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Sample records for agents mycophenolic acid

  1. Synthesis and biological activity of ester derivatives of mycophenolic acid and acridines/acridones as potential immunosuppressive agents.

    PubMed

    Cholewinski, Grzegorz; Iwaszkiewicz-Grzes, Dorota; Trzonkowski, Piotr; Dzierzbicka, Krystyna

    2016-12-01

    Improved derivatives of mycophenolic acid (MPA) are necessary to reduce the frequency of adverse effects, this drug exerts in treated patients. In this study, MPA was coupled with N-(ω-hydroxyalkyl)-9-acridone-4-carboxamides or N-(ω-hydroxyalkyl)acridine-4-carboxamides to give respective ester conjugates upon Yamaguchi protocol. This esterification required protection of phenol group in MPA. Designed conjugates revealed higher potency in vitro than parent MPA. Acridine derivatives were more active than acridone analogs and length of the alkyl linker between MPA and heterocyclic units influenced the observed cytotoxicity. Derivatives 2b, 2d, 3a, 3b displayed the most promising immunosuppressive activity.

  2. Mycophenolic Acid Production by Penicillium brevicompactum on Solid Media

    PubMed Central

    Bartman, C. D.; Doerfler, D. L.; Bird, B. A.; Remaley, A. T.; Peace, J. N.; Campbell, I. M.

    1981-01-01

    When grown on Czapek-Dox agar, Penicillium brevicompactum produced mycophenolic acid after a vegetative mycelium had been formed and as aerial hyphae were developing. Nutrients were still plenteous in the agar when the synthesis began. If aerial hyphal development was prevented by placing a dialysis membrane over the growing fungus, no mycophenolic acid was produced. When the dialysis membrane was peeled back and, as a consequence, production of aerial hyphae began, mycophenolic acid biosynthesis was observed. We concluded that mycophenolic acid was produced only by P. brevicompactum colonies that possessed an aerial mycelium. PMID:16345733

  3. Production of mycophenolic acid by Penicillium roqueforti strains.

    PubMed Central

    Lafont, P; Debeaupuis, J P; Gaillardin, M; Payen, J

    1979-01-01

    Sixteen strains of Penicillium roqueforti Thom, isolated from blue-molded cheeses, were studied. In vitro, all of these strains produced mycophenolic acid, some on the order of 0.8 to 4 mg/g od dry culture. The greatest yields were obtained after 10 days of incubation of cultures at 15 degrees C. However, under some experimental conditions, mycophenolic acid was not alone responsible for the toxicity of culture extracts to chicken embryos. PMID:453818

  4. Bioavailability of a generic of the immunosuppressive agent mycophenolate mofetil in pediatric patients.

    PubMed

    González-Ramírez, Rodrigo; González-Bañuelos, Jessica; Villa, María de la Salud; Jiménez, Braulio; García-Roca, Pilar; Cruz-Antonio, Leticia; Castañeda-Hernández, Gilberto; Medeiros, Mara

    2014-09-01

    The use of generic immunosuppressive agents is controversial, especially for the treatment of pediatric patients, as information on the bioavailability of generic immunosuppressants in children is particularly scarce. The aim of the study was to compare the bioavailabilities of two products containing mycophenolate mofetil, the innovator and a generic, in children. Pediatric patients with end-stage renal disease on the waiting list for renal transplantation received a single oral dose of mycophenolate mofetil as either the innovator product (CellCept(®) , Roche) or the generic (Tevacept(®) , Teva Pharmaceuticals). A nine point pharmacokinetic profile was obtained. Mycophenolic acid concentration was quantitated in plasma by HPLC, plasma concentration-against-time curves were constructed, and bioavailability parameters were determined. Pharmaceutical quality analysis of both formulations, including drug content and dissolution profile, was also performed. There were no statistically significant differences between formulations in bioavailability parameters. Interindividual variability was very important, but individual values of AUC, an indicator of the extent of drug absorption, were within the same range for both formulations. The two formulations exhibited similar drug content and dissolution profiles, as well as comparable mycophenolic acid plasma levels in an end-stage renal failure population. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Mycophenolate

    MedlinePlus

    ... attack of the transplanted organ by the immune system of the person receiving the organ) in people ... agents. It works by weakening the body's immune system so it will not attack and reject the ...

  6. Mycophenolic acid production by Penicillium brevicompactum in two media.

    PubMed

    Doerfler, D L; Bartman, C D; Campbell, I M

    1979-08-01

    Penicillium brevicompactum produces mycophenolic acid as it grows vegetatively, not only on a simple medium where growth is slow but also on a richer medium where growth is less restricted. The implications of this finding on the association of fungal secondary metabolism with the idiophase in liquid and solid culture are discussed.

  7. Determination of mycophenolic acid and mycophenolate mofetil by high-performance liquid chromatography using postcolumn derivatization.

    PubMed

    Renner, U D; Thiede, C; Bornhäuser, M; Ehninger, G; Thiede, H M

    2001-01-01

    An efficient method to lower the optical detection limit is described using the displacement of an absorption and emission band of an analyte after a polarity change in different solvents. This solvatochromic effect was used in a RP-HPLC assay for the fluorescence detection of mycophenolic acid (6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acid, MPA) and the prodrug mycophenolate mofetil (MMF), the N-(2-hydroxyethyl)morpholino ester of MPA. The rational to use fluorescence detection is based on the behavior of MMF and MPA, which fluoresce in a basic medium (pH >9.5). Following a simple protein precipitation, the analytes were separated in an isocratic RP-HPLC system. The postcolumn generation of the phenolate anions of MPA and MMF was achieved by addition of an aqueous sodium hydroxide solution regulated by a newly developed continuous-flow liquid control system. MPAG, not directly accessible for fluorescence detection, was analyzed after enzymatic deglucuronidation to MPA. Compared to published quantification limits for MPA and MMF by UV detection, this method is more than 100-fold more sensitive, with a lower limit of quantification of 45 fmol for both MPA and MMF.

  8. Applications of ultrasound to enhance mycophenolic acid production.

    PubMed

    Zhao, Yupeng; Ang, Woon T; Xing, James; Zhang, Jian; Chen, Jie

    2012-09-01

    Reducing production costs for fermentation-based drugs (e.g., antibiotics) is crucial for the long-term sustainability of healthcare. In this study, we propose a novel low-intensity pulsed ultrasound (LIPUS) stimulation scheme using a nominal frequency of 1.5 MHz with a 20% duty cycle (200 μs ultrasound on and 800 μs ultrasound off) to increase production of fermentation-based drugs. We chose Penicillium brevicompactum as a model system to demonstrate the performance of our LIPUS system. Penicillium brevicompactum can produce mycophenolic acid (MPA), an immunosuppressive agent commonly used to prevent rejection after organ transplantation. We have stimulated Penicillium brevicompactum in 50 mL shake flasks using LIPUS during its fermentation. After a series of screening experiments to optimize ultrasound parameters (e.g., ultrasound intensities, treatment duration and treatment frequency per day), it was concluded that ultrasound stimulation can increase MPA production by as much as 60% when treated eight times a day for 10-min durations at an intensity (spatial peak temporal average) of 200 mW/cm(2). These findings elucidate a new approach to reduce the cost of producing fermentation-based drugs. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

  9. Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

    PubMed

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

  10. Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

    PubMed Central

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  11. Mycophenolic Acid-Induced Developmental Defects in Zebrafish Embryos.

    PubMed

    Jiang, Ling-Ling; Liu, Mei-Hui; Li, Jian-Ying; He, Zhi-Heng; Li, Huan; Shen, Ning; Wei, Ping; He, Ming-Fang

    2016-11-01

    With the increasing use of mycophenolic acid (MPA) in solid organ transplantation, some clinical studies indicate that it is also a human teratogen. However, it is unknown by which mechanism MPA acts as a teratogen. Mycophenolic acid was a selective blocker of de novo purine synthesis, and its immunosuppressive effect is mediated by the inhibition of inosine monophosphate dehydrogenase, which could be a target for MPA-induced toxicity as well. The aim of our study was to examine the direct influence of MPA exposure on zebrafish (Danio rerio) embryos. Morphological defects including tail curvature and severe pericardial edema in zebrafish embryos caused by MPA (3.7-11.1 µmol/L) were found in a dose-dependent manner. The teratogenic index (25% lethal concentration value (LC25)/no observed adverse effect level ratio) was 16, which indicated MPA as a teratogen. Quantitative polymerase chain reaction analysis revealed that the expression level of impdh1b and impdh2 was significantly reduced by MPA treatment at 8 µmol/L (equals to LC25 level). All the toxic effects could be partially reversed by the addition of 33.3 µmol/L guanosine. Our results indicated that MPA impairs the development of zebrafish embryos via inhibition of impdh activity, which subsequently caused a guanosine nucleotide depletion in vivo.

  12. Determination of mycophenolic acid, penicillic acid, patulin, sterigmatocystin, and aflatoxins in cheese.

    PubMed

    Siriwardana, M G; Lafont, P

    1979-07-01

    A method has been developed for detection of aflatoxins, mycophenolic acid, patulin, penicillic acid, and sterigmatocystin in cheese. It is based on selective extraction with a mixture of equal volumes of 5% sodium chloride, methanol, and aceton, precipitation of caseins at -25 C, defatting with hexane, and removal of extraneous matter by transfer of mycotoxins to chloroform and ethyl acetate. The extract is purified further by column chromatography. Mycotoxins are quantitated on thin layer chromatograms by fluorescence comparisons. Mycophenolic acid, patulin, and penicillic acid are visualized with diethylamine. The limits of detection in cheese are about 20 micrograms/kg for mycophenolic acid, patulin, and sterigmatocystin, 30 microgram/kg for pencillic acid, and 1 microgram/kg for aflatoxins B1 and M1.

  13. Kinetically controlled drug resistance: how Penicillium brevicompactum survives mycophenolic acid.

    PubMed

    Sun, Xin E; Hansen, Bjarne Gram; Hedstrom, Lizbeth

    2011-11-25

    The filamentous fungus Penicillium brevicompactum produces the immunosuppressive drug mycophenolic acid (MPA), which is a potent inhibitor of eukaryotic IMP dehydrogenases (IMPDHs). IMPDH catalyzes the conversion of IMP to XMP via a covalent enzyme intermediate, E-XMP*; MPA inhibits by trapping E-XMP*. P. brevicompactum (Pb) contains two MPA-resistant IMPDHs, PbIMPDH-A and PbIMPDH-B, which are 17- and 10(3)-fold more resistant to MPA than typically observed. Surprisingly, the active sites of these resistant enzymes are essentially identical to those of MPA-sensitive enzymes, so the mechanistic basis of resistance is not apparent. Here, we show that, unlike MPA-sensitive IMPDHs, formation of E-XMP* is rate-limiting for both PbIMPDH-A and PbIMPDH-B. Therefore, MPA resistance derives from the failure to accumulate the drug-sensitive intermediate.

  14. Molecular basis for mycophenolic acid biosynthesis in Penicillium brevicompactum.

    PubMed

    Regueira, Torsten Bak; Kildegaard, Kanchana Rueksomtawin; Hansen, Bjarne Gram; Mortensen, Uffe H; Hertweck, Christian; Nielsen, Jens

    2011-05-01

    Mycophenolic acid (MPA) is the active ingredient in the increasingly important immunosuppressive pharmaceuticals CellCept (Roche) and Myfortic (Novartis). Despite the long history of MPA, the molecular basis for its biosynthesis has remained enigmatic. Here we report the discovery of a polyketide synthase (PKS), MpaC, which we successfully characterized and identified as responsible for MPA production in Penicillium brevicompactum. mpaC resides in what most likely is a 25-kb gene cluster in the genome of Penicillium brevicompactum. The gene cluster was successfully localized by targeting putative resistance genes, in this case an additional copy of the gene encoding IMP dehydrogenase (IMPDH). We report the cloning, sequencing, and the functional characterization of the MPA biosynthesis gene cluster by deletion of the polyketide synthase gene mpaC of P. brevicompactum and bioinformatic analyses. As expected, the gene deletion completely abolished MPA production as well as production of several other metabolites derived from the MPA biosynthesis pathway of P. brevicompactum. Our work sets the stage for engineering the production of MPA and analogues through metabolic engineering.

  15. Risk evaluation and mitigation strategies: a focus on the mycophenolic acid preparations.

    PubMed

    Rostas, Sara; Kim, Miae; Gabardi, Steven

    2014-03-01

    To review risks associated with mycophenolic acid (MPA) preparations and evaluate their required risk evaluation and mitigation strategies (REMS) elements. Articles were identified through a non-date-limited MEDLINE and EMBASE search using the terms fetal toxicity, teratogenicity, risk evaluation and mitigation strategies, REMS, MPA, mycophenolate mofetil, entericcoated MPA, and organ transplant. Information from the Food and Drug Administration (FDA) and the manufacturers of the MPA preparations was also evaluated. The MPA preparations are associated with several potential risks, including gastrointestinal disturbances and myelosuppression; however, their impact on the fetus in pregnant patients taking 1 of these agents poses the greatest risk. The FDA approved REMS programs for all MPA products, both innovator and generic preparations, in September 2012. With evidence of increased risk of miscarriage and birth defects associated with MPA use, the FDA instituted a REMS program that contains both a medication guide and elements to assure safe use (ETASU). The medication guides for the MPA products, which were previously FDA approved, should continue to be distributed to patients who get either an initial prescription filled or a refill. The ETASU requires prescribers to complete training and obtain patient signatures on the Patient-Prescriber Acknowledgment Form. A single, national, voluntary pregnancy registry specific to this medication has been established, and pregnant patients should be encouraged to participate. Although the impact of the MPA REMS on clinical practice is not clear, it is a step toward increasing the understanding of fetal risks with MPA.

  16. Pharmacokinetics of mycophenolic acid in kidney transplant recipients treated with a low dose (1 gram/day) of mycophenolate mofetil.

    PubMed

    Julasareekul, Wichian; Eiam-Ong, Somchai; Bejraputra, Ornanong; Seublinvong, Tada

    2003-08-01

    Pharmacokinetic studies of mycophenolic acid (MPA) were performed in 16 stable Thai kidney transplant recipients treated with 1 g/d of mycophenolate mofetil (MMF). The complete area under the blood concentration-time curve (AUC) of MPA was determined using the linear trapezoidal rule from 8 concentrations at, 0, 1, 2, 3, 4, 6, 8, and 12 h after MMF administration. The mean values of AUC(0-12) were 37.54 + 0.80 microg x h/ml. MPA concentrations at 8 h after dosing, not the trough or maximum levels, showed the best correlation with AUC(0-12) (r2 = 0.72). The equation model of abbreviated AUC of MPA, derived by multiple linear regression analysis, that had the highest correlation (r2) and lowest absolute prediction error (APE) was: AUC = 0.6 C1 + 1.9 C3 + 8.68 C8 + 4.65 (r2 = 0.92, APE = 2.05 +/- 0.32%). The best abbreviated AUC equations obtained by linear trapezoidal rule were: AUC = 4.5 C0 + C1 + 1.5 C2 + 5 C4 (r2 = 0.78, APE = 5.78 +/- 1.14%) and AUC = 5 C0 + C1 + C2 + 5 C3 (r2 = 0.76, APE = 6.21 +/- 1.46%).

