Yemane; Woodhead, Jon; Hellstrom, John; Wang, Yongjin; Kong, Xinggong; Spötl, Christoph; Wang, Xianfeng; Calvin Alexander, E.

    2013-06-01

    We have developed techniques for measuring 234U and 230Th on Faraday cups with precisions of 1-3 epsilon units (1 ɛ-unit=1 part in 104) using multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). Using a Thermo-Scientific Neptune with desolvation nebulization, we obtained ionization/transmission efficiencies of 1-2% for both U and Th. We set up protocols to correct for tailing, prepared U and Th gravimetric standards, tested a Th mass fractionation correction procedure based on U isotopes, and identified natural calcite samples likely to be in U-Th isotopic secular equilibrium. The measured atomic ratios, 234U/238U=54.970 (±0.019)×10-6 and 230Th/238U=16.916 (±0.018)×10-6, for these calcite samples were identical within errors (quoted 2σ uncertainties calculated combining all sources of error). Half-life values calculated from these ratios are consistent with previous values, but have much smaller errors: 245,620±260 a for 234U and 75,584±110 a for 230Th (quoted 2σ uncertainties calculated using all sources of error). In calculating a 230Th age, some of the systematic errors included in estimating the full error in the half-lives effectively cancel. Removing these uncertainties (uncertainty in the 238U half-life value, uncertainty in our gravimetric uranium and thorium standards, and uncertainty in the absolute isotopic composition of the uranium standard), yields effective uncertainties for the purposes of 230Th dating of ±70 a for the 234U half-life value and ±30 a for the 230Th half-life value. Under ideal circumstances, with our methods, the 2σ uncertainty in age, including uncertainty in half-life values is ±10 a at 10 ka, ±100 a at 130 ka, ±300 a at 200 ka, ±1 ka at 300 ka, ±2 ka at 400 ka, ±6 ka at 500 ka, and ±12 ka at 600 ka. The isotopic composition of a sample with an age <800 ka can clearly be resolved from the isotopic composition of a sample in secular equilibrium, assuming closed system behavior. Using these

  7. 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

  8. 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

  9. Increased Use Of Prescription Drugs Reduces Medical Costs In Medicaid Populations.

    PubMed

    Roebuck, M Christopher; Dougherty, J Samantha; Kaestner, Robert; Miller, Laura M

    2015-09-01

    We used data on more than 1.5 million Medicaid enrollees to examine the impact of changes in prescription drug use on medical costs. For three distinct groups of enrollees, we estimated the effects of aggregate prescription drug use-and, more specifically, the use of medications to treat eight chronic noncommunicable diseases-on total nondrug, inpatient, outpatient, and other Medicaid spending. We found that a 1 percent increase in overall prescription drug use was associated with decreases in total nondrug Medicaid costs by 0.108 percent for blind or disabled adults, 0.167 percent for other adults, and 0.041 percent for children. Reductions in combined inpatient and outpatient spending from increased drug utilization in Medicaid were similar to an estimate for Medicare by the Congressional Budget Office. Moving forward, policy makers evaluating proposed changes that alter medication use among the nearly seventy million Medicaid recipients should consider the net effects on program spending to ensure that scarce federal and state health care dollars are allocated efficiently. PMID:26355062

  10. Drug interactions with selective serotonin reuptake inhibitors, especially with other psychotropics.

    PubMed

    2001-02-01

    (1) Selective serotonin reuptake inhibitors (SSRIs) are involved in many drug interactions with potentially serious clinical consequences. (2) These interactions involve all SSRIs but particularly fluoxetine, which is the best-studied antidepressant in this family. (3) Because of their long elimination half-life (particularly fluoxetine) the risk of interactions persists for several days or even weeks after SSRI withdrawal. (4) Drug interactions with clinical consequences usually involve combinations of an SSRI with other psychotropics, especially monoamine oxidase inhibitor (MAOI) and tricyclic antidepressants, clozapine, lithium, methadone, etc. (5) The clinical consequences of drug interactions with SSRI are either due to overdosing of the drug combined, or to a serotonin syndrome with neuromuscular and vegetative (autonomic) symptoms. (6) Interactions with a number of other drugs have been reported, especially carbamazepine, phenytoin and oral anticoagulants, with a risk of overdose of these drugs. (7) The risk of hyponatraemia linked to SSRIs seems to be increased during concomitant treatment with diuretics. PMID:11503857

  11. 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

  12. Amorphous Solid Dispersions or Prodrugs: Complementary Strategies to Increase Drug Absorption.

    PubMed

    Rumondor, Alfred C F; Dhareshwar, Sundeep S; Kesisoglou, Filippos

    2016-09-01

    Maximizing oral bioavailability of drug candidates represents a challenge in the pharmaceutical industry. In recent years, there has been an increase in the use of amorphous solid dispersions (ASDs) to address this issue, where a growing number of solid dispersion formulations have been introduced to the market. However, an increase in solubility or dissolution rate through ASD does not always result in sufficient improvement of oral absorption because solubility limitations may still exist at high doses. Chemical modification in the form of a prodrug may offer an alternative approach for these cases. Although prodrugs have been primarily used to improve membrane permeability, examples are available in which prodrugs have been used to increase drug solubility beyond what can be achieved via formulation approaches. In this mini review, the role of ASDs and prodrugs as 2 complementary approaches in improving oral bioavailability of drug candidates is discussed. We discuss the fundamental principles of absorption and bioavailability, and review available literature on both solid dispersions and prodrugs, providing a summary of their use and examples of successful applications, and cover some of the biopharmaceutics evaluation aspects for these approaches. PMID:26886316

  13. Increased Risk for ESBL-Producing Bacteria from Co-administration of Loperamide and Antimicrobial Drugs for Travelers’ Diarrhea1

    PubMed Central

    Mero, Sointu; Kirveskari, Juha; Lääveri, Tinja

    2016-01-01

    Antimicrobial drug treatment of travelers’ diarrhea is known to increase the risk for colonization with extended-spectrum β-lactamase-producing Enterobacteriaceae. Among 288 travelers with travelers’ diarrhea, the colonization rate without medications was 21%. For treatment with loperamide only, the rate was 20%; with antimicrobial drugs alone, 40%; and with loperamide and antimicrobial drugs, 71%. PMID:26691898

  14. Increased Risk for ESBL-Producing Bacteria from Co-administration of Loperamide and Antimicrobial Drugs for Travelers' Diarrhea.

    PubMed

    Kantele, Anu; Mero, Sointu; Kirveskari, Juha; Lääveri, Tinja

    2016-01-01

    Antimicrobial drug treatment of travelers' diarrhea is known to increase the risk for colonization with extended-spectrum β-lactamase-producing Enterobacteriaceae. Among 288 travelers with travelers' diarrhea, the colonization rate without medications was 21%. For treatment with loperamide only, the rate was 20%; with antimicrobial drugs alone, 40%; and with loperamide and antimicrobial drugs, 71%. PMID:26691898

  15. [Quantum-pharmacological aspects of cardiovascular drugs studying].

    PubMed

    Zahorodnyĭ, M I; Nebesna, T Iu; Kazakova, O O; Horchakova, N O; Svintsits'kyĭ, A S; Chekman, I S

    2013-01-01

    Quantum pharmacology allows to study the mechanisms of action of cardiovascular drugs, to predict pharmacological activity and identify the most pronounced pharmacodynamic efficacy and therapeutic activity of new compounds. Calculation of quantum-pharmacological parameters for molecules of beta-blockers (propranolol, atenolol, metoprolol, carvedilol) in aqueous media, research its hydrophobic interaction with receptors allow to form a theoretical basis for the development of new generations of more effective and safe medicines for hypertension treatment. Increased hydrophobicity leads to poor solubility of carvedilol in water and high--in the lipids. The clinical pharmacology of the drug is shown by such indicators as the therapeutic dose, half-life and degree of metabolism in the liver. Due to enhanced interaction with adrenergic receptor effective dose of carvedilol is an order of magnitude lower than other beta-blockers, even with the relatively low bioavailability. Reduced bioavailability of carvedilol versus atenolol, metoprolol and propranolol is caused by elevated metabolism during the first pass through the liver, which is also due to the hydrophobicity of the drug. High solubility in lipids appears to extend the half-life of carvedilol. QSAR studies make an important contribution to the study of the properties of chemical compounds and their pharmacological activity. Software, used for computation of studied properties, has a significant role. A large number of descriptors allows a qualitative and quantitative assessment of the molecules of chemical compounds and prediction of their influence on cardiovascular system. PMID:23951907

  16. TOP2 gene disruption reduces drug susceptibility by increasing intracellular ergosterol biosynthesis in Candida albicans.

    PubMed

    Zheng, Hao; Jiang, Yuan-Ying; Wang, Yan; Jia, Xin-Ming; Yan, Tian-Hua; Gao, Ping-Hui; Yan, Lan; Jiang, Ling-Huo; Ji, Hui; Cao, Yong-Bing

    2010-07-01

    In this study the role of the TOP2 gene in fungal drug susceptibility was investigated by disrupting and overexpressing the gene in Candida albicans. MIC determination and a spot assay showed that a top2Delta/Delta null mutant (strain T2bc) was more resistant to the antifungals tested than the wild-type (strain CAI4). Real-time RT-PCR and rhodamine 6G efflux examination showed that TOP2 did not influence the activity of drug efflux pumps. Sterol analysis with GC/high-resolution MS indicated that the intracellular ergosterol composition of the top2Delta/Delta mutant was significantly increased. Subsequently, fluorescence polarization measurements also revealed that Top2-deprived cells displayed a decrease in membrane fluidity, resulting in enhanced passive diffusion of the drugs. Quantitative real-time RT-PCR analysis further confirmed that the ERG11 gene, an essential gene in ergosterol biosynthesis, was upregulated. These results demonstrate a close relationship between the TOP2 gene and drug susceptibility in C. albicans. PMID:20223895

  17. How might we increase success in marine-based drug discovery?

    PubMed

    Desbois, Andrew P

    2014-09-01

    Drug discovery from marine organisms has been underway for > 60 years and there have been notable successes in discovering, developing and introducing clinical agents derived from marine sources. Such examples include: the analgesic ziconotide and the anti cancer compound trabectedin. However, in light of the pressing need for new drugs, particularly those with anti-infective and anticancer properties, there is strong justification for increased exploration of marine organisms as sources of novel compounds. This article considers approaches that might enhance our chances of delivering new medicines from marine-based drug discovery efforts. Consideration is given to the organisms and habitats deserving of more attention and how we might make best use of these marine genetic resources. In particular, the opportunities offered by synthetic biology are highlighted because these methods allow drug discoverers to explore pathways in 'non-culturable' species and turn on natural product biosynthesis genes that are difficult to activate under laboratory conditions (so-called 'silent' gene clusters). PMID:24909595

  18. 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

  19. 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

  20. Increases and decreases in drug use attributed to housing status among street-involved youth in a Canadian setting

    PubMed Central

    2014-01-01

    Background Among a cohort of drug-using street-involved youth, we sought to identify the prevalence of reporting increases and decreases in illicit drug use due to their current housing status and to identify factors associated with reporting these changes. Findings This longitudinal study was based on data collected between June 2008 and May 2012 from a prospective cohort of street-involved youth aged 14–26 in Vancouver, Canada. At semi-annual study follow-up visits, youth were asked if their drug use was affected by their housing status. Using generalized estimating equations, we identified factors associated with perceived increases and decreases in drug use attributed to housing status. Among our sample of 536 participants at baseline, 164 (31%) youth reported increasing their drug use due to their housing situation and 71 (13%) reported decreasing their drug use. In multivariate analysis, factors that were positively associated with perceived increases in drug use attributed to housing status included the following: being homeless, engaging in sex work and drug dealing. Regular employment was negatively associated with increasing drug use due to housing status. Among those who reported decreasing their drug use, only homelessness was significant in bivariate analysis. Conclusion Perceived changes in drug use due to housing status were relatively common in this setting and were associated with being homeless and, among those who increased their drug use, engaging in risky income generation activities. These findings suggest that structural factors, particularly housing and economic opportunities, may be crucial interventions for reducing or limiting drug use among street-involved youth. PMID:24721725

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

    PubMed

    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

  2. The proarrhythmic antihistaminic drug terfenadine increases spontaneous calcium release in human atrial myocytes.

    PubMed

    Hove-Madsen, Leif; Llach, Anna; Molina, Cristina E; Prat-Vidal, Cristina; Farré, Jordi; Roura, Santiago; Cinca, Juan

    2006-12-28

    Spontaneous calcium release from the sarcoplasmic reticulum in cardiac myocytes plays a central role in cardiac arrhythmogenesis. Compounds intended for therapeutical use that interfere with intracellular calcium handling may therefore have an undesired proarrhythmic potential. Here we have used isolated human atrial myocytes to compare the effect of the proarrhythmic antihistaminic drug terfenadine with the non-proarrhythmic antihistaminic drugs fexofenadine and rupatadine on intracellular calcium homeostasis. Perforated patch-clamp technique was used to measure ionic currents and to detect spontaneous calcium release from the sarcoplasmic reticulum. Our results show that the compound terfenadine, with known arrhythmogenic effects, inhibits L-type calcium current (I(Ca)) with an IC(50) of 185 nM when cells are stimulated at 1.0 Hz. The inhibitory effect of 0.3 muM terfenadine increased from 19+/-4% at stimulation frequency of 0.2 Hz to 63+/-6% at 2.0 Hz. Moreover, terfenadine also increased spontaneous calcium release from the sarcoplasmic reticulum. At a concentration of 1 muM, terfenadine significantly increased the spontaneous Na-Ca exchange current (I(NCX)) frequency from 0.48+/-0.25 to 1.93+/-0.67 s(-1). In contrast, fexofenadine and rupatadine did not change I(Ca) or the frequency of spontaneous I(NCX). We conclude that the proarrhythmic antihistaminic drug terfenadine alters intracellular calcium handling in isolated human atrial myocytes. This experimental model may be suitable to screen for potential arrhythmogenic side-effects of compounds intended for therapeutical use. PMID:17078945

  3. 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

  4. Lipid-based drug carriers for prodrugs to enhance drug delivery.

    PubMed

    Zaro, Jennica L

    2015-01-01

    The combination of lipid drug delivery systems with prodrugs offers several advantages including improved pharmacokinetics, increased absorption, and facilitated targeting. Lipidization and use of lipid carriers can increase the pharmacological half-life of the drug, thus improving pharmacokinetics and allowing less frequent dosing. Lipids also offer advantages such as increased absorption through the intestines for oral drug absorption and to the CNS for brain delivery. Furthermore, the use of lipid delivery systems can enhance drug targeting. Endogenous proteins bind lipids in the blood and carry them to the liver to enable targeting of this organ. Drugs with significant side effects in the stomach can be specifically delivered to enterocytes by exploiting lipases for prodrug activation. Finally, lipids can be used to target the lymphatic system, thus bypassing the liver and avoiding first-pass metabolism. Lymphatic targeting is also important for antiviral drugs in the protection of B and T lymphocytes. In this review, both lipid-drug conjugates and lipid-based carriers will be discussed. An overview, including the chemistry and assembly of the systems, as well as examples from the clinic and in development, will be provided. PMID:25269430

  5. Overexpression of Pyruvate Dehydrogenase Kinase 3 Increases Drug Resistance and Early Recurrence in Colon Cancer

    PubMed Central

    Lu, Chun-Wun; Lin, Shau-Chieh; Chien, Chun-Wei; Lin, Shih-Chieh; Lee, Chung-Ta; Lin, Bo-Wen; Lee, Jenq-Chang; Tsai, Shaw-Jenq

    2011-01-01

    The switch of cellular metabolism from mitochondrial respiration to glycolysis is the hallmark of cancer cells and is associated with tumor malignancy. Pyruvate dehydrogenase kinase-1 (PDK1) and PDK3 participate in the metabolic switch of cancer cells; however, the medical significance of PDK1 and PDK3 in cancer progression is not known. Here, we assessed the expression profiles of PDK1 and PDK3 in colorectal cancer. Western blot analysis (n = 74) demonstrated that PDK3 was markedly increased in colon cancer compared to that in adjacent normal tissues, whereas PDK1 was decreased in cancer cells. In addition, PDK3 expression was positively correlated with that of hypoxia inducible factor-1α (HIF-1α) in cancer cells. Further analysis using immunohistochemical staining revealed that PDK3 levels were positively associated with severity of cancer and negatively associated with disease-free survival. In vitro studies using several colon cancer cell lines showed that PDK3 expression was controlled by HIF-1α and contributed to hypoxia-induced increased drug resistance, perhaps explaining why patients with PDK3 overexpression have a greater incidence of treatment failure. Taken together, our findings suggest that PDK3 plays an important role in the metabolic switch and drug resistance of colon cancer and is potentially a novel target for cancer therapy. PMID:21763680

  6. Increased Cerebellar-Default-Mode-Network Connectivity in Drug-Naive Major Depressive Disorder at Rest

    PubMed Central

    Guo, Wenbin; Liu, Feng; Liu, Jianrong; Yu, Miaoyu; Zhang, Zhikun; Liu, Guiying; Xiao, Changqing; Zhao, Jingping

    2015-01-01

    Abstract The default-mode network (DMN) has been implicated in the neurobiology of major depressive disorder (MDD), and the cerebellum is suggested to be involved in high-order cognitive network such as the DMN. However, the specific contribution of the cerebellum to the DMN alterations remains equivocal. This study was conducted to examine the cerebellar-DMN connectivity in drug-naive MDD directly by using the cerebellum Crus I as seeds. Forty-four drug-naive MDD patients and 44 healthy controls participated in the resting-state scan. Functional connectivity (FC) was applied to analyze the images. Significantly increased FCs were observed between the right Crus I and the right inferior frontal cortex (orbital part)/superior temporal pole, bilateral MPFC (orbital part), and left middle temporal gyrus in the patients compared with the controls. There was a significantly positive correlation between the z values of the right Crus I–bilateral MPFC (orbital part) connectivity and the scores of Automatic Thoughts Questionnaire in the patients (r = 0.329, P = 0.029). The findings reveal that depressed patients have increased cerebellar-DMN connectivity with clinical significance, and thus highlight the contribution of the cerebellum to the DMN alterations in neurobiology of MDD. PMID:25738471

  7. 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

  8. Characteristics and effect of antiinflammatory drugs on adriamycin-induced inflammation in the mouse paw.

    PubMed

    Siegel, D M; Giri, S N; Scheinholtz, R M; Schwartz, L W

    1980-06-01

    A subplantar injection of 5--100 micrograms adriamycin in the mouse hind paw produced a biphasic inflammatory response. The first phase peaked at 2 h while the second, more severe phase peaked at four to five days. The magnitude of inflammation was dose related. Administration of [EH]adriamycin revealed that 78% of the drug was lost from the paw within one day. The loss of the remaining drug followed a biphasic decay curve. The first-phase half-life was 1.2 days, and the second-phase half-life was 16.0 days. Vascular permeability, as measured by the leakage of intravenously administered [125I]albumin, was increased between day 4 and day 8. Pathologically, the paw had mild edema and hemorrhage by 4 h after adriamycin injection. The most severe pathological response was seen at 5 days with diffuse inflammation characterized by edema of the dermis, cellular debris, and mononuclear inflammatory cells. By 10 days the inflammatory response was still present but the edema was milder. The antihistamine diphenhydramine, an H1-blocker, inhibited the first phase of inflammation at the highest dose tested but had no effect on the second phase of inflammation. The antihistamine metiamide, an H2-blocker; the antiserotonin drug, p-chlorophenylalanine; and the antiinflammatory drugs, aspirin, hydrocortisone, and ibuprofen failed to antagonize adriamycin-induced inflammation at 2 h or 5 days after adriamycin injection. Indomethacin reduced the inflammation after 5 days but only at toxic dose levels. PMID:6446523

  9. 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

  10. Drugs for increasing oxygen and their potential use in doping: a review.

    PubMed

    Gaudard, Aurelie; Varlet-Marie, Emmanuelle; Bressolle, Francoise; Audran, Michel

    2003-01-01

    Blood oxygenation is a fundamental factor in optimising muscular activity. Enhancement of oxygen delivery to tissues is associated with a substantial improvement in athletic performance, particularly in endurance sports. Progress in medical research has led to the identification of new chemicals for the treatment of severe anaemia. Effective and promising molecules have been created and sometimes used for doping purposes. The aim of this review is to present methods, and drugs, known to be (or that might be) used by athletes to increase oxygen transport in an attempt to improve endurance capacity. These methods and drugs include: (i) blood transfusion; (ii) endogenous stimulation of red blood cell production at altitude, or using hypoxic rooms, erythropoietins (EPOs), EPO gene therapy or EPO mimetics; (iii) allosteric effectors of haemoglobin; and (iv) blood substitutes such as modified haemoglobin solutions and perfluorochemicals. Often, new chemicals are used before safety tests have been completed and athletes are taking great health risks. Such new chemicals have also created the need for new instrumental strategies in doping control laboratories, but not all of these chemicals are detectable. Further progress in analytical research is necessary. PMID:12656640

  11. 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

  12. Syringe Sharing and HIV Incidence Among Injection Drug Users and Increased Access to Sterile Syringes

    PubMed Central

    Small, Will; Buchner, Chris; Zhang, Ruth; Li, Kathy; Montaner, Julio; Wood, Evan

    2010-01-01

    Objectives. We assessed the effects of syringe exchange program (SEP) policy on rates of HIV risk behavior and HIV incidence among injection drug users. Methods. Using a multivariate generalized estimating equation and Cox regression methods, we examined syringe borrowing, syringe lending, and HIV incidence among a prospective cohort of 1228 injection drug users in Vancouver, British Columbia. Results. We observed substantial declines in rates of syringe borrowing (from 20.1% in 1998 to 9.2% in 2003) and syringe lending (from 19.1% in 1998 to 6.8% in 2003) following SEP policy change. These declines coincided with a statistically significant increase in the proportion of participants accessing sterile syringes from nontraditional SEP sources (P < .001). In multivariate analyses, the period following the change in SEP policy was independently associated with a greater than 40% reduction in syringe borrowing (adjusted odds ratio [AOR] = 0.57; 95% confidence interval [CI] = 0.49, 0.65) and lending (AOR = 0.52; 95% CI = 0.45, 0.60), as well as declining HIV incidence (adjusted hazard ratio = 0.13; 95% CI = 0.06, 0.31). Conclusions. Widespread syringe distribution appears to be a more effective SEP policy than do more restrictive SEP policies that limit syringe access. Efforts should be made to ensure that SEP policies and program design serve to maximize rather than hinder syringe access. PMID:20558797

  13. Improvement of biodistribution and therapeutic index via increase of polyethylene glycol on drug-carrying liposomes in an HT-29/luc xenografted mouse model.