  17. Pharmacokinetic Assessment of Drug‐Drug Interactions of Isavuconazole With the Immunosuppressants Cyclosporine, Mycophenolic Acid, Prednisolone, Sirolimus, and Tacrolimus in Healthy Adults

    PubMed Central

    Groll, Andreas H.; Desai, Amit; Han, David; Howieson, Corrie; Kato, Kota; Akhtar, Shahzad; Kowalski, Donna; Lademacher, Christopher; Lewis, William; Pearlman, Helene; Mandarino, Debra; Yamazaki, Takao

    2016-01-01

    Abstract This report summarizes phase 1 studies that evaluated pharmacokinetic interactions between the novel triazole antifungal agent isavuconazole and the immunosuppressants cyclosporine, mycophenolic acid, prednisolone, sirolimus, and tacrolimus in healthy adults. Healthy subjects received single oral doses of cyclosporine (300 mg; n = 24), mycophenolate mofetil (1000 mg; n = 24), prednisone (20 mg; n = 21), sirolimus (2 mg; n = 22), and tacrolimus (5 mg; n = 24) in the presence and absence of clinical doses of oral isavuconazole (200 mg 3 times daily for 2 days; 200 mg once daily thereafter). Coadministration with isavuconazole increased the area under the concentration‐time curves (AUC0–∞) of tacrolimus, sirolimus, and cyclosporine by 125%, 84%, and 29%, respectively, and the AUCs of mycophenolic acid and prednisolone by 35% and 8%, respectively. Maximum concentrations (Cmax) of tacrolimus, sirolimus, and cyclosporine were 42%, 65%, and 6% higher, respectively; Cmax of mycophenolic acid and prednisolone were 11% and 4% lower, respectively. Isavuconazole pharmacokinetics were mostly unaffected by the immunosuppressants. Two subjects experienced elevated creatinine levels in the cyclosporine study; most adverse events were not considered to be of clinical concern. These results indicate that isavuconazole is an inhibitor of cyclosporine, mycophenolic acid, sirolimus, and tacrolimus metabolism. PMID:27273343

  18. Mycophenolic acid mediated disruption of the intestinal epithelial tight junctions.

    PubMed

    Qasim, Muhammad; Rahman, Hazir; Ahmed, Raees; Oellerich, Michael; Asif, Abdul R

    2014-04-01

    Gastrointestinal toxicity is a common adverse effect of mycophenolic acid (MPA) treatment in organ transplant patients, through poorly understood mechanisms. Phosphorylation of myosin light chain 2 (MLC2) is associated with epithelial tight junction (TJ) modulation which leads to defective epithelial barrier function, and has been implicated in GI diseases. The aim of this study was to investigate whether MPA could induce epithelial barrier permeability via MLC2 regulation. Caco-2 monolayers were exposed to therapeutic concentrations of MPA, and MLC2 and myosin light chain kinase (MLCK) expression were analyzed using PCR and immunoblotting. Epithelial cell permeability was assessed by measuring transepithelial resistance (TER) and the flux of paracellular permeability marker FITC-dextran across the epithelial monolayers. MPA increased the expression of MLC2 and MLCK at both the transcriptional and translational levels. In addition, the amount of phosphorylated MLC2 was increased after MPA treatment. Confocal immunofluorescence analysis showed redistribution of TJ proteins (ZO-1 and occludin) after MPA treatment. This MPA mediated TJ disruption was not due to apoptosis or cell death. Additionally ML-7, a specific inhibitor of MLCK was able to reverse both the MPA mediated decrease in TER and the increase in FITC-dextran influx, suggesting a modulating role of MPA on epithelial barrier permeability via MLCK activity. These results suggest that MPA induced alterations in MLC2 phosphorylation and may have a role in the patho-physiology of intestinal epithelial barrier disruption and may be responsible for the adverse effects (GI toxicity) of MPA on the intestine. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Mycophenolic acid exposure after administration of mycophenolate mofetil in the presence and absence of cyclosporin in renal transplant recipients.

    PubMed

    Kuypers, Dirk R; Ekberg, Henrik; Grinyó, Josep; Nashan, Björn; Vincenti, Flavio; Snell, Paul; Mamelok, Richard D; Bouw, Rene M

    2009-01-01

    The pharmacokinetics of mycophenolic acid (MPA) are complex, with large interindividual variability over time. There are also well documented interactions with cyclosporin, and assessment of MPA exposure is therefore necessary when reducing or stopping cyclosporin therapy. Here we report on the pharmacokinetic and pharmacodynamic behaviour of MPA in renal transplant patients on standard dose, reduced dose and no cyclosporin. The CAESAR study, a prospective 12-month study in primary renal allograft recipients, was designed to determine whether mycophenolate mofetil-based regimens containing either low-dose cyclosporin or low-dose cyclosporin withdrawn by 6 months could minimize nephrotoxicity and improve renal function without an increase in acute rejection compared with a mycophenolate mofetil-based regimen containing standard-dose cyclosporin. A subset of patients from the CAESAR study contributed to this pharmacokinetic analysis of MPA exposure. Blood samples were taken over one dosing interval on day 7 and at months 3, 7 and 12 post-transplantation. The sampling time points were predose, 20, 40 and 75 minutes and 2, 3, 4, 6, 8 and 12 hours after mycophenolate mofetil dosing. Assessments included plasma concentrations of MPA and mycophenolic acid glucuronide (MPAG) and cyclosporin trough concentrations. The area under the plasma concentration-time curve (AUC) from 0 to 12 hours (AUC(12)) for MPA was the primary pharmacokinetic parameter, and the AUC(12) for MPAG was the secondary parameter. In total, 536 de novo renal allograft recipients were randomized in the CAESAR study. Of these, 114 patients were entered into the pharmacokinetic substudy and 110 patients contributed to the pharmacokinetic analysis. There was a rapid rise in MPA concentrations (median time to peak concentration 0.72-1.25 hours). At day 7 and month 3, the MPA AUC(12) values were similar in the cyclosporin withdrawal and low-dose cyclosporin groups (patients with the same cyclosporin target

  20. Disposition of Mycophenolic Acid, Brevianamide A, Asperphenamate, and Ergosterol in Solid Cultures of Penicillium brevicompactum

    PubMed Central

    Bird, B. A.; Campbell, I. M.

    1982-01-01

    When Penicillium brevicompactum was grown between layers of dialysis membrane on Czapek-Dox agar for 3 days, no synthesis of mycophenolic acid, brevianamide A, asperphenamate, or ergosterol occurred. After removal of the uppermost membrane layer, aerial mycelium developed and all four metabolites were formed. The bulk of the mycophenolic acid that was formed was excreted into the medium, the bulk of the brevianamide A and asperphenamate was found in the aerial hyphae, and ergosterol was found in both vegetative and aerial mycelia. PMID:16345939

  1. Production of Mycophenolic Acid by Penicillium brevicompactum Using Solid State Fermentation.

    PubMed

    Patel, Gopal; Patil, Mahesh D; Soni, Surbhi; Chisti, Yusuf; Banerjee, Uttam Chand

    2017-05-01

    Solid-state fermentation using the microfungus Penicillium brevicompactum for the production of mycophenolic acid is reported in this paper. Of the initial substrates tested (whole wheat, cracked wheat, long grain Basmati rice, and short grain Parmal rice), Parmal rice proved to be the best. Under initial conditions, using steamed Parmal rice with 80% (w/w) initial moisture content, a maximum mycophenolic acid concentration of 3.4 g/kg substrate was achieved in 12 days of fermentation at 25 °C. The above substrate was supplemented with the following additional nutrients (g/L packed substrate): glucose 40.0, peptone 54.0, KH2PO4 8.0, MgSO4⋅7H2O 2.0, glycine 7.0, and methionine 1.65 (initial pH 5.0). A small amount of a specified trace element solution was also added. The final mycophenolic acid concentration was increased to nearly 4 g/kg substrate by replacing glucose with molasses. Replacing Parmal rice with rice bran as substrate further improved the mycophenolic acid production to nearly 4.5 g/kg substrate.

  2. In vitro study of antiviral activity of mycophenolic acid on Brazilian orthobunyaviruses.

    PubMed

    Livonesi, Márcia Cristina; Moro de Sousa, Ricardo Luiz; Moraes Figueiredo, Luiz Tadeu

    2007-01-01

    Oropouche, Caraparu, Guama, Guaroa and Tacaiuma are ssRNA viruses that belong to the genus Orthobunyavirus and have been associated with human febrile illnesses and/or encephalitis. In this study, we evaluated the antiviral action of mycophenolic acid (MPA) on theseorthobunyaviruses to achieve a therapeutic agent to treat the diseases caused by these viruses. The in vitro antiviral evaluation to MPA was done by using plaque assay at different periods of treatment. Results showed that MPA at a concentration of 10 microg/ml has significant antiviral activity on Tacaiuma virus when treatment was initiated either 24 h before or 2 h after viral infection. Moreover, MPA has an inhibitory effect on Guama virus replication, but only when treatment was initiated before cell infection. Addition of guanosine in the culture reverted the inhibitory effect of MPA on Tacaiuma and Guama viruses, suggesting that the antiviral activity of this substance was via depletion of the intracellular guanosine pool. Our results suggest that MPA would not be a good therapeutic agent to treat the diseases caused by Oropouche, Caraparu, Guama, Guaroa, and Tacaiuma viruses. (c) 2007 S. Karger AG, Basel.

  3. Evaluation of limited sampling strategies for mycophenolic acid after mycophenolate mofetil intake in adult kidney transplant recipients.

    PubMed

    Barraclough, Katherine A; Isbel, Nicole M; Franklin, Michael E; Lee, Katie J; Taylor, Paul J; Campbell, Scott B; Petchey, William G; Staatz, Christine E

    2010-12-01

    Multiple limited sampling strategies (LSSs) have been proposed for estimation of mycophenolic acid (MPA) area under the concentration-time curve from 0 to 12 hours postdose (AUC 0-12) after mycophenolate mofetil intake. The aim of this study was to provide summary information on all published LSSs for MPA and to evaluate their predictive performance in an independent population of kidney transplant recipients. Seventy-eight LSSs for MPA were identified. Sixty-nine full AUC profiles were collected from 45 subjects (25 cotreated with cyclosporine and 20 with tacrolimus). Predicted MPA AUC 0-12, calculated by applying the relevant concentration measurements within the LSS equations, was compared with full AUC calculated by using all concentration measurements in the linear trapezoidal rule. Four error indices (median prediction error, median percentage prediction error [MPPE], root median squared prediction error, and median absolute percentage prediction error [MAPE]) were used to evaluate bias and imprecision. Twelve of the 25 LSSs for cyclosporine-cotreated recipients and one of the 53 LSSs for tacrolimus-cotreated recipients displayed acceptable (less than 15%) bias and imprecision. In the cyclosporine group, two equations demonstrated the highest predictive power, one that used four time points in the first 6 hours postdose (r2 = 0.84, MPPE 1.6%, MAPE 7.8%) and one that used four time points in the first 4 hours postdose (r2 = 0.76, MPPE -0.8%, MAPE 10.2%). In the tacrolimus group, an equation that used two time points in the first 4 hours postdose was superior (r2 = 0.80, MPPE -3.0%, MAPE 13.6%). Application of the LSSs most appropriate for cyclosporine-cotreated patients to the tacrolimus-cotreated group resulted in clinically unacceptable bias and imprecision and vice versa. High variability in performance of LSSs highlights the importance of validating any LSS before applying it to an alternative population. Attention to comedication use is of particular

  4. Intra-individual variability of mycophenolic acid concentration according to renal function in liver transplant recipients receiving mycophenolate monotherapy

    PubMed Central

    Song, Gi-Won; Jung, Dong-Hwan; Park, Gil-Chun; Ahn, Chul-Soo; Moon, Deok-Bog; Ha, Tae-Yong; Kim, Ki-Hun; Lee, Sung-Gyu

    2017-01-01

    Backgrounds/Aims Mycophenolate mofetil (MMF) has wide inter- and intra-individual variability of mycophenolic acid (MPA) after liver transplantation (LT). On this study, we aimed to analyse the intra-individual variability of MPA concentration in stable adult LT recipients receiving MMF monotherapy and develop a method to determine the target level in the situation of wide intra-individual variability. Methods This retrospective cross-sectional study included 30 LT recipients. All patients received MMF monotherapy at a dose of 500 mg twice daily for ≥2 years and were divided into two groups based on renal function. MPA concentration-associated values were presented as mean with standard deviation and coefficient of variation (CV). Results The normal renal function group (n=15) showed a mean 12-hour MPA concentration of 2.5±0.5 µg/ml (range, 1.8±0.5 to 3.6±0.7 µg/ml) and a mean CV of 20.4±7.7% (range, 8.7% to 39.4%). In the renal dysfunction group (n=15), the 12-hour MPA concentration fluctuated more widely with a mean value of 3.7±0.9 µg/ml (range, 2.8±0.8 to 5.1±1.2 µg/ml) and a mean CV of 24.5±4.9% (range, 17.1% to 37.5%). The 12-hour MPA concentration was significantly higher in the renal dysfunction group, as compared to the normal renal function group (p=0.001); whereas, the CV was not significantly different between the two groups (p=0.093). Conclusions We determined the inter- and intra-individual variability of 12-hour MPA concentration after LT. The results suggested that therapeutic drug monitoring of MPA is necessary due to the inter-individual and intra-individual variability of MMF pharmacokinetics, especially in LT recipients with renal dysfunction. PMID:28317040

  5. Influence of lansoprazole and rabeprazole on mycophenolic acid pharmacokinetics one year after renal transplantation.

    PubMed

    Miura, Masatomo; Satoh, Shigeru; Inoue, Kazuyuki; Kagaya, Hideaki; Saito, Mitsuru; Suzuki, Toshio; Habuchi, Tomonori

    2008-02-01

    Peptic ulcer disease is a common complication after organ transplantation, and long-term administration of antiulcer agents is needed in many renal transplant recipients. Although several drug interactions with mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil (MMF), have been reported, little is known about the interaction between MPA and proton pump inhibitors (PPIs). The present study investigated the drug interaction between MMF and lansoprazole or rabeprazole and the impact of cytochrome (CYP) 2C19, and multidrug resistance (MDR)1 C3435T polymorphisms on these drug interactions at 1 year after renal transplantation. Retrospectively, 61 recipients were divided into 3 groups: MMF and tacrolimus as combination immunosuppressive therapy, together with either 30 mg lansoprazole (n = 22) or 10 mg rabeprazole (n = 17), or without PPI (n = 22). One year after transplantation, plasma concentrations of MPA were measured by high-performance liquid chromatography. The mean dose-unadjusted and -adjusted Cmax of MPA with 30 mg lansoprazole were significantly lower than those without PPI (11.8 vs. 17.8 microg/mL, P = 0.0197, and 22.6 vs. 33.1 ng/mL/mg MMF, P = 0.0222, respectively). In recipients having the CYP2C19 *1/*2+*1/*3 or MDR1 C3435T CC genotype, the mean dose-adjusted AUC0-12 of MPA with 30 mg lansoprazole was significantly smaller than that with 10 mg rabeprazole or without PPI. The plasma concentration of MPA was influenced by 30 mg lansoprazole but not 10 mg rabeprazole. Because of the greater gastric acid secretion-inhibitory effect of 30 mg lansoprazole in recipients having the CYP2C19 *1/*2+*1/*3 (intermediate metabolizer) or MDR1 C3435T CC genotype, the elution and hydrolysis of MMF might be decreased. Although the clinical relevance might be minor, the fact that administration of 30 mg lansoprazole in patients having the CYP2C19 *2 or *3 allele or the MDR1 C3435T CC genotype diminishes the absorption of MPA in the

  6. Identification and Functional Analysis of the Mycophenolic Acid Gene Cluster of Penicillium roqueforti.

    PubMed

    Del-Cid, Abdiel; Gil-Durán, Carlos; Vaca, Inmaculada; Rojas-Aedo, Juan F; García-Rico, Ramón O; Levicán, Gloria; Chávez, Renato

    2016-01-01

    The filamentous fungus Penicillium roqueforti is widely known as the ripening agent of blue-veined cheeses. Additionally, this fungus is able to produce several secondary metabolites, including the meroterpenoid compound mycophenolic acid (MPA). Cheeses ripened with P. roqueforti are usually contaminated with MPA. On the other hand, MPA is a commercially valuable immunosuppressant. However, to date the molecular basis of the production of MPA by P. roqueforti is still unknown. Using a bioinformatic approach, we have identified a genomic region of approximately 24.4 kbp containing a seven-gene cluster that may be involved in the MPA biosynthesis in P. roqueforti. Gene silencing of each of these seven genes (named mpaA, mpaB, mpaC, mpaDE, mpaF, mpaG and mpaH) resulted in dramatic reductions in MPA production, confirming that all of these genes are involved in the biosynthesis of the compound. Interestingly, the mpaF gene, originally described in P. brevicompactum as a MPA self-resistance gene, also exerts the same function in P. roqueforti, suggesting that this gene has a dual function in MPA metabolism. The knowledge of the biosynthetic pathway of MPA in P. roqueforti will be important for the future control of MPA contamination in cheeses and the improvement of MPA production for commercial purposes.