    PubMed

    Chow, Tong-Hsien; Lin, Yi-Yu; Hwang, Jeng-Jong; Wang, Hsin-Ell; Tseng, Yun-Long; Wang, Shyh-Jen; Liu, Ren-Shyan; Lin, Wuu-Jyh; Yang, Chung-Shi; Ting, Gann

    2009-06-01

    Liposomes modified with a high concentration of polyethylene glycol (PEG) could significantly prolong the retention time of the carried drug in the circulation, thus improving the drug accumulation in the tumor. In this study, 6 mol% rather than 0.9 mol% PEGylated liposomes (100 nm in diameter) encapsulated with indium-111 were used in a human colorectal carcinoma HT-29/luc tumor-bearing mouse model for comparing the PEGylation effect. Pharmacokinetics, biodistribution, passive-targeted assay, bioluminescence imaging (BLI) and tumor growth measurements were used for the spatial and temporal distribution, tumor localization and therapeutic evaluation of the drug. Pharmacokinetic studies indicated that the terminal half-life (T((1/2))lambdaz) and C(max) of 6 mol% PEG (111)In liposomes were similar to those of 0.9 mol% PEG (111)In liposomes. In the blood, the total body clearance (Cl) of 6 mol% PEG (111)In liposomes was about 1.7-fold lower and the area under the curve (AUC) was 1.7-fold higher than those of 0.9 mol% PEG (111)In liposomes. These results showed that the long-term circulation and localization of 6 mol% PEGylated liposomes was more appropriate for use in the tumor-bearing animal model. In addition, the biodistribution of 6 mol% PEG (111)In liposomes showed significantly lower uptake in the liver, spleen, kidneys, small intestine and bone marrow than those of 0.9 mol% PEG (111)In liposomes. The clearance rate of both drugs from the blood decreased with time, with the maximum at 24 h post intravenous (i.v.) injection. Prominent tumor uptake and the highest tumor/muscle ratios were found at 48 h post injection. Both AUC and relative ratio of the AUCs (RR-AUC) also showed that 6 mol% PEGylated liposomes significantly reduced the uptake of drugs in the reticuloendothelial system (RES), yet enhanced the uptake in the tumor. Gamma scintigraphy at 48 h post injection also demonstrated more distinct tumor uptake with 6 mol% PEG (111)In liposomes as compared to

  14. 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

  15. 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

  16. The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery.

    PubMed Central

    Groothuis, D. R.

    2000-01-01

    Drug delivery to brain tumors has been a controversial subject. Some believe the blood-brain barrier is not important, while others believe it is the major obstacle in treatment and have devised innovative approaches to circumvent it. These approaches can be divided into two categories: those that attempt to increase drug delivery of intravascularly administered drugs by manipulating either the drugs or capillary permeability, and those that attempt to increase drug delivery by local administration. Several strategies have been developed to increase the fraction of intravascular drug reaching the tumor, including intra-arterial administration, barrier disruption, new ways of packaging drugs, and, most recently, inhibiting drug efflux from tumor. When given intravascularly, all drugs have a common drawback: the body acts as a sink, and, even in the best situations, only a small fraction of administered drug actually reaches the tumor. A consequence is that systemic toxicity is usually the dose-limiting factor. When given locally, such as into the cerebrospinal fluid or directly into the tumor, 100% of an administered dose is delivered to the target site. However, local delivery is associated with variable and unpredictable spatial distribution and variation in drug concentration. The major dose-limiting factor of most local delivery methods will be neurotoxicity. The relative advantages and disadvantages of the different methods of circumventing the blood-brain barrier are presented in this review, and special attention is given to convection-enhanced delivery, which has particular promise for the local delivery of large therapeutic agents such as monoclonal antibodies, antisense oligonucleotides, or viral vectors. PMID:11302254

  17. [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

  18. 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.

  19. 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

  20. 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

  1. 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

  2. Sideromimic Modification of Lactivicin Dramatically Increases Potency against Extensively Drug-Resistant Stenotrophomonas maltophilia Clinical Isolates.

    PubMed

    Calvopiña, Karina; Umland, Klaus-Daniel; Rydzik, Anna M; Hinchliffe, Philip; Brem, Jürgen; Spencer, James; Schofield, Christopher J; Avison, Matthew B

    2016-07-01

    Acetamido derivatives of the naturally antibacterial non-β-lactam lactivicin (LTV) have improved activity against their penicillin binding protein targets and reduced hydrolysis by β-lactamases, but penetration into Gram-negative bacteria is still relatively poor. Here we report that modification of the LTV lactone with a catechol-type siderophore increases potency 1,000-fold against Stenotrophomonas maltophilia, a species renowned for its insusceptibility to antimicrobials. The MIC90 of modified lactone compound 17 (LTV17) against a global collection of extensively drug-resistant clinical S. maltophilia isolates was 0.063 μg · ml(-1) Sideromimic modification does not reduce the ability of LTVs to induce production of the L1 and L2 β-lactamases in S. maltophilia and does not reduce the rate at which LTVs are hydrolyzed by L1 or L2. We conclude, therefore, that lactivicin modification with a siderophore known to be preferentially used by S. maltophilia substantially increases penetration via siderophore uptake. LTV17 has the potential to be developed as a novel antimicrobial for treatment of infections by S. maltophilia More generally, our work shows that sideromimic modification in a species-targeted manner might prove useful for the development of narrow-spectrum antimicrobials that have reduced collateral effects. PMID:27139464

  3. Do non-steroidal anti-inflammatory drugs increase colonic permeability?

    PubMed Central

    Jenkins, A P; Trew, D R; Crump, B J; Nukajam, W S; Foley, J A; Menzies, I S; Creamer, B

    1991-01-01

    Urinary excretion of orally administered lactulose and 51 chromium labelled ethylenediamine tetra-acetate (51Cr-EDTA) was measured in 12 healthy adult subjects and in six patients with ileostomies to assess intestinal permeability. In normal subjects, 24 hour urinary recovery of 51Cr-EDTA was significantly greater than that of lactulose (mean (SEM) 2.27 (0.15) v 0.50 (0.08)% oral dose; p less than 0.001), but in ileostomy patients recovery of the two markers was the same. In normal subjects, therefore, the difference between the two markers may arise from bacterial break-down of lactulose but not of 51Cr-EDTA in the distal bowel, urinary excretion of lactulose representing small intestinal permeation and that of 51Cr-EDTA representing both small and large intestinal permeation. The markers were then given simultaneously to nine patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) for rheumatoid arthritis and osteoarthritis. The 24 hour urinary recovery of 51Cr-EDTA in the patients was significantly greater than normal (4.64 (1.20) v 2.27 (0.15)% oral dose; p less than 0.01), but that of lactulose was not significantly affected. Moreover, the increase in 51Cr-EDTA recovery was most noticeable in the later urine collections. Both of these findings suggest that NSAIDs may increase colonic permeability. PMID:1899408

  4. 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

  5. Sub-nanosecond Half-life Measurement of the Yrast I{sup π}=5{sup −} State in the N=78 Nucleus {sup 136}{sub 58}Ce using Fast-timing Coincident Gamma-ray Spectroscopy

    SciTech Connect

    Alharbi, T.; Regan, P.H.; Mărginean, N.; Podolyák, Zs.; Bajoga, A.; Britton, R.; Bucurescu, D.; Deleanu, D.; Filipescu, D.; Ghită, D.; Glodariu, T.; Mihai, C.; Mulholland, K.; Mărginean, R.; Negret, A.; Nita, C.R.; Patel, Z.; Roberts, O.J.; Stroe, L.; Sava, T.; and others

    2014-06-15

    We report on the measurement of the half-life of the yrast I{sup π}=5{sup −} state in the transitional nucleus {sup 136}Ce using a combined HPGe-LaBr3(Ce) scintillator gamma-ray detection array. The measured value for the E1 decay is approximately half a nanosecond, which corresponds to an E1 decay strength of approximately 2×10{sup −6} Wu. This value is in line with single-particle type E1 decays in this mass region and suggests no sign of additional K-hindrance associated with axially symmetric quadrupole deformations observed for lighter cerium isotopes.

  6. 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±0.18nM) and formed nanoparticles with an average diameter (~12nm) above the threshold (~7nm) 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±0.87h vs 0.32±0.14h). Tumor uptake of ABD-hTRAIL 8-48h 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. PMID:26951928

  7. 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

  8. 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

    ..., (76 FR 3825, January 21, 2011), FDA recounted the actions it had already implemented, as well as those... of availability of this report on October 4, 2011 (76 FR 61366), FDA sought public comment on these... HUMAN SERVICES Food and Drug Administration Food and Drug Administration Transparency...

  9. 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.

  10. 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. PMID:27140986

  11. Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda

    PubMed Central

    Smith, Kyle D.; Achan, Beatrice; Hullsiek, Kathy Huppler; McDonald, Tami R.; Okagaki, Laura H.; Alhadab, Ali A.; Akampurira, Andrew; Rhein, Joshua R.; Meya, David B.; Boulware, David R.

    2015-01-01

    Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/μl, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC50 of 4 μg/ml and an MIC90 of 8 μg/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC50 to 8 μg/ml and an MIC90 value of 32 μg/ml, with 31% of isolates with a fluconazole MIC of ≥16 μg/ml. We observed an amphotericin B MIC50 of 0.5 μg/ml and an MIC90 of 1 μg/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC50 of 4 μg/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P = 0.52). PMID:26324276

  12. 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

  13. 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

  14. 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

  15. Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization

    PubMed Central

    Nofsinger, Rebecca; Clas, Sophie-Dorothee; Sanchez, Rosa I.; Walji, Abbas; Manser, Kimberly; Nissley, Becky; Balsells, Jaume; Nair, Amrithraj; Dang, Qun; Bennett, David Jonathan; Hafey, Michael; Wang, Junying; Higgins, John; Templeton, Allen; Coleman, Paul; Grobler, Jay; Smith, Ronald; Wu, Yunhui

    2014-01-01

    Prodrugs are chemistry-enabled drug delivery modifications of active molecules designed to enhance their pharmacokinetic, pharmacodynamic and/or biopharmaceutical properties. Ideally, prodrugs are efficiently converted in vivo, through chemical or enzymatic transformations, to the active parent molecule. The goal of this work is to enhance the colonic absorption of a drug molecule with a short half-life via a prodrug approach to deliver sustained plasma exposure and enable once daily (QD) dosing. The compound has poor absorption in the colon and by the addition of a promoiety to block the ionization of the molecule as well as increase lipophilicity, the relative colonic absorption increased from 9% to 40% in the retrograde dog colonic model. A combination of acceptable solubility and stability in the gastrointestinal tract (GI) as well as permeability was used to select suitable prodrugs to optimize colonic absorption. PMID:24566521

  16. 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

  17. 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

  18. 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

  19. 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

  20. Targeting the chromatin remodeling enzyme BRG1 increases the efficacy of chemotherapy drugs in breast cancer cells.

    PubMed

    Wu, Qiong; Sharma, Soni; Cui, Hang; LeBlanc, Scott E; Zhang, Hong; Muthuswami, Rohini; Nickerson, Jeffrey A; Imbalzano, Anthony N

    2016-05-10

    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

  1. 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.

  2. A sequential algorithm for the non-linear dual-sorption model of percutaneous drug absorption.

    PubMed

    Gumel, A B; Kubota, K; Twizell, E H

    1998-08-15

    A sequential algorithm is developed for the non-linear dual-sorption model developed by Chandrasekaran et al. [1,2] which monitors pharmacokinetic profiles in percutaneous drug absorption. In the experimental study of percutaneous absorption, it is often observed that the lag-time decreases with the increase in the donor concentration when two or more donor concentrations of the same compound are used. The dual-sorption model has sometimes been employed to explain such experimental results. In this paper, it is shown that another feature observed after vehicle removal may also characterize the dual-sorption model. Soon after vehicle removal, the plots of the drug flux versus time become straight lines on a semilogarithmic scale as in the linear model, but the half-life is prolonged thereafter when the dual-sorption model prevails. The initial half-life after vehicle removal with a low donor concentration is longer than that with a higher donor concentration. These features, if observed in experiments, may be used as evidence to confirm that the dual-sorption model gives an explanation to the non-linear kinetic behaviour of a permeant. PMID:9727298

  3. Virtual Clinical Trials, an Essential Step in Increasing the Effectiveness of the Drug Development Process.

    PubMed

    Lehrach, Hans

    2015-01-01

    Every patient is different--his/her genomes, environment, disease history and exposure to drugs. Tumours, in particular, are often heterogeneous in their genetic make-up and their response to drugs, both within and between samples. Classic clinical trials basically ignore this complexity or, as in stratified medicine, attempt to reduce it to an analysis of a small number of still enormously heterogeneous patient groups. Medicine, however, is not the only area in which we are faced with such complex 'n = 1' (every individual case is different) situations. The weather we experience today, characterised by tens of terabytes of measurement data, has never occurred before and will never occur again. Similar to the situation in medicine, we cannot predict the development of today's weather by looking for identical weather conditions in the past, and we cannot, in real life, test drugs for every individual patient in clinical trials with large numbers of biologically identical patient replicas. We can, however, do it with the help of models duplicating the 'n = 1' situation on the computer, an approach which will also have to be used in both patient treatment and prevention as well as drug development in the future if we do not want to continue to make dangerous and expensive mistakes in real life. PMID:26536612

  4. Increasingly accurate dynamic molecular models of G-protein coupled receptor oligomers: Panacea or Pandora's box for novel drug discovery?

    PubMed Central

    Filizola, Marta

    2009-01-01

    For years conventional drug design at G-protein coupled receptors (GPCRs) has mainly focused on the inhibition of a single receptor at a usually well-defined ligand-binding site. The recent discovery of more and more physiologically relevant GPCR dimers/oligomers suggests that selectively targeting these complexes or designing small molecules that inhibit receptor-receptor interactions might provide new opportunities for novel drug discovery. To uncover the fundamental mechanisms and dynamics governing GPCR dimerization/oligomerization, it is crucial to understand the dynamic process of receptor-receptor association, and to identify regions that are suitable for selective drug binding. This minireview highlights current progress in the development of increasingly accurate dynamic molecular models of GPCR oligomers based on structural, biochemical, and biophysical information that has recently appeared in the literature. In view of this new information, there has never been a more exciting time for computational research into GPCRs than at present. Information-driven modern molecular models of GPCR complexes are expected to efficiently guide the rational design of GPCR oligomer-specific drugs, possibly allowing researchers to reach for the high-hanging fruits in GPCR drug discovery, i.e. more potent and selective drugs for efficient therapeutic interventions. PMID:19465029

  5. 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

  6. 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

  7. 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. PMID:27135539

  8. Ergotism in Thailand caused by increased access to antiretroviral drugs: a global warning.

    PubMed

    Avihingsanon, Anchalee; Ramautarsing, Reshmie A; Suwanpimolkul, Gompol; Chetchotisakd, Ploenchan; Bowonwatanuwong, Chureeratana; Jirajariyavej, Supunnee; Kantipong, Patcharee; Tantipong, Hutsaya; Ohata, June Pirapon; Suankratay, Chusana; Ruxrungtham, Kiat; Burger, David M

    2014-01-01

    Ergotism is a toxic condition resulting from overexposure to the ergot compounds produced by various fungi of the genus Claviceps. Traditionally, such exposure was due to ingestion of infected grains, but long-term or excessive use of medications containing ergot derivatives or drug-drug interactions between these medications can result in ergotism. Ergotamine, typically used to treat migraine, has less than 5% bioavailability due to extensive first-pass metabolism by cytochrome P450 3A4 (CYP3A4). Concurrent intake of ergotamine and strong CYP3A4 inhibitors, such as the HIV protease inhibitors (PIs), can lead to clinical ergotism. A total of 13 cases of clinical ergotism in HIV-infected patients has been published since 1997 (most recently reviewed by Frohlich et al). PMID:24531557

  9. Approaches to Increasing Ethical Compliance in China with Drug Trial Standards of Practice.

    PubMed

    Rosenberg, Jacob

    2016-03-29

    Zeng et al.'s Ethics Review highlights some of the challenges associated with clinical research in China. They found that only a minority of published clinical trials of anti-dementia drugs reported that they fulfilled the basic ethical principles as outlined in the Declaration of Helsinki. With recent reports of scientific misconduct from China, there is an urgent need to find approaches to compel researchers to adhere to ethical research practices. This problem does not call for a simple solution, but if forces are joined with governmental regulations, education in ethics issues for medical researchers, and strong reinforcement by Chinese journal editors not to publish studies with these flaws, then research ethics and publication standards will probably improve. Other solutions to foster ethical practice of drug trials are discussed including Chinese initiatives directed at managing conflict of interest from the pharmaceutical industry and educating clinical researchers. PMID:27031489

  10. 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. PMID:26463060

  11. Human immunodeficiency virus among people who inject drugs: is risk increasing in Europe?

    PubMed

    Hedrich, D; Kalamara, E; Sfetcu, O; Pharris, A; Noor, A; Wiessing, L; Hope, V; Van de Laar, M

    2013-01-01

    In most European Union (EU)/European Economic Area (EEA) countries, between 2010 and 2012, reports of new human immunodeficiency virus (HIV) diagnoses among people who inject drugs have been stable or declining. HIV outbreaks in Greece and Romania, first reported in 2011, continue and economic conditions hinder provision of effective response coverage. When measured against some established thresholds, prevention coverage remains inadequate in at least one-third of EU/EEA countries. Urgent consideration to scale up prevention efforts is merited. PMID:24308980

  12. Increased dissolution rate and oral bioavailability of hydrophobic drug glyburide tablets produced using supercritical CO₂ silica dispersion technology.

    PubMed

    Guan, Jibin; Han, Jihong; Zhang, Dong; Chu, Chunxia; Liu, Hongzhuo; Sun, Jin; He, Zhonggui; Zhang, Tianhong

    2014-04-01

    The aim of this study was to design a silica-supported solid dispersion of a water-insoluble drug, glyburide, to increase its dissolution rate and oral absorption using supercritical fluid (SCF) technology. DSC and PXRD results indicated that the encapsulated drug in the optimal solid dispersion was in an amorphous state and the product was stable for 6 months. Glyburide was adsorbed onto the porous silica, as confirmed by the SEM images and BET analysis. Furthermore, FT-IR spectroscopy confirmed that there was no change in the chemical structure of glyburide after the application of SCF. The glyburide silica-based dispersion could also be compressed into tablet form. In vitro drug release analysis of the silica solid dispersion tablets demonstrated faster release of glyburide compared with the commercial micronized tablet. In an in vivo test, the AUC of the tablets composed of the new glyburide silica-based solid dispersion was 2.01 times greater than that of the commercial micronized glyburide tablets. In conclusion, SCF technology presents a promising approach to prepare silica-based solid dispersions of hydrophobic drugs because of its ability to increase their release and oral bioavailability. PMID:24184803

  13. Increasing the Number of Adverse Drug Reactions Reporting: the Role of Clinical Pharmacy Residents

    PubMed Central

    Baniasadi, Shadi; Habibi, Maryam; Haghgoo, Roodabeh; Karimi Gamishan, Masoumeh; Dabaghzadeh, Fatemeh; Farasatinasab, Maryam; Farsaei, Shadi; Gharekhani, Afshin; Kafi, Hamidreza; Karimzadeh, Iman; Kharazmkia, Ali; Najmeddin, Farhad; Nikvarz, Naemeh; Oghazian, Mohammad Bagher; Rezaee, Haleh; Sadeghi, Kourosh; Tafazzoli, Ali; Shahsavari, Nahid; Fahimi, Fanak

    2014-01-01

    Detection of adverse drug reactions (ADRs) in hospitals provides an important measure of the burden of drug related morbidity on the healthcare system. Spontaneous reporting of ADRs is scare and several obstacles to such reporting have been identified formerly. This study aimed to determine the role of clinical pharmacy residents in ADR reporting within a hospital setting. Clinical pharmacy residents were trained to report all suspected ADRs through ADR-reporting yellow cards. The incidence, pattern, seriousness, and preventability of the reported ADRs were analyzed. During the period of 12 months, for 8559 patients, 202 ADR reports were received. The most frequently reported reactions were due to anti-infective agents (38.38%). Rifampin accounted for the highest number of the reported ADRs among anti-infective agents. The gastro-intestinal system was the most frequently affected system (21.56%) of all reactions. Fifty four of the ADRs were reported as serious reactions. Eighteen of the ADRs were classified as preventable. Clinical pharmacy residents' involvement in the ADR reporting program could improve the ADR reporting system. PMID:24734083

  14. Increased risk for hepatitis C associated with solvent use among Canadian Aboriginal injection drug users

    PubMed Central

    2010-01-01

    Background Solvent abuse is a particularly serious issue affecting Aboriginal people. Here we examine the association between solvent use and socio-demographic variables, drug-related risk factors, and pathogen prevalence in Aboriginal injection drug users (IDU) in Manitoba, Canada. Methods Data originated from a cross-sectional survey of IDU from December 2003 to September 2004. Associations between solvent use and variables of interest were assessed by multiple logistic regression. Results A total of 266 Aboriginal IDU were included in the analysis of which 44 self-reported recent solvent use. Hepatitis C infection was 81% in solvent-users, compared to 55% in those reporting no solvent use. In multivariable models, solvent-users were younger and more likely to be infected with hepatitis C (AOR: 3.5; 95%CI: 1.3,14.7), to have shared needles in the last six months (AOR: 2.6; 95%CI:1.0,6.8), and to have injected talwin & Ritalin (AOR: 10.0; 95%CI: 3.8,26.3). Interpretation High hepatitis C prevalence, even after controlling for risky injection practices, suggests that solvent users may form closed networks of higher risk even amongst an already high-risk IDU population. Understanding the social-epidemiological context of initiation and maintenance of solvent use is necessary to address the inherent inequalities encountered by this subpopulation of substance users, and may inform prevention strategies for other marginalized populations. PMID:20642835

  15. 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. PMID:26010239

  16. 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

  17. Incorporating Stage-Specific Drug Action into Pharmacological Modeling of Antimalarial Drug Treatment.

    PubMed

    Hodel, Eva Maria; Kay, Katherine; Hastings, Ian M

    2016-05-01

    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 10(4)) 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

  18. Antipsychotic drugs increase N-acetylaspartate and N-acetylaspartylglutamate in SH-SY5Y human neuroblastoma cells.

    PubMed

    Arun, Peethambaran; Madhavarao, Chikkathur N; Moffett, John R; Namboodiri, Aryan M A

    2008-08-01

    N-Acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) are related neuronal metabolites associated with the diagnosis and treatment of schizophrenia. NAA is a valuable marker of neuronal viability in magnetic resonance spectroscopy, a technique which has consistently shown NAA levels to be modestly decreased in the brains of schizophrenia patients. However, there are conflicting reports on the changes in brain NAA levels after treatment with antipsychotic drugs, which exert their therapeutic effects in part by blocking dopamine D(2) receptors. NAAG is reported to be an agonist of the metabotropic glutamate 2/3 receptor, which is linked to neurotransmitter release modulation, including glutamate release. Alterations in NAAG metabolism have been implicated in the development of schizophrenia possibly via dysregulation of glutamate neurotransmission. In the present study we have used high performance liquid chromatography to determine the effects of the antipsychotic drugs haloperidol and clozapine on NAA and NAAG levels in SH-SY5Y human neuroblastoma cells, a model system used to test the responses of dopaminergic neurons in vitro. The results indicate that the antipsychotic drugs haloperidol and clozapine increase both NAA and NAAG levels in SH-SY5Y cells in a dose and time dependant manner, providing evidence that NAA and NAAG metabolism in neurons is responsive to antipsychotic drug treatment. PMID:18631215

  19. 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

  20. Localized Increase of Tissue Oxygen Tension by Magnetic Targeted Drug Delivery

    PubMed Central

    Liong, Celine; Ortiz, Daniel; Ao-ieong, Eilleen; Navati, Mahantesh S.; Friedman, Joel M.; Cabrales, Pedro

    2014-01-01

    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-coaded PMNPs (L35-PMNPs) were intravenously infused (10 mg/kg) to hamster instrumented with the dorsal window chamber model. 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 L35-PMNPs administration with and without magnetic field. The tissue PO2 untreated control animals was 25.2 mmHg. L35-PMNP 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-PMNP with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamics 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 increase O2 in

  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. Effect of non-steroidal anti-inflammatory drugs on the increasing the incidence of colonic anastomosis in rats

    PubMed Central

    Ji, Chengdong; Xiong, Yuanchang; Pan, Xin; Guo, Xuan; Li, Zhen; Qian, Shuwen; Xu, Chang; Yu, De-Hua; Liao, Wan-Qing

    2015-01-01

    Background: Anastomotic leakage is one of serious complications of colorectal surgery. Research is inconsistent about whether non-steroidal anti-inflammatory drugs influence the healing of colorectal anastomoses and increase the incidence of anastomotic leakage. Objective: To study the influence of NSAIDs on the healing of rat colonic anastomoses. Design: This was an animal randomized-control trial. This study was approved by the ethical committee of Yangpu Hospital, Tongji University. Intervention: 90 healthy Sprague-Dawley rats were randomly divided into 6 groups of 15 rats/group. Trail was performed in C (cotrol group) with no drugs, group M with morphine for analgesia, group F with flurbiprofen axeil, group L with lornoxicam, and group P with parecoxib sodium. Main outcome measures: The main outcomes measures were serological indexes including vascular endothelial growth factor, prostaglandin E2, hydroxyproline, and C reactive protein; histological specimens from the anastomotic stoma tissue including the collagen proportion, and hydroxyproline, cycloxygenase-2, and vascular endothelial growth factor content; physical indicators, including stoma fracture pressure, fracture strength and anastomotic leakage. Results: No significant difference was observed among the indices of each group (P > 0.05). A significant difference occurred after operation (P < 0.05), with the data for groups K and M being dramatically higher than those for group F. Limitation: The study was nonblinded. Conclusion: The postoperative usages of non-steroidal anti-inflammatory drugs can decrease the strength of anastomotic tissue, and increase the incidence of anastomotic leakage. PMID:26261490

  3. Kinetic models for the release of the anticancer drug doxorubicin from biodegradable polylactide/metal oxide-based hybrids.

    PubMed

    Mhlanga, Nikiwe; Ray, Suprakas Sinha

    2015-01-01

    For decades, studies on drug-release kinetics have been an important topic in the field of drug delivery because they provide important insights into the mechanism of drug release from carriers. In this work, polylactide (PLA), doxorubicin (DOX), and metal oxide (MO) (titanium dioxide, magnetic iron oxide, and zinc oxide) spheres were synthesised using the solvent-evaporation technique and were tested for sustained drug release. The efficacy of a dosage system is determined by its ability to deliver the drug at a sustained rate, afford an increased plasma half-life, a minimum exposure of toxic drugs to healthy cells and a high drug pay load. Mathematical models were used to elucidate the release mechanism of the drug from the spheres. The release fitted a zero-order model with a correlation coefficient in the range of 0.9878-0.9891 and the release mechanism followed an anomalous release, meaning drug release was afforded through both diffusion and the dissolution of PLA. Therefore, PLA/DOX/MO released the same amount of drug per unit time. Consequently, the potential for PLA use as a carrier was ascertained. PMID:25450549

  4. 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

  5. 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.

  6. Cytochrome P450s in the development of target-based anticancer drugs.

    PubMed

    Purnapatre, Kedar; Khattar, Sunil K; Saini, Kulvinder Singh

    2008-01-18

    Enzymes of the cytochrome P450 (CYP) superfamily are the major determinants of half-life and execute pharmacological effects of many therapeutic drugs. In new drug discovery research, recombinant (human) CYPs are also used for identifying active or inactive metabolites that could lead to increased potency or toxicity of a molecule. In addition, CYP inhibition by anticancer drugs might lead to adverse drug reactions, multiple-drug resistance, and drug-drug interactions. During the discovery and pre-clinical evaluation of a New Chemical Entity (NCE), large amounts of purified recombinant CYPs are required for studying metabolism and pharmacokinetic parameters. Therefore, present research efforts are focused to over-express these human CYPs in bacteria, yeast, insect and mammalian cells, followed by their purification on an industrial scale to facilitate identification of novel anticancer drugs. This review summarizes the merits and limitations of these expression systems for an optimized production of individual CYP isoforms, and their usefulness in the discovery and development of target-based, safe and efficacious NCEs for the treatment of cancer. PMID:18053638

  7. Actovegin, a non-prohibited drug increases oxidative capacity in human skeletal muscle.

    PubMed

    Søndergård, Stine D; Dela, Flemming; Helge, Jørn W; Larsen, Steen

    2016-10-01

    Actovegin, a deproteinized haemodialysate of calf blood, is suggested to have ergogenic properties, but this potential effect has never been investigated in human skeletal muscle. To investigate this purported ergogenic effect, we measured the mitochondrial respiratory capacity in permeabilized human skeletal muscle fibres acutely exposed to Actovegin in a low and in a high dose. We found that Actovegin, in the presence of complex I-linked substrates increased the oxidative phosphorylation (OXPHOS) capacity significantly in a concentration-dependent manner (19 ± 3, 31 ± 4 and 45 ± 4 pmol/mg/s). Maximal OXPHOS capacity with complex I and II-linked substrate was increased when the fibres were exposed to the high dose of Actovegin (62 ± 6 and 77 ± 6 pmol/mg/s) (p < .05). The respiratory capacity of the electron transfer system as well as Vmax and Km were also increased in a concentration-dependent manner after Actovegin exposure (70 ± 6, 79 ± 6 and 88 ± 7 pmol/mg/s; 13 ± 2, 25 ± 3 and 37 ± 4 pmol/mg/s; 0.08 ± 0.02, 0.21 ± 0.03 and 0.36 ± 0.03 mM, respectively) (p < .05). In summary, we report for the first time that Actovegin has a marked effect on mitochondrial oxidative function in human skeletal muscle. Mitochondrial adaptations like this are also seen after a training program in human subjects. Whether this improvement translates into an ergogenic effect in athletes and thus reiterates the need to include Actovegin on the World Anti-Doping Agency's active list remains to be investigated. PMID:26744809

  8. Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons.

    PubMed

    Singer, Bryan F; Bubula, Nancy; Li, Dongdong; Przybycien-Szymanska, Magdalena M; Bindokas, Vytautas P; Vezina, Paul

    2016-07-01

    Repeated exposure to amphetamine leads to both associative conditioning and nonassociative sensitization. Here we assessed the contribution of neuronal ensembles in the nucleus accumbens (NAcc) to these behaviors. Animals exposed to amphetamine IP or in the ventral tegmental area (VTA) showed a sensitized locomotor response when challenged with amphetamine weeks later. Both exposure routes also increased ΔFosB levels in the NAcc. Further characterization of these ΔFosB+ neurons, however, revealed that amphetamine had no effect on dendritic spine density or size, indicating that these neurons do not undergo changes in dendritic spine morphology that accompany the expression of nonassociative sensitization. Additional experiments determined how neurons in the NAcc contribute to the expression of associative conditioning. A discrimination learning procedure was used to expose rats to IP or VTA amphetamine either Paired or Unpaired with an open field. As expected, compared with Controls, Paired rats administered IP amphetamine subsequently showed a conditioned locomotor response when challenged with saline in the open field, an effect accompanied by an increase in c-Fos+ neurons in the medial NAcc. Further characterization of these c-Fos+ cells revealed that Paired rats showed an increase in the density of dendritic spines and the frequency of medium-sized spines in the NAcc. In contrast, Paired rats previously exposed to VTA amphetamine showed neither conditioned locomotion nor conditioned c-Fos+ expression. Together, these results suggest a role for c-Fos+ neurons in the medial NAcc and rapid changes in the morphology of their dendritic spines in the expression of conditioning evoked by amphetamine-paired contextual stimuli. PMID:26979294

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. The influence of neighborhood characteristics on the relationship between discrimination and increased drug-using social ties among illicit drug users

    PubMed Central

    Crawford, Natalie D.; Borrell, Luisa N.; Galea, Sandro; Ford, Chandra; Latkin, Carl; Fuller, Crystal M.

    2013-01-01

    Objective Social discrimination may isolate drug users into higher risk relationships, particularly in disadvantaged neighborhood environments where drug trade occurs. Design We used negative binomial regression accounting for clustering of individuals within their recruitment neighborhood to investigate the relationship between high-risk drug ties with various forms of social discrimination, neighborhood minority composition, poverty and education. Results Results show that experiencing discrimination due to drug use is significantly associated with more drug ties in neighborhoods with fewer blacks. Conclusion Future social network and discrimination research should assess the role of neighborhood social cohesion. PMID:23054418

  16. 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

  17. CHEMOTHERAPY, WITHIN-HOST ECOLOGY AND THE FITNESS OF DRUG-RESISTANT MALARIA PARASITES

    PubMed Central

    Huijben, Silvie; Nelson, William A.; Wargo, Andrew R.; Sim, Derek G.; Drew, Damien R.; Read, Andrew F.

    2011-01-01

    A major determinant of the rate at which drug-resistant malaria parasites spread through a population is the ecology of resistant and sensitive parasites sharing the same host. Drug treatment can significantly alter this ecology by removing the drug-sensitive parasites, leading to competitive release of resistant parasites. Here, we test the hypothesis that the spread of resistance can be slowed by reducing drug treatment and hence restricting competitive release. Using the rodent malaria model Plasmodium chabaudi, we found that low-dose chemotherapy did reduce competitive release. A higher drug dose regimen exerted stronger positive selection on resistant parasites for no detectable clinical gain. We estimated instantaneous selection coefficients throughout the course of replicate infections to analyze the temporal pattern of the strength and direction of within-host selection. The strength of selection on resistance varied through the course of infections, even in untreated infections, but increased immediately following drug treatment, particularly in the high-dose groups. Resistance remained under positive selection for much longer than expected from the half life of the drug. Although there are many differences between mice and people, our data do raise the question whether the aggressive treatment regimens aimed at complete parasite clearance are the best resistance-management strategies for humans. PMID:20584075

  18. Double Methotrexate-Modified Neuropeptide Y Analogues Express Increased Toxicity and Overcome Drug Resistance in Breast Cancer Cells.

    PubMed

    Böhme, David; Krieghoff, Jan; Beck-Sickinger, Annette G

    2016-04-14

    Bioconjugates containing the neuropeptide Y (NPY) analogue [F(7),P(34)]-NPY as targeting moiety are able to deliver toxic agents specifically to breast cancer cells that overexpress the human Y1-receptor (hY1R). To increase their activity, multiple toxophores can be attached to one peptide. Herein, synthesis and characterization of [F(7),P(34)]-NPY conjugates containing two methotrexate (MTX) molecules are presented. First, carboxytetramethylrhodamine was linked to [F(7),P(34)]-NPY by amide or enzymatic linkage. The conjugate containing the enzymatic cleavage site showed high extracellular stability and fast intracellular release. Then, MTX was introduced at positions four and 22 of [F(7),P(34)]-NPY, connected by enzymatic or amide linkage. The toxicity of the analogues on breast cancer cells was hY1R-mediated and dependent on the used linkage and amount of toxophores. Furthermore, conjugates revealed higher potency than MTX on MTX-resistant cells. These results emphasize that peptide-drug conjugates can overcome drug resistance and that the attachment of multiple cleavable toxophores enhances the efficiency of this smart delivery system. PMID:26985967

  19. 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

  20. Changes in Expression of Virulence Mechanisms in Three Related Salmonella Typhimurium Mutants with Increasing Multi-Drug Resistance Properties, as Determined by Microarray Analysis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Salmonella Typhimurium is a common cause of Salmonellosis and has been associated with multi-drug resistance. Previously, the wild-type strain (Salmonella Typhimurium ATCC 14028) was exposed to increasing concentrations of nalidixic acid to derive naturally occurring drug resistant isolates. Three d...

  1. Increased density of neurons containing NADPH diaphorase and nitric oxide synthase in the cerebral cortex of patients with HIV-1 infection and drug abuse.

    PubMed

    Kuljis, Rodrigo O; Shapshak, Paul; Alcabes, Philip; Rodríguez de la Vega, Pura; Fujimura, Robert; Petito, Carol K

    2002-01-01

    To determine whether nitrogen monoxide (nitric oxide; NO) synthase (NOS) and NADPH diaphorase (NDP) co-containing cerebrocortical neurons (NOSN) neurons are affected in patients infected with human immunodeficiency virus type 1 (HIV-1) with and without associated intake of drugs of abuse, we examined the temporal neocortex of 24 individuals: 12 HIV-1 positive (including 3 drug users, 9 non-drug users) and 12 HIV-1 negative (including 6 drug users, and 6 non-drug users). Histochemical labeling for NDP-an enzymatic domain co-expressed in the NOS enzyme-was employed to visualize NOSN. Drug abuse and HIV-1 infection cause independently an increase in NOSN density, but combined they result in up to a 38-fold increase in NOSN density, suggesting that the combination of these factors induces NOS expression powerfully in neurons that normally do not synthesize NDP/NOS. This is associated with an increase in the proportion of NOSN displaying dystrophic changes, indicating that NOSN undergo massive degeneration in association with NOS synthesis induction. The increase in density of NOSN in HIV-1 infected drug abusers may be among the important sources of NO mediating cerebrocortical dysfunction, and the degeneration of NOS-containing local circuit neurons in patients with HIV-1 infection or drug abuse may underlie in part their neuropsychiatric manifestations. PMID:16873197

  2. 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

  3. 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

  4. Clotrimazole, an antifungal drug possessing diverse actions, increases the vulnerability to cadmium in lymphocytes dissociated from rat thymus.

    PubMed

    Oyama, Tomohiro M; Oyama, Toshihisa B; Oyama, Keisuke; Matsui, Hiroko; Horimoto, Kanna; Nishimura, Yumiko; Oyama, Yasuo

    2006-12-01

    Since clotrimazole, known as an antifungal drug, exerts diverse actions on cellular functions, it is expected that clotrimazole can be used for other purposes. This antifungal drug protects the cells overloaded with Ca(2+) by A23187, a calcium ionophore. Therefore, the agent may prevent the cells from death induced by heavy metals such as CdCl(2), PbCl(2), or HgCl(2) that are respectively proposed to increase intracellular Ca(2+) concentration. To test this possibility, we have examined the effect of clotrimazole on the cells simultaneously treated with CdCl(2), PbCl(2), or HgCl(2) using rat thymocytes and a flow cytometer with fluorescent probes. The simultaneous application of clotrimazole and CdCl(2) significantly decreased cell viability, even though the concentrations of both were ineffective at affecting the viability. The significant decrease in cell viability was not due to the inhibition of Ca(2+)-ATPase and Ca(2+)-dependent K(+) channels that were induced by clotrimazole. The simultaneous application increased the population of cells with phosphatidylserine exposed on membrane surface, indicating the change in asymmetrical distribution of membrane phospholipids. Furthermore, the cytotoxicity induced by the combination of clotrimazole and CdCl(2) under nominally Ca(2+)-free condition was more profound than that under normal Ca(2+) condition. Therefore, the membrane may be a target for the cytotoxic action of clotrimazole and CdCl(2) that were simultaneously applied. It is also the case for PbCl(2), but not the case for HgCl(2). It is concluded that clotrimazole can modulate the cytotoxicity of some heavy metals. PMID:17055140

  5. 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.

  6. Sulfation of Lower Chlorinated Polychlorinated Biphenyls Increases Their Affinity for the Major Drug-Binding Sites of Human Serum Albumin.

    PubMed

    Rodriguez, Eric A; Li, Xueshu; Lehmler, Hans-Joachim; Robertson, Larry W; Duffel, Michael W

    2016-05-17

    The disposition of toxicants is often affected by their binding to serum proteins, of which the most abundant in humans is serum albumin (HSA). There is increasing interest in the toxicities of environmentally persistent polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms (LC-PCBs) due to their presence in both indoor and outdoor air. PCB sulfates derived from metabolic hydroxylation and sulfation of LC-PCBs have been implicated in endocrine disruption due to high affinity-binding to the thyroxine-carrying protein, transthyretin. Interactions of these sulfated metabolites of LC-PCBs with HSA, however, have not been previously explored. We have now determined the relative HSA-binding affinities for a group of LC-PCBs and their hydroxylated and sulfated derivatives by selective displacement of the fluorescent probes 5-dimethylamino-1-naphthalenesulfonamide and dansyl-l-proline from the two major drug-binding sites on HSA (previously designated as Site I and Site II). Values for half-maximal displacement of the probes indicated that the relative binding affinities were generally PCB sulfate ≥ OH-PCB > PCB, although this affinity was site- and congener-selective. Moreover, specificity for Site II increased as the numbers of chlorine atoms increased. Thus, hydroxylation and sulfation of LC-PCBs result in selective interactions with HSA which may affect their overall retention and toxicity. PMID:27116425

  7. Behavioral stereotypies induced by "binge' cocaine administration are independent of drug-induced increases in corticosterone levels.

    PubMed

    Spangler, R; Zhou, Y; Schlussman, S D; Ho, A; Kreek, M J

    1997-07-01

    Cocaine administration causes dramatic stereotypic behavior and elevation of circulating corticosterone levels in rodents. The present study tested the possible role of increased corticosterone in mediating stereotypic behavior caused by "binge' pattern cocaine administration. Animals were administered saline or cocaine intraperitoneally for 3 days, with or without pretreatment with a D1 (SCH 23390, 2 mg/kg) or D2 (sulpiride, 50 mg/kg) dopamine receptor antagonist. Three days of cocaine "binges' significantly increased corticosterone levels in vehicle pretreated rats (P < 0.01). Both SCH 23390 and sulpiride pretreatment daily significantly attenuated this increase (P < 0.01). Cocaine administration caused stereotypic behaviors in vehicle pretreatment rats (P < 0.01). These behavioral responses were blocked by the D1 dopamine receptor antagonist SCH 23390, but not by the D2 antagonist sulpiride. These findings reaffirm the dominant role of the D1 receptor in mediating behavioral stereotypy caused by elevations of extracellular dopamine in the synaptic cleft. The fact that the dose of sulpiride used in these studies prevented the elevation of plasma corticosterone caused by cocaine, without blocking the stereotypy caused by cocaine, indicates that this stereotypic behavior does not require drug-induced elevation in circulating levels of corticosterone. PMID:9134155

  8. Induction of microsomal drug metabolism in man and in the rat by exposure to petroleum.

    PubMed Central

    Harman, A W; Frewin, D B; Priestly, B G

    1981-01-01

    To determine the effect of petroleum exposure on the activity of hepatic mixed function oxidase enzymes, salivary elimination kinetics of antipyrine were determined in 19 petrol station attendants and compared with 19 controls. Antipyrine half life in petrol station attendants was shorter than in controls. Microsomal preparations (10 000 x g supernatants) were prepared from six male Porton rats exposed to petrol vapour (5 ppm at an air flow rate of 41/min for eight hours a day for three weeks) and six control rats maintained under the same conditions without exposure to petrol vapour. The rates of oxidative metabolism of antipyrine, aminopyrine, ethylmorphine, aniline, and benzo(a)pyrene were all increased by more than 45% in the petrol-exposed rats. The results indicate that petrol vapour is a moderately potent inducer of mixed function oxidase activity in rats, and that occupational exposure to petroleum may result in enhanced microsomal drug metabolism. PMID:7470408

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions.

    PubMed

    Kosoglou, Teddy; Statkevich, Paul; Johnson-Levonas, Amy O; Paolini, John F; Bergman, Arthur J; Alton, Kevin B

    2005-01-01

    Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of 'parent' ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5'-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral

  15. Roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of PEO-b-PCL with increasing PCL content for two hydrophobic Cucurbitacin drugs.

    PubMed

    Patel, Sarthak K; Lavasanifar, Afsaneh; Choi, Phillip

    2009-09-14

    Molecular dynamics (MD) simulation was used to study the roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) with increasing PCL content for two water insoluble anticancer drugs: Cucurbitacin B (CuB) and Cucurbitacin I (CuI). In particular, random binary mixture models containing 10-12 wt % drug and remaining PEO-b-PCL with three different PCL/PEO (w/w) ratios (0.5, 1, and 2) were used to calculate their Flory-Huggins interaction parameters (chi). The MD simulation results show that, for both CuB and CuI, the computed chi decreases (i.e., affinity increases) with increasing PCL/PEO ratio. Such results are consistent with our experimental observation that increasing the PCL/PEO (w/w) ratio from 1 to 4.8 significantly increases the drug loading capacity of micelles formed by PEO-b-PCL for both drugs. Analysis of the energy data shows that increasing affinity (loading) at higher PCL/PEO ratio is attributed to the increase in favorable polar interactions and to the formation of additional hydrogen bonds (H-bonds) between the drugs and the PCL block rather than to the increase in the hydrophobic characteristics of the diblock copolymer as one would normally expect. In fact, the nonpolar intermolecular interactions became more unfavorable at higher PCL/PEO ratio. Analysis of the radial distribution functions of the model mixtures indicates that at high PCL/PEO ratio, multiple H-bond sites on the PCL block interacted with single H-bond sites on the drug molecules. However, at low PCL/PEO ratio, only single H-bonds formed between various H-bond sites on the drug molecules and those of the PCL and PEO blocks. It seems that formation of H-bonds between multiple H-bond sites on the PCL block and single H-bond sites on the drug molecules is responsible for inducing drug/PEO-b-PCL affinity. The finding also explains the experimental observation that release rates

  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. 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

  20. miR-335 Targets SIAH2 and Confers Sensitivity to Anti-Cancer Drugs by Increasing the Expression of HDAC3

    PubMed Central

    Kim, Youngmi; Kim, Hyuna; Park, Deokbum; Jeoung, Dooil

    2015-01-01

    We previously reported the role of histone deacetylase 3 (HDAC3) in response to anti-cancer drugs. The decreased expression of HDAC3 in anti-cancer drug-resistant cancer cell line is responsible for the resistance to anti-cancer drugs. In this study, we investigated molecular mechanisms associated with regulation of HDAC3 expression. MG132, an inhibitor of proteasomal degradation, induced the expression of HDAC3 in various anti-cancer drug-resistant cancer cell lines. Ubiquitination of HDAC3 was observed in various anti-cancer drug-resistant cancer cell lines. HDAC3 showed an interaction with SIAH2, an ubiquitin E3 ligase, that has increased expression in various anti-cancer drug-resistant cancer cell lines. miRNA array analysis showed the decreased expression of miR-335 in these cells. Targetscan analysis predicted the binding of miR-335 to the 3′-UTR of SIAH2. miR-335-mediated increased sensitivity to anti-cancer drugs was associated with its effect on HDAC3 and SIAH2 expression. miR-335 exerted apoptotic effects and inhibited ubiquitination of HDAC3 in anti-cancer drug-resistant cancer cell lines. miR-335 negatively regulated the invasion, migration, and growth rate of cancer cells. The mouse xenograft model showed that miR-335 negatively regulated the tumorigenic potential of cancer cells. The down-regulation of SIAH2 conferred sensitivity to anti-cancer drugs. The results of the study indicated that the miR-335/SIAH2/HDAC3 axis regulates the response to anti-cancer drugs. PMID:25997740

  1. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

    PubMed

    Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

    2015-04-01

    Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed. PMID:25691367

  2. Non-steroidal anti-inflammatory drugs increase insulin release from beta cells by inhibiting ATP-sensitive potassium channels

    PubMed Central

    Li, J; Zhang, N; Ye, B; Ju, W; Orser, B; Fox, J E M; Wheeler, M B; Wang, Q; Lu, W-Y

    2007-01-01

    Background and purpose: Some non-steroidal anti-inflammatory drugs (NSAIDs) incidentally induce hypoglycemia, which is often seen in diabetic patients receiving sulphonylureas. NSAIDs influence various ion channel activities, thus they may cause hypoglycemia by affecting ion channel functions in insulin secreting beta cells. This study investigated the effects of the NSAID meclofenamic acid (MFA) on the electrical excitability and the secretion of insulin from pancreatic beta cells. Experimental approach: Using patch clamp techniques and insulin secretion assays, the effects of MFA on the membrane potential and transmembrane current of INS-1 cells, and insulin secretion were studied. Key results: Under perforated patch recordings, MFA induced a rapid depolarization in INS-1 cells bathed in low (2.8mM), but not high (28mM) glucose solutions. MFA, as well as acetylsalicylic acid (ASA) and flufenamic acid (FFA), excited the cells by inhibiting ATP-sensitive potassium channels (KATP). In whole cell recordings, KATP conductance consistently appeared when intracellular ATP was diluted. Intracellular glibenclamide prevented the development of KATP activity, whereas intracellular MFA had no effect. At low glibenclamide concentrations, MFA induced additional inhibition of the KATP current. Live cell Ca2+ imaging displayed that MFA elevated intracellular Ca2+ at low glucose concentrations. Furthermore, MFA dose-dependently increased insulin release under low, but not high, glucose conditions. Conclusions and Implications: MFA blocked KATP through an extracellular mechanism and thus increased insulin secretion. As some NSAIDs synergistically inhibit KATP activity together with sulphonylureas, the risk of NSAID-induced hypoglycemia should be considered when glucose-lowering compounds are administered. PMID:17435793

  3. Effect of increase in orientational order of lipid chains and head group spacing on non steroidal anti-inflammatory drug induced membrane fusion.