  7. Identification and Functional Analysis of the Mycophenolic Acid Gene Cluster of Penicillium roqueforti

    PubMed Central

    Del-Cid, Abdiel; Gil-Durán, Carlos; Vaca, Inmaculada; Rojas-Aedo, Juan F.; García-Rico, Ramón O.; Levicán, Gloria; Chávez, Renato

    2016-01-01

    The filamentous fungus Penicillium roqueforti is widely known as the ripening agent of blue-veined cheeses. Additionally, this fungus is able to produce several secondary metabolites, including the meroterpenoid compound mycophenolic acid (MPA). Cheeses ripened with P. roqueforti are usually contaminated with MPA. On the other hand, MPA is a commercially valuable immunosuppressant. However, to date the molecular basis of the production of MPA by P. roqueforti is still unknown. Using a bioinformatic approach, we have identified a genomic region of approximately 24.4 kbp containing a seven-gene cluster that may be involved in the MPA biosynthesis in P. roqueforti. Gene silencing of each of these seven genes (named mpaA, mpaB, mpaC, mpaDE, mpaF, mpaG and mpaH) resulted in dramatic reductions in MPA production, confirming that all of these genes are involved in the biosynthesis of the compound. Interestingly, the mpaF gene, originally described in P. brevicompactum as a MPA self-resistance gene, also exerts the same function in P. roqueforti, suggesting that this gene has a dual function in MPA metabolism. The knowledge of the biosynthetic pathway of MPA in P. roqueforti will be important for the future control of MPA contamination in cheeses and the improvement of MPA production for commercial purposes. PMID:26751579

  8. Mycophenolate mofetil as a steroid-sparing agent in sarcoid-associated renal disease.

    PubMed

    Zaidi, Anita A; DeVita, Maria V; Michelis, Michael F; Rosenstock, Jordan L

    2015-01-01

    Steroids are the mainstay of treatment for renal sarcoidosis. Many patients with sarcoidosis are chronically dependent on steroids and there is limited data on the use of steroid-sparing agents. This is a case of a patient that has remained in remission using mycophenolate mofetil (MMF) as a steroid-sparing agent. The patient is a 56-year-old female with a history of sarcoidosis diagnosed by lymph node biopsy who developed 3 episodes of acute kidney injury (AKI) in the setting of exacerbations of her sarcoidosis, each responding to prednisone treatment. Due to possible lifelong need for prednisone, MMF was started as a steroid-sparing treatment. She tolerated the MMF well and has now been steroidfree for 22 months. There have been only a few case reports about the use of MMF as a steroid-sparing agent in sarcoid-associated renal disease, in which patients could be successfully weaned off steroids. This is the longest reported follow-up of a patient being off steroids while on MMF. It is also notable for the patient having a relapse on the MMF which responded to an increased dose. MMF should be studied further as a potential steroid-sparing agent in the treatment of sarcoid associated renal disease.

  9. Open label randomized controlled trial assessing the efficacy of mycophenolate sodium against other conventional immunosuppressive agents in active systemic lupus erythematosus patients without renal involvement.

    PubMed

    Yahya, Fariz; Jasmin, Raja; Ng, Chin Teck; Cheah, Tien Eang; Sockalingam, Sargunan

    2013-12-01

    Mycophenolate is an immunosuppressive agent which has been used in systemic lupus erythematosus (SLE) patients who have failed conventional therapy. However, the use of mycophenolate sodium in extra-renal SLE involvement has yet to be established. This study aimed to assess the efficacy of mycophenolate sodium in extra-renal SLE. A total of 14 SLE patients without renal involvement were randomized either to receive mycophenolate sodium or other immunosuppressive agents. Patients were assessed monthly from baseline until week 16. Assessment parameters included SLE Disease Activity Index (SLEDAI) score, other organ-specific parameters and immunological parameters, including anti-double stranded DNA and C3. Steroid-sparing effect of mycophenolate sodium was also evaluated. Mycophenolate sodium produced a significant reduction in SLEDAI scores (P < 0.05) after 16 weeks of treatment. Mixed responses were detected in terms of organ-specific clinical changes. A positive trend was observed in improvement of immunological parameters and steroid dose reduction. No major adverse events were reported in this study. Mycophenolate sodium is a safe alternative therapy in SLE patients with extra-renal involvement. The reduction in SLEDAI scores and the observation of no major safety concerns suggest that a larger prospective study of mycophenolate sodium in non-renal SLE is warranted. © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  10. Regulated expression of the MRP8 and MRP14 genes in human promyelocytic leukemic HL-60 cell treated with the differentiation-inducing agents mycophenolic acid and 1{alpha},25-Dihydroxyvitamin D{sub 3}

    SciTech Connect

    Warner-Bartnicki, A.L.; Murao, S.; Collart, F.R.; Huberman, E.

    1992-12-31

    The calcium-binding proteins MRP8 and MEP14 are present in mature monomyelocytic cells and are induced during differentiation. Previous studies have demonstrated that the proteins may mediate the growth arrest in differentiating HL-60 cells. We determined the levels of a protein complex (PC) containing MRP8 and MRP14 and investigated the mechanism by which the genes encoding these proteins are regulated in HL-60 cells treated with the differentiation-inducing agent mycophenorc acid (MPA)While the PC was barely detectable in untreated cells, MPA treatment resulted in elevated levels of the PC which were maximal at 3-4 d, and were found to directly parallel gains in the steady-state levels of MRP8 and MRP14 MRNA. Transcription studies with the use of nuclear run-on experiments revealed increased transcription initiation at the MRP8 and MRP14 promoters after MPA treatment. 1{alpha},25-Dihydroxyvitamin D{sub 3}, which induces HL-60 cell differentiation by another mechanism, was also found to increase transcription initiation at the MRP8 and MRP14 promoters. Our results suggest that this initiation is the major control of maturation agent-mediated increases in MRP8 and MRPl4 gene expression, and support a role for the PC in terminal differentiation of human monomyelocytic cells.

  11. The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function

    PubMed Central

    Kannegieter, Nynke M.; Hesselink, Dennis A.; Dieterich, Marjolein; Kraaijeveld, Rens; Rowshani, Ajda T.; Leenen, Pieter J. M.; Baan, Carla C.

    2017-01-01

    Monocytes and macrophages play key roles in many disease states, including cellular and humoral rejection after solid organ transplantation (SOT). To suppress alloimmunity after SOT, immunosuppressive drug therapy is necessary. However, little is known about the effects of the immunosuppressive drugs tacrolimus and mycophenolic acid (MPA) on monocyte activation and function. Here, the effect of these immunosuppressants on monocytes was investigated by measuring phosphorylation of three intracellular signaling proteins which all have a major role in monocyte function: p38MAPK, ERK and Akt. In addition, biological functions downstream of these signaling pathways were studied, including cytokine production, phagocytosis and differentiation into macrophages. To this end, blood samples from healthy volunteers were spiked with diverse concentrations of tacrolimus and MPA. Tacrolimus (200 ng/ml) inhibited phosphorylation of p38MAPK by 30% (mean) in CD14+ monocytes which was significantly less than in activated CD3+ T cells (max 60%; p < 0.05). This immunosuppressive agent also partly inhibited p-AKT (14%). MPA, at a therapeutic concentration showed the strongest effect on p-AKT (27% inhibition). p-ERK was inhibited with a maximum of 15% after spiking with either tacrolimus or MPA. The production of IL-1β and phagocytosis by monocytes were not affected by tacrolimus concentrations, whereas MPA did inhibit IL-1β production by 50%. Monocyte/macrophage polarization was shifted to an M2-like phenotype in the presence of tacrolimus, while MPA increased the expression of M2 surface markers, including CD163 and CD200R, on M1 macrophages. These results show that tacrolimus and MPA do not strongly affect monocyte function, apart from a change in macrophage polarization, to a clinically relevant degree. PMID:28122021

  12. [Establishment of a genetic transformation system for Penicillium brevicompactum to produce mycophenolic acid].

    PubMed

    Ren, Zhihong; Su, Caiyun; Yan, Jing; Dai, Meng; Zhao, Ying; Wang, Hongyi; Dai, Mingwei; Zhang, Jia

    2013-11-04

    We established a genetic transformation system for Penicillium brevicompactum to produce mycophenolic acid. We developed protoplast transformation methods mediated by Polyethylene glycol, using phleomycin resistance gene (Sh ble) as a dominant selection marker. The frequency of transformation was up to 2 - 3 transformants per microg DNA; analysis of the transformants by PCR showed that the foreign DNA had been integrated into the host genome. The transformants retained stable after generation. The establishment of the genetic transformation system of Penicillium brevicompactum could serve as the basis for the research of molecular biology and the breeding of gene engineering of the fungus.

  13. Successful Treatment of Fibrosing Organising Pneumonia Causing Respiratory Failure with Mycophenolic Acid.

    PubMed

    Paul, Christina; Lin-Shaw, Ammy; Joseph, Mariamma; Kwan, Keith; Sergiacomi, Gianluigi; Mura, Marco

    2016-01-01

    Organising pneumonia (OP) is usually promptly responsive to corticosteroid treatment. We describe a series of 3 cases of severe, progressive, biopsy-proven fibrosing OP causing respiratory failure. All cases presented with peribronchial and subpleural consolidations, had a fibro-inflammatory infiltrative component in the alveolar septa, and only had a partial and unsatisfactory response to corticosteroids. However, they responded to mycophenolic acid (MPA) treatment with resolution of respiratory failure as well as clinical and functional improvement. MPA as an additional treatment option for aggressive forms of fibrosing OP and interstitial lung disease needs to be further explored. © 2016 S. Karger AG, Basel.

  14. Influence of carboxylesterase 2 genetic polymorphisms on mycophenolic acid pharmacokinetics in Japanese renal transplant recipients.

    PubMed

    Fujiyama, N; Miura, M; Satoh, S; Inoue, K; Kagaya, H; Saito, M; Habuchi, T; Suzuki, T

    2009-05-01

    Mycophenolic acid (MPA), converted from the prodrug mycophenolate mofetil (MMF), is generated by intestinal and hepatic esterases. The role of carboxylesterase (CES) in MMF hydrolysis was examined in vitro using human liver microsomes. V(max) and K(m) values of MMF hydrolysis in pooled human liver microsomes were 1368 +/- 44 nmol min(-1) mg(-1) protein and 1030 +/- 65 microM, respectively. Hydrolytic activity was inhibited by the CES inhibitors phenylmethylsulfonylfluoride, bis-p-nitorophenylphosphate and diisopropylfluorophosphate, with IC(50) values of 77.1, 3.59 and 0.0312 microM, respectively. Eighty Japanese renal transplant recipients that received repeated-doses of MMF, tacrolimus and prednisolone,were evaluated for MPA pharmacokinetics 28 days after transplantation to investigate the relationship between MPA pharmacokinetics and CES2 genetic polymorphisms. No significant differences in MPA pharmacokinetics were observed between CES2 A4595G, C8721T orA-1548G genotype groups. CES2 allelic variants also did not appear to affect plasma MPA concentrations between individuals. In conclusion, the study demonstrated that while CES1 and/or CES2 are involved in the hydrolysis of MMF to MPA, CES2 allelic variants appeared to make only a minor contribution to inter-personal differences in MPA pharmacokinetics.

  15. Nonrelapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation.

    PubMed

    McDermott, Cara L; Sandmaier, Brenda M; Storer, Barry; Li, Hong; Mager, Donald E; Boeckh, Michael J; Bemer, Meagan J; Knutson, Jennifer; McCune, Jeannine S

    2013-08-01

    We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft.

  16. Non-relapse mortality and mycophenolic acid exposure in nonmyeloablative hematopoietic cell transplantation

    PubMed Central

    McDermott, Cara L.; Sandmaier, Brenda M.; Storer, Barry; Li, Hong; Mager, Donald E.; Boeckh, Michael J.; Bemer, Meagan J.; Knutson, Jennifer; McCune, Jeannine S.

    2013-01-01

    We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplant. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (N=132) or unrelated (N=176) donors, and received post-grafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in nine patients, eight of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades 3–4 acute graft versus host disease (aGVHD) and increased non-relapse mortality, but not with day 28 T-cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades 3–4 aGVHD and non-relapse mortality in patients receiving an unrelated donor graft. PMID:23660171

  17. Mycophenolic Acid Inhibits Migration and Invasion of Gastric Cancer Cells via Multiple Molecular Pathways

    PubMed Central

    Dun, Boying; Sharma, Ashok; Teng, Yong; Liu, Haitao; Purohit, Sharad; Xu, Heng; Zeng, Lingwen; She, Jin-Xiong

    2013-01-01

    Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA’s antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA’s overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment. PMID:24260584

  18. Do cytostatic drugs reach drinking water? The case of mycophenolic acid.

    PubMed

    Franquet-Griell, Helena; Ventura, Francesc; Boleda, M Rosa; Lacorte, Silvia

    2016-01-01

    Mycophenolic acid (MPA) has been identified as a new river contaminant according to its wide use and high predicted concentration. The aim of this study was to monitor the impact of MPA in a drinking water treatment plant (DWTP) that collects water downstream Llobregat River (NE Spain) in a highly densified urban area. During a one week survey MPA was recurrently detected in the DWTP intake (17-56.2 ng L(-1)). The presence of this compound in river water was associated to its widespread consumption (>2 tons in 2012 in Catalonia), high excretion rates and low degradability. The fate of MPA in waters at each treatment step of the DWTP was analyzed and complete removal was observed after pretreatment with chlorine dioxide. So far, MPA has not been described as water contaminant and its presence associated with its consumption in anticancer treatments is of relevance to highlight the importance of monitoring this compound. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid.

    PubMed

    Sintchak, M D; Fleming, M A; Futer, O; Raybuck, S A; Chambers, S P; Caron, P R; Murcko, M A; Wilson, K P

    1996-06-14

    The structure of inosine-5'-monophosphate dehydrogenase (IMPDH) in complex with IMP and mycophenolic acid (MPA) has been determined by X-ray diffraction. IMPDH plays a central role in B and T lymphocyte replication. MPA is a potent IMPDH inhibitor and the active metabolite of an immunosuppressive drug recently approved for the treatment of allograft rejection. IMPDH comprises two domains: a core domain, which is an alpha/beta barrel and contains the active site, and a flanking domain. The complex, in combination with mutagenesis and kinetic data, provides a structural basis for understanding the mechanism of IMPDH activity and indicates that MPA inhibits IMPDH by acting as a replacement for the nicotinamide portion of the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule.

  20. Polymerase chain reaction (PCR) identification of Penicillium brevicompactum, a grape contaminant and mycophenolic acid producer.

    PubMed

    Patiño, B; Medina, A; Doménech, M; González-Jaén, M T; Jiménez, M; Vázquez, C

    2007-02-01

    Penicillium brevicompactum is a ubiquitous fungal species that contaminates diverse substrates and commodities and produces an array of metabolites toxic to human and animals. The present work has obtained evidence, by liquid chromatography (LC)-ion-trap mass spectrometry, of the ability of P. brevicompactum strains isolated from grapes to produce mycophenolic acid, a potent immunosuppressor. In order to facilitate early diagnosis of this species on commodities for human and animal consumption, a rapid, sensitive and specific polymerase chain reaction (PCR) assay for P. brevicompactum was developed. The specific primers were designed based on the ITS1-5.8S-ITS2ITS (Internal Transcribed Spacers of rRNA genes) multicopy region. This method provides a useful aid to detect the presence of this fungal species in grapes and other commodities in order to prevent the toxins produced entering the food chain.

  1. [Production of mycophenolic acid by fungi of the genus Penicillium link].

    PubMed

    Vinokurova, N G; Ivanushkina, N E; Kochkina, G A; Arinbasarov, M U; Ozerskaia, S M

    2005-01-01

    Out of 36 strains of fungi of the genus Penicillium, some of which were isolated from ancient permafrost soils, 14 strains synthesized mycophenolic acid (MPA). Maximal (over 500 mg/l) accumulation of MPA in culture liquid was observed in P. brevicompactum strains (VKM F-457, VKM F-477, and VKM F-1150). This was the first study to detect MPA in representatives of the species P. rugulosum; in three strains of this species (VKM FW-665, VKM FW-717, and VKM FW-733), the level of MPA accumulation exceeded 300 mg/l. The time course of the synthesis of MPA by the P. rugulosum strain VKM FW-733 was studied. It was shown that the synthesis of this metabolite was dramatically intensified at the stationary growth phase (ten days).

  2. Determination of Mycophenolic Acid in Plasma Samples Using the Terbium-Sensitized Luminescence Method

    NASA Astrophysics Data System (ADS)

    Shayanfar, A.; Ghavimi, H.; Zolali, E.; Jouyban, A.

    2015-09-01

    The objectives of this work were to provide an analytical method, for the quantitative determination of the mycophenolic acid (MFA) in plasma samples and its application to quantification of the MFA in rat plasma after oral administration. In order to remove the fluorescence interferences of the plasma, the samples were precipitated by acetonitrile in 1:8 ratio and then a few parameters were optimized and the fluorescence intensity measured at 545 nm using an excitation wavelength of 347 nm. Under the optimized concentration, the method provided a linear range between 1.0 and 10.0 mg/l with a correlation coefficient of 0.998. MFA was detected and the validation was performed according to the FDA guidelines. Linearity, accuracy, precision, and selectivity of the developed method were suitable for th determination of the MFA in plasma samples. The proposed analytical approach was applied to determine the MFA concentration in a rat plasma-time profile study.

  3. Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients.

    PubMed

    Colom, Helena; Lloberas, Núria; Andreu, Franc; Caldés, Ana; Torras, Joan; Oppenheimer, Federico; Sanchez-Plumed, Jaime; Gentil, Miguel A; Kuypers, Dirk R; Brunet, Mercè; Ekberg, Henrik; Grinyó, Josep M

    2014-06-01

    Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure.