    PubMed

    Roy, Sutapa Mondal; Bansode, Amol S; Sarkar, Munna

    2010-12-21

    Membrane fusion is a key event in many biological processes. The fusion process, both in vivo and in vitro, is induced by different agents which include mainly proteins and peptides. For protein- and peptide-mediated membrane fusion, conformational reorganization serves as a driving force. Small drug molecules do not share this advantage; hence, drug induced membrane fusion occurring in absence of any other fusogenic agent and at physiologically relevant concentration of the drugs is a very rare event. To date, only three drugs, namely, meloxicam (Mx), piroxicam (Px), and tenoxicam (Tx), belonging to the oxicam group of non steroidal anti-inflammatory drugs (NSAIDs), have been shown by us to induce fusion at very low drug to lipid ratio without the aid of any other fusogenic agent. In our continued effort to understand the interplay of different physical and chemical parameters of both the participating drugs and the membrane on the mechanism of this drug induced membrane fusion, we present here the effect of increase in orientational order of the lipid chains and increase in head group spacing. This is achieved by studying the effect of low concentration cholesterol (<10 mol %) at temperatures above the chain-melting transition. Low concentration cholesterol (<10 mol %), above the gel to fluid transition temperature, is mainly known to increase orientational order of the lipid chains and increase head group spacing. To isolate the effect of these parameters, small unilameller vesicles (SUVs) formed by dimyristoylphosphatidylcholine (DMPC) with an average diameter of 50-60 nm were used as simple model membranes. Fluorescence assays were used to probe the time dependence of lipid mixing, content mixing, and leakage and also used to determine the partitioning of the drugs in the membrane bilayer. Differential scanning calorimetry (DSC) was used to study the effect of drugs in the presence of cholesterol on the chain-melting temperature which reflects the fluidization

  4. [Treatment of overactive bladder in older women increased doses of antimuscarinic drugs safe and effective alternative to existing methods].

    PubMed

    Kosilov, K V; Loparev, S A; Krasnykh, M A; Kosilova, L V

    2014-01-01

    The study included 95 female patients of 65 to 74 years (average age 67,1 years), who previously (more than 6 months before this study) took a course of monotherapy with hydrochloride trospium in higher dosages with unstable or weak effect. In this study, all patients were divided into three groups and were treated with two antimuscarinic drugs. The majority of older women suffering from OAB and treatment-resistant taking one antimuscarinic drug in high doses showed a significant positive progress in a state by adding a second antimuscarinic agent. The received side effects do not exceed thereof in comparison with treatment with a single drug. PMID:25051773

  5. The self-assembly of anticancer camptothecin-dipeptide nanotubes: a minimalistic and high drug loading approach to increased efficacy.

    PubMed

    Kim, Se Hye; Kaplan, Jonah A; Sun, Yuan; Shieh, Aileen; Sun, Hui-Lung; Croce, Carlo M; Grinstaff, Mark W; Parquette, Jon R

    2015-01-01

    20-(S)-Camptothecin (CPT)-conjugated dipeptides are reported that preassemble into nanotubes with diameters ranging from 80-120 nm. These nanoassemblies maintain a high (∼47 %) drug loading and exhibit greater drug stability (i.e., resistance to lactone hydrolysis), and consequently greater efficacy against several human cancer cells (HT-29, A549, H460, and H23) in vitro compared with the clinically used prodrug irinotecan. A key and defining feature of this system is the use of the CPT-conjugated dipeptide as both the drug and precursor to the nanostructured carrier, which simplifies the overall fabrication process. PMID:25384556

  6. A win-win solution in oral delivery of lipophilic drugs: supersaturation via amorphous solid dispersions increases apparent solubility without sacrifice of intestinal membrane permeability.

    PubMed

    Miller, Jonathan M; Beig, Avital; Carr, Robert A; Spence, Julie K; Dahan, Arik

    2012-07-01

    Recently, we have revealed a trade-off between solubility increase and permeability decrease when solubility-enabling oral formulations are employed. We have shown this trade-off phenomenon to be ubiquitous, and to exist whenever the aqueous solubility is increased via solubilizing excipients, regardless if the mechanism involves decreased free fraction (cyclodextrins complexation, surfactant micellization) or simple cosolvent solubilization. Discovering a way to increase drug solubility without concomitant decreased permeability represents a major advancement in oral delivery of lipophilic drugs and is the goal of this work. For this purpose, we sought to elucidate the solubility-permeability interplay when increased apparent solubility is obtained via supersaturation from an amorphous solid dispersion (ASD) formulation. A spray-dried ASD of the lipophilic drug progesterone was prepared in the hydrophilic polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which enabled supersaturation up to 4× the crystalline drug's aqueous solubility (8 μg/mL). The apparent permeability of progesterone from the ASD in HPMC-AS was then measured as a function of increasing apparent solubility (supersaturation) in the PAMPA and rat intestinal perfusion models. In contrast to previous cases in which apparent solubility increases via cyclodextrins, surfactants, and cosolvents resulted in decreased apparent permeability, supersaturation via ASD resulted in no decrease in apparent permeability with increasing apparent solubility. As a result, overall flux increased markedly with increasing apparent solubility via ASD as compared to the other formulation approaches. This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches. That is, increased apparent solubility may be achieved without the expense of apparent intestinal membrane permeability. Thus, supersaturation via ASDs presents a

  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. PMID:2275236

  8. Increment in Drug Loading on an Antibody-Drug Conjugate Increases Its Binding to the Human Neonatal Fc Receptor in Vitro.

    PubMed

    Brachet, Guillaume; Respaud, Renaud; Arnoult, Christophe; Henriquet, Corinne; Dhommée, Christine; Viaud-Massuard, Marie-Claude; Heuze-Vourc'h, Nathalie; Joubert, Nicolas; Pugnière, Martine; Gouilleux-Gruart, Valérie

    2016-04-01

    Antibody-drug conjugates, such as brentuximab vedotin (BTXv), are an innovative category of monoclonal antibodies. BTXv is bioconjugated via the chemical reduction of cysteine residues involved in disulfide bonds. Species of BTXv containing zero, two, four, six, or eight vedotin molecules per antibody coexist in the stock solution. We investigated the influence of drug loading on the binding of the antibody to FcRn, a major determinant of antibody pharmacokinetics in humans. We developed a hydrophobic interaction chromatography (HIC) method for separating the different species present in the stock solution of BTXv, and we purified and characterized the collected species before use. We assessed the binding of these different species to FcRn in a cellular assay based on flow cytometry and surface plasmon resonance. HIC separated the different species of BTXv and allowed their collection at adequate levels of purity. Physicochemical characterization showed that species with higher levels of drug loading tended to form more aggregates. FcRn binding assays showed that the most conjugated species, particularly those with saturated loading, interacted more strongly than unconjugated BTXv with the FcRn. PMID:26900766

  9. CONDITIONS THAT INCREASE DRUG MARKET INVOLVEMENT: THE INVITATIONAL EDGE AND THE CASE OF MEXICANS IN SOUTH TEXAS.

    PubMed

    Valdez, Avelardo; Kaplan, Charles

    2007-01-01

    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. 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

  11. 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

  12. Second phase HCV RNA decline during telaprevir based therapy increases with drug effectiveness: implications for treatment duration

    PubMed Central

    Guedj, Jeremie; Perelson, Alan S.

    2011-01-01

    Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase decay to the treatment effectiveness, whereas the second phase decay is attributed to the progressive loss of infected cells. Here we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found that the second phase slope of viral decline to be strongly correlated with the treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Since telaprevir is not known to increase the death rate of infected cells, our results suggest the second phase slope of viral decline is driven not only by the death of infected cells but may also involve other mechanisms, such as a treatment effectiveness-dependent degradation of intracellular viral RNA. As a consequence of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. PMID:21384401

  13. 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

  14. Role of enterohepatic recirculation in drug disposition: cooperation and complications.

    PubMed

    Malik, Mohd Yaseen; Jaiswal, Swati; Sharma, Abhisheak; Shukla, Mahendra; Lal, Jawahar

    2016-05-01

    Enterohepatic recirculation (EHC) concerns many physiological processes and notably affects pharmacokinetic parameters such as plasma half-life and AUC as well as estimates of bioavailability of drugs. Also, EHC plays a detrimental role as the compounds/drugs are allowed to recycle. An in-depth comprehension of this phenomenon and its consequences on the pharmacological effects of affected drugs is important and decisive in the design and development of new candidate drugs. EHC of a compound/drug occurs by biliary excretion and intestinal reabsorption, sometimes with hepatic conjugation and intestinal deconjugation. EHC leads to prolonged elimination half-life of the drugs, altered pharmacokinetics and pharmacodynamics. Study of the EHC of any drug is complicated due to unavailability of the apposite model, sophisticated procedures and ethical concerns. Different in vitro and in vivo methods for studies in experimental animals and humans have been devised, each having its own merits and demerits. Involvement of the different transporters in biliary excretion, intra- and inter-species, pathological and biochemical variabilities obscure the study of the phenomenon. Modeling of drugs undergoing EHC has always been intricate and exigent models have been exploited to interpret the pharmacokinetic profiles of drugs witnessing multiple peaks due to EHC. Here, we critically appraise the mechanisms of bile formation, factors affecting biliary drug elimination, methods to estimate biliary excretion of drugs, EHC, multiple peak phenomenon and its modeling. PMID:26987379

  15. 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

  16. Drugs, drugs--who has the drugs?

    PubMed

    Blair, James

    2012-01-01

    Drug diversion, although on the increase, is not the only problem involving drugs that hospital security officials should be concerned with. Growing drug shortages, offshore production, counterfeiting, and weaknesses in the drug supply chain in case of a world-wide pandemic, are even greater causes for concern, the author claims. PMID:22423518

  17. A Mutation in the 5′ Untranslated Region Increases Stability of norA mRNA, Encoding a Multidrug Resistance Transporter of Staphylococcus aureus

    PubMed Central

    Fournier, Bénédicte; Truong-Bolduc, Que Chi; Zhang, Xiamei; Hooper, David C.

    2001-01-01

    NorA, a multidrug efflux pump in Staphylococcus aureus, protects the cell from multiple drugs, including quinolones. The flqB mutation (T→G) in the 5′ untranslated region upstream of norA causes norA overexpression of 4.9-fold in cis, as measured in norA::blaZ fusions. The transcriptional initiation site of norA was unchanged in mutant and wild-type strains, but the half-life of norA mRNA was increased 4.8-fold in the flqB mutant compared to the wild-type strain. Computer-generated folding of the first 68 nucleotides of the norA transcript predicts an additional stem-loop and changes in a putative RNase III cleavage site in the flqB mutant. PMID:11244079

  18. The development of folate-PAMAM dendrimer conjugates for targeted delivery of anti-arthritic drugs and their pharmacokinetics and biodistribution in arthritic rats.

    PubMed

    Chandrasekar, Durairaj; Sistla, Ramakrishna; Ahmad, Farhan J; Khar, Roop K; Diwan, Prakash V

    2007-01-01

    The aim of this study was to synthesize folate-dendrimer conjugates as suitable vehicle for site specific delivery of anti-arthritic drug (indomethacin) to inflammatory regions and to determine its targeting efficiency, biodistribution in adjuvant induced arthritic rats. Folic acid was coupled to the surface amino groups of G4-PAMAM dendrimer (G4D) via a carbodiimide reaction and loaded with indomethacin. The conjugates were characterized by (1)H-NMR and IR spectroscopy. The drug content and percent encapsulation efficiency increased with increasing folate content for the dendrimer conjugates. The in vitro release rate was decreased for the folate conjugates when compared with unconjugated dendrimer (DNI). The plasma concentration profile showed a biphasic curve indicating rapid distribution followed by slow elimination. The AUC(0-infinity), half-life and residence time of indomethacin in inflamed paw was higher for folate-dendrimer conjugates. The time-averaged relative drug exposure (r(e)) of the drug in paw and overall drug targeting efficiency (T(e)) were higher for folate conjugate with 21 folate moieties (4.1 and 2.78, respectively) when compared with DNI (1.91 and 1.88, respectively). This study demonstrated the superiority of active targeting over dendrimer mediated passive targeting and also for the first time, folate-mediated targeting of an anti-arthritic drug to the inflammatory tissues. PMID:16996126

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. Buoyancy-generating agents for stomach-specific drug delivery: an overview with special emphasis on floating behavior.

    PubMed

    Ishak, Rania A H

    2015-01-01

    Gastric retentive drug delivery provides a promising technology exhibiting an extended gastric residence and a drug release independent of patient related variables. It is usually useful in improving local gastric treatment as well as overcoming drug-related problems .i.e. drugs having narrow absorption window, short half-life or low intestinal solubility. Buoyancy is considered one of the most promising approaches for gastro-retention of dosage forms. Floating drug delivery systems have a bulk density lower than gastric fluids and thus remain buoyant in the stomach causing an increase in gastric residence time. The buoyancy of these systems is attained by the aid of substances responsible to generate the low density. Various agents with different mechanisms were adopted either gas-generating agents, air entrapping swellable polymers, inherent low density substances, porous excipients, hollow/porous particles inducing preparation techniques or sublimating agents. Therefore, this review gives an exclusive descriptive classification of the different categories of these buoyancy-generating agents while representing the related research works. An overview is also conducted to describe relevant techniques assessing the floating behavior of such dosage forms either in vitro or in vivo. Finally, a collection representing FDA-approved floating pharmaceutical products is adopted with emphasis on the buoyancy-generating agent type used in each product. PMID:25877444

  7. Functionalized magnetic nanoparticles as vehicles for the delivery of the antitumor drug gemcitabine to tumor cells. Physicochemical in vitro evaluation.

    PubMed

    Viota, J L; Carazo, A; Munoz-Gamez, J A; Rudzka, K; Gómez-Sotomayor, R; Ruiz-Extremera, A; Salmerón, J; Delgado, A V

    2013-04-01

    Gemcitabine is a chemotherapy drug used in different carcinomas, although because it displays a short biological half-life, its plasmatic levels can quickly drop below the effective threshold. Nanoparticle-based drug delivery systems can provide an alternative approach for regulating the bioavailability of this and most other anticancer drugs. In this work we describe a new model of composite nanoparticles consisting of a core of magnetite nanoparticles, coated with successive layers of high molecular weight poly(acrylic acid) and chitosan, and a final layer of folic acid. The possibility of using these self-assembled nanostructures for gemcitabine vehiculization is explored. First, the surface charge of the composite particles is studied by means of electrophoretic mobility measurements as a function of pH for poly(acrylic acid) (carbopol) of different molecular weights. The adsorption of folic acid, aimed at increasing the chances of the particles to pass the cell membrane, is followed up by optical absorbance measurements, which were also employed for drug adsorption determinations. As a main result, it is shown that gemcitabine adsorbs onto the surface of chitosan/carbopol-coated magnetite nanoparticles. In vitro experiments show that the functionalized magnetic nanoparticles are able to deliver the drug to the nuclei of liver, colon and breast tumor cells. PMID:23827558

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. Mitochondrial DNA Haplogroup A Decreases the Risk of Drug Addiction but Conversely Increases the Risk of HIV-1 Infection in Chinese Addicts.

    PubMed

    Zhang, A-Mei; Hu, Qiu-Xiang; Liu, Feng-Liang; Bi, Rui; Yang, Bi-Qing; Zhang, Wen; Guo, Hao; Logan, Ian; Zheng, Yong-Tang; Yao, Yong-Gang

    2016-08-01

    Drug addiction is one of the most serious social problems in the world today and addicts are always at a high risk of acquiring HIV infection. Mitochondrial impairment has been reported in both drug addicts and in HIV patients undergoing treatment. In this study, we aimed to investigate whether mitochondrial DNA (mtDNA) haplogroup could affect the risk of drug addiction and HIV-1 infection in Chinese. We analyzed mtDNA sequence variations of 577 Chinese intravenous drug addicts (289 with HIV-1 infection and 288 without) and compared with 2 control populations (n = 362 and n = 850). We quantified the viral load in HIV-1-infected patients with and without haplogroup A status and investigated the potential effect of haplogroup A defining variants m.4824A > G and m.8794C > T on the cellular reactive oxygen species (ROS) levels by using an allotopic expression assay. mtDNA haplogroup A had a protective effect against drug addiction but appeared to confer an increased risk of HIV infection in addicts. HIV-1-infected addicts with haplogroup A had a trend for a higher viral load, although the mean viral load was similar between carriers of haplogroup A and those with other haplogroup. Hela cells overexpressing allele m.8794 T showed significantly decreased ROS levels as compared to cells with the allele m.8794C (P = 0.03). Our results suggested that mtDNA haplogroup A might protect against drug addiction but increase the risk of HIV-1 infection. The contradictory role of haplogroup A might be caused by an alteration in mitochondrial function due to a particular mtDNA ancestral variant. PMID:26162319

  14. 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

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

    PubMed Central

    2006-01-01

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

  16. 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

  17. Testing for the undetectable in drug-facilitated sexual assault using hair analyzed by tandem mass spectrometry as evidence.

    PubMed

    Kintz, Pascal; Villain, Marion; Ludes, Bertrand

    2004-04-01

    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 H, antagonists), or anesthetics (gamma-hydroxybutyrate, ketamine), drugs of abuse such as cannabis, ecstasy, or lysergide, or more often ethanol. Drugs 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). In these situations, blood or even urine can be of little interest. This is the reason why this laboratory developed an original approach based on hair testing. Hair was suggested as a valuable specimen in situations where, as a result of a delay in reporting the crime, natural processes have eliminated the drug from typical biologic specimens. Although there are many papers focused on the identification of drugs in hair following chronic drug use, those dealing with a single dose are very scarce. The experience of the authors is documented in cases involving zolpidem, GHB, lorazepam, methylenedioxymethamphetamine, and flunitrazepam. The expected concentrations in hair are in the low picogram per milligram range for the hypnotics. Drug exposure is demonstrated by hair segmentation. Hair analysis may be a useful adjunct to conventional drug testing in sexual assault. It should not be considered as an alternative to blood and urine analyses but as a complement. MS/MS technologies appear to be a prerequisite. PMID:15228167

  18. Duloxetine: clinical pharmacokinetics and drug interactions.

    PubMed

    Knadler, Mary Pat; Lobo, Evelyn; Chappell, Jill; Bergstrom, Richard

    2011-05-01

    Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate

  19. 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.

  20. 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

  1. 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

  2. Decreased expression of nucleophosmin/B23 increases drug sensitivity of adriamycin-resistant Molt-4 leukemia cells through mdr-1 regulation and Akt/mTOR signaling.

    PubMed

    Wang, Lingyan; Chen, Buyuan; Lin, Minhui; Cao, Yanqin; Chen, Yingyu; Chen, Xinji; Liu, Tingbo; Hu, Jianda

    2015-03-01

    Nucleophosmin/B23 (NPM) is a nuclear protein with prosurvival and ribosomal RNA processing functions. However, the potential role of NPM involved in drug-resistance in leukemia has not been investigated clearly. In this study, we generated an adriamycin (ADM)-resistant lymphoblastic cell line Molt-4/ADR (MAR) by stepwise induction. Cell proliferation, sensitivity to chemotherapy agents and expressions of drug resistance related molecules were assessed. The IC50 of Molt-4 cells were 0.58±0.11μmol/L and MAR cells were 22.56±1.94μmol/L, meaning MAR cells were 38.63 fold resistant to Molt-4 cells. Furthermore, MAR cells gained an expression of mdr-1 (P-gp) and a higher expression of NPM compared to Molt-4 cells. Knockdown of NPM by RNA interference (RNAi) suppressed the viability of both Molt-4 and MAR cells. After NPM RNAi, the IC50 of MAR and Molt-4 cells were 3.83±0.38μmol/L and 0.19±0.02μmol/L respectively. Both of them revealed an increase of drug sensitivity with down-regulation of mdr-1 and Akt/mTOR signaling. Knockdown of mdr-1 could also reverse the drug resistance, with no change in NPM expression. It could be concluded that knockdown of NPM reversed the drug resistance by down-regulating P-gp and Akt/mTOR signal pathway, indicating that NPM may serve as a potential modulator in drug resistance. PMID:25457413

  3. 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

  4. 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

  5. Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure.

    PubMed

    Elsby, Robert; Martin, Paul; Surry, Dominic; Sharma, Pradeep; Fenner, Katherine

    2016-03-01

    The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant

  6. 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. PMID:26513413

  7. 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

  8. Metronidazole pharmacokinetics during rapid growth in turkeys - relation to changes in haemodynamics and drug metabolism.

    PubMed

    Świtała, M; Poźniak, B; Pasławska, U; Grabowski, T; Motykiewicz-Pers, K; Bobrek, K

    2016-08-01

    Whereas interspecies variation in pharmacokinetics is a commonly investigated issue, variations in drug kinetics within a species are less documented. The aim of the study was to assess the influence of age-related changes in haemodynamics on the pharmacokinetics of metronidazole (MTZ) and its hydroxy metabolite (MTZ-OH) in turkeys. MTZ was administered intravenously and orally at a dose of 25 mg/kg. Plasma drug and metabolite concentrations were assessed by high-performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental analysis. Haemodynamic parameters (heart rate, stroke volume, cardiac output) were assessed by echocardiography and extraction ratio for MTZ was calculated based on total body clearance (ClB ). Between the 5th and 15th week of age, ClB of MTZ decreased from 3.6 to 1.2 mL/min/kg causing a twofold increase in the mean residence time (MRT) and elimination half-life (T1/2el ). The MTZ-OH production decreased threefold and its MRT and T1/2el increased. Although heart rate significantly decreased with age, cardiac output increased. Extraction ratio was low in all age groups. It is concluded that significant age-dependent decrease in ClB of MTZ in turkeys resulted from decreased perfusion of the clearing organs and their reduced metabolic capacity. This phenomenon is probably species specific and may apply to other therapeutic agents. PMID:26813708

  9. 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

  10. 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.

  11. Increased multi-drug resistance and reduced apoptosis in osteosarcoma side population cells are crucial factors for tumor recurrence

    PubMed Central

    WANG, YANG; TENG, JIA-SONG

    2016-01-01

    The present study investigated the characteristic features of cancer stem cells (CSCs) using an aggressive human osteosarcoma cell line OS-65. Hoechst 33342 dye exclusion was used to distinguish the cancer stem-like side population (SP) cells from OS-65 cells. Furthermore, the SP cells were characterized via chemoresistance and cell death assays, reverse transcription-quantitative polymerase chain reaction and immunofluorescence. The present study identified ~3.3% of cancer stem-like SP cells from OS-65 cells whose prevalence is reduced significantly (0.9%) following treatment with verapamil. It was demonstrated that osteosarcoma SP cells are highly efficient at generating additional sarcospheres as transcriptional regulation of stemness genes, including SOX2, OCT-4 and NANOG, is highly upregulated. Notably, these SP cells demonstrated high resistance against chemotherapeutic drugs and apoptosis via elevated transcriptional regulation of several ATPase binding cassette (ABC) transporter and anti-apoptotic proteins, including ABCG2, ABCB1/MDR1 ABCB5, B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein, respectively. The results of the present study suggested that CSCs may be a novel therapeutic target for the prevention of tumor relapse. PMID:27347020

  12. Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle

    PubMed Central

    Meisel, Christian; Schulze-Bonhage, Andreas; Freestone, Dean; Cook, Mark James; Achermann, Peter; Plenz, Dietmar

    2015-01-01

    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. PMID:26554021

  13. 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.

  14. 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

  15. ALTERATION OF AKT ACTIVITY INCREASES CHEMOTHERAPEUTIC DRUG AND HORMONAL RESISTANCE IN BREAST CANCER YET CONFERS AN ACHILLES HEEL BY SENSITIZATION TO TARGETED THERAPY

    PubMed Central

    Sokolosky, Melissa L.; Lehmann, Brian D.; Taylor, Jackson R.; Navolanic, Patrick M.; Chappell, William H.; Abrams, Stephen L.; Stadelman, Kristin M.; Wong, Ellis WT; Misaghian, Negin; Horn, Stefan; Bäsecke, Jörg; Libra, Massimo; Stivala, Franca; Ligresti, Giovanni; Tafuri, Agostino; Milella, Michele; Zarzycki, Marek; Dzugaj, Andrzej; Chiarini, Francesca; Evangelisti, Camilla; Martelli, Alberto M.; Terrian, David M.; Franklin, Richard A.; Steelman, Linda S.

    2008-01-01

    The PI3K/PTEN/Akt/mTOR pathway plays critical roles in the regulation of cell growth. The effects of this pathway on drug resistance and cellular senescence of breast cancer cells has been a focus of our laboratory. Introduction of activated Akt or mutant PTEN constructs which lack lipid phosphatase [PTEN(G129E)] or lipid and protein phosphatase [PTEN(C124S)] activity increased the resistance of the cells to the chemotherapeutic drug doxorubicin, and the hormonal drug tamoxifen. Activated Akt and PTEN genes also inhibited the induction of senescence after doxorubicin treatment; a phenomenon associated with unrestrained proliferation and tumorigenesis. Interference with the lipid phosphatase domain of PTEN was sufficient to activate Akt/mTOR/p70S6K as MCF-7 cells transfected with the mutant PTEN gene lacking the lipid phosphatase activity [PTEN(G129E)] displayed elevated levels of activated Akt and p70S6K compared to empty vector transfected cells. Cells transfected with mutant PTEN or Akt constructs were hypersensitive to mTOR inhibitors when compared with the parental or empty vector transfected cells. Akt-transfected cells were cultured for over two months in tamoxifen from which tamoxifen and doxorubicin resistant cells were isolated that were >10-fold more resistant to tamoxifen and doxorubicin than the original Akt-transfected cells. These cells had a decreased induction of both activated p53 and total p21Cip1 upon doxorubicin treatment. Furthermore, these cells had an increased inactivation of GSK-3β and decreased expression of the estrogen receptor-α. In these drug resistant cells, there was an increased activation of ERK which is associated with proliferation. These drug resistant cells were hypersensitive to mTOR inhibitors and also sensitive to MEK inhibitors, indicating that the enhanced p70S6K and ERK expression was relevant to their drug and hormonal resistance. Given that Akt is overexpressed in greater than 50% of breast cancers, our results point

  16. 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

  17. Switching from posaconazole suspension to tablets increases serum drug levels in leukemia patients without clinically relevant hepatotoxicity.

    PubMed

    Jung, Dong Sik; Tverdek, Frank P; Kontoyiannis, Dimitrios P

    2014-11-01

    We evaluated posaconazole serum concentrations and hepatotoxicity in 12 leukemia patients who transitioned from posaconazole suspension to tablets. Patients who switched to tablets had significantly increased posaconazole concentrations (median: suspension, 748 ng/ml; tablet, 1,910 ng/ml; P < 0.01) without clinically relevant hepatotoxicity. PMID:25199774

  18. 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

  19. 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

  20. 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

  1. 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

    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

  2. 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

  3. 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

  4. The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery.

    PubMed

    Bern, Malin; Sand, Kine Marita Knudsen; Nilsen, Jeannette; Sandlie, Inger; Andersen, Jan Terje

    2015-08-10

    Albumin is the most abundant protein in blood and acts as a molecular taxi for a plethora of small insoluble substances such as nutrients, hormones, metals and toxins. In addition, it binds a range of medical drugs. It has an unusually long serum half-life of almost 3weeks, and although the structure and function of albumin has been studied for decades, a biological explanation for the long half-life has been lacking. Now, recent research has unravelled that albumin-binding cellular receptors play key roles in the homeostatic regulation of albumin. Here, we review our current understanding of albumin homeostasis with a particular focus on the impact of the cellular receptors, namely the neonatal Fc receptor (FcRn) and the cubilin-megalin complex, and we discuss their importance on uses of albumin in drug delivery. PMID:26055641

  5. 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

  6. Impact of a Quality Improvement Intervention to Increase Brief Alcohol and Drug Interventions on a Level I Trauma Service.

    PubMed

    Thomas, Princess; Seale, J Paul; Johnson, J Aaron; Dhabliwala, Jason; Kitchens, Debra; Okosun, Ike S; Stokes, Nathan A; Ashley, Dennis

    2016-05-01

    Screening and brief intervention (SBI) decreases alcohol use and related consequences among trauma patients. Although SBI is required in Level I and II trauma centers, implementation often is difficult. This study used the Plan-Do-Study-Act approach to identify and implement measures to increase the number of patients receiving SBI at a Level I trauma center. A multidisciplinary Quality Improvement Committee with representation from the Trauma Service and SBI Team met monthly during 2011. Stepwise interventions included identifying a resident "champion" responsible for screening, brief intervention, and referral to treatment, including an SBI report at monthly trauma conferences, and incorporating SBI into the trauma order set. Outcomes measures were number of patients screened, patients screening positive, and the number of patients receiving SBI. At baseline, 170 of 362 patients (47%) were screened, 68/170 (40%) had positive screens, and 30/68 (44% of those with positive screens) received SBI services. Quarter 2 saw increases in patients screened-275/437 (63%), patients screening positive (106/275; 39%) and those receiving SBI (60/106; 57%). Increases culminated in Quarter 4 with screening 401/466 (86%; P < 0.001) patients, 208/401 (52%; P < 0.001) patients screening positive, and 114 patients (55%; P = 0.296) receiving services. Use of similar quality improvement measures nationwide could improve rates of provision of this important service. PMID:27215730

  7. Lipid-shelled vehicles: engineering for ultrasound molecular imaging and drug delivery

    PubMed Central

    Ferrara, Katherine W.; Borden, Mark A; Zhang, Hua

    2009-01-01

    Conspectus Ultrasound pressure waves can map the location of lipid-stabilized gas microbubbles 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 18F (half life ~2 hours) 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 64Cu (half life 12.7 hours)—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 polyethylene glycol coating. Vascular targeting has been demonstrated

  8. 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

  9. shRNA-mediated silencing of sorcin increases drug chemosensitivity in myeloma KM3/DDP and U266/ADM cell lines.

    PubMed

    Xu, Ping; Jiang, Yong-Fang; Wang, Jing-Hua

    2015-01-01

    Sorcin is a penta-EF hand calcium binding protein, which is involved in the resistance to chemotherapeutics in cancer cells, and is overexpressed in various cancer cells. However, tumor relapse combined with the development of drug resistance remains a significant problem. Here, we demonstrated that silencing of Sorcin in chemotherapy resistance myeloma U266/ADM and KM3/DDP cell lines resulted in reduced cell proliferation, cell cycle arrest and cell apoptosis. Sorcin siRNA successfully silenced Sorcin mRNA and protein expression. Silencing of Sorcin also significantly reduced the mRNA and protein expression levels of MDR1, MRP1, GST-π, Survinvin, Livin, Bcl-2, Cyclin-D1, phospho-Src, C-myc, p21, NF-κB and phospho-AKT, while p53 expression and caspase-3 and caspase-8 activity significantly increased when compared with control group. Silencing of Sorcin significantly increased the sensitivity of KM3/DDP cells to cisplatin and the sensitivity of U266/ADM to adriamycin, compared to cells untransfected and transfected with negative control shRNA. In addition, intracellular accumulation of Rhodamine 123 significantly increased in KM3/DDP and U266/ADM cells. In summary, our studies indicate that drug resistance can be effectively reversed in cisplatin-resistance and adriamycin-resistant myeloma cells through delivery of siRNAs targeting Sorcin. Assessment of potential as a target for human myeloma treatment is clearly warranted. PMID:26045737

  10. 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. PMID:25982099

  11. 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

  12. 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

  13. Pharmacology of drugs for hyperuricemia. Mechanisms, kinetics and interactions.

    PubMed

    Pea, F

    2005-01-01

    The pharmacological profile of drugs for hyperuricemia is reviewed. These agents may reduce the amount of uric acid in blood by means of two different ways: (1) by reducing uric acid production through the inhibition of the enzyme xanthine oxidase (as allopurinol); (2) by increasing uric acid clearance through an inhibition of its renal tubular reabsorption (as probenecid), or through its metabolic conversion to a more soluble compound (as urate oxidase). Allopurinol is rapidly converted in the body to the active metabolite oxypurinol whose total body exposure may be 20-fold greater than that of the parent compound due to a much longer elimination half-life. Allopurinol undergoes several pharmacokinetic interactions with concomitant administered drugs, some of which may be potentially hazardous (especially with mercaptopurine and azathioprine). Probenecid is an uricosuric agent which undergoes extensive hepatic metabolism and whose elimination after high doses may become dose dependent. It may inhibit renal tubular secretion of several coadministered agents, including methotrexate and sulphonylureas. Rasburicase is a recombinant form of the enzyme urate oxidase which catalyzes the conversion of uric acid to the more soluble compound allantoin. Unlike allopurinol, it does not promote accumulation of hypoxanthine and xanthine in plasma, thus preventing the risk of xanthine nephropathy. Rasburicase showed no significant accumulation in children after administration of either 0.15 or 0.20 mg/kg/daily for 5 days. Rasburicase probably undergoes peptide hydrolysis and in in vitro studies was shown neither to inhibit or induce cytochrome P450 isoenzymes nor to interact with several drugs, so that no relevant interaction is expected during cotreatment in patients. PMID:15604604

  14. 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

  15. Interspecies allometric analysis of the comparative pharmacokinetics of 44 drugs across veterinary and laboratory animal species.

    PubMed

    Riviere, J E; Martin-Jimenez, T; Sundlof, S F; Craigmill, A L

    1997-12-01

    The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vdss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (51/2 beta) were determined for this selected group of drugs by using the empirically determined function Y = a Wb. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric

  16. Increased corticolimbic connectivity in cocaine dependence versus pathological gambling is associated with drug severity and emotion-related impulsivity.

    PubMed

    Contreras-Rodríguez, Oren; Albein-Urios, Natalia; Vilar-López, Raquel; Perales, Jose C; Martínez-Gonzalez, Jose M; Fernández-Serrano, Maria J; Lozano-Rojas, Oscar; Clark, Luke; Verdejo-García, Antonio

    2016-05-01

    Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine-targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting-state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co-morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed-based analyses to characterize the connectivity of regions displaying between-group differences. We examined the relationships between seed-based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large-scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed-based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision-making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus-outcome learning. Orbitofrontal-subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large-scale ventral corticostriatal-amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect. PMID:25818325

  17. 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. PMID:21461647

  18. Stronger inhibition by nonsteroid anti-inflammatory drugs of cyclooxygenase-1 in endothelial cells than platelets offers an explanation for increased risk of thrombotic events.

    PubMed

    Mitchell, Jane A; Lucas, Ruth; Vojnovic, Ivana; Hasan, Kamrul; Pepper, John R; Warner, Timothy D

    2006-12-01

    Recent data have suggested that regular consumption of nonsteroid anti-inflammatory drugs (NSAIDs), particularly selective inhibitors of cyclo-oxygenase-2 (COX-2), is associated with an increased risk of thrombotic events. It has been suggested that this is due to NSAIDs reducing the release from the endothelium of the antithrombotic mediator prostaglandin I2 as a result of inhibition of endothelial COX-2. Here, however, we show that despite normal human vessels and endothelial cells containing cyclo-oxygenase-1 (COX-1) without any detectable COX-2, COX-1 in vessels or endothelial cells is more readily inhibited by NSAIDs and COX-2-selective drugs than COX-1 in platelets (e.g., log IC50+/-SEM values for endothelial cells vs. platelets: naproxen -5.59+/-0.07 vs. -4.81+/-0.04; rofecoxib -4.93+/-0.04 vs. -3.75+/-0.03; n=7). In broken cell preparations, the selectivities of the tested drugs toward endothelial cell over platelet COX-1 were lost. These observations suggest that variations in cellular conditions, such as endogenous peroxide tone and substrate supply, and not the isoform of cyclo-oxygenase present, dictate the effects of NSAIDs on endothelial cells vs. platelets. This may well be because the platelet is not a good representative of COX-1 activity within the body as it produces prostanoids in an explosive burst that does not reflect tonic release from other cells. The results reported here can offer an explanation for the apparent ability of NSAIDs and COX-2-selective inhibitors to increase the risk of myocardial infarction and stroke. PMID:17142796

  19. Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Show a Largely Reduced Affinity for the Target Antigen.

    PubMed

    Selis, Fabio; Focà, Giuseppina; Sandomenico, Annamaria; Marra, Carla; Di Mauro, Concetta; Saccani Jotti, Gloria; Scaramuzza, Silvia; Politano, Annalisa; Sanna, Riccardo; Ruvo, Menotti; Tonon, Giancarlo

    2016-01-01

    PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and stability toward proteases, however their size lowers to some extent their potential because of a reduced ability to penetrate tissues, especially those of tumor origin. Fab or otherwise engineered smaller fragments are an alternative but are less stable and are much less well retained in circulation. We have here investigated the effects of various PEGylations on the binding properties and in vivo half-life of Fab fragments derived from the enzymatic splitting of Trastuzumab. We find that PEGylation increases the half-life of the molecules but also strongly affects the ability to recognize the target antigen in a way that is dependent on the extent and position of the chemical modification. Data thus support the concept that polyethylene glycol (PEG) conjugation on Trastuzumab Fabs increases half-life but reduces their affinity and this is a fine balance, which must be carefully considered for the design of strategies based on the use of antibody fragments. PMID:27043557

  20. Pegylated Trastuzumab Fragments Acquire an Increased in Vivo Stability but Show a Largely Reduced Affinity for the Target Antigen

    PubMed Central

    Selis, Fabio; Focà, Giuseppina; Sandomenico, Annamaria; Marra, Carla; Di Mauro, Concetta; Saccani Jotti, Gloria; Scaramuzza, Silvia; Politano, Annalisa; Sanna, Riccardo; Ruvo, Menotti; Tonon, Giancarlo

    2016-01-01

    PEGylation of biomolecules is a major approach to increase blood stream half-life, stability and solubility of biotherapeutics and to reduce their immunogenicity, aggregation potential and unspecific interactions with other proteins and tissues. Antibodies have generally long half-lives due to high molecular mass and stability toward proteases, however their size lowers to some extent their potential because of a reduced ability to penetrate tissues, especially those of tumor origin. Fab or otherwise engineered smaller fragments are an alternative but are less stable and are much less well retained in circulation. We have here investigated the effects of various PEGylations on the binding properties and in vivo half-life of Fab fragments derived from the enzymatic splitting of Trastuzumab. We find that PEGylation increases the half-life of the molecules but also strongly affects the ability to recognize the target antigen in a way that is dependent on the extent and position of the chemical modification. Data thus support the concept that polyethylene glycol (PEG) conjugation on Trastuzumab Fabs increases half-life but reduces their affinity and this is a fine balance, which must be carefully considered for the design of strategies based on the use of antibody fragments. PMID:27043557

  1. Artefact or reality? Increases in persons notified to the Regional Drug Misuse Database in the South West of England, 1996-2001.

    PubMed

    Wilkinson, Stephen; Soteriou, Tony; Gray, Selena; Orme, Judy; Myles, Judy

    2004-03-01

    The incidence of new persons and repeat attenders presenting for treatment for problem drug misuse in the South West of England more than doubled from 1996-1997 to 2000-2001. During this time there was an increase in the number and severity of chronic cases, both in terms of the prevalence of heroin and crack-cocaine use and in the frequency of injecting and sharing injecting equipment. Growth in the availability of treatment, changes in notification practice and sub-regional variation make it difficult to be confident about real rates of increase, or age, gender and substance misuse changes, but the size of these changes mean they are unlikely to be purely artefactal. PMID:15044564

  2. Melatonergic drugs in development

    PubMed Central

    Carocci, Alessia; Catalano, Alessia; Sinicropi, Maria Stefania

    2014-01-01

    Melatonin (N-acetyl-5-methoxytryptamine) is widely known as “the darkness hormone”. It is a major chronobiological regulator involved in circadian phasing and sleep-wake cycle in humans. Numerous other functions, including cyto/neuroprotection, immune modulation, and energy metabolism have been ascribed to melatonin. A variety of studies have revealed a role for melatonin and its receptors in different pathophysiological conditions. However, the suitability of melatonin as a drug is limited because of its short half-life, poor oral bioavailability, and ubiquitous action. Due to the therapeutic potential of melatonin in a wide variety of clinical conditions, the development of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Therefore, the field of melatonergic receptor agonists comprises a great number of structurally different chemical entities, which range from indolic to nonindolic compounds. Melatonergic agonists are suitable for sleep disturbances, neuropsychiatric disorders related to circadian dysphasing, and metabolic diseases associated with insulin resistance. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of central nervous system-related pathologies. An overview of recent advances in the field of investigational melatonergic drugs will be presented in this review. PMID:25258560

  3. Poly(styrene)-b-poly(DL-lactide) copolymer-based nanoparticles for anticancer drug delivery.

    PubMed

    Lee, Jae-Young; Kim, Jung Sun; Cho, Hyun-Jong; Kim, Dae-Duk

    2014-01-01

    Poly(styrene)-b-poly(DL-lactide) (PS-PDLLA) copolymer-based nanoparticles (NPs) of a narrow size distribution, negative zeta potential, and spherical shape were fabricated for the delivery of docetaxel (DCT). The particle size was consistently maintained in serum for 24 hours and a sustained drug release pattern was observed for 10 days in the tested formulations. The cytotoxicity of the developed blank NPs was negligible in prostate cancer (PC-3) cells. Cellular uptake and distribution of the constructed NPs containing a hydrophobic fluorescent dye was monitored by confocal laser scanning microscopy (CLSM) for 24 hours. Anti-tumor efficacy of the PS-PDLLA/DCT NPs in PC-3 cells was significantly more potent than that of the group treated with commercially available DCT, Taxotere (P<0.05). Blood biochemistry tests showed that no serious toxicity was observed with the blank NPs in the liver and kidney. In a pharmacokinetic study of DCT in rats, in vivo clearance of PS-PDLLA/DCT NPs decreased while the half-life in blood increased compared to the Taxotere-treated group (P<0.05). The PS-PDLLA NPs are expected to be a biocompatible and efficient nano-delivery system for anticancer drugs. PMID:24940058

  4. Poly(styrene)-b-poly(DL-lactide) copolymer-based nanoparticles for anticancer drug delivery

    PubMed Central

    Lee, Jae-Young; Kim, Jung Sun; Cho, Hyun-Jong; Kim, Dae-Duk

    2014-01-01

    Poly(styrene)-b-poly(DL-lactide) (PS-PDLLA) copolymer-based nanoparticles (NPs) of a narrow size distribution, negative zeta potential, and spherical shape were fabricated for the delivery of docetaxel (DCT). The particle size was consistently maintained in serum for 24 hours and a sustained drug release pattern was observed for 10 days in the tested formulations. The cytotoxicity of the developed blank NPs was negligible in prostate cancer (PC-3) cells. Cellular uptake and distribution of the constructed NPs containing a hydrophobic fluorescent dye was monitored by confocal laser scanning microscopy (CLSM) for 24 hours. Anti-tumor efficacy of the PS-PDLLA/DCT NPs in PC-3 cells was significantly more potent than that of the group treated with commercially available DCT, Taxotere® (P<0.05). Blood biochemistry tests showed that no serious toxicity was observed with the blank NPs in the liver and kidney. In a pharmacokinetic study of DCT in rats, in vivo clearance of PS-PDLLA/DCT NPs decreased while the half-life in blood increased compared to the Taxotere-treated group (P<0.05). The PS-PDLLA NPs are expected to be a biocompatible and efficient nano-delivery system for anticancer drugs. PMID:24940058