  4. In Vitro Influence of Mycophenolic Acid on Selected Parameters of Stimulated Peripheral Canine Lymphocytes

    PubMed Central

    Guzera, Maciej; Szulc-Dąbrowska, Lidia; Cywińska, Anna; Archer, Joy; Winnicka, Anna

    2016-01-01

    Mycophenolic acid (MPA) is an active metabolite of mycophenolate mofetil, a new immunosuppressive drug effective in the treatment of canine autoimmune diseases. The impact of MPA on immunity is ambiguous and its influence on the canine immune system is unknown. The aim of the study was to determine markers of changes in stimulated peripheral canine lymphocytes after treatment with MPA in vitro. Twenty nine healthy dogs were studied. Phenotypic and functional analysis of lymphocytes was performed on peripheral blood mononuclear cells cultured with mitogens and different MPA concentrations– 1 μM (10−3 mol/m3), 10 μM or 100 μM. Apoptotic cells were detected by Annexin V and 7-aminoactinomycin D (7-AAD). The expression of antigens (CD3, CD4, CD8, CD21, CD25, forkhead box P3 [FoxP3] and proliferating cell nuclear antigen [PCNA]) was assessed with monoclonal antibodies. The proliferation indices were analyzed in carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled cells. All analyses were performed using flow cytometry. The influence of MPA on apoptosis was dependent on the mechanism of cell activation and MPA concentration. MPA caused a decrease in the expression of lymphocyte surface antigens, CD3, CD8 and CD25. Its impact on the expression of CD4 and CD21 was negligible. Its negative influence on the expression of FoxP3 was dependent on cell stimulation. MPA inhibited lymphocyte proliferation. In conclusion, MPA inhibited the activity of stimulated canine lymphocytes by blocking lymphocyte activation and proliferation. The influence of MPA on the development of immune tolerance–expansion of Treg cells and lymphocyte apoptosis–was ambiguous and was dependent on the mechanism of cellular activation. The concentration that MPA reaches in the blood may lead to inhibition of the functions of the canine immune system. The applied panel of markers can be used for evaluation of the effects of immunosuppressive compounds in the dog. PMID:27138877

  5. Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus.

    PubMed

    Eickenberg, Sebastian; Mickholz, Eva; Jung, Elisabeth; Nofer, Jerzy-Roch; Pavenstadt, Hermann J; Jacobi, Annett M

    2012-01-01

    Clinical trials revealed a high efficacy of mycophenolate mofetil (MMF)in inducing and maintaining remission in patients with class III-V-lupus nephritis. Also extrarenal manifestations respond to MMF treatment. However, few attempts have been undertaken to delineate its mechanism of action in systemic lupus erythematosus (SLE) a disease characterized by enhanced B cell activation. Clinical and paraclinical parameters of 107 patients with SLE were recorded consecutively and analyzed retrospectively. Patients were divided into treatment groups (MMF: n=39, azathioprine (AZA) n=30 and controls without immunosuppressive therapy n=38). To further delineate the effect of mycophenolic acid (MPA) on naive and memory B cells in vitro assays were performed. Although patients taking AZA flared more frequently than patients on MMF or controls, the analysis of clinical parameters did not reveal significant differences.However, profound differences in paraclinical parameters were found. B cell frequencies and numbers were significantly higher in patients taking MMF compared to those on AZA but lower numbers and frequencies of plasmablasts were detected compared to AZA-treated patients or controls. Notably, MMF treatment was associated with a significantly higher frequency and number of transitional B cells as well as naive B cells compared to AZA treatment. Differences in T cell subsets were not significant. MPA abrogated in vitro proliferation of purified B cells completely but had only moderate impact on B cell survival. The thorough inhibition of B cell activation and plasma cell formation by MMF might explain the favorable outcomes of previous clinical trials in patients with SLE, since enhanced B cell proliferation is a hallmark of this disease.

  6. Simultaneous determination of mycophenolate mofetil and its active metabolite, mycophenolic acid, by differential pulse voltammetry using multi-walled carbon nanotubes modified glassy carbon electrode.

    PubMed

    Madrakian, Tayyebeh; Soleimani, Mohammad; Afkhami, Abbas

    2014-09-01

    A highly sensitive electrochemical sensor for the simultaneous determination of mycophenolate mofetil (MPM) and mycophenolic acid (MPA) was fabricated by multi-walled carbon nanotubes modified glassy carbon electrode (MWCNTs/GCE). The electrochemical behavior of these two drugs was studied at the modified electrode using cyclic voltammetry and adsorptive differential pulse voltammetry. MPM and MPA were oxidized at the GCE during an irreversible process. DPV analysis showed two oxidation peaks at 0.87V and 1.1V vs. Ag/AgCl for MPM and an oxidation peak at 0.87V vs. Ag/AgCl for MPA in phosphate buffer solution of pH5.0. The MWCNTs/GCE displayed excellent electrochemical activities toward oxidation of MPM and MPA relative to the bare GCE. The experimental design algorithm was used for optimization of DPV parameters. The electrode represents linear responses in the range 5.0×10(-6) to 1.6×10(-4)molL(-1) and 2.5×10(-6)molL(-1) to 6.0×10(-5)molL(-1) for MPM and MPA, respectively. The detection limit was found to be 9.0×10(-7)molL(-1) and 4.0×10(-7)molL(-1) for MPM and MPA, respectively. The modified electrode showed a good sensitivity and stability. It was successfully applied to the simultaneous determination of MPM and MPA in plasma and urine samples.

  7. Mizoribine and mycophenolate mofetil.

    PubMed

    Ishikawa, H

    1999-07-01

    Both mizoribine (MZR) and mycophenolate mofetil (MMF) are immunosuppressive agents that inhibit the proliferation of lymphocytes selectively, via inhibition of IMPDH. MZR is a nucleoside of the imidazole class, isolated from the culture medium of the mold Eupenicillium brefeldianum M-2166. Although this compound has been found to have weak antimicrobial activity against Candida albicans, it has proved ineffective against experimental candidiasis. Unlike azathioprine, this compound is not taken up by nucleic acids in the cell. Instead, after phosphorylation MZR-5 -monophosphate inhibits GMP synthesis by the antagonistic blocking of IMPDH (Ki = 10(-8)M) and GMP- synthetase (Ki =10(-5) M). The drug has been found to inhibit both humoral and cellular immunity, and on this basis it was developed in Japan as an immunosuppressant. MZR has been shown in animal experiments to lack oncogenicity, and has been shown clinically to be associated with a low incidence of severe adverse reactions. MZR has been registered in Japan for the prevention of rejection in renal transplantation, and for the treatment of lupus nephritis, rheumatoid arthritis and the nephrotic syndrome. MMF is the morpholinoethyl ester prodrug of mycophenolic acid (MPA), which was first isolated in 1896 from the culture media of several Penicillium species. MPA has been evaluated for its unique properties as an anticancer, antiviral, antifungal and antibacterial agent, as well as for its therapeutic use in psoriasis and rheumatoid arthritis. MMF was designed to enhance the oral bioavailability of the parent compound. After beneficial effects were observed in animals, the clinical efficacy of MMF as an immunosuppressant in renal transplantation was studied in the United States. In 1995 the US Food and Drug Administration (FDA) approved the use of MMF for the prevention of rejection in renal transplantation, the drug also available on a number of European markets.

  8. The Immunosuppressant Mycophenolic Acid Alters Nucleotide and Lipid Metabolism in an Intestinal Cell Model

    PubMed Central

    Heischmann, Svenja; Dzieciatkowska, Monika; Hansen, Kirk; Leibfritz, Dieter; Christians, Uwe

    2017-01-01

    The study objective was to elucidate the molecular mechanisms underlying the negative effects of mycophenolic acid (MPA) on human intestinal cells. Effects of MPA exposure and guanosine supplementation on nucleotide concentrations in LS180 cells were assessed using liquid chromatography-mass spectrometry. Proteomics analysis was carried out using stable isotope labeling by amino acids in cell culture combined with gel-based liquid chromatography-mass spectrometry and lipidome analysis using 1H nuclear magnetic resonance spectroscopy. Despite supplementation, depletion of guanosine nucleotides (p < 0.001 at 24 and 72 h; 5, 100, and 250 μM MPA) and upregulation of uridine and cytidine nucleotides (p < 0.001 at 24 h; 5 μM MPA) occurred after exposure to MPA. MPA significantly altered 35 proteins mainly related to nucleotide-dependent processes and lipid metabolism. Cross-reference with previous studies of MPA-associated protein changes widely corroborated these results, but showed differences that may be model- and/or method-dependent. MPA exposure increased intracellular concentrations of fatty acids, cholesterol, and phosphatidylcholine (p < 0.01 at 72 h; 100 μM MPA) which corresponded to the changes in lipid-metabolizing proteins. MPA affected intracellular nucleotide levels, nucleotide-dependent processes, expression of structural proteins, fatty acid and lipid metabolism in LS180 cells. These changes may compromise intestinal membrane integrity and contribute to gastrointestinal toxicity. PMID:28327659

  9. Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cells.

    PubMed

    Iwaszkiewicz-Grzes, Dorota; Cholewinski, Grzegorz; Kot-Wasik, Agata; Trzonkowski, Piotr; Dzierzbicka, Krystyna

    2017-03-01

    The main activity of mycophenolic acid 1 (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives could inhibit the maturation of DC, as shown by the decreased expression of B7 family receptors. It was confirmed in the mixed leucocyte reaction (MLR), in which T cells challenged with DCs pretreated with the analogs showed decreased proliferation and reduced cytokine secretion. The most interesting activity in this series of studies, that is, the suppression of CD86 receptor expression, decreased cytokine production and suppressed mixed leucocyte reaction, exhibited (mycophenoyl-N-3-propyl)-9-acridone-4-carboxamide ester 5a and (mycophenoyl-N-5-pentyl)-9-acridone-4-carboxamide ester 5b. These compounds reduced also the secretion of IL-2 and IL-15. In addition, they increased secretion of suppressive IL-10. Equally promising results were obtained for the N-mycophenoyl-D-glutamic acid 4b, which previously gave the highest value of selectivity. Acridone derivatives of MPA are therefore good immunosuppressive drug candidates for further testing.

  10. Impairment of mycophenolate mofetil absorption by calcium polycarbophil.

    PubMed

    Kato, Ryuji; Ooi, Kazuya; Ikura-Mori, Megumi; Tsuchishita, Yoshimasa; Hashimoto, Hiroshi; Yoshimura, Hironori; Uenishi, Kohji; Kawai, Masayuki; Tanaka, Kazuhiko; Ueno, Kazuyuki

    2002-11-01

    The effect of calcium polycarbophil on the absorption of mycophenolate mofetil, an immunosuppressive agent, was evaluated in healthy subjects. In vitro studies were performed to further evaluate the mechanism of the potential interaction. In the in vitro study, the release of mycophenolate mofetil from a cellulose membrane in the presence or absence of metal cations was measured using the dissolution test procedure. In the in vivo study, a randomized crossover design with two phases was used. In one phase, 6 male healthy volunteers received 1000 mg of mycophenolate mofetil alone (treatment 1); in the other phase, they received 1000 mg of mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 2). They received 30 mg of lansoprazole for 5 days and, on the 6th day, received mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 3). The serum concentration of mycophenolic acid was measured by high-performance liquid chromatography. In the in vitro study, the release from a cellulose membrane in the presence of calcium or iron ions was slower than that in the absence of these metal ions. In the in vivo study, the AUC0-12 and C(max) in treatment 2 were less than those in treatment 1. About 50% and 25% decreases in AUC0-12 in treatment 2 and treatment 3 were observed compared with those in treatment 1, respectively. These findings suggest that when mycophenolate mofetil and calcium polycarbophil were coadministered concomitantly, a decrease in mycophenolate mofetil absorption was observed. Therefore, it appears clear that the concomitant administration of mycophenolate mofetil and calcium polycarbophil should be avoided.

  11. Labelled acetone and levulinic acid are formed when [14C]acetate is being converted to mycophenolic acid in Penicillium brevicompactum.

    PubMed

    Nulton, C P; Campbell, I M

    1978-02-01

    Evidence is presented that is compatible with the hypothesis that the farnesyl unit involved in the biosynthesis of mycophenolic acid in Penicillium brevicompactum is degraded by two successive oxidative cleavages at the double bonds distal from the phthalide nucleus. Acetone and levulinic acid are two non-aromatic degradation products.

  12. Simultaneous determination of mycophenolic acid and its glucuronide and glycoside derivatives in canine and feline plasma by UHPLC-UV.

    PubMed

    Rivera, Sol Maiam; Hwang, Julianne K; Slovak, Jeniffer E; Court, Michael H; Villarino, Nicolas F

    2017-02-01

    Cats and dogs can suffer from multiple autoimmune diseases. Mycophenolic acid (MPA) is a potentially useful immunosuppressant drug in cats and dogs, because of its well-documented efficacy in controlling autoimmune disease in humans. However, the pharmacokinetics and pharmacodynamics in these species remain to be determined. We have developed and validated a sensitive, precise, accurate and reproducible method that provides consistent quantification of MPA and its major derivatives, MPA phenol glucoside and MPA phenol glucuronide, in canine and feline plasma using ultra-high-pressure liquid chromatography coupled to an ultraviolet detector. The main advantages of this novel method include a small sample volume, easy sample preparation, a short chromatographic analysis time and the option to select either phenolphthalein β-d-glucuronide or mycophenolic acid carboxybutoxy ether as internal standard. Results of validation indicate that this analytical method is suitable to study the plasma disposition of MPA and its derivatives in dogs and cats.

  13. The Novel Immunosuppressive Agent Mycophenolate Mofetil Markedly Potentiates the Antiherpesvirus Activities of Acyclovir, Ganciclovir, and Penciclovir In Vitro and In Vivo

    PubMed Central

    Neyts, Johan; Andrei, Graciela; De Clercq, Erik

    1998-01-01

    The immunosuppressive agent mycophenolate mofetil (MMF) has been approved for use in kidney transplant recipients and may thus be used concomitantly for the treatment of intercurrent herpesvirus infections with drugs such as acyclovir (ACV), ganciclovir (GCV), and penciclovir (PCV). We found that MMF and its parent compound mycophenolic acid (at concentrations that are attainable in plasma) strongly potentiate the antiherpesvirus (herpes simplex virus [HSV] type 1 [HSV-1], HSV-2, thymidine kinase-deficient [TK−] HSV-1, both wild-type and TK− varicella-zoster virus, and human cytomegalovirus) activities of ACV, PCV, and GCV (up to 350-fold increases in their activities). The mechanism of potentiation was found to reside in the depletion of endogenous dGTP pools, which favored the inhibitory effect of the triphosphate of ACV, GCV, or PCV on the viral DNA polymerase. The combination of topically applied 5% MMF with 0.1% ACV strongly protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used singly had no protective effect. Interestingly, the combination of topically applied 5% MMF with 5% ACV was also highly effective in protecting against TK− HSV-2-induced cutaneous lesions (that were refractory to ACV treatment) in athymic nude mice. Topical therapy with MMF was very well tolerated, and no signs of irritation were observed. When given perorally at 200 mg/kg of body weight/day, MMF potentiated to some extent the growth retardation induced by GCV in young NMRI mice. These observations may have clinical implications (i) for those transplant recipients who receive both MMF and either ACV, GCV, or PCV and (ii) for the treatment of ACV-resistant mucocutaneous HSV infections. PMID:9527762

  14. Renal graft function and low-dose cyclosporine affect mycophenolic acid pharmacokinetics in kidney transplantation.

    PubMed

    Cortinovis, Monica; Gotti, Eliana; Pradini, Silvia; Gaspari, Flavio; Perico, Norberto

    2011-09-15

    In kidney transplantation, the pharmacokinetics of mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is influenced by concomitant immunosuppressive therapy, including cyclosporine (CsA). However, whether in the setting of immunosuppressive therapy minimization CsA still affects MPA pharmacokinetics, particularly in relation to varying degree of renal graft function deterioration, remains ill defined. One hundred thirty-five complete MPA profiles were sequentially collected from 56 kidney transplant recipients given MMF and low-dose CsA as part of their immunosuppressive therapy. MPA pharmacokinetic parameters were correlated with blood CsA area under the curve (AUC0-12) and graft function as measured glomerular filtration rate (GFR). The relative contribution of CsA exposure and GFR to MPA kinetics in relation to other clinical parameters was determined by multivariate analysis. Dose-adjusted MPA AUC0-12 negatively correlated with CsA AUC0-12. MPA exposure significantly increased when CsA AUC0-12 was below 2000 ng hr/mL. Stratification of MPA profiles according to stages of renal dysfunction showed that dose-adjusted MPA AUC0-12 was higher (P<0.001) in patients with severe (stage 4: 70.37±27.93 μg hr/mL/g MMF) than in those with mild (stage 2: 47.46±11.66 μg hr/mL/g MMF) or moderate (stage 3; 47.48±15.22 μg hr/mL/g MMF) renal insufficiency. At multivariate analysis GFR, serum albumin and hemoglobin levels, use of gastroprotective medications, and time posttransplant were identified as independent determinants of MPA AUC0-12. In stable renal transplant recipients given MMF, tapering CsA dose and deterioration of renal graft function contribute to increased MPA exposure. Thus, monitoring plasma MPA pharmacokinetics should be advised, especially in patients on minimized CsA therapy with severe renal insufficiency.

  15. A comprehensive characterization of the impact of mycophenolic acid on the metabolism of Jurkat T cells.

    PubMed

    Fernández-Ramos, Ana A; Marchetti-Laurent, Catherine; Poindessous, Virginie; Antonio, Samantha; Petitgas, Céline; Ceballos-Picot, Irène; Laurent-Puig, Pierre; Bortoli, Sylvie; Loriot, Marie-Anne; Pallet, Nicolas

    2017-09-05

    Metabolic reprogramming is critical for T cell fate and polarization and is regulated by metabolic checkpoints, including Myc, HIF-1α, AMPK and mTORC1. Our objective was to determine the impact of mycophenolic acid (MPA) in comparison with rapamycin (Rapa), an inhibitor of mTORC1, on the metabolism of Jurkat T cells. We identified a drug-specific transcriptome signature consisting of the key enzymes and transporters involved in glycolysis, glutaminolysis or nucleotide synthesis. MPA produced an early and transient drop in the intracellular ATP content related to the inhibition of de novo synthesis of purines, leading to the activation of the energy sensor AMPK. MPA decreases glycolytic flux, consistent with a reduction in glucose uptake, but also in the oxidation of glutamine. Additionally, both drugs reduce aerobic glycolysis. The expression of HIF-1α and Myc, promoting the activation of glycolysis and glutaminolysis, was inhibited by MPA and Rapa. In conclusion, we report that MPA profoundly impacts the cellular metabolism of Jurkat T cells by generating an energetic distress, decreasing the glycolytic and glutaminolytic fluxes and by targeting HIF-1α and Myc. These findings open interesting perspectives for novel combinatorial therapeutic strategies targeting metabolic checkpoints to block the proliferation of T cells.

  16. Cytoskeletal reorganization by mycophenolic acid alters mesangial cell migration and contractility.

    PubMed

    Dubus, Isabelle; L'Azou, Beatrice; Gordien, Myriam; Delmas, Yahsou; Labouyrie, Jean-Pierre; Bonnet, Jacques; Combe, Christian

    2003-11-01

    Cytoskeleton alterations are a hallmark of mesangial cell activation during glomerulosclerosis. The aim of this study was to investigate whether mycophenolic acid (MPA) affects cytoskeletal organization and motility of human mesangial cells. Using the IP15 cell line, we found that treatment with 1 micromol/L MPA inhibited both receptor-dependent (angiotensin II) and receptor-independent (KCl) contractile responses, as well as serum-induced migration activity, suggesting alterations in the intracellular mechanisms that control mesangial cell motility. Immunofluorescence studies of MPA-treated cells provided evidence for decreased membrane disassembly/reassembly of alpha-smooth muscle actin and F-actin fibers, which was correlated with sustained quantitative and qualitative modifications of actin-associated proteins: calponin was overexpressed and became associated with actin fibers, whereas phosphorylation levels of cofilin and myosin light chain increased, suggesting both an activation of the mechanisms responsible for actin polymerization and an inhibition of actin-depolymerizing processes. These observations support a stabilizing effect of MPA on the mesangial actin cytoskeleton, which constitutes an additive action by which MPA, beyond its anti-inflammatory, antiproliferative and antifibrotic properties, might protect against excessive mesangial activation in the context of various glomerulopathies and kidney transplantation.

  17. Suppression of autophagy by mycophenolic acid contributes to inhibition of HCV replication in human hepatoma cells

    PubMed Central

    Fang, Shoucai; Su, Jinming; Liang, Bingyu; Li, Xu; Li, Yu; Jiang, Junjun; Huang, Jiegang; Zhou, Bo; Ning, Chuanyi; Li, Jieliang; Ho, Wenzhe; Li, Yiping; Chen, Hui; Liang, Hao; Ye, Li

    2017-01-01

    Previous studies have shown that mycophenolic acid (MPA) has an anti-HCV activity. However, the mechanism of MPA-mediated inhibition of HCV replication remains to be determined. This study investigated whether MPA has an effect on autophagy, a cellular machinery required for HCV replication, thereby, inhibits HCV replication in Huh7 cells. MPA treatment of Huh7 cells could suppress autophagy, evidenced by decreased LC3B-II level and conversion of LC3B-I to LC3B-II, decreased autophagosome formation, and increased p62 level compared to MPA-untreated cells. Tunicamycin treatment or HCV infection could induce cellular autophagy, however, MPA also exhibited its inhibitory effect on tunicamycin- or HCV infection-induced autophagy. The expression of three autophagy-related genes, Atg3, Atg5, and Atg7 were identified to be inhibited by MPA treatment. Over-expression of these genes could partly recover HCV replication inhibited by MPA; however, silencing their expression by siRNAs could enhance the inhibitory effect of MPA on HCV. Collectively, these results reveal that suppression of autophagy by MPA plays a role in its anti-HCV activity. Down-regulating the expression of three autophagy-related genes by MPA involves in its antiviral mechanism. PMID:28276509

  18. Molecular Basis for Mycophenolic Acid Biosynthesis in Penicillium brevicompactum▿†

    PubMed Central

    Regueira, Torsten Bak; Kildegaard, Kanchana Rueksomtawin; Hansen, Bjarne Gram; Mortensen, Uffe H.; Hertweck, Christian; Nielsen, Jens

    2011-01-01

    Mycophenolic acid (MPA) is the active ingredient in the increasingly important immunosuppressive pharmaceuticals CellCept (Roche) and Myfortic (Novartis). Despite the long history of MPA, the molecular basis for its biosynthesis has remained enigmatic. Here we report the discovery of a polyketide synthase (PKS), MpaC, which we successfully characterized and identified as responsible for MPA production in Penicillium brevicompactum. mpaC resides in what most likely is a 25-kb gene cluster in the genome of Penicillium brevicompactum. The gene cluster was successfully localized by targeting putative resistance genes, in this case an additional copy of the gene encoding IMP dehydrogenase (IMPDH). We report the cloning, sequencing, and the functional characterization of the MPA biosynthesis gene cluster by deletion of the polyketide synthase gene mpaC of P. brevicompactum and bioinformatic analyses. As expected, the gene deletion completely abolished MPA production as well as production of several other metabolites derived from the MPA biosynthesis pathway of P. brevicompactum. Our work sets the stage for engineering the production of MPA and analogues through metabolic engineering. PMID:21398490

  19. Production of mycophenolic acid by Penicillium brevicompactum-A comparison of two methods of optimization.

    PubMed

    Patel, Gopal; Patil, Mahesh D; Soni, Surbhi; Khobragade, Taresh P; Chisti, Yusuf; Banerjee, Uttam Chand

    2016-09-01

    Production of mycophenolic acid (MPA) by submerged fermentation using the microfungus Penicillium brevicompactum MTCC 8010 is reported here. Screening experiments were used to identify: the suitable media composition; the optimal initial pH; and the optimal incubation temperature to maximize the production of MPA in batch cultures. The initial concentrations of the selected sources of carbon (glucose), nitrogen (peptone) and the precursors (methionine, glycine) were then optimized by: (1) one-at-a-time variation of factors; and (2) a central composite design (CCD) of experiments, in a 12-day batch culture at an initial pH of 5.0, an incubation temperature of 25 °C, and an agitation speed of 200 rpm. The medium optimized using the one-at-a-time variation yielded a peak MPA titer of 1232 ± 90 mg/L. The medium optimized by the CCD method yielded a 40% higher MPA titer of 1737 ± 55 mg/L. The latter value was nearly 9-fold greater than the titer achieved prior to optimization.

  20. Virtual High-Throughput Screening Identifies Mycophenolic Acid as a Novel RNA Capping Inhibitor

    PubMed Central

    Tremblay-Létourneau, Maude; Despins, Simon; Bougie, Isabelle; Bisaillon, Martin

    2011-01-01

    The RNA guanylyltransferase (GTase) is involved in the synthesis of the m7Gppp-RNA cap structure found at the 5′ end of eukaryotic mRNAs. GTases are members of the covalent nucleotidyl transferase superfamily, which also includes DNA and RNA ligases. GTases catalyze a two-step reaction in which they initially utilize GTP as a substrate to form a covalent enzyme-GMP intermediate. The GMP moiety is then transferred to the diphosphate end of the RNA transcript in the second step of the reaction to form the Gppp-RNA structure. In the current study, we used a combination of virtual database screening, homology modeling, and biochemical assays to search for novel GTase inhibitors. Using this approach, we demonstrate that mycophenolic acid (MPA) can inhibit the GTase reaction by preventing the catalytic transfer of the GMP moiety onto an acceptor RNA. As such, MPA represents a novel type of inhibitor against RNA guanylyltransferases that inhibits the second step of the catalytic reaction. Moreover, we show that the addition of MPA to S. cerevisiae cells leads to a reduction of capped mRNAs. Finally, biochemical assays also demonstrate that MPA can inhibit DNA ligases through inhibition of the second step of the reaction. The biological implications of these findings for the MPA-mediated inhibition of members of the covalent nucleotidyl superfamily are discussed. PMID:21935470

  1. Strain-Specific Synthesis of Mycophenolic Acid by Penicillium roqueforti in Blue-Veined Cheese

    PubMed Central

    Engel, Günter; von Milczewski, Karl Ernst; Prokopek, Dieter; Teuber, Michael

    1982-01-01

    Twenty of 80 strains of Penicillium roqueforti were able to produce up to 600 mg of mycophenolic acid (MPA) liter−1 in 2% yeast extract-5% sucrose broth. Sixty-two of these strains had been isolated from the main blue-veined cheese varieties of western Europe or from starter cultures. Of these 62 dairy strains, only 7 had MPA-producing potential in vitro. These seven strains had all been isolated during the period 1975 to 1981 from the blue cheese of one individual factory. In cheese from the market, MPA (up to 5 mg kg−1) was only found in samples of this same factory. With MPA-producing and -nonproducing strains for the experimental manufacture of blue cheese, MPA synthesis in cheese was only detected with strains which form MPA in yeast extract-sucrose broth. The maximum MPA level at 4 mg kg−1 was similar to that in commercial cheese. Toxicity of MPA was tested with two established human cell lines (Detroit 98 and Girardi Heart) and one established pig kidney cell line (AmII). PMID:16346004

  2. An additional Meyerozyma guilliermondii IMH3 gene confers mycophenolic acid resistance in fungal CTG clade species.

    PubMed

    Defosse, Tatiana A; Mélin, Céline; Clastre, Marc; Besseau, Sébastien; Lanoue, Arnaud; Glévarec, Gaëlle; Oudin, Audrey; Dugé de Bernonville, Thomas; Vandeputte, Patrick; Linder, Tomas; Bouchara, Jean-Philippe; Courdavault, Vincent; Giglioli-Guivarc'h, Nathalie; Papon, Nicolas

    2016-09-01

    The fungal CTG clade comprises a number of well-known yeasts that impact human health or with high biotechnological potential. To further extend the set of molecular tools dedicated to these microorganisms, the initial focus of this study was to develop a mycophenolic acid (MPA) resistance cassette. Surprisingly, while we were carrying out preliminary susceptibility testing experiments in a set of yeast species, Meyerozyma guilliermondii, although not being a MPA producer, was found to be primarily resistant toward this drug, whereas a series of nine related species were susceptible to MPA. Using comparative and functional genomic approaches, we demonstrated that all MPA-susceptible CTG clade species display a single gene, referred to as IMH3.1, encoding the MPA target inosine monophosphate dehydrogenase (IMPDH) and that MPA resistance relies on the presence in the M. guilliermondii genome of an additional IMPDH-encoding gene (IMH3.2). The M. guilliermondii IMH3.2 gene displays marked differences compared to IMH3.1 including the lack of intron, a roughly 160-fold higher transcription level and a serine residue at position 251. Placed under the control of the M. guilliermondii actin 1 gene promoter, IMH3.2 was successfully used to transform Lodderomyces elongisporus, Clavispora lusitaniae, Scheffersomyces stipitis and Candida parapsilosis.

  3. Pharmacokinetics, Electrophysiological, and Morphological Effects of the Intravitreal Injection of Mycophenolic Acid in Rabbits

    PubMed Central

    Gasparin, Fabio; Aguiar, Renata Genaro; Ioshimoto, Gabriela Lourençon; Silva-Cunha, Armando; Fialho, Silvia Ligório; Liber, André Mauricio; Nagy, Balázs Vince; Oiwa, Nestor Norio; Costa, Marcelo Fernandes; Joselevitch, Christina; Ventura, Dora Fix

    2014-01-01

    Abstract Purpose: To determine the half-life of mycophenolic acid (MPA) in the vitreous of New Zealand albino rabbits after intravitreal injection and the retinal toxicity of different doses of MPA. Methods: Ten micrograms of MPA (Roche Bioscience, Palo Alto, CA) was injected in the vitreous of 16 rabbits, animals were sacrificed at different time-points, and vitreous samples underwent high-performance liquid chromatography. For functional and morphological studies, 5 doses of MPA (0.05, 0.5, 2, 10, and 100 μg) were injected in the vitreous of 20 rabbits. As control, contralateral eyes were injected with aqueous vehicle. Electroretinograms (ERGs) were recorded before injection and at days 7, 15, and 30. Animals were sacrificed on day 30 and retinas were analyzed under light microscopy. Results: MPA half-life in the vitreous was 5.0±0.3 days. ERG revealed photoreceptor functional impairment in eyes injected with 0.5 μg and higher on day 30, while eyes injected with 100 μg presented the same changes already from day 15. No morphological change was found. Conclusions: MPA vitreous half-life is 5.0 days. Intravitreal injection of 0.5 μg MPA and higher causes dose- and time-related photoreceptor sensitivity decrease in rabbits. The MPA dose of 0.05 μg may be safe for intravitreal use in rabbits. PMID:24828287

  4. Functional characterization of MpaG', the O-methyltransferase involved in the biosynthesis of mycophenolic acid.

    PubMed

    Zhang, Wei; Cao, Shaona; Qiu, Li; Qi, Fengxia; Li, Zhong; Yang, Ying; Huang, Shaohua; Bai, Fali; Liu, Changning; Wan, Xiaobo; Li, Shengying

    2015-03-02

    Mycophenolic acid (MPA, 1) is a clinically important immunosuppressant. In this report, a gene cluster mpa' responsible for the biosynthesis of 1 was identified from Penicillium brevicompactum NRRL 864. The S-adenosyl-L-methionine-dependent (SAM-dependent) O-methyltransferase encoded by the mpaG' gene was functionally and kinetically characterized in vitro. MpaG' catalyzes the methylation of demethylmycophenolic acid (DMMPA, 6) to form 1. It also showed significant substrate flexibility by methylating two structural derivatives of 6 prepared by organic synthesis. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Circadian variation of cytotoxicity and genotoxicity induced by an immunosuppressive agent "Mycophenolate Mofetil" in rats.

    PubMed

    Dridi, Ichrak; Grissa, Intissar; Ezzi, Lobna; Chakroun, Sana; Ben-Cherif, Wafa; Haouas, Zohra; Aouam, Karim; Ben-Attia, Mossadok; Reinberg, Alain; Boughattas, Naceur A

    2016-01-01

    Immunosuppressive drugs such as Mycophenolate Mofetil (MMF) are used to suppress the immune system activity in transplant patients and reduce the risk of organ rejection. The present study investigates whether the potential cytotoxicity and genotoxicity varied according to MMF dosing-time in Wistar Rat. A potentially toxic MMF dose (300 mg/kg) was acutely administered by the i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). Rats were sacrificed 3 days following injection, blood and bone marrow were removed for determination of cytotoxicity and genotoxicity analysis. The genotoxic effect of this pro-drug was investigated using the comet assay and the micronucleus test. Hematological changes were also evaluated according to circadian dosing time. MMF treatment induced a significant decrease at 7 HALO in red blood cells, in the hemoglobin rate and in white blood cells. These parameters followed a circadian rhythm in controls or in treated rats with an acrophase located at the end of the light-rest phase. A significant, thrombocytopenia was observed according to MMF circadian dosing time. Furthermore, abnormally shaped red cells, sometimes containing micronuclei, poikilocytotic in red cells and hypersegmented neutrophil nuclei were observed with MMF treatment. The micronucleus test revealed damage to chromosomes in rat bone marrow; the comet assay showed significant DNA damage. This damage varied according to circadian MMF dosing time. The injection of MMF in the middle of the dark-activity phase produced a very mild hematological toxicity and low genotoxicity. Conversely, it induced maximum hematological toxicity and genotoxicity when the administration occurred in the middle of the light-rest phase, which is physiologically analogous to the end of the activity of the diurnal phase in human patients.