  5. Acute Nicotine Administration Increases BOLD fMRI Signal in Brain Regions Involved in Reward Signaling and Compulsive Drug Intake in Rats

    PubMed Central

    Alexander, Jon C.; Perez, Pablo D.; Bauzo-Rodriguez, Rayna; Hall, Gabrielle; Klausner, Rachel; Guerra, Valerie; Zeng, Huadong; Igari, Moe; Febo, Marcelo

    2015-01-01

    Background: Acute nicotine administration potentiates brain reward function and enhances motor and cognitive function. These studies investigated which brain areas are being activated by a wide range of doses of nicotine, and if this is diminished by pretreatment with the nonselective nicotinic receptor antagonist mecamylamine. Methods: Drug-induced changes in brain activity were assessed by measuring changes in the blood oxygen level dependent (BOLD) signal using an 11.1-Tesla magnetic resonance scanner. In the first experiment, nicotine naïve rats were mildly anesthetized and the effect of nicotine (0.03–0.6mg/kg) on the BOLD signal was investigated for 10min. In the second experiment, the effect of mecamylamine on nicotine-induced brain activity was investigated. Results: A high dose of nicotine increased the BOLD signal in brain areas implicated in reward signaling, such as the nucleus accumbens shell and the prelimbic area. Nicotine also induced a dose-dependent increase in the BOLD signal in the striato-thalamo-orbitofrontal circuit, which plays a role in compulsive drug intake, and in the insular cortex, which contributes to nicotine craving and relapse. In addition, nicotine induced a large increase in the BOLD signal in motor and somatosensory cortices. Mecamylamine alone did not affect the BOLD signal in most brain areas, but induced a negative BOLD response in cortical areas, including insular, motor, and somatosensory cortices. Pretreatment with mecamylamine completely blocked the nicotine-induced increase in the BOLD signal. Conclusions: These studies demonstrate that acute nicotine administration activates brain areas that play a role in reward signaling, compulsive behavior, and motor and cognitive function. PMID:25552431

  6. Immunosuppressive drugs and fertility.

    PubMed

    Leroy, Clara; Rigot, Jean-Marc; Leroy, Maryse; Decanter, Christine; Le Mapihan, Kristell; Parent, Anne-Sophie; Le Guillou, Anne-Claire; Yakoub-Agha, Ibrahim; Dharancy, Sébastien; Noel, Christian; Vantyghem, Marie-Christine

    2015-01-01

    Immunosuppressive drugs are used in the treatment of inflammatory and autoimmune diseases, as well as in transplantation. Frequently prescribed in young people, these treatments may have deleterious effects on fertility, pregnancy outcomes and the unborn child. This review aims to summarize the main gonadal side effects of immunosuppressants, to detail the effects on fertility and pregnancy of each class of drug, and to provide recommendations on the management of patients who are seen prior to starting or who are already receiving immunosuppressive treatment, allowing them in due course to bear children. The recommendations for use are established with a rather low level of proof, which needs to be taken into account in the patient management. Methotrexate, mycophenolate, and le- and teri-flunomide, cyclophosphamide, mitoxanthrone are contraindicated if pregnancy is desired due to their teratogenic effects, as well as gonadotoxic effects in the case of cyclophosphamide. Anti-TNF-alpha and mTOR-inhibitors are to be used cautiously if pregnancy is desired, since experience using these drugs is still relatively scarce. Azathioprine, glucocorticoids, mesalazine, anticalcineurins such as cyclosporine and tacrolimus, ß-interferon, glatiramer-acetate and chloroquine can be used during pregnancy, bearing in mind however that side effects may still occur. Experience is limited concerning natalizumab, fingolimod, dimethyl-fumarate and induction treatments. Conclusion: At the time of prescription, patients must be informed of the possible consequences of immunosuppressants on fertility and of the need for contraception. Pregnancy must be planned and the treatment modified if necessary in a pre-conception time period adapted to the half-life of the drug, imperatively in relation with the prescriber of the immunosuppressive drugs. PMID:26490561

  7. Noscapine Increases the Sensitivity of Drug-Resistant Ovarian Cancer Cell Line SKOV3/DDP to Cisplatin by Regulating Cell Cycle and Activating Apoptotic Pathways.

    PubMed

    Shen, Wei; Liang, Bingfeng; Yin, Jie; Li, Xiurong; Cheng, Jianxin

    2015-05-01

    Cisplatin is a first-line chemotherapy drug against ovarian cancer. However, its strong toxic side effects and the development of cisplatin resistance in human cancer cells seriously influence the effects of chemotherapy and quality of life in patients. Noscapine (Nos), a non-toxic benzylisoquinoline alkaloid extracted from opium, has been recently reported to have anti-cancer activity, but the mechanism of that effect has not been clearly established. In the present study, we investigated cytotoxicity of Nos in combination with cisplatin (DDP) in drug-resistant human ovarian cancer cell line SKOV3/DDP in vitro and in vivo null mice xenograft model. Cell proliferation was measured by MTT assay, flow cytometry was used to analyze cell cycle and apoptosis, protein expression of several apoptotic factors was investigated by flow cytometry and immunohistochemical method, and their mRNA expression levels were determined by real-time PCR. In vitro experiments showed that Nos significantly inhibited proliferation of SKOV3/DDP cells. DDP/Nos-combined treatment notably enhanced DDP-induced inhibition of cell proliferation and increased the pro-apoptotic effect of DDP in SKOV3/DDP cells. DDP/Nos administration increased the proportion of G2/M cells, reduced both protein and mRNA expression of anti-apoptotic factors XIAP, surviving and NF-kB, and augmented protein and mRNA levels of pro-apoptotic caspase-3. In vivo experiments revealed that Nos/DDP treatment increased the apoptotic rate of xenograft tumors in null mice. Tumor volume decreased from 1.733 ± 0.155 g in mice treated with DDP alone to 1.191 ± 0.106 g in animals treated with Nos/DDP. These observations suggest that Nos increases the anti-cancer activity of DDP against the drug-resistant ovarian cancer cell line SKOV3/DDP by modulating the cell cycle and activating apoptotic pathways. The study provides a new chemotherapy strategy for the treatment of DDP-resistant human ovarian cancer. PMID:25510462

  8. Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep.

    PubMed

    Lanusse, C E; Prichard, R K

    1992-03-01

    The influence of methimazole (MTZ) on the pharmacokinetics of netobimin (NTB) and its metabolites was investigated in adult sheep. NTB zwitterion suspension was administered at 20 mg kg-1 by intraruminal injection either alone or with simultaneous administration of MTZ intramuscularly at 1.5 mg kg-1. Blood samples were taken serially over a 120-h period and plasma was analysed by HPLC for NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO), and albendazole sulphone (ABZSO2). NTB parent drug showed fast absorption, low area under the plasma concentration-time curve (AUC) and was rapidly removed from plasma after both treatments. The presence of MTZ did increase significantly the ABZ AUC (138 per cent) and mean residence time (MRT) (86 per cent). Concomitant treatment with MTZ resulted in a notably higher ABZSO plasma profile with significantly longer elimination half-life (t1/2 beta) (390 per cent) and MRT (252 per cent) and with significantly higher AUC (95 per cent). Also, MTZ induced significant increases in ABZSO2 t1/2 beta, AUC, and MRT. We have demonstrated a pharmacokinetic interaction between MTZ and NTB metabolites. MTZ may alter the liver biotransformation of ABZ metabolites which results in pronounced changes in the disposition kinetics of anthelmintically active metabolites. PMID:1550912

  9. Clinical significance of increased cerebellar default-mode network connectivity in resting-state patients with drug-naive somatization disorder

    PubMed Central

    Wang, Houliang; Guo, Wenbin; Liu, Feng; Chen, Jindong; Wu, Renrong; Zhang, Zhikun; Yu, Miaoyu; Li, Lehua; Zhao, Jingping

    2016-01-01

    Abstract The cerebellum has been proven to be connected to the brain network, as in the default-mode network (DMN), among healthy subjects and patients with psychiatric disorders. However, whether or not abnormal cerebellar DMN connectivity exists and what its clinical significance is among drug-naive patients with somatization disorder (SD) at rest remain unclear. A total of 25 drug-naive patients with SD and 28 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, patients with SD showed increased left/right Crus I-left/right angular gyrus (AG) connectivity and Lobule IX-left superior medial prefrontal cortex (MPFC) connectivity. The FC values of the left/right Crus I-right AG connectivity of the patients were positively correlated with their scores in the somatization subscale of the symptom checklist-90 (Scl-90). A trend level of correlations was observed between the FC values of the left Crus I-left AG connectivity of the patients and their scores for the somatization subscale of Scl-90, as well as between the FC values of their Lobule IX-left superior MPFC connectivity and their scores for the Eysenck personality questionnaire (EPQ) extraversion. Our findings show the increased cerebellar DMN connectivity in patients with SD and therefore highlight the importance of the DMN in the neurobiology of SD. Increased cerebellar DMN connectivities are also correlated with their somatization severity and personality, both of which bear clinical significance. PMID:27428190

  10. Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

    PubMed Central

    Ma, Yao-Ying; Henley, Sandy M.; Toll, Jeff; Jentsch, James D.; Evans, Christopher J.; Levine, Michael S.; Cepeda, Carlos

    2013-01-01

    To examine the mechanisms of drug relapse, we first established a model for cocaine IVSA (intravenous self-administration) in mice, and subsequently examined electrophysiological alterations of MSNs (medium-sized spiny neurons) in the NAc (nucleus accumbens) before and after acute application of cocaine in slices. Three groups were included: master mice trained by AL (active lever) pressings followed by IV (intravenous) cocaine delivery, yoked mice that received passive IV cocaine administration initiated by paired master mice, and saline controls. MSNs recorded in the NAc shell in master mice exhibited higher membrane input resistances but lower frequencies and smaller amplitudes of sEPSCs (spontaneous excitatory postsynaptic currents) compared with neurons recorded from saline control mice, whereas cells in the NAc core had higher sEPSCs frequencies and larger amplitudes. Furthermore, sEPSCs in MSNs of the shell compartment displayed longer decay times, suggesting that both pre- and postsynaptic mechanisms were involved. After acute re-exposure to a low-dose of cocaine in vitro, an AP (action potential)-dependent, persistent increase in sEPSC frequency was observed in both NAc shell and core MSNs from master, but not yoked or saline control mice. Furthermore, re-exposure to cocaine induced membrane hyperpolarization, but concomitantly increased excitability of MSNs from master mice, as evidenced by increased membrane input resistance, decreased depolarizing current to generate APs, and a more negative Thr (threshold) for firing. These data demonstrate functional differences in NAc MSNs after chronic contingent versus non-contingent IV cocaine administration in mice, as well as synaptic adaptations of MSNs before and after acute re-exposure to cocaine. Reversing these functional alterations in NAc could represent a rational target for the treatment of some reward-related behaviors, including drug addiction. PMID:24000958

  11. High-dose green tea polyphenol intake decreases CYP3A expression in a liver-specific manner with increases in blood substrate drug concentrations.

    PubMed

    Ikarashi, Nobutomo; Ogawa, Sosuke; Hirobe, Ryuta; Kusunoki, Yoshiki; Kon, Risako; Ochiai, Wataru; Sugiyama, Kiyoshi

    2016-06-30

    In recent years, the intake of functional foods containing high-doses of green tea polyphenols (GP) has been increasing. In this study, the long-term safety of high-dose GP was assessed from a pharmacokinetic point of view by focusing on the drug-metabolizing enzyme, cytochrome P450 (CYP). Mice were fed a diet containing 3% GP for 4weeks, and the CYP expression levels and activity were determined. The GP-treated group showed a significant decrease in the hepatic CYP3A and an increase in the hepatic CYP2C expression compared with the control group. CYP1A, CYP2D, and CYP2E expression were not different between the GP-treated and the control groups. In the small intestine, there were no differences in the CYP3A protein levels between the groups. The increase in the plasma triazolam concentration in the GP-treated group was observed. Although no changes were found in the hepatic CYP3A levels in mice receiving a diet containing 0.1% GP for 4weeks, a significant decrease was seen in the hepatic CYP3A level in mice receiving a diet containing 3% GP for only 1week. This study revealed that the intake of a high-dose GP results in a liver-specific decrease in the CYP3A expression level. The results also indicated that the effects of GP on CYP3A were not observed following the intake of a low-dose GP. In the future, caution should be taken in cases when functional foods containing a high-dose GP are concomitantly consumed with a CYP3A substrate drug. PMID:27130545

  12. Determining the "Half-Life" of Nuclear Education.

    ERIC Educational Resources Information Center

    Lenda, Michael P.; Learn, George A., Jr.

    1980-01-01

    Described is a study to determine the long-range impact of the Pennsylvania Nuclear Science Prolect. Findings include that fewer than one-half participants are still teaching the pilot program, that school/teachers who "dropped out" averaged three years from initial involvement, and that student interest and scheduling problems are two main…

  13. Biological Half-Life of Cardiolite[R

    ERIC Educational Resources Information Center

    Jesse, Kenneth

    2008-01-01

    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[R], a substance containing a molecule to which…

  14. HALF-LIFE OF POLYCHLORINATED BIPHENYLS IN OCCUPATIONALLY EXPOSED WORKERS

    EPA Science Inventory

    In 1977 and 1985, serum polychlorinated biphenyl (PCB) concentrations were determined for 58 workers in a Bloomington, Indiana, factory that used PCBs in capacitor manufacture until 1977. ess chlorinated PCBs were quantitated as Aroclor 1242, and more highly chlorinated PCBs were...

  15. Using an Authentic Radioisotope to Teach Half-Life

    ERIC Educational Resources Information Center

    Liddicoat, Scott; Sebranek, John

    2005-01-01

    Traditionally nuclear chemistry appears in the last few chapters of chemistry textbooks and is not normally considered a mainstream topic. In addition, some science teachers lack the training or equipment to teach nuclear chemistry. Yet nuclear chemistry is a very important topic that should be taught in all chemistry classrooms. Learning about…

  16. What Is the Half-Life of Basketball Teams?

    NASA Astrophysics Data System (ADS)

    Hrepic, Zdeslav

    2013-10-01

    What do basketball teams have in common with radioactive nuclei? It turns out, there is more here than first meets the eye. The National Collegiate Athletic Association (NCAA) basketball tournaments feeds fans' craving when NBA competitions are not in swing, and the college tournament time has been referred to as "March Madness" or the "Big Dance" as many fans participate in "bracketing," i.e., predicting winners.

  17. What Is the Half-Life of Basketball Teams?

    ERIC Educational Resources Information Center

    Hrepic, Zdeslav

    2013-01-01

    What do basketball teams have in common with radioactive nuclei? It turns out, there is more here than first meets the eye. The National Collegiate Athletic Association (NCAA) basketball tournaments feeds fans' craving when NBA competitions are not in swing, and the college tournament time has been referred to as "March Madness" or…

  18. BIOLOGICAL HALF-LIFE OF TRITIUM IN CHICKENS AND EGGS

    EPA Science Inventory

    Previous studies of tritium transport in the environment suggest that although water is the main route for human intake, other routes should not be ignored. The importance of eggs as a step in the pathway for human intake of tritium was assessed by intravenously administering a s...

  19. Multilevel Community-Based Intervention to Increase Access to Sterile Syringes Among Injection Drug Users Through Pharmacy Sales in New York City

    PubMed Central

    Fuller, Crystal M.; Galea, Sandro; Caceres, Wendy; Blaney, Shannon; Sisco, Sarah; Vlahov, David

    2007-01-01

    Objectives. Research has indicated that there is minimal use of pharmacies among injection drug users (IDUs) in specific neighborhoods and among Black and Hispanic IDUs. We developed a community-based participatory research partnership to determine whether a multilevel intervention would increase sterile syringe access through a new policy allowing nonprescription syringe sales in pharmacies. Methods. We targeted Harlem, NY (using the South Bronx for comparison), and disseminated informational material at community forums, pharmacist training programs, and counseling or outreach programs for IDUs. We compared cross-sectional samples in 3 target populations (pre- and postintervention): community members (attitudes and opinions), pharmacists (opinions and practices), and IDUs (risk behaviors). Results. Among community members (N = 1496) and pharmacists (N = 131), negative opinions of IDU syringe sales decreased in Harlem whereas there was either no change or an increase in negative opinions in the comparison community. Although pharmacy use by IDUs (N=728) increased in both communities, pharmacy use increased significantly among Black IDUs in Harlem, but not in the comparison community; syringe reuse significantly decreased in Harlem, but not in the comparison community. Conclusions. Targeting the individual and the social environment through a multilevel community-based intervention reduced high-risk behavior, particularly among Black IDUs. PMID:17138929

  20. Drug dosage in continuous venoveno hemofiltration in critically ill children.

    PubMed

    Assadi, Farahnak; Shahrbaf, Fatemeh Ghane

    2016-01-01

    The dosage of drugs in patients requiring continuous renal replacement therapy need to be adjusted based on a number of variables that that affect pharmacokinetics (PK) including patient weight, CRRT modality (convention, vs. diffusion), blood and/or effluent flow, hemofilter characteristics, physiochemical drug properties, volume of distribution, protein binding and half-life as well as residual renal function. There is a paucity of data on PK studies in children with acute kidney injury requiring CRRT. When possible, therapeutic drug monitoring should be utilized for those medications where serum drug concentrations can be obtained in a clinically relevant time frame. Also, a patient-centered team approach that includes an intensive care unit pharmacist is recommended to prevent medication-related errors and enhance safe and effective medication use is highly recommended. The aim of this article is to review the current guidelines for drug dosing in critically ill children who require continuous venovenous hemofiltration. PMID:26709896

  1. Inclusion complexes of chloramphenicol with β-cyclodextrin and aminoacids as a way to increase drug solubility and modulate ROS production.

    PubMed

    Aiassa, Virginia; Zoppi, Ariana; Albesa, Inés; Longhi, Marcela R

    2015-05-01

    The aim of this study was to improve the solubility of chloramphenicol and reduce the production of reactive oxygen species (ROS) in leucocytes induced by this drug, using complexation. Multicomponent complexes were prepared by the addition of β-cyclodextrin with glycine or cysteine. Nuclear magnetic resonance and phase solubility studies provided information at the molecular level on the structure of the complexes and their association binding constants, respectively. In the solid state, all systems were extensively characterized by Fourier-transform infrared spectroscopy, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Antimicrobial activity of inclusion complexes was investigated by agar diffusion methods. Finally ROS determination by chemiluminescence was used to investigate the effect of complex formation on the potential toxicity in human leucocytes. These studies revealed that multicomponent complexes can increase the aqueous solubility of chloramphenicol as well as reducing the stress by ROS production in leucocytes and maintaining its microbiological activity. PMID:25659705

  2. Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug

    PubMed Central

    Svensson, Elin M.; Murray, Stephen; Karlsson, Mats O.; Dooley, Kelly E.

    2015-01-01

    Objectives Bedaquiline is the first drug of a new class approved for the treatment of TB in decades. Bedaquiline is metabolized by cytochrome P450 (CYP) 3A4 to a less-active M2 metabolite. Its terminal half-life is extremely long (5–6 months), complicating evaluations of drug–drug interactions. Rifampicin and rifapentine, two anti-TB drugs now being optimized to shorten TB treatment duration, are potent inducers of CYP3A4. This analysis aimed to predict the effect of repeated doses of rifampicin or rifapentine on the steady-state pharmacokinetics of bedaquiline and its M2 metabolite from single-dose data using a model-based approach. Methods Pharmacokinetic data for bedaquiline and M2 were obtained from a Phase I study involving 32 individuals each receiving two doses of bedaquiline, alone or together with multiple-dose rifampicin or rifapentine. Sampling was performed over 14 days following each bedaquiline dose. Pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Models were used to simulate potential dose adjustments. Results Rifamycin co-administration increased bedaquiline clearance substantially: 4.78-fold [relative standard error (RSE) 9.10%] with rifampicin and 3.96-fold (RSE 5.00%) with rifapentine. Induction of M2 clearance was equally strong. Average steady-state concentrations of bedaquiline and M2 are predicted to decrease by 79% and 75% when given with rifampicin or rifapentine, respectively. Simulations indicated that increasing the bedaquiline dosage to mitigate the interaction would yield elevated M2 concentrations during the first treatment weeks. Conclusions Rifamycin antibiotics reduce bedaquiline concentrations substantially. In line with current treatment guidelines for drug-susceptible TB, concomitant use is not recommended, even with dose adjustment. PMID:25535219

  3. Red blood cell ghosts as promising drug carriers to target wound infections.

    PubMed

    Berikkhanova, Kulzhan; Omarbaev, Rustam; Gulyayev, Alexandr; Shulgau, Zarina; Ibrasheva, Dilbar; Adilgozhina, Gulsim; Sergazy, Shynggys; Zhumadilov, Zhaxybay; Askarova, Sholpan

    2016-09-01

    Autologous red blood cell ghosts (RBC ghosts) can carry cytokines to the sites of inflammation. The targeting moiety of the RBC ghosts is associated with the nature of purulent inflammation, where the erythrocytes are phagocyted and encapsulated drugs are released. In the present study we have investigated the healing potential of RBC ghosts loaded with cytokine IL-1β and antibiotic. Additionally, the pharmacokinetic properties of RBC ghosts loaded with IL-1β were studied. 35 Male Wistar rats (250-300g) were used in the pharmacokinetic study and in a wound infection model where a suspension of Staphylococcus aureus was placed into a surgical cut of the skin and subcutaneous tissue in the femoral region. In order to monitor progression of the wound repair processes, wound swabs or aspiration biopsies were taken for analyses on the 1st-6th days. Wound repair dynamics assessment was based on suppression of S. aureus growth, signs of pain, time of disappearance of pus and infiltration around the wound. Visual observations, as well as microbiological and cytological analysis of wound exudates demonstrated a significant acceleration of healing processes in a group of animals treated with a local injection of IL-1β and ceftriaxone encapsulated into RBC ghosts when compared to the animals treated either with a local or IM injection of free drugs. For the pharmacokinetic study, single IV injections of either free or encapsulated IL-1β were made and the concentration of IL-1β in serum samples and tissue homogenates were determined. Encapsulation in RBC ghosts improved pharmacokinetic profiles of IL-1β by increasing the half-life, reducing its clearance, and increasing the deposition of the drug in the liver, spleen and lungs. These data suggest that RBC ghosts are effective drug carriers for targeted delivery of cytokines to the sites of inflammation, and have a potential for improving the treatment outcomes of purulent diseases. PMID:27062487

  4. Molecular Dynamics and Physical Stability of Amorphous Nimesulide Drug and Its Binary Drug-Polymer Systems.

    PubMed

    Knapik, J; Wojnarowska, Z; Grzybowska, K; Tajber, L; Mesallati, H; Paluch, K J; Paluch, M

    2016-06-01

    In this article we study the effectiveness of three well-known polymers: inulin, Soluplus, and PVP in stabilizing the amorphous form of nimesulide (NMS) drug. The recrystallization tendency of pure drug as well as measured drug-polymer systems were examined at isothermal conditions by broadband dielectric spectroscopy (BDS) and at nonisothermal conditions by differential scanning calorimetry (DSC). Our investigation has shown that the crystallization half-life time of pure NMS at 328 K is equal to 33 min. We found that this time can be prolonged to 40 years after adding 20% w/w PVP to NMS. This polymer proved to be the best NMS stabilizer, while the worst stabilization effect was exhibited by inulin. Additionally, our DSC, BDS, and FTIR studies indicate that for suppression of NMS recrystallization in the NMS-PVP system, the two mechanisms are responsible: the polymeric steric hindrances and the antiplastization effect exerted by the excipient. PMID:27149568

  5. Increase of Transmitted Drug Resistance among HIV-Infected Sub-Saharan Africans Residing in Spain in Contrast to the Native Population

    PubMed Central

    Yebra, Gonzalo; de Mulder, Miguel; Pérez-Elías, María Jesús; Pérez-Molina, José Antonio; Galán, Juan Carlos; Llenas-García, Jara; Moreno, Santiago; Holguín, África

    2011-01-01

    Background The prevalence of transmitted HIV drug resistance (TDR) is stabilizing or decreasing in developed countries. However, this trend is not specifically evaluated among immigrants from regions without well-implemented antiretroviral strategies. Methods TDR trends during 1996–2010 were analyzed among naïve HIV-infected patients in Spain, considering their origin and other factors. TDR mutations were defined according to the World Health Organization list. Results Pol sequence was available for 732 HIV-infected patients: 292 native Spanish, 226 sub-Saharan Africans (SSA), 114 Central-South Americans (CSA) and 100 from other regions. Global TDR prevalence was 9.7% (10.6% for Spanish, 8.4% for SSA and 7.9% for CSA). The highest prevalences were found for protease inhibitors (PI) in Spanish (3.1%), for non-nucleoside reverse transcriptase inhibitors (NNRTI) in SSA (6.5%) and for nucleoside reverse transcriptase inhibitors (NRTI) in both Spanish and SSA (6.5%). The global TDR rate decreased from 11.3% in 2004–2006 to 8.4% in 2007–2010. Characteristics related to a decreasing TDR trend in 2007-10 were Spanish and CSA origin, NRTI- and NNRTI-resistance, HIV-1 subtype B, male sex and infection through injection drug use. TDR remained stable for PI-resistance, in patients infected through sexual intercourse and in those carrying non-B variants. However, TDR increased among SSA and females. K103N was the predominant mutation in all groups and periods. Conclusion TDR prevalence tended to decrease among HIV-infected native Spanish and Central-South Americans, but it increased up to 13% in sub-Saharan immigrants in 2007–2010. These results highlight the importance of a specific TDR surveillance among immigrants to prevent future therapeutic failures, especially when administering NNRTIs. PMID:22046345

  6. High levels of Hsp90 co-chaperone p23 promotes tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance

    PubMed Central

    Simpson, Natalie E.; Lambert, W. Marcus; Watkins, Renecia; Giashuddin, Shah; Huang, S. Joseph; Oxelmark, Ellinor; Arju, Rezina; Hochman, Tsivia; Goldberg, Judith D.; Schneider, Robert J.; Reiz, Luiz Fernando Lima; Soares, Fernando Augusto; Logan, Susan K.; Garabedian, Michael J.