  6. Genetic basis for mycophenolic acid production and strain-dependent production variability in Penicillium roqueforti.

    PubMed

    Gillot, Guillaume; Jany, Jean-Luc; Dominguez-Santos, Rebeca; Poirier, Elisabeth; Debaets, Stella; Hidalgo, Pedro I; Ullán, Ricardo V; Coton, Emmanuel; Coton, Monika

    2017-04-01

    Mycophenolic acid (MPA) is a secondary metabolite produced by various Penicillium species including Penicillium roqueforti. The MPA biosynthetic pathway was recently described in Penicillium brevicompactum. In this study, an in silico analysis of the P. roqueforti FM164 genome sequence localized a 23.5-kb putative MPA gene cluster. The cluster contains seven genes putatively coding seven proteins (MpaA, MpaB, MpaC, MpaDE, MpaF, MpaG, MpaH) and is highly similar (i.e. gene synteny, sequence homology) to the P. brevicompactum cluster. To confirm the involvement of this gene cluster in MPA biosynthesis, gene silencing using RNA interference targeting mpaC, encoding a putative polyketide synthase, was performed in a high MPA-producing P. roqueforti strain (F43-1). In the obtained transformants, decreased MPA production (measured by LC-Q-TOF/MS) was correlated to reduced mpaC gene expression by Q-RT-PCR. In parallel, mycotoxin quantification on multiple P. roqueforti strains suggested strain-dependent MPA-production. Thus, the entire MPA cluster was sequenced for P. roqueforti strains with contrasted MPA production and a 174bp deletion in mpaC was observed in low MPA-producers. PCRs directed towards the deleted region among 55 strains showed an excellent correlation with MPA quantification. Our results indicated the clear involvement of mpaC gene as well as surrounding cluster in P. roqueforti MPA biosynthesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Dried Blood Spot Sampling for Tacrolimus and Mycophenolic Acid in Children: Analytical and Clinical Validation.

    PubMed

    Martial, Lisa C; Hoogtanders, Karin E J; Schreuder, Michiel F; Cornelissen, Elisabeth A; van der Heijden, Jac; Joore, Manuela A; Van Maarseveen, Erik M; Burger, David M; Croes, Sander; Brüggemann, Roger J M; Aarnoutse, Rob E

    2017-08-01

    Tacrolimus and mycophenolic acid (MPA) are the backbone of immunosuppressive therapy after pediatric kidney transplantation. Dosing of these drugs is individualized by therapeutic drug monitoring. Dried blood spot (DBS) sampling may prove beneficial over conventional venous sampling. We aimed to develop and clinically validate a DBS method for tacrolimus and MPA in children. A joint DBS liquid chromatography-mass spectrometry assay for tacrolimus and MPA was developed. DBS-specific items included the hematocrit effect and influence of spot volume. Subsequently, a clinical validation study among children aged 2-18 years was performed to assess the agreement between observed and DBS-predicted venous concentrations. Agreement of the methods was assessed with Passing-Bablok regression, Bland-Altman plots, and quantification of the DBS predictive performance in terms of bias (median percentage prediction error) and precision (median absolute percentage prediction error), both should be <15%. A total of 40 tacrolimus and 32 MPA samples were available from 28 children. Conversion factors were used to predict venous concentrations from DBS. For tacrolimus, 95% of the individual ratios of predicted and observed concentrations were within a range of 0.74-1.28, with 85% of these ratios between 0.80 and 1.20 (Bland-Altman plots). For MPA, the 95% limits of agreement represented a broader range of 0.49-1.49%, and 72% of individual ratios were between the 0.80 and 1.20 limits. Median percentage prediction error and median absolute percentage prediction error were less than 15% for both drugs. A DBS assay was developed for tacrolimus and MPA. Tacrolimus venous concentrations could be adequately predicted from DBS. DBS analysis of MPA seemed to be a semiquantitative measurement at the most when compared with conventional plasma analysis, considering the high variability between observed and predicted concentrations. Next, home-based DBS sampling of tacrolimus for the purpose of

  8. Estimation of Mycophenolic Acid Area Under the Curve With Limited-Sampling Strategy in Chinese Renal Transplant Recipients Receiving Enteric-Coated Mycophenolate Sodium

    PubMed Central

    Jia, Yichen; Peng, Bo; Li, Long; Wang, Jina; Wang, Xuanchuan; Qi, Guisheng; Rong, Ruiming; Wang, Liming; Qiu, Jianxin; Xu, Ming

    2017-01-01

    Background: The enteric-coated mycophenolate sodium (EC-MPS), whose active constituent is mycophenolic acid (MPA), has been widely clinically used for organ transplant recipients. However, its absorption is delayed due to its special designed dosage form, which results in difficulty to monitor the exposure of the MPA in patients receiving the EC-MPS. This study was aimed at developing a relatively practical and precise model with limited sampling strategy to estimate the 12-hour area under the concentration–time curve (AUC0–12 h) of MPA for Chinese renal transplant recipients receiving EC-MPS. Methods: A total of 36 Chinese renal transplant recipients receiving the EC-MPS and tacrolimus were recruited in this study. The time point was 2 weeks after the transplantation for all the patients. The MPA concentrations were measured with enzyme-multiplied immunoassay technique for 11 blood specimens collected predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after the morning dose of EC-MPS. The measured AUC was calculated with these 11 points of MPA concentrations with the linear trapezoidal rule. Limited sampling strategy was used to develop models for estimated AUC in the model group (n = 18). The bias and precision of different models were evaluated in the validation group (n = 18). Results: C4 showed the strongest correlation with the measured AUC. The best 3 time point equation was 6.629 + 8.029 × C0 + 0.592 × C3 + 1.786 × C4 (R2 = 0.910; P < 0.001), whereas the best 4 time point equation was 3.132 + 5.337 × C0 + 0.735 × C3 + 1.783 × C4 + 3.065 × C8 (R2 = 0.959; P < 0.001). When evaluated in the validation group, the 4 time point model had a much better performance than the 3 time point model: for the 4 time point model: R2 = 0.873, bias = 0.505 [95% confidence interval (CI), −10.159 to 11.170], precision = 13.370 (95% CI, 5.186–21.555), and 77.8% of estimated AUCs was within 85%–115% of the measured AUCs; for the 3 time point model: R2

  9. [Studies on the breeding by ion implantation and cultivation of mycophenolic acid producing strain].

    PubMed

    Liu, Mei; Zhang, Peng; Cui, Xiao-Lan; Ren, Xiao; Zhang, Hua

    2006-10-01

    Mycophenolic acid is produced by aerobic fermentation of several Penicillium species. It has a broad spectrum of activity like antitumor activity, antiviral, anti-psoriatic, immunosuppressive and anti-inflammatory activity. It also exhibits antibacterial and antifungal activities. The immunosuppressive effect of MPA has been important in treatment of organ rejection after organ transplant surgery. There is a continuous need to find improved process for efficiently obtaining superior MPA producing mutants. In recent years, the ion implantation technique has been widely applied in many fields and has been drawn morn concern. However there is no report in the field of mutational breeding of MPA producing strain. Penicillium brevicompactum M-51 was derived from MPA producing strain F-663 by varied mutational methods including U.V. and microwave irradiation. In the process of increasing the production of MPA from P. brevicompactum M-51, a mutant strain M-163 was obtained by means of N+ ion implantation. An decline-increase-decline tendency of strain survival rates was observed when the strain was implanted by N+ ion with dose from 20 2.6 x 10(13) ions/cm2 to 180 x 2.6 x 10(13) ions/cm2 under implantation energy 15 keV. It apparently appeared "saddle shape". And under the implantation dose of 140 x 2.6 x 10(13) ions/cm2, the variation rate and the positive variation rate of the strain had reached the highest values 88.9% and 63.4%, respectively. The HPLC results showed that MPA yield of P. brevicompactum M-163 was improved by 30.1%, and its productivity was rather stable through successive transfer of cultures. The effect of seed growth time on yield of MPA was studied, and the best seed age was 24h after incubation. In the mean time, the fermentative condition of M-163 was studied through orthogonal design. The major ingredients being investigated included carbon and nitrogen sources. Finally the optimized fermentation medium was obtained. The yield of MPA reached 2819g

  10. Differential proteome analysis of human embryonic kidney cell line (HEK-293) following mycophenolic acid treatment

    PubMed Central

    2011-01-01

    Background Mycophenolic acid (MPA) is widely used as a post transplantation medicine to prevent acute organ rejection. In the present study we used proteomics approach to identify proteome alterations in human embryonic kidney cells (HEK-293) after treatment with therapeutic dose of MPA. Following 72 hours MPA treatment, total protein lysates were prepared, resolved by two dimensional gel electrophoresis and differentially expressed proteins were identified by QTOF-MS/MS analysis. Expressional regulations of selected proteins were further validated by real time PCR and Western blotting. Results The proliferation assay demonstrated that therapeutic MPA concentration causes a dose dependent inhibition of HEK-293 cell proliferation. A significant apoptosis was observed after MPA treatment, as revealed by caspase 3 activity. Proteome analysis showed a total of 12 protein spots exhibiting differential expression after incubation with MPA, of which 7 proteins (complement component 1 Q subcomponent-binding protein, electron transfer flavoprotein subunit beta, cytochrome b-c1 complex subunit, peroxiredoxin 1, thioredoxin domain-containing protein 12, myosin regulatory light chain 2, and profilin 1) showed significant increase in their expression. The expression of 5 proteins (protein SET, stathmin, 40S ribosomal protein S12, histone H2B type 1 A, and histone H2B type 1-C/E/F/G/I) were down-regulated. MPA mainly altered the proteins associated with the cytoskeleton (26%), chromatin structure/dynamics (17%) and energy production/conversion (17%). Both real time PCR and Western blotting confirmed the regulation of myosin regulatory light chain 2 and peroxiredoxin 1 by MPA treatment. Furthermore, HT-29 cells treated with MPA and total kidney cell lysate from MMF treated rats showed similar increased expression of myosin regulatory light chain 2. Conclusion The emerging use of MPA in diverse pathophysiological conditions demands in-depth studies to understand molecular basis of

  11. Comparative metabolism of mycophenolic acid by glucuronic acid and glucose conjugation in human, dog, and cat liver microsomes.

    PubMed

    Slovak, J E; Mealey, K; Court, M H

    2017-04-01

    Use of the immunosuppressant mycophenolic acid (MPA) in cats is limited because MPA elimination depends on glucuronidation, which is deficient in cats. We evaluated formation of major (phenol glucuronide) and minor (acyl glucuronide, phenol glucoside, and acyl glucoside) MPA metabolites using liver microsomes from 16 cats, 26 dogs, and 48 humans. All MPA metabolites were formed by human liver microsomes, while dog and cat liver microsomes formed both MPA glucuronides, but only one MPA glucoside (phenol glucoside). Intrinsic clearance (CLint) of MPA for phenol glucuronidation by cat liver microsomes was only 15-17% that of dog and human liver microsomes. However, CLint for acyl glucuronide and phenol glucoside formation in cat liver microsomes was similar to or greater than that for dog and human liver microsomes. While total MPA conjugation CLint was generally similar for cat liver microsomes compared with dog and human liver microsomes, relative contributions of each pathway varied between species with phenol glucuronidation predominating in dog and human liver microsomes and phenol glucosidation predominating in cat liver microsomes. MPA conjugation variation between cat liver microsomes was threefold for total conjugation and for phenol glucosidation, sixfold for phenol glucuronidation, and 11-fold for acyl glucuronidation. Our results indicate that total MPA conjugation is quantitatively similar between liver microsomes from cats, dogs, and humans despite large differences in the conjugation pathways that are utilized by these species.

  12. Effect of mycophenolic acid on TNFα-induced expression of cell adhesion molecules in human venous endothelial cells in vitro

    PubMed Central

    Hauser, Ingeborg A; Johnson, David R; Thévenod, Frank; Goppelt-Strübe, Margarete

    1997-01-01

    Mycophenolic acid (MPA) is an inhibitor of inosine-5′-monophosphate dehydrogenase and therefore interferes with cellular GTP biosynthesis. Recently, MPA has been used as an antiproliferative and immunosuppressive agent. In the present study, the effect of MPA on the expression of the endothelial cell adhesion molecules (CAMs), intercellular (I) CAM-1, vascular (V) CAM-1 and endothelial (E)-selectin, was investigated in tumour necrosis factor-α (TNFα)-activated cultured human venous endothelial cells (EC).Surface expression of CAMs was measured by flow cytometry and mRNA expression by Northern blot analysis. Transcriptional activation of CAMs by the nuclear factor NF-κB was determined by an electromobility shift assay. The function of CAMs was studied by a static adhesion assay with human monocyte-like undifferentiated U937 cells.Pretreatment of TNFα- (5  ng ml−1, 12 h) activated EC with MPA (10 μM, 24 h) increased the binding of U937 cells, which had not been treated with MPA, by ≈amp;2 fold. MPA-pretreatment of EC did not affect TNFα-induced surface expression of ICAM-1. However, VCAM-1 and E-selectin were increased 2–3 fold and remained elevated up to 24 h, by which time TNFα-activated control EC had returned to baseline levels of expression. The effect of MPA on the surface expression of CAMs was half-maximal at ≈amp;1 μM and required ⩾12 h of pretreatment. Guanosine (0.3 mM), a precursor of GTP, did not prevent the effect of MPA on the expression of CAMs in TNFα-activated EC.Kinetics of mRNA expression of CAMs mirrored protein expression: mRNA for ICAM-1 was unaffected, whereas TNFα-induced mRNA expression for E-selectin and VCAM-1 was prolonged and increased by MPA. This effect was not due to increased transcription mediated by the nuclear transcription factor NF-κB. However, half-life for E-selectin mRNA was increased 10 fold by MPA, whereas ICAM-1 mRNA half-life was unchanged.The data demonstrate that apart from its

  13. A Limited Sampling Schedule to Estimate Mycophenolic Acid Area Under the Concentration-Time Curve in Hematopoietic Cell Transplantation Recipients

    PubMed Central

    Li, Hong; Mager, Donald E.; Bemer, Meagan J.; Salinger, David H.; Vicini, Paolo; Sandmaier, Brenda M.; Nash, Richard; McCune, Jeannine S.

    2011-01-01

    Mycophenolate mofetil (MMF) is a key component of post-grafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSS) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2 hr MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of one and two compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSS were derived using a simulation approach based on the scaled mean squared error. A five-sample schedule of 2, 2.5, 3, 5, and 6 hr from the start of the infusion precisely estimated MPA AUC0–12 hr for Q12 hr IV MMF. A comparable schedule (2, 2.5, 3, 4 and 6 hr) similarly estimated MPA AUC0–8hr for Q8 hr dosing. PMID:22174435

  14. A limited sampling schedule to estimate mycophenolic Acid area under the concentration-time curve in hematopoietic cell transplantation recipients.

    PubMed

    Li, Hong; Mager, Donald E; Bemer, Meagan J; Salinger, David H; Vicini, Paolo; Sandmaier, Brenda M; Nash, Richard; McCune, Jeannine S

    2012-11-01

    Mycophenolate mofetil (MMF) is a key component of postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients. The plasma area under the curve (AUC) of its active metabolite, mycophenolic acid (MPA), is associated with MMF efficacy and toxicity. This study developed a population pharmacokinetic model of MPA in HCT recipients and created limited sampling schedules (LSSs) to enable individualized pharmacotherapy. A retrospective evaluation of MPA concentration-time data following a 2-hour MMF intravenous (IV) infusion was conducted in 77 HCT recipients. The final model consisted of 1 and 2 compartments for MMF and MPA pharmacokinetics, respectively. The mean estimated values (coefficient of variation, %) for total systemic clearance, distributional clearance, and central and peripheral compartment volumes of MPA were 36.9 L/h (34.5%), 15.3 L/h (80.4%), 11.9 L (71.7%), and 182 L (127%), respectively. No covariates significantly explained variability among individuals. Optimal LSSs were derived using a simulation approach based on the scaled mean squared error. A 5-sample schedule of 2, 2.5, 3, 5, and 6 hours from the start of the infusion precisely estimated MPA AUC(0-12 h) for Q12-hour IV MMF. A comparable schedule (2, 2.5, 3, 4, and 6 hours) similarly estimated MPA AUC(0-8) (h) for Q8-hour dosing.