    2010-01-01

    p23 is an Hsp90 co-chaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls catalytic activity of certain kinases, regulates protein-DNA dynamics and is upregulated in several cancers. We previously demonstrated that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients. PMID:20847343

  7. Hetero-modification of TRAIL trimer for improved drug delivery and in vivo antitumor activities

    PubMed Central

    Pan, Li-Qiang; Zhao, Wen-Bin; Lai, Jun; Ding, Ding; Wei, Xiao-Yue; Li, Yang-Yang; Liu, Wen-Hui; Yang, Xiao-Yue; Xu, Ying-Chun; Chen, Shu-Qing

    2015-01-01

    Poor pharmacokinetics and resistance within some tumor cell lines have been the major obstacles during the preclinical or clinical application of TRAIL (tumor-necrosis-factor (TNF)-related apoptosis-inducing ligand). The half-life of TRAIL114-281 (114 to 281 amino acids) was revealed to be no more than 30 minutes across species. Therefore maleimido activated PEG (polyethylene glycol) and MMAE (Monomethyl Auristatin E) were applied to site-specifically conjugate with the mutated cysteines from different monomers of TRAIL successively, taking advantage of steric effects involved within TRAIL mutant conjugations. As a result, TRAIL trimer was hetero-modified for different purposes. And the resulting PEG-TRAIL-vcMMAE conjugate exhibited dramatically improved half-life (11.54 h), favourable in vivo targeting capability and antitumor activities while no sign of toxicity in xenograft models, suggesting it’s a viable therapeutic and drug delivery strategy. PMID:26445897

  8. Motion Compensated Ultrasound Imaging Allows Thermometry and Image Guided Drug Delivery Monitoring from Echogenic Liposomes.

    PubMed

    Ektate, Kalyani; Kapoor, Ankur; Maples, Danny; Tuysuzoglu, Ahmet; VanOsdol, Joshua; Ramasami, Selvarani; Ranjan, Ashish

    2016-01-01

    Ultrasound imaging is widely used both for cancer diagnosis and to assess therapeutic success, but due to its weak tissue contrast and the short half-life of commercially available contrast agents, it is currently not practical for assessing motion compensated contrast-enhanced tumor imaging, or for determining time-resolved absolute tumor temperature while simultaneously reporting on drug delivery. The objectives of this study were to: 1) develop echogenic heat sensitive liposomes (E-LTSL) and non-thermosensitive liposomes (E-NTSL) to enhance half-life of contrast agents, and 2) measure motion compensated temperature induced state changes in acoustic impedance and Laplace pressure of liposomes to monitor temperature and doxorubicin (Dox) delivery to tumors. LTSL and NTSL containing Dox were co-loaded with an US contrast agent (perfluoropentane, PFP) using a one-step sonoporation method to create E-LTSL and E-NTSL. To determine temperature induced intensity variation with respect to the state change of E-LTSL and E-NTSL in mouse colon tumors, cine acquisition of 20 frames/second for about 20 min (or until wash out) at temperatures of 42°C, 39.5°C, and 37°C was performed. A rigid rotation and translation was applied to each of the "key frames" to adjust for any gross motion that arose due to motion of the animal or the transducer. To evaluate the correlation between ultrasound (US) intensity variation and Dox release at various temperatures, treatment (5 mg Dox/kg) was administered via a tail vein once tumors reached a size of 300-400 mm(3), and mean intensity within regions of interest (ROIs) defined for each sample was computed over the collected frames and normalized in the range of [0,1]. When the motion compensation technique was applied, a > 2-fold drop in standard deviation in mean image intensity of tumor was observed, enabling a more robust estimation of temporal variations in tumor temperatures for 15-20 min. due to state change of E-LTSL and E

  9. Motion Compensated Ultrasound Imaging Allows Thermometry and Image Guided Drug Delivery Monitoring from Echogenic Liposomes

    PubMed Central

    Ektate, Kalyani; Kapoor, Ankur; Maples, Danny; Tuysuzoglu, Ahmet; VanOsdol, Joshua; Ramasami, Selvarani; Ranjan, Ashish

    2016-01-01

    Ultrasound imaging is widely used both for cancer diagnosis and to assess therapeutic success, but due to its weak tissue contrast and the short half-life of commercially available contrast agents, it is currently not practical for assessing motion compensated contrast-enhanced tumor imaging, or for determining time-resolved absolute tumor temperature while simultaneously reporting on drug delivery. The objectives of this study were to: 1) develop echogenic heat sensitive liposomes (E-LTSL) and non-thermosensitive liposomes (E-NTSL) to enhance half-life of contrast agents, and 2) measure motion compensated temperature induced state changes in acoustic impedance and Laplace pressure of liposomes to monitor temperature and doxorubicin (Dox) delivery to tumors. LTSL and NTSL containing Dox were co-loaded with an US contrast agent (perfluoropentane, PFP) using a one-step sonoporation method to create E-LTSL and E-NTSL. To determine temperature induced intensity variation with respect to the state change of E-LTSL and E-NTSL in mouse colon tumors, cine acquisition of 20 frames/second for about 20 min (or until wash out) at temperatures of 42°C, 39.5°C, and 37°C was performed. A rigid rotation and translation was applied to each of the “key frames” to adjust for any gross motion that arose due to motion of the animal or the transducer. To evaluate the correlation between ultrasound (US) intensity variation and Dox release at various temperatures, treatment (5 mg Dox/kg) was administered via a tail vein once tumors reached a size of 300-400 mm3, and mean intensity within regions of interest (ROIs) defined for each sample was computed over the collected frames and normalized in the range of [0,1]. When the motion compensation technique was applied, a > 2-fold drop in standard deviation in mean image intensity of tumor was observed, enabling a more robust estimation of temporal variations in tumor temperatures for 15-20 min. due to state change of E-LTSL and E

  10. Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis.

    PubMed

    Zhang, Ruiguang; Li, Yan; Wang, Zhongliang; Chen, Lingjuan; Dong, Xiaorong; Nie, Xiu

    2015-11-01

    Non-small cell lung cancer is commonly seen with higher morbidity and mortality. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein, which is involved in multiple human diseases including cancers. However, the mechanisms of HMGB1 in non-small cell lung cancer remain unclear. The goal of the present study is to identify the relationship between HMGB1 and the progresssion of non-small cell lung cancer and investigate the molecular mechanism of HMGB1 in non-small lung cancer cell lines. Firstly, we detected the expression levels of HMGB1 by by real-time PCR and western blotting analysis, and the results demonstrated that HMGB1 was much higher expressed in non-small cell lung cancer cell lines, including A549, SPC-1-1, NCI-2170, SK-MES-1, and NCI-H1299, compared with that of WI-38. Next, 5 μM of adriamycin (AMD), 20 μM of cisplatin (DDP), and 50 μM of methotrexate (MTX) were used to treat A549 cells and SPC-A-1 cells for 48 h. The results showed that treatment with chemotherapy drugs significantly increased the levels of HMGB1 in A549 cells and SPC-A-1 cells. Moreover, the expression levels of HMGB1 increased in a time-dependent manner being treated with DDP. Then, the endogenous HMGB1 expression was successfully interferred with shRNA specific to HMGB1 in A549 and SPC-A-1 cells, which was detected by western blotting analysis. Then, the cisplatin-sensitive A549 cells and cisplatin-resistant A549/DDP cells were treated with increasing concentrations of cisplatin for 24, 48, and 72 h; cell viability were analyzed by MTT assay; and IC50 values were calculated. The results demonstrated that the expression level of HMGB1 in A549/DDP cells was much higher than that of A549 cells; moreover, transfection with HMGB1 shRNA in A549/DDP cells decreased the IC50 value of cisplatin in A549/DDP cells. The expression levels of autophagy-related proteins beclin-1 and LC3-II were significantly higher in A549/DDP cells or the A549 cells treated with

  11. Pharmacokinetics and drug interactions of eslicarbazepine acetate.

    PubMed

    Bialer, Meir; Soares-da-Silva, Patricio

    2012-06-01

    Eslicarbazepine acetate (ESL) is a novel once-daily antiepileptic drug (AED) approved in Europe since 2009 that was found to be efficacious and well tolerated in a phase III clinical program in adult patients with partial onset seizures previously not controlled with treatment with one to three AEDs, including carbamazepine (CBZ). ESL shares with CBZ and oxcarbazepine (OXC) the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11 position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11-epoxide. Unlike OXC, which is metabolized to both eslicarbazepine and (R)-licarbazepine, ESL is extensively converted to eslicarbazepine. The systemic exposure to eslicarbazepine after ESL oral administration is approximately 94% of the parent dose, with minimal exposure to (R)-licarbazepine and OXC. After ESL oral administration, the effective half-life (t(1/2,eff) ) of eslicarbazepine was 20-24 h, which is approximately two times longer than its terminal half-life (t(1/2)). At clinically relevant doses (400-1,600 mg/day) ESL has linear pharmacokinetics (PK) with no effects of gender or moderate liver impairment. However, because eslicarbazepine is eliminated primarily (66%) by renal excretion, dose adjustment is recommended for patients with renal impairment. Eslicarbazepine clearance is induced by phenobarbital, phenytoin, and CBZ and it dose-dependently decreases plasma exposure of oral contraceptive and simvastatin. PMID:22612290

  12. Downregulation of miR-363 increases drug resistance in cisplatin-treated HepG2 by dysregulating Mcl-1.

    PubMed

    Ou, Yangyang; Zhai, Denggao; Wu, Nan; Li, Xiaoli

    2015-11-01

    Systemic therapy with cytotoxic agents provides marginal benefit in hepatocellular carcinoma (HCC) treatment especially for patients with advanced HCC. Cisplatin is one of the most active cytotoxic agents for HCC treatment. However, acquisition of cisplatin resistance is common, and one important underlying mechanism of such resistance is apoptosis-resistance. In this study, we found that miR-363 levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. MiR-363 levels were also lower in cisplatin-resistant HepG2 (HepG2-R) cells than in HepG2 cells. Exogenous miR-363 significantly overcame cisplatin resistance in HepG2-R cells, whereas miR-363 knockdown increased the cell viability during cisplatin treatment. We further demonstrated that miR-363 directly targeted to Mcl-1 3'-UTR (3'-Untranslated Regions). Downregulation of miR-363 resulted in upregulation of Mcl-1 which is a key member of anti-apoptotic Bcl-2 family and increased drug resistance. We finally demonstrated that miR-363 decreased cisplatin resistance of HCC cell, partly by targeting Mcl-1. These data suggest that the combination of miR-363 and cisplatin may represent a novel approach in treatment for HCC, thus offering a new target for chemotherapy of HCC. PMID:26143754

  13. Nitrosyl-cobinamide, a new and direct nitric oxide releasing drug effective in vivo.

    PubMed

    Broderick, Kate E; Alvarez, Luis; Balasubramanian, Mahesh; Belke, Darrell D; Makino, Ayako; Chan, Adriano; Woods, Virgil L; Dillmann, Wolfgang H; Sharma, Vijay S; Pilz, Renate B; Bigby, Timothy D; Boss, Gerry R

    2007-12-01

    A limited number of nitric oxide (NO)-generating drugs are available for clinical use for acute and chronic conditions. Most of these agents are organic nitrates, which do not directly release NO; tolerance to the drugs develops, in part, as a consequence of their conversion to NO. We synthesized nitrosyl-cobinamide (NO-Cbi) from cobinamide, a structural analog of cobalamin (vitamin B12). NO-Cbi is a direct NO-releasing agent that we found was stable in water, but under physiologic conditions, it released NO with a half-life of 30 mins to 1 h. We show in five different biological systems that NO-Cbi is an effective NO-releasing drug. First, in cultured rat vascular smooth muscle cells, NO-Cbi induced phosphorylation of vasodilator-stimulated phosphoprotein, a downstream target of cGMP and cGMP-dependent protein kinase. Second, in isolated Drosophila melanogaster Malpighian tubules, NO-Cbi-stimulated fluid secretion was similar to that stimulated by Deta-NONOate and a cGMP analog. Third, in isolated mouse hearts, NO-Cbi increased coronary flow much more potently than nitroglycerin. Fourth, in contracted mouse aortic rings, NO-Cbi induced relaxation, albeit to a lesser extent than sodium nitroprusside. Fifth, in intact mice, a single NO-Cbi injection rapidly reduced blood pressure, and blood pressure returned to normal after 45 mins; repeated NO-Cbi injections induced the expected fall in blood pressure. These studies indicate that NO-Cbi is a useful NO donor that can be used experimentally in the laboratory; moreover, it could be developed into a vasodilating drug for treating hypertension and potentially other diseases such as angina and congestive heart failure. PMID:18040067

  14. Evaluating the Pharmacodynamic Effect of Antimalarial Drugs in Clinical Trials by Quantitative PCR

    PubMed Central

    Marquart, Louise; Baker, Mark; O'Rourke, Peter

    2015-01-01

    The ongoing development of new antimalarial drugs and the increasing use of controlled human malaria infection (CHMI) studies to investigate their activity in early-stage clinical trials require the development of methods to analyze their pharmacodynamic effect. This is especially so for studies where quantitative PCR (qPCR) is becoming the preferred method for assessing parasite clearance as the study endpoint. We report the development and validation of an analytic approach for qPCR-determined parasite clearance data. First, in a clinical trial with the licensed antimalarial combination sulfadoxine-pyrimethamine (S/P), qPCR data were collected from 12 subjects and used to determine qPCR replicate variability and to identify outliers. Then, an iterative analytic approach based on modeling the log-linear decay of parasitemia following drug treatment was developed to determine the parasite reduction ratio (PRR) and parasite clearance half-life, both measures of parasite clearance. This analytic approach was then validated with data from 8 subjects enrolled in a second study with the licensed antimalarial drug mefloquine. By this method, the PRR and parasite clearance half-lives for S/P and Mefloquine were determined to be 38,878 (95% confidence interval [95% CI], 17,396 to 86,889) at 3.15 (95% CI, 2.93 to 3.41) days and 157 (95% CI, 130 to 189) at 6.58 (95% CI, 6.35 to 6.83) days for the respective studies. No serious adverse events occurred in the two trials, and pharmacokinetic values were within expected ranges for sulfadoxine and pyrimethamine. The robust statistical method that we have developed to analyze qPCR-derived pharmacodynamic data from CHMI studies will facilitate the assessment of the activity of a range of experimental antimalarial drugs now entering clinical trials. (This trial was registered with the Australian New Zealand Clinical Trials Registry under registration numbers ACTRN12611001203943 and ACTRN12612000323820.) PMID:25963983

  15. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria.

    PubMed

    Charman, Susan A; Arbe-Barnes, Sarah; Bathurst, Ian C; Brun, Reto; Campbell, Michael; Charman, William N; Chiu, Francis C K; Chollet, Jacques; Craft, J Carl; Creek, Darren J; Dong, Yuxiang; Matile, Hugues; Maurer, Melanie; Morizzi, Julia; Nguyen, Tien; Papastogiannidis, Petros; Scheurer, Christian; Shackleford, David M; Sriraghavan, Kamaraj; Stingelin, Lukas; Tang, Yuanqing; Urwyler, Heinrich; Wang, Xiaofang; White, Karen L; Wittlin, Sergio; Zhou, Lin; Vennerstrom, Jonathan L

    2011-03-15

    Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death. PMID:21300861

  16. Increased Uptake of HCV Testing through a Community-Based Educational Intervention in Difficult-to-Reach People Who Inject Drugs: Results from the ANRS-AERLI Study

    PubMed Central

    Roux, Perrine; Rojas Castro, Daniela; Ndiaye, Khadim; Debrus, Marie; Protopopescu, Camélia; Le Gall, Jean-Marie; Haas, Aurélie; Mora, Marion; Spire, Bruno; Suzan-Monti, Marie; Carrieri, Patrizia

    2016-01-01

    Aims The community-based AERLI intervention provided training and education to people who inject drugs (PWID) about HIV and HCV transmission risk reduction, with a focus on drug injecting practices, other injection-related complications, and access to HIV and HCV testing and care. We hypothesized that in such a population where HCV prevalence is very high and where few know their HCV serostatus, AERLI would lead to increased HCV testing. Methods The national multisite intervention study ANRS-AERLI consisted in assessing the impact of an injection-centered face-to-face educational session offered in volunteer harm reduction (HR) centers (“with intervention”) compared with standard HR centers (“without intervention”). The study included 271 PWID interviewed on three occasions: enrolment, 6 and 12 months. Participants in the intervention group received at least one face-to-face educational session during the first 6 months. Measurements The primary outcome of this analysis was reporting to have been tested for HCV during the previous 6 months. Statistical analyses used a two-step Heckman approach to account for bias arising from the non-randomized clustering design. This approach identified factors associated with HCV testing during the previous 6 months. Findings Of the 271 participants, 127 and 144 were enrolled in the control and intervention groups, respectively. Of the latter, 113 received at least one educational session. For the present analysis, we selected 114 and 88 participants eligible for HCV testing in the control and intervention groups, respectively. In the intervention group, 44% of participants reported having being tested for HCV during the previous 6 months at enrolment and 85% at 6 months or 12 months. In the control group, these percentages were 51% at enrolment and 78% at 12 months. Multivariable analyses showed that participants who received at least one educational session during follow-up were more likely to report HCV testing

  17. Increased Duration of Heating Boosts Local Drug Deposition during Radiofrequency Ablation in Combination with Thermally Sensitive Liposomes (ThermoDox) in a Porcine Model

    PubMed Central

    Swenson, Christine E.; Haemmerich, Dieter; Maul, Donald H.; Knox, Bridget; Ehrhart, Nicole; Reed, Robert A.

    2015-01-01

    Introduction Radiofrequency ablation (RFA) is used for the local treatment of liver cancer. RFA is effective for small (<3cm) tumors, but for tumors > 3 cm, there is a tendency to leave viable tumor cells in the margins or clefts of overlapping ablation zones. This increases the possibility of incomplete ablation or local recurrence. Lyso-Thermosensitive Liposomal Doxorubicin (LTLD), is a thermally sensitive liposomal doxorubicin formulation for intravenous administration, that rapidly releases its drug content when exposed to temperatures >40°C. When used with RFA, LTLD releases its doxorubicin in the vasculature around the zone of ablation-induced tumor cell necrosis, killing micrometastases in the ablation margin. This may reduce recurrence and be more effective than thermal ablation alone. Purpose The purpose of this study was to optimize the RFA procedure used in combination with LTLD to maximize the local deposition of doxorubicin in a swine liver model. Pigs were anaesthetized and the liver was surgically exposed. Each pig received a single, 50 mg/m2 dose of the clinical LTLD formulation (ThermoDox®). Subsequently, ablations were performed with either 1, 3 or 6 sequential, overlapping needle insertions in the left medial lobe with total ablation time of 15, 45 or 90 minutes respectively. Two different RFA generators and probes were evaluated. After the final ablation, the ablation zone (plus 3 cm margin) was dissected out and examined for doxorubicin concentration by LC/MS and fluorescence. Conclusion The mean Cmax of plasma total doxorubicin was 26.5 μg/ml at the end of the infusion. Overall, increased heat time from 15 to 45 to 90 minutes shows an increase in both the amount of doxorubicin deposited (up to ~100 μg/g) and the width of the ablation target margin to which doxorubicin is delivered as determined by tissue homogenization and LC/MS detection of doxorubicin and by fluorescent imaging of tissues. PMID:26431204

  18. Laser based synthesis of nanofunctionalized particulates for pulmonary based controlled drug delivery applications

    NASA Astrophysics Data System (ADS)

    Singh, R. K.; Kim, W.-S.; Ollinger, M.; Craciun, V.; Coowantwong, I.; Hochhaus, G.; Koshizaki, N.

    2002-09-01

    There is an urgent need to develop controlled drug release systems for the delivery of drugs via the pulmonary route. A key issue in pulmonary dry delivery systems is to reduce the amount of biodegradable polymers that are added to control the drug release. We have synthesized nanofunctionalized drug particles using the pulsed laser deposition on particles (PLDP) (e.g. budesonide) in an effort to control the architecture and thickness of a nanoscale polymer coating on the drug particles. In vitro studies indicated that the dry half-life release for budesonide can be enhanced from 1.2 to over 60 min by a nanoscale coating on the drug particle. Extensive studies have been conducted to characterize the bonding and composition of the polymer film deposited on drug particles.