  15. Effects of Phenylglyoxal and N-ethylmaleimide Concentration on Mycophenolic Acid Production by Penicillium brevi-compactum ATCC16024

    PubMed Central

    Ardestani, Fatemeh

    2016-01-01

    Mycophenolic acid is a secondary extracellular metabolite of Penicillium strains with numerous pharmaceutical properties such as antibiotic and immunosuppressive uses. The aim of this work is the survey of the effect of phenylglyoxal and n-ethylmaleimide concentration in culture medium on mycophenolic acid production by Penicillium brevi-compactum ATCC16024 was investigated. Batch submerged fermentation was performed in 250 mL shake flasks at 24 °C and 200 rpm in a rotary shaker for 300 h using a basic culture medium containing different concentrations of phenylglyoxal and n-ethylmaleimide ranged from 0 to 20 mg. L-1. For the basic medium without any amounts of phenylglyoxal and n-ethylmaleimide (control), maximum MPA production, product yield and productivity of process was in order, 1.5042 g. L-1, 20.3 mg. g-1 consumed glucose and 5.37 mg. L-1h-1. Maximum produced MPA of 2.9032 g. L-1, MPA yield of 39.23 mg. g-1 of consumed glucose, productivity of 10.37 mg. L-1 h-1 and total enhancement of 93.11% was obtained when the culture medium was contained 18 mg. L-1 of phenylglyoxal, represented more than 93% raising in compare to control. Maximum MPA concentration, yield and productivity in order was obtained 3.1123 g. L-1, 42.06 mg. g-1 of consumed glucose and 11.11 mg. L-1 h-1, with using 6 mg. L-1 of n-ethylmaleimide. N-ethylmaleimide was caused to 2.138 folds (106.89%) increase in MPA production by P. brevi-compactum ATCC16024. PMID:28243291

  16. Simultaneous determination of mycophenolic acid and its glucuronides in human plasma using isocratic ion pair high-performance liquid chromatography.

    PubMed

    Mino, Yasuaki; Naito, Takafumi; Matsushita, Tomomi; Kagawa, Yoshiyuki; Kawakami, Junichi

    2008-02-13

    Therapeutic drug monitoring (TDM) of mycophenolic acid (MPA) following administration of mycophenolate mofetil (MMF) or the enteric-coated sodium salt of MPA formulations, seems beneficial because of the large intra- and inter-individual variability in MPA pharmacokinetics. MPA is an active component from these oral formulations and are further metabolised to inactive phenolic glucuronide (MPAG) and active acyl glucuronide (AcMPAG). This study aims to determine simultaneously these three metabolites of MMF using isocratic ion pair HPLC and to evaluate the short-term stability of AcMPAG in human plasma. Samples were prepared using solid phase extraction. Chromatographic separation was achieved over an RP column (TSKgel ODS-80Ts, 150 mm x 4.6 mm i.d., 5 microm particle size) with acetonitrile and 30 mM tetra-n-butylammonium bromide containing 5 mM ammonium acetate at pH 9.0 (33/67, v/v) as the mobile phase. The flow rate of the mobile phase was 1ml/min, and the wavelength of determination by UV detection was 250 nm (run time, 16 min). Calibration curves for MPA, MPAG and AcMPAG in human plasma were linear over a concentration range of 0.05-50, 0.1-400 and 0.08-8 microg/ml, respectively. Intra- and inter-assay R.S.D. were<6.5%. Extraction efficiencies were more than 85% for all analytes. Since AcMPAG was unstable in human plasma, plasma acidification was needed for the quantification of AcMPAG. Large interindividual variability was observed in the AcMPAG pharmacokinetics in the early period after renal transplantation. In conclusion, a simple, accurate and reproducible HPLC method to measure simultaneously these three MMF metabolites has been established. The method will be helpful in evaluating pharmacokinetics of MPA and its glucuronides.

  17. Inhibitory effect of ciprofloxacin on β-glucuronidase-mediated deconjugation of mycophenolic acid glucuronide.

    PubMed

    Kodawara, Takaaki; Masuda, Satohiro; Yano, Yoshitaka; Matsubara, Kazuo; Nakamura, Toshiaki; Masada, Mikio

    2014-07-01

    The interaction between mycophenolate (MPA) and quinolone antibiotics such as ciprofloxacin is considered to reduce the enterohepatic recycling of MPA, which is biotransformed in the intestine from MPA glucuronide (MPAG) conjugate excreted via the biliary system; however, the molecular mechanism underlying this biotransformation of MPA is still unclear. In this study, an in vitro system was established to evaluate β-glucuronidase-mediated deconjugation and to examine the influence of ciprofloxacin on the enzymatic deconjugation of MPAG and MPA resynthesis. Resynthesis of MPA via deconjugation of MPAG increased in a time-dependent manner from 5 to 60 min in the presence of β-glucuronidase. Ciprofloxacin and phenolphthalein-β-d-glucuronide (PhePG), a typical β-glucuronidase substrate, significantly decreased the production of MPA from MPAG in the β-glucuronidase-mediated deconjugation system. In addition, enoxacin significantly inhibited the production of MPA from MPAG, while levofloxacin and ofloxacin had no inhibitory effect on MPA synthesis. Pharmacokinetic analysis revealed that ciprofloxacin showed a dose-dependent inhibitory effect on MPA production from MPAG via β-glucuronidase with a half-maximal inhibitory concentration (IC50 ) value of 30.4 µm. While PhePG inhibited the β-glucuronidase-mediated production of MPA from MPAG in a competitive manner, ciprofloxacin inhibited MPA synthesis via noncompetitive inhibition. These findings suggest that the reduction in the serum MPA concentration during the co-administration of ciprofloxacin is at least in part due to the decreased enterohepatic circulation of MPA because of noncompetitive inhibition of deconjugation of MPAG by intestinal β-glucuronidase. Copyright © 2014 John Wiley & Sons, Ltd.

  18. Validation of limited sampling strategy for the estimation of mycophenolic acid exposure in Chinese adult liver transplant recipients.

    PubMed

    Hao, Chen; Erzheng, Chen; Anwei, Mao; Zhicheng, Yu; Baiyong, Shen; Xiaxing, Deng; Weixia, Zhang; Chenghong, Peng; Hongwei, Li

    2007-12-01

    Mycophenolate mofetil (MMF) is indicated as immunosuppressive therapy in liver transplantation. The abbreviated models for the estimation of mycophenolic acid (MPA) area under the concentration-time curve (AUC) have been established by limited sampling strategies (LSSs) in adult liver transplant recipients. In the current study, the performance of the abbreviated models to predict MPA exposure was validated in an independent group of patients. A total of 30 MPA pharmacokinetic profiles from 30 liver transplant recipients receiving MMF in combination with tacrolimus were used to compare 8 models' performance with a full 10 time-point MPA-AUC. Linear regression analysis and Bland-Altman analysis were used to compare the estimated MPA-AUC0-12h from each model against the measured MPA-AUC0-12h. A wide range of agreement was shown when estimated MPA-AUC0-12h was compared with measured MPA-AUC0-12h, and the range of coefficient of determination (r2) was from 0.479 to 0.936. The model based on MPA pharmacokinetic parameters C1h, C2h, C6h, and C8h had the best ability to predict measured MPA-AUC0-12h, with the best coefficient of determination (r2=0.936), the excellent prediction bias (2.18%), the best prediction precision (5.11%), and the best prediction variation (2SD=+/-7.88 mg.h/L). However, the model based on MPA pharmacokinetic sampling time points C1h, C2h, and C4h was more suitable when concerned with clinical convenience, which had shorter sampling interval, an excellent coefficient of determination (r2=0.795), an excellent prediction bias (3.48%), an acceptable prediction precision (14.37%), and a good prediction variation (2SD=+/-13.23 mg.h/L). Measured MPA-AUC0-12h could be best predicted by using MPA pharmacokinetic parameters C1h, C2h, C6h, and C8h. The model based on MPA pharmacokinetic parameters C1h, C2h, and C4h was more feasible in clinical application.

  19. The Effects of Unbound Mycophenolic Acid (MPA) on Inosine Monophosphate Dehydrogenase (IMPDH) Inhibition in Pediatric Kidney Transplant Patients

    PubMed Central

    Smits, Thomas A.; Cox, Shareen; Fukuda, Tsuyoshi; Sherbotie, Joseph; Ward, Robert; Goebel, Jens; Vinks, Alexander A.

    2015-01-01

    Background Mycophenolic acid (MPA) is a key immunosuppressive drug that acts through inhibition of inosine monophosphate dehydrogenase (IMPDH). MPA is commonly measured as part of therapeutic drug monitoring as the total concentration in plasma. However, it has been postulated that the free (unbound) fraction of MPA (fMPA) is responsible for the immunosuppressive effects. In this study, a sensitive low volume high performance liquid chromatography (HPLC) assay was developed to measure fMPA concentrations in order to explore the relationship between fMPA and IMPDH activity. Methods To obtain fMPA concentrations, plasma samples were filtrated using Centrifree® Ultrafiltration Devices. The ultrafiltrate was analyzed by HPLC using a Kinetex® C18 column (2.6 μm, 3.0 × 75 mm). fMPA concentrations were compared to total MPA concentrations available in 28 pediatric kidney transplant patients at 3 consecutive occasions post-transplantation. The relationship between fMPA and IMPDH activity was analyzed using an Emax-model. Results The HPLC-assay using 25μL of the ultrafiltrates was validated over a range from 2.5 to 1000 μg/L with good accuracy, precision and reproducibility. Total and free MPA concentrations were well correlated (R2 = 0.85, P < 0.0001) although large intra-and inter-individual variability in the bound MPA fractions was observed. The overall relationship between fMPA concentrations and IMPDH inhibition using the Emax-model was comparable to that of total MPA as previously reported. The model estimated EC50 (164.5 μg/L) is in good agreement with reported in vitro EC50 values. Conclusions This study provides a simple HPLC method for the measurement of fMPA and a pharmacologically reasonable EC50-estimate. The good correlation between total and free MPA concentrations suggests that routine measurement of fMPA to characterize mycophenolate PK/PD does not seem warranted although the large variability in the bound fractions of MPA warrants further study

  20. Effects of light intensity and light wavelength on the production of mycophenolic acid by Penicillium brevicompactum in batch cultures.

    PubMed

    Shu, Chin-Hang; Peng, Jeng-Chin; Tsai, Chieh-Chung

    2010-05-05

    The influence of different light sources and light intensity on mycophenolic acid (MPA) by Penicillium brevicompactum in batch culture was significant and demonstrated in this study. MPA batch cultures under various light sources including fluorescent light, red LED light (630nm) and blue LED light (470nm), were investigated in a light controlled photo-bioreactor. Results of cultures under fluorescent light indicated that optimal maximum cell density and maximum MPA concentration (Pmax) achieved at 1400lux were 9.40 and 0.48gL(-1), respectively. Results of culture under LED lights indicated that the optimal culture condition for cell growth was red LED light at 600lux with cell yield, 0.88gg(-1), while that for MPA formation was blue LED light at 600lux with specific product yield, 0.056gg(-1). Red LED light stimulated both cell growth and MPA formation; however, blue LED light inhibited cell growth but stimulated MPA formation. A novel two-stage LED light process has been successfully demonstrated to optimize MPA fermentation of P. brevicompactum, and the highest Pmax of 0.56gL(-1) was achieved with 87% improvement as compared with that of the batch in the dark. Copyright © 2010 Elsevier Inc. All rights reserved.

  1. Change in pharmacokinetics of mycophenolic acid as a function of age in rats and effect of coadministered amoxicillin/clavulanate.

    PubMed

    Ishizaki, Junko; Tsuda, Tomoko; Suga, Yukio; Ito, Satsuki; Arai, Kunizo; Sai, Yoshimichi; Miyamoto, Ken-Ichi

    2012-01-01

    Changes of mycophenolic acid (MPA) pharmacokinetics with aging were investigated in rats. We also compared the effect of concomitant amoxicillin/clavulanate combination (CVA/AMPC) on the pharmacokinetics of MPA in 4-week-old and 12-week-old rats (the package insert of CVA/AMPC warns of possible interaction with MPA). Four-week-old rats showed a 1.4-fold higher total body clearance of MPA and a lower volume of distribution of MPA (65%), compared to the values in 12-week-old rats. However, the difference in MPA pharmacokinetics disappeared when enterohepatic circulation was eliminated by bile duct cannulation (BDC). Concomitant CVA/AMPC significantly reduced plasma MPA concentration in intact rats of both age groups, and the age-dependent difference of MPA pharmacokinetics was no longer apparent. The effect of CVA/AMPC was not seen in rats that had undergone BDC, suggesting that the drug-drug interaction can be attributed to inhibition of enterohepatic circulation by CVA/AMPC. These results indicate that the aging-related alteration of MPA pharmacokinetics is a consequence of immature enterohepatic circulation in 4-week-old rats. Higher doses of MPA may be necessary in juveniles.

  2. Inosine Monophosphate Dehydrogenase (IMPDH) Activity as a Pharmacodynamic Biomarker of Mycophenolic Acid Effects in Pediatric Kidney Transplant Recipients

    PubMed Central

    Fukuda, Tsuyoshi; Goebel, Jens; Thøgersen, Håvard; Maseck, Denise; Cox, Shareen; Logan, Barbara; Sherbotie, Joseph; Seikaly, Mouin; Vinks, Alexander A.

    2013-01-01

    Monitoring inosine monophosphate dehydrogenase (IMPDH) activity as a biomarker of mycophenolic acid (MPA)–induced immunosuppression may serve as a novel approach in pharmacokinetics (PK)/pharmacodynamics (PD)–guided therapy. The authors prospectively studied MPA pharmacokinetics and IMPDH inhibition in 28 pediatric de novo kidney transplant recipients. Pretransplant IMPDH activity and full PK/PD profiles were obtained at 3 different occasions: 1 to 3 days, 4 to 9 days, and approximately 6 months after transplant. Large intra- and interpatient variability was noted in MPA pharmacokinetics and exposure and IMPDH inhibition. MPA exposure (AUC0-12 h) was low early posttransplant and increased over time and stabilized at months 3 to 6. Mean pretransplant IMPDH activity (6.4 ± 4.6 nmol/h/mg protein) was lower than previously reported in adults. In most of the patients, IMPDH enzyme activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory Emax model (EC50 = 0.97 mg/L). This study suggests the importance of early PK/PD monitoring to improve drug exposure. Because IMPDH inhibition is well correlated to MPA concentration, pre-transplant IMPDH activity may serve as an early marker to guide the initial level of MPA exposure required in a pediatric population. PMID:20418509

  3. Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach.

    PubMed

    Daher Abdi, Z; Essig, M; Rizopoulos, D; Le Meur, Y; Prémaud, A; Woillard, J B; Rérolle, J P; Marquet, P; Rousseau, A

    2013-06-01

    This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.

  4. Identifying the differences in mechanisms of mycophenolic acid controlling fucose content of glycoproteins expressed in different CHO cell lines.

    PubMed

    Zhang, An; Tsang, Valerie Liu; Markely, Lam R; Kurt, Lutfiye; Huang, Yao-Ming; Prajapati, Shashi; Kshirsagar, Rashmi

    2016-11-01

    In the biopharmaceutical industry, glycosylation is a critical quality attribute that can modulate the efficacy of a therapeutic glycoprotein. Obtaining a consistent glycoform profile is desired because molecular function can be defined by its carbohydrate structures. Specifically, the fucose content of oligosaccharides in glycoproteins is one of the most important attributes that can significantly affect antibody-dependent cellular cytotoxicity (ADCC) activity. It is therefore important to understand the fucosylation pathway and be able to control fucosylation at the desired level to match predecessor materials in late stage and biosimilar programs. Several strategies were explored in this study and mycophenolic acid (MPA) was able to finely modulate the fucose content with the least undesired side effects. However, the response was significantly different between CHO cell lines of different lineages. Further experiments were then performed for a deeper understanding of the mechanism of fucosylation in different CHO cell lines. Results indicated that changes in the intracellular nucleotide involved in fucosylation pathway after MPA treatment are the main cause of the differences in fucosylation level response in different CHO cell lines. Differences in MPA metabolism in the various CHO cell lines directly resulted in different levels of afucosylation measured in antibodies produced by the CHO cell lines. Biotechnol. Bioeng. 2016;113: 2367-2376. © 2016 Wiley Periodicals, Inc.