  19. Enhancing benefits or increasing harms: community responses for HIV among men who have sex with men, transgender women, female sex workers, and people who inject drugs.

    PubMed

    Baral, Stefan; Holland, Claire E; Shannon, Kate; Logie, Carmen; Semugoma, Paul; Sithole, Bhekie; Papworth, Erin; Drame, Fatou; Beyrer, Chris

    2014-08-15

    Studies completed over the past 15 years have consistently demonstrated the importance of community-level determinants in potentiating or mitigating risks for the acquisition and transmission of HIV. Structural determinants are especially important in mediating HIV risk among key populations, including men who have sex with men, people who inject drugs, sex workers of all genders, and transgender women. The objective of this systematic review was to synthesize the evidence characterizing the community-level determinants that potentiate or mitigate HIV-related outcomes for key populations. The results of the review suggest that although health communication programs represent community-level strategies that have demonstrated the effectiveness in increasing the uptake of HIV testing and decreasing the experienced stigma among people living with HIV, there are limited studies focused on key populations in low- and middle-income settings. Moreover, interpretation from the 22 studies that met inclusion and exclusion criteria reinforce the importance of the continued measurement of community-level determinants of HIV risks and of the innovation in tools to effectively address these risks as components of the next generation of the HIV response. Consequently, the next generation of effective HIV prevention science research must improve our understanding of the multiple levels of HIV risk factors, while programming for key populations must address each of these risk levels. Failure to do so will cost lives, harm communities, and undermine the gains of the HIV response. PMID:25007203

  20. 12(S)-HETE increases intracellular Ca(2+) in lymph-endothelial cells disrupting their barrier function in vitro; stabilization by clinical drugs impairing calcium supply.

    PubMed

    Nguyen, Chi Huu; Brenner, Stefan; Huttary, Nicole; Li, Yuanfang; Atanasov, Atanas Georgiev; Dirsch, Verena M; Holzner, Silvio; Stadler, Serena; Riha, Juliane; Krieger, Sigurd; Milovanovic, Danijela; Fristiohardy, Adryan; Simonitsch-Klupp, Ingrid; Dolznig, Helmut; Saiko, Philipp; Szekeres, Thomas; Giessrigl, Benedikt; Jäger, Walter; Krupitza, Georg

    2016-09-28

    Secretion of 12(S)-HETE by breast cancer emboli provokes "circular chemorepellent induced defects" (CCIDs) in the adjacent lymphatic vasculature facilitating their intravasation and lymph node metastasis which determines prognosis. Therefore, elucidating the mechanism of lymph endothelial cell (LEC) wall disintegration may provide cues for anti-metastatic intervention. The role of intracellular free Ca(2+) for CCID formation was investigated in LECs using MCF-7 or MDA-MB231 breast cancer cell spheroids in a three-dimensional cell co-culture model. 12(S)-HETE elevated the Ca(2+) level in LEC by activating PLC/IP3. Downstream, the Ca(2+)-calmodulin kinase MYLK contributed to the phosphorylation of Ser19-MLC2, LEC contraction and CCID formation. Approved clinical drugs, lidoflazine, ketotifen, epiandrosterone and cyclosporine, which reportedly disturb cellular calcium supply, inhibited 12(S)-HETE-induced Ca(2+) increase, Ser19-MLC2 phosphorylation and CCID formation. This treatment strategy may reduce spreading of breast cancer through lymphatics. PMID:27390016

  1. Plasma sterilization of poly lactic acid ultrasound contrast agents: surface modification and implications for drug delivery.

    PubMed

    Eisenbrey, John R; Hsu, Jennifer; Wheatley, Margaret A

    2009-11-01

    Poly lactic acid (PLA) ultrasound contrast agents (CA) have been developed previously in our laboratory for ultrasound (US) imaging, as well as surface coated with doxorubicin to create a potential targeted platform of chemotherapeutic delivery using focused US. However, we have previously found it impossible to sterilize these agents while at the same time maintaining their acoustic properties, a task that would probably require fabrication within a clean facility. The purpose of this paper is to investigate the feasibility of using plasma to sterilize these CA while maintaining maximum echogenicity, a step that would greatly facilitate in vivo investigations. Effects of plasma exposure time (1, 3 and 6 min) and intensity (low-10 mA, 6.8 W; medium-15 mA, 10.5 W; and high-25 mA, 18 W) on the CAs' acoustic properties, surface morphology, zeta potential, capacity to carry chemotherapeutics and overall sterility are described. Both increases in plasma intensity and exposure time increased CA zeta potential and also significantly increased drug payload. High-intensity plasma exposure for 3 min was found to be an optimal sterilization protocol for maximal (100%) preservation of CA echogenicity. Plasma exposure resulted in sterile samples and maintained original CA enhancement of 20 dB and acoustic half-life over 75 min, while increasing CA zeta potential by 11 mV and doxorubicin loading efficiency by 10%. This study not only shows how a highly temperature- and pressure-sensitive agent can be sterilized using plasma, but also that surface modification can be used to increase surface binding of the drug. PMID:19766380

  2. Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell

    SciTech Connect

    Xu, Ning; Zhang, Jianjun; Shen, Conghuan; Luo, Yi; Xia, Lei; Xue, Feng; Xia, Qiang

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer miR-199a-5p levels were significantly decreased after cisplatin treatment. Black-Right-Pointing-Pointer Cisplatin treatment induced autophagy activation. Black-Right-Pointing-Pointer Cisplatin-induced downregulation of miR-199a-5p increases drug resistance by activating autophagy in HCC cell. -- Abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In the study, we found that miR-199a-5p levels were significantly reduced in HCC patients treated with cisplatin-based chemotherapy. Cisplatin treatment also resulted in decreased miR-199a-5p levels in human HCC cell lines. Forced expression of miR-199a-5p promoted cisplatin-induced inhibition of cell proliferation. Cisplatin treatment activated autophagy in Huh7 and HepG2 cells, which increased cell proliferation. We further demonstrated that downregulated miR-199a-5p enhanced autophagy activation by targeting autophagy-associated gene 7 (ATG7). More important, autophagy inhibition abrogated miR-199a-5p downregulation-induced cell proliferation. These data demonstrated that miR-199a-5p/autophagy signaling represents a novel pathway regulating chemoresistance, thus offering a new target for chemotherapy of HCC.

  3. Erbium:YAG laser resurfacing increases skin permeability and the risk of excessive absorption of antibiotics and sunscreens: the influence of skin recovery on drug absorption.

    PubMed

    Lee, Woan-Ruoh; Shen, Shing-Chuan; Al-Suwayeh, Saleh A; Li, Yi-Ching; Fang, Jia-You

    2012-06-01

    While laser skin resurfacing is expected to result in reduced barrier function and increased risk of drug absorption, the extent of the increment has not yet been systematically investigated. We aimed to establish the skin permeation profiles of tetracycline and sunscreens after exposure to the erbium:yttrium-aluminum-garnet (Er:YAG) laser during postoperative periods. Physiological and histopathological examinations were carried out for 5 days after laser treatment on nude mice. Percutaneous absorption of the permeants was determined by an in vitro Franz cell. Ablation depths varied in reaching the stratum corneum (10 μm, 2.5 J/cm²) to approach the epidermis (25 μm, 6.25 J/cm²) and upper dermis (40 μm, 10 J/cm²). Reepithelialization evaluated by transepidermal water loss was complete within 2-4 days and depended on the ablation depth. Epidermal hyperplasia was observed in the 40-μm-treated group. The laser was sufficient to disrupt the skin barrier and allow the transport of the permeants into and across the skin. The laser fluence was found to play an important role in modulating skin absorption. A 25-μm ablation depth increased tetracycline flux 84-fold. A much smaller enhancement (3.3-fold) was detected for tetracycline accumulation within the skin. The laser with different fluences produced enhancement of oxybenzone skin deposition of 3.4-6.4-fold relative to the untreated group. No penetration across the skin was shown regardless of whether titanium dioxide was applied to intact or laser-treated skin. However, laser resurfacing increased the skin deposition of titanium dioxide from 46 to 109-188 ng/g. Tetracycline absorption had recovered to the level of intact skin after 5 days, while more time was required for oxybenzone absorption. The in vivo skin accumulation and plasma concentration revealed that the laser could increase tetracycline absorption 2-3-fold. The experimental results indicated that clinicians should be cautious when determining the

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

    PubMed

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

    2015-07-01

    Whether mini-tablets (tablets, diameters ≤6mm) belong to single- or multiple-unit dosage forms is still questionable. Accordingly, Pharmacopoeial evaluation procedures for mini-tablets are lacking. In this study, the aforementioned points were discussed. Moreover, their potential for oral controlled delivery was assessed. The antidepressant venlafaxine hydrochloride (Vx), a highly soluble drug undergoing first pass effect, low bioavailability and short half-life was selected as a challenging payload. In an attempt to weigh up mini-tablets versus pellets as multiparticulate carriers, Vx-loaded mini-tablets were compared to formulated pellets of the same composition and the innovator Effexor(®)XR pellets. Formulations were prepared using various polymer hydrogels in the core and ethyl cellulose film coating with increasing thickness. Mini-tablets (diameter 2mm) showed extended Vx release (<60%, 8h). Indeed, release profiles comparable to Effexor(®)XR pellets were obtained. Remarkably higher coating thickness was required for pellets to provide equivalent retardation. Ethyl cellulose in the core ensured faster release due to polymer migration to the surface and pore formation in the coat. mini-tablets showed higher stability to pellets upon storage. Industrially speaking, mini-tablets proved to be superior to pellets in terms of manufacturing, product quality and economical aspects. Results point out the urgent need for standardized evaluation procedures for mini-tablets. PMID:25869450

  5. Plasma drug concentrations and physiological measures in 'dance party' participants.

    PubMed

    Irvine, Rodney J; Keane, Michael; Felgate, Peter; McCann, Una D; Callaghan, Paul D; White, Jason M

    2006-02-01

    The increasing use of (+/-) 3,4-methylenedioxymethamphetamine (MDMA) in the setting of large dance parties ('raves') and clubs has been the source of some concern, because of potential acute adverse events, and because animal studies suggest that MDMA has the potential to damage brain serotonin (5-HT) neurons. However, it is not yet known whether MDMA, as used in the setting of dance parties, leads to plasma levels of MDMA that are associated with toxicity to 5-HT neurons in animals. The present study sought to address this question. Plasma MDMA concentrations, vital signs, and a variety of blood and urine measures were obtained prior to, and hours after, individuals attended a dance party. After the dance party, subjects were without clinical complaints, had measurable amounts of residual MDMA in plasma, and nearly half of the subjects also tested positive for methamphetamine, another amphetamine analog that has been shown to have 5-HT neurotoxic potential in animals. Plasma concentrations of MDMA did not correlate with self-reported use of 'ecstasy' and, in some subjects, overlapped with those that have been associated with 5-HT neurotoxicity in non-human primates. Additional subjects were likely to have had similar concentrations while at the dance party, when one considers the reported time of drug ingestion and the plasma half-life of MDMA in humans. Hematological and biochemical analyses were generally unremarkable. Moderate increases in blood pressure, heart rate and body temperature were observed in the subjects with the highest MDMA plasma concentrations. These findings are consistent with epidemiological findings that most people who use MDMA at dance parties do not develop serious clinical complications, and suggest that some of these individuals may be at risk for developing MDMA-induced toxicity to brain serotonin neurons. PMID:16192986

  6. Post-insertion of poloxamer 188 strengthened liposomal membrane and reduced drug irritancy and in vivo precipitation, superior to PEGylation.

    PubMed

    Zhang, Wenli; Wang, Guangji; See, Esther; Shaw, John P; Baguley, Bruce C; Liu, Jianping; Amirapu, Satya; Wu, Zimei

    2015-04-10

    The ultimate aim of this study was to develop asulacrine (ASL)-loaded long-circulating liposomes to prevent phlebitis during intravenous (i.v.) infusion for chemotherapy. Poly(ethylene)glycol (PEG) and poloxamer 188-modified liposomes (ASL-PEGL and ASL-P188L) were developed, and ASL was loaded using a remote loading method facilitated with a low concentration of sulfobutyl ether-β-cyclodextrin as a drug solubilizer. The liposomes were characterized in terms of morphology, size, release properties and stability. Pharmacokinetics and venous tissue tolerance of the formulations were simultaneously studied in rabbits following one-hour i.v. infusion via the ear vein. The irritancy was assessed using a rat paw-lift/lick model after subplantar injections. High drug loading 9.0% w/w was achieved with no drug leakage found from ASL-PEGL or ASL-P188L suspended in a 5% glucose solution at 30days. However, a rapid release (leakage) from ASL-PEGL was observed when PBS was used as release medium, partially related to the use of cyclodextrin in drug loading. Post-insertion of poloxamer 188 to the liposomes appeared to be able to restore the drug retention possibly by increasing the packing density of phospholipids in the membrane. In rabbits (n=5), ASL-P188L had a prolonged half-life with no drug precipitation or inflammation in the rabbit ear vein in contrast to ASL solution. Following subplantar (footpad) injections in rats ASL solution induced paw-lick/lift responses in all rats whereas ASL-P188L caused no response (n=8). PEGylation showed less benefit possibly due to the drug 'leakage'. In conclusion, drug precipitation in the vein and the drug mild irritancy may both contribute to the occurrence of phlebitis caused by the ASL solution, and could both be prevented by encapsulation of the drug in liposomes. Poloxamer 188 appeared to be able to 'seal' the liposomal membrane and enhance drug retention. The study also highlighted the importance of bio-relevant in vitro release

  7. [Therapeutic drug monitoring of felbamate].

    PubMed

    Tribut, Olivier; Bentué-Ferrer, Danièle; Verdier, Marie-Clémence

    2010-01-01

    Felbamate is a derivative of meprobamate used in second-line partial epilepsy and in the Lennox-Gastaut syndrome. Felbamate is well absorbed and has linear kinetics: C(max) and AUC increasing linearly with dose. The metabolism takes place in the liver. Metabolites represent 40 to 60% of excretion and are eliminated via the urine. The half-life is between 15 and 23 hours. Clearance is dependent on renal function. There is a concentration - efficacy and concentration - toxicity relationship. These arguments are in favour of a TDM but the therapeutic range is not clearly established. Potentially fatal side effects can be caused by felbamate (aplastic anemia, acute liver failure), which limits its use because they are dose-independant. PMID:20205993

  8. Second-phase hepatitis C virus RNA decline during telaprevir-based therapy increases with drug effectiveness: implications for treatment duration.

    PubMed

    Guedj, Jeremie; Perelson, Alan S

    2011-06-01

    Hepatitis C virus (HCV) RNA decay during antiviral therapy is characterized by a rapid first phase, followed by a slower second phase. The current understanding of viral kinetics attributes the magnitude of the first phase of decay to treatment effectiveness, whereas the second phase of decay is attributed to the progressive loss of infected cells. Here, we analyzed data from 44 patients treated with telaprevir, a potent HCV protease inhibitor. Using a viral kinetic model that accounts for the pharmacokinetics of telaprevir, we found the second-phase slope of viral decline to be strongly correlated with treatment effectiveness and to be roughly four-fold more rapid than has been reported with interferon-based therapies. Because telaprevir is not known to increase the death rate of infected cells, our results suggest that the second-phase slope of viral decline is driven not only by the death of infected cells, but may also involve other mechanisms, such as a treatment-effectiveness-dependent degradation of intracellular viral RNA. As a result of the enhanced viral decay caused by the high antiviral effectiveness of telaprevir, we predict that if drug resistance could be avoided by using an appropriate combination of antiviral agents, treatment duration needed to clear HCV might be dramatically shortened. Indeed, we predict that in 95% of fully compliant patients, the last virus particle should be eliminated by week 7 of therapy. If the remaining infected hepatocytes act as a potential reservoir for the renewal of infection, no more than 10 weeks of treatment should be sufficient to clear the infection in 95% of fully compliant patients. However, if patients miss doses, treatment duration would need to be extended. PMID:21384401

  9. Pharmacokinetics of naftopidil, a novel anti-hypertensive drug, in patients with hepatic dysfunction.

    PubMed Central

    Farthing, M. J.; Alstead, E. M.; Abrams, S. M.; Haug, G.; Johnston, A.; Hermann, R.; Niebch, G.; Ruus, P.; Molz, K. H.; Turner, P.

    1994-01-01

    The pharmacokinetics of naftopidil, a novel alpha-1 adrenoceptor-blocking antihypertensive, were investigated in ten patients (9M/1F) with hepatic dysfunction after oral administration (50 mg, tablet) and after an intravenous infusion of 5.0 mg over 2 minutes. Results were compared to a control group of 12 healthy subjects (6M/6F) of a previous investigation, which was carried out according to the identical study protocol. The pharmacokinetic parameters obtained for the i.v. administration were comparable in both groups (half life 3.6 +/- 3.4 hours in liver-impaired subjects versus 3.3 +/- 2.1 hours in controls; clearance 11.9 +/- 4.7 ml/minute/kg versus 11.0 +/- 1.6 ml/minute/kg). Following oral administration the plasma levels and half-life times of naftopidil were significantly increased in liver impairment (t1/2 16.6 +/- 19.3 hours versus 5.4 +/- 3.2 hours in controls; P = 0.012). Mean values for the absolute bioavailability in patients with hepatic dysfunction were significantly higher (mean 75%, median 53%, range 13.4-211.0%) compared to healthy subjects (mean 17%, median 16%, range 6.7-29.6%, P = 0.001). Reduction of functional hepatic blood flow in chronic liver disease or, as evidenced in one case as a consequence of shunt surgery, is the probable cause of the observed alteration in naftopidil kinetics. This phenomenon occurred only following the oral 50 mg dose whereas the intravenous 5 mg dose obviously still could be normally handled. Naftopidil demethylation and hydroxylation were both less and non-uniformly affected. The pharmacokinetic findings suggest that in patients with severe hepatic impairment or evidence for marked changes in hepatic blood flow the dose of naftopidil may require adjustment to the lower end of the therapeutic range and/or may be limited to once daily. However, before definite conclusions can be drawn, further steady-state studies are required. Despite the pharmacokinetic discrepancies no difference in drug tolerability was seen

  10. Smart blood cell and microvesicle-based Trojan horse drug delivery: Merging expertise in blood transfusion and biomedical engineering in the field of nanomedicine.

    PubMed

    Wu, Yu-Wen; Goubran, Hadi; Seghatchian, Jerard; Burnouf, Thierry

    2016-04-01

    Therapeutic and diagnostic applications of nanomedicine are playing increasingly important roles in human health. Various types of synthetic nanoparticles, including liposomes, micelles, and other nanotherapeutic platforms and conjugates, are being engineered to encapsulate or carry drugs for treating diseases such as cancer, cardiovascular disorders, neurodegeneration, and inflammations. Nanocarriers are designed to increase the half-life of drugs, decrease their toxicity and, ideally, target pathological sites. Developing smart carriers with the capacity to deliver drugs specifically to the microenvironment of diseased cells with minimum systemic toxicity is the goal. Blood cells, and potentially also the liposome-like micro- and nano-vesicles they generate, may be regarded as ideally suited to perform such specific targeting with minimum immunogenic risks. Blood cell membranes are "decorated" with complex physiological receptors capable of targeting and communicating with other cells and tissues and delivering their content to the surrounding pathological microenvironment. Blood cells, such as erythrocytes, have been developed as permeable carriers to release drugs to diseased tissues or act as biofactory allowing enzymatic degradation of a pathological substrate. Interestingly, attempts are also being made to improve the targeting capacity of synthetic nanoparticles by "decorating" their surface with blood cell membrane receptor-like biochemical structures. Research is needed to further explore the benefits that blood cell-derived microvesicles, as a Trojan horse delivery systems, can bring to the arsenal of therapeutic micro- and nanotechnologies. This short review focuses on the therapeutic roles that red blood cells and platelets can play as smart drug-delivery systems, and highlights the benefits that blood transfusion expertise can bring to this exciting and novel biomedical engineering field. PMID:27179926

  11. Recent Applications of Liposomes in Ophthalmic Drug Delivery

    PubMed Central

    Mishra, Gyan P.; Bagui, Mahuya; Tamboli, Viral; Mitra, Ashim K.

    2011-01-01

    Liposomal formulations were significantly explored over the last decade for the ophthalmic drug delivery applications. These formulations are mainly composed of phosphatidylcholine (PC) and other constituents such as cholesterol and lipid-conjugated hydrophilic polymers. Liposomes are biodegradable and biocompatible in nature. Current approaches for topical delivery of liposomes are focused on improving the corneal adhesion and permeation by incorporating various bioadhesive and penetration enhancing polymers. In the case of posterior segment disorders improvement in intravitreal half life and targeted drug delivery to the retina is achieved by liposomes. In this paper we have attempted to summarize the applications of liposomes in the field of ophthalmic drug delivery by citing numerous investigators over the last decade. PMID:21490757

  12. Increased Access to Care and Appropriateness of Treatment at Private Sector Drug Shops with Integrated Management of Malaria, Pneumonia and Diarrhoea: A Quasi-Experimental Study in Uganda

    PubMed Central

    Awor, Phyllis; Wamani, Henry; Tylleskar, Thorkild; Jagoe, George; Peterson, Stefan

    2014-01-01

    Introduction Drug shops are a major source of care for children in low income countries but they provide sub-standard care. We assessed the feasibility and effect on quality of care of introducing diagnostics and pre-packaged paediatric-dosage drugs for malaria, pneumonia and diarrhoea at drug shops in Uganda. Methods We adopted and implemented the integrated community case management (iCCM) intervention within registered drug shops. Attendants were trained to perform malaria rapid diagnostic tests (RDTs) in each fever case and count respiratory rate in each case of cough with fast/difficult breathing, before dispensing recommended treatment. Using a quasi-experimental design in one intervention and one non-intervention district, we conducted before and after exit interviews for drug seller practices and household surveys for treatment-seeking practices in May–June 2011 and May–June 2012. Survey adjusted generalized linear models and difference-in-difference analysis was used. Results 3759 (1604 before/2155 after) household interviews and 943 (163 before/780 after) exit interviews were conducted with caretakers of children under-5. At baseline, no child at a drug shop received any diagnostic testing before treatment in both districts. After the intervention, while no child in the non-intervention district received a diagnostic test, 87.7% (95% CI 79.0–96.4) of children with fever at the intervention district drug shops had a parasitological diagnosis of malaria, prior to treatment. The prevalence ratios of the effect of the intervention on treatment of cough and fast breathing with amoxicillin and diarrhoea with ORS/zinc at the drug shop were 2.8 (2.0–3.9), and 12.8 (4.2–38.6) respectively. From the household survey, the prevalence ratio of the intervention effect on use of RDTs was 3.2 (1.9–5.4); Artemisinin Combination Therapy for malaria was 0.74 (0.65–0.84), and ORS/zinc for diarrhoea was 2.3 (1.2–4.7). Conclusion iCCM can be utilized to improve

  13. Reversal of medetomidine-induced sedation in reind