  5. Involvement of a Natural Fusion of a Cytochrome P450 and a Hydrolase in Mycophenolic Acid Biosynthesis

    PubMed Central

    Hansen, Bjarne Gram; Mnich, Ewelina; Nielsen, Kristian Fog; Nielsen, Jakob Blæsbjerg; Nielsen, Morten Thrane; Mortensen, Uffe Hasbro

    2012-01-01

    Mycophenolic acid (MPA) is a fungal secondary metabolite and the active component in several immunosuppressive pharmaceuticals. The gene cluster coding for the MPA biosynthetic pathway has recently been discovered in Penicillium brevicompactum, demonstrating that the first step is catalyzed by MpaC, a polyketide synthase producing 5-methylorsellinic acid (5-MOA). However, the biochemical role of the enzymes encoded by the remaining genes in the MPA gene cluster is still unknown. Based on bioinformatic analysis of the MPA gene cluster, we hypothesized that the step following 5-MOA production in the pathway is carried out by a natural fusion enzyme MpaDE, consisting of a cytochrome P450 (MpaD) in the N-terminal region and a hydrolase (MpaE) in the C-terminal region. We verified that the fusion gene is indeed expressed in P. brevicompactum by obtaining full-length sequence of the mpaDE cDNA prepared from the extracted RNA. Heterologous coexpression of mpaC and the fusion gene mpaDE in the MPA-nonproducer Aspergillus nidulans resulted in the production of 5,7-dihydroxy-4-methylphthalide (DHMP), the second intermediate in MPA biosynthesis. Analysis of the strain coexpressing mpaC and the mpaD part of mpaDE shows that the P450 catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoic acid (DHMB). DHMB is then converted to DHMP, and our results suggest that the hydrolase domain aids this second step by acting as a lactone synthase that catalyzes the ring closure. Overall, the chimeric enzyme MpaDE provides insight into the genetic organization of the MPA biosynthesis pathway. PMID:22544261

  6. Involvement of a natural fusion of a cytochrome P450 and a hydrolase in mycophenolic acid biosynthesis.

    PubMed

    Hansen, Bjarne Gram; Mnich, Ewelina; Nielsen, Kristian Fog; Nielsen, Jakob Blæsbjerg; Nielsen, Morten Thrane; Mortensen, Uffe Hasbro; Larsen, Thomas Ostenfeld; Patil, Kiran Raosaheb

    2012-07-01

    Mycophenolic acid (MPA) is a fungal secondary metabolite and the active component in several immunosuppressive pharmaceuticals. The gene cluster coding for the MPA biosynthetic pathway has recently been discovered in Penicillium brevicompactum, demonstrating that the first step is catalyzed by MpaC, a polyketide synthase producing 5-methylorsellinic acid (5-MOA). However, the biochemical role of the enzymes encoded by the remaining genes in the MPA gene cluster is still unknown. Based on bioinformatic analysis of the MPA gene cluster, we hypothesized that the step following 5-MOA production in the pathway is carried out by a natural fusion enzyme MpaDE, consisting of a cytochrome P450 (MpaD) in the N-terminal region and a hydrolase (MpaE) in the C-terminal region. We verified that the fusion gene is indeed expressed in P. brevicompactum by obtaining full-length sequence of the mpaDE cDNA prepared from the extracted RNA. Heterologous coexpression of mpaC and the fusion gene mpaDE in the MPA-nonproducer Aspergillus nidulans resulted in the production of 5,7-dihydroxy-4-methylphthalide (DHMP), the second intermediate in MPA biosynthesis. Analysis of the strain coexpressing mpaC and the mpaD part of mpaDE shows that the P450 catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoic acid (DHMB). DHMB is then converted to DHMP, and our results suggest that the hydrolase domain aids this second step by acting as a lactone synthase that catalyzes the ring closure. Overall, the chimeric enzyme MpaDE provides insight into the genetic organization of the MPA biosynthesis pathway.

  7. Diabetes Mellitus Reduces Activity of Human UDP-Glucuronosyltransferase 2B7 in Liver and Kidney Leading to Decreased Formation of Mycophenolic Acid Acyl-Glucuronide Metabolite

    PubMed Central

    Dostalek, Miroslav; Court, Michael H.; Hazarika, Suwagmani

    2011-01-01

    Mycophenolic acid (MPA) is an immunosuppressive agent commonly used after organ transplantation. Altered concentrations of MPA metabolites have been reported in diabetic kidney transplant recipients, although the reason for this difference is unknown. We aimed to compare MPA biotransformation and UDP-glucuronosyltransferase (UGT) expression and activity between liver (n = 16) and kidney (n = 8) from diabetic and nondiabetic donors. Glucuronidation of MPA, as well as the expression and probe substrate activity of UGTs primarily responsible for MPA phenol glucuronide (MPAG) formation (UGT1A1 and UGT1A9), and MPA acyl glucuronide (AcMPAG) formation (UGT2B7), was characterized. We have found that both diabetic and nondiabetic human liver microsomes and kidney microsomes formed MPAG with similar efficiency; however, AcMPAG formation was significantly lower in diabetic samples. This finding is supported by markedly lower glucuronidation of the UGT2B7 probe zidovudine, UGT2B7 protein, and UGT2B7 mRNA in diabetic tissues. UGT genetic polymorphism did not explain this difference because UGT2B7*2 or *1c genotype were not associated with altered microsomal UGT2B7 protein levels or AcMPAG formation. Furthermore, mRNA expression and probe activities for UGT1A1 or UGT1A9, both forming MPAG but not AcMPAG, were comparable between diabetic and nondiabetic tissues, suggesting the effect may be specific to UGT2B7-mediated AcMPAG formation. These findings suggest that diabetes mellitus is associated with significantly reduced UGT2B7 mRNA expression, protein level, and enzymatic activity of human liver and kidney, explaining in part the relatively low circulating concentrations of AcMPAG in diabetic patients. PMID:21123165

  8. A new class of IMP dehydrogenase with a role in self-resistance of mycophenolic acid producing fungi

    PubMed Central

    2011-01-01

    Background Many secondary metabolites produced by filamentous fungi have potent biological activities, to which the producer organism must be resistant. An example of pharmaceutical interest is mycophenolic acid (MPA), an immunosuppressant molecule produced by several Penicillium species. The target of MPA is inosine-5'-monophosphate dehydrogenase (IMPDH), which catalyses the rate limiting step in the synthesis of guanine nucleotides. The recent discovery of the MPA biosynthetic gene cluster from Penicillium brevicompactum revealed an extra copy of the IMPDH-encoding gene (mpaF) embedded within the cluster. This finding suggests that the key component of MPA self resistance is likely based on the IMPDH encoded by mpaF. Results In accordance with our hypothesis, heterologous expression of mpaF dramatically increased MPA resistance in a model fungus, Aspergillus nidulans, which does not produce MPA. The growth of an A. nidulans strain expressing mpaF was only marginally affected by MPA at concentrations as high as 200 μg/ml. To further substantiate the role of mpaF in MPA resistance, we searched for mpaF orthologs in six MPA producer/non-producer strains from Penicillium subgenus Penicillium. All six strains were found to hold two copies of IMPDH. A cladistic analysis based on the corresponding cDNA sequences revealed a novel group constituting mpaF homologs. Interestingly, a conserved tyrosine residue in the original class of IMPDHs is replaced by a phenylalanine residue in the new IMPDH class. Conclusions We identified a novel variant of the IMPDH-encoding gene in six different strains from Penicillium subgenus Penicillium. The novel IMPDH variant from MPA producer P. brevicompactum was shown to confer a high degree of MPA resistance when expressed in a non-producer fungus. Our study provides a basis for understanding the molecular mechanism of MPA resistance and has relevance for biotechnological and pharmaceutical applications. PMID:21923907

  9. A new class of IMP dehydrogenase with a role in self-resistance of mycophenolic acid producing fungi.

    PubMed

    Hansen, Bjarne G; Genee, Hans J; Kaas, Christian S; Nielsen, Jakob B; Regueira, Torsten B; Mortensen, Uffe H; Frisvad, Jens C; Patil, Kiran R

    2011-09-16

    Many secondary metabolites produced by filamentous fungi have potent biological activities, to which the producer organism must be resistant. An example of pharmaceutical interest is mycophenolic acid (MPA), an immunosuppressant molecule produced by several Penicillium species. The target of MPA is inosine-5'-monophosphate dehydrogenase (IMPDH), which catalyses the rate limiting step in the synthesis of guanine nucleotides. The recent discovery of the MPA biosynthetic gene cluster from Penicillium brevicompactum revealed an extra copy of the IMPDH-encoding gene (mpaF) embedded within the cluster. This finding suggests that the key component of MPA self resistance is likely based on the IMPDH encoded by mpaF. In accordance with our hypothesis, heterologous expression of mpaF dramatically increased MPA resistance in a model fungus, Aspergillus nidulans, which does not produce MPA. The growth of an A. nidulans strain expressing mpaF was only marginally affected by MPA at concentrations as high as 200 μg/ml. To further substantiate the role of mpaF in MPA resistance, we searched for mpaF orthologs in six MPA producer/non-producer strains from Penicillium subgenus Penicillium. All six strains were found to hold two copies of IMPDH. A cladistic analysis based on the corresponding cDNA sequences revealed a novel group constituting mpaF homologs. Interestingly, a conserved tyrosine residue in the original class of IMPDHs is replaced by a phenylalanine residue in the new IMPDH class. We identified a novel variant of the IMPDH-encoding gene in six different strains from Penicillium subgenus Penicillium. The novel IMPDH variant from MPA producer P. brevicompactum was shown to confer a high degree of MPA resistance when expressed in a non-producer fungus. Our study provides a basis for understanding the molecular mechanism of MPA resistance and has relevance for biotechnological and pharmaceutical applications.

  10. High prevalence of potential drug interactions affecting mycophenolic acid pharmacokinetics in nonmyeloablative hematopoietic stem cell transplant recipients

    PubMed Central

    Jaklič, Alenka; Collins, Carol J.; Mrhar, Aleš; Sorror, Mohamed L.; Sandmaier, Brenda M.; Bemer, Meagan J.; Locatelli, Igor; McCune, Jeannine S.

    2013-01-01

    Objective: Mycophenolic acid (MPA) exposure is associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients. Various drug interaction studies, predominantly in healthy volunteers or solid organ transplant recipients, have identified medications which impact MPA pharmacokinetics. Recipients of nonmyeloablative HCT, however, have an increased burden of comorbidities, potentially increasing the number of concomitant medications and potential drug interactions (PDI) affecting MPA exposure. Thus, we sought to be the first to characterize these PDI in nonmyeloablative HCT recipients. Materials and methods: We compiled PDI affecting MPA pharmacokinetics and characterized the prevalence of PDI in nonmyeloablative HCT recipients. A comprehensive literature evaluation of four databases and PubMed was conducted to identify medications with PDI affecting MPA pharmacokinetics. Subsequently, a retrospective medication review was conducted to characterize the cumulative PDI burden, defined as the number of PDI for an individual patient over the first 21 days after allogeneic graft infusion, in 84 nonmyeloablative HCT recipients. Results: Of the 187 concomitant medications, 11 (5.9%) had a PDI affecting MPA pharmacokinetics. 87% of 84 patients had one PDI, with a median cumulative PDI burden of 2 (range 0 – 4). The most common PDI, in descending order, were cyclosporine, omeprazole and pantoprazole. Conclusion: Only a minority of medications (5.9%) have a PDI affecting MPA pharmacokinetics. However, the majority of nonmyeloablative HCT recipients had a PDI, with cyclosporine and the proton pump inhibitors being the most common. A better understanding of PDI and their management should lead to safer medication regimens for nonmyeloablative HCT recipients. PMID:23782584

  11. Validation of an LC-MS/MS method for the quantification of mycophenolic acid in human kidney transplant biopsies.

    PubMed

    Md Dom, Zaipul I; Noll, Benjamin D; Coller, Janet K; Somogyi, Andrew A; Russ, Graeme R; Hesselink, Dennis A; van Gelder, Teun; Sallustio, Benedetta C

    2014-01-15

    Mycophenolic acid (MPA) has a low therapeutic index and large inter-individual pharmacokinetic variability necessitating therapeutic drug monitoring to individualise dosing after transplantation. There is an ongoing discrepancy as to whether plasma MPA concentrations sufficiently predict kidney rejection or toxicity and whether immunosuppressant concentrations within the graft tissue may better predict transplant outcomes. The aim of the study was to develop an LC-MS/MS method for the quantification of MPA concentrations in human kidney biopsies taken as part of routine clinical procedures. A total of 4 surplus human kidney biopsies obtained from 4 different kidney transplant recipients were available to use for this study. MPA was also quantified in 2 kidney samples from rats administered MPA to assess tissue extraction reproducibility. Human kidney biopsies and rat kidneys were homogenised mechanically and underwent liquid-liquid extraction before analysis by LC-MS/MS. MPA-free human kidney tissue was used in calibrators and quality control samples. Analyte detection was achieved from multiple reaction monitoring of the ammonium adducts of both MPA (m/z 321.1→207.3) and N-phthaloyl-l-phenylalanine (PPA, internal standard, m/z 296.2→250.2) using positive electrospray ionisation. The method was linear (calibration curves R(2)>0.99, n=10), precise, and accurate with coefficients of variation and bias less than 15%. Extraction efficiencies for MPA and PPA were approximately 97% and 86%, respectively, and matrix effects were minimal. In 4 kidney transplant recipients, tissue MPA concentrations ranged from 1.3 to 7.7ng/mg of tissue, however, the correlation between blood (C0) and tissue MPA concentrations could not be established. The method was successfully applied to the quantification of MPA in human kidney biopsies without the need to alter current clinical protocols.

  12. Brevianamides and Mycophenolic Acid Derivatives from the Deep-Sea-Derived Fungus Penicillium brevicompactum DFFSCS025.

    PubMed

    Xu, Xinya; Zhang, Xiaoyong; Nong, Xuhua; Wang, Jie; Qi, Shuhua

    2017-02-17

    Four new compounds (1-4), including two brevianamides and two mycochromenic acid derivatives along with six known compounds were isolated from the deep-sea-derived fungus Penicillium brevicompactum DFFSCS025. Their structures were elucidated by spectroscopic analysis. Moreover, the absolute configurations of 1 and 2 were determined by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compound 9 showed moderate cytotoxicity against human colon cancer HCT116 cell line with IC50 value of 15.6 μM. In addition, 3 and 5 had significant antifouling activity against Bugula neritina larval settlement with EC50 values of 13.7 and 22.6 μM, respectively. The NMR data of 6, 8, and 9 were assigned for the first time.

  13. Brevianamides and Mycophenolic Acid Derivatives from the Deep-Sea-Derived Fungus Penicillium brevicompactum DFFSCS025

    PubMed Central

    Xu, Xinya; Zhang, Xiaoyong; Nong, Xuhua; Wang, Jie; Qi, Shuhua

    2017-01-01

    Four new compounds (1–4), including two brevianamides and two mycochromenic acid derivatives along with six known compounds were isolated from the deep-sea-derived fungus Penicillium brevicompactum DFFSCS025. Their structures were elucidated by spectroscopic analysis. Moreover, the absolute configurations of 1 and 2 were determined by quantum chemical calculations of the electronic circular dichroism (ECD) spectra. Compound 9 showed moderate cytotoxicity against human colon cancer HCT116 cell line with IC50 value of 15.6 μM. In addition, 3 and 5 had significant antifouling activity against Bugula neritina larval settlement with EC50 values of 13.7 and 22.6 μM, respectively. The NMR data of 6, 8, and 9 were assigned for the first time. PMID:28218640

  14. Effects of topically applied rapamycin and mycophenolic acid on TNCB-induced atopic dermatitis-like skin lesions in NC/Nga mice.

    PubMed

    Jung, Kyung Eun; Lee, Ye Jin; Ryu, Yun Hee; Kim, Jung Eun; Kim, Hei Sung; Kim, Beom Joon; Kang, Hoon; Park, Young Min

    2015-06-01

    Rapamycin (RPM) and mycophenolic acid (MPA) are immunosuppressive drugs approved for use in preventing transplant rejection. These drugs have also been used in the field of dermatology as glucocorticoid sparing agents for autoimmune and inflammatory disorders such as atopic dermatitis (AD). The aim of this study was to investigate the therapeutic effect of topically applied RPM and/or MPA on AD-like skin lesions in NC/Nga mice. RPM (0.04% - 4%), MPA (0.2% - 5%), and formulations of both agents at various ratios were administrated topically to NC/Nga mice with 2-chloro-1,3,5-trinitrobenzene (TNCB)-induced AD-like skin lesions. The therapeutic effects of topical RPM, MPA, and the mixed formulations in TNCB-treated NC/Nga mice were assessed by measuring skin severity scores, ear thickness, and histological changes in the lesioned skin including mast cell count and total serum IgE levels. Expression of interleukin (IL)-4, and interferon (IFN)-γ was also assessed. Topical 4% RPM and/or 1% MPA treatment significantly improved clinical signs of AD such as erythema, edema, excoriation, and dryness on day 29 (P<0.05). In addition, 4% RPM, 1% MPA, and the mixed formulations significantly decreased epidermal thickening, dermal edema, and cellular infiltration into the dermis compared with the vehicle. RPM (4%) and/or MPA (1%) significantly reduced the expression of IL-4 and IFN-γ mRNA and protein levels compared with the vehicle (P<0.05). No significant change in the levels of total serum IgE was induced by topical 4% RPM and/or 1% MPA. The present results demonstrated that topical 4% RPM and/or 1% MPA improved TNCB-induced AD-like lesions of NC/Nga mice by suppressing expression of Th2-related cytokines (IL-4) and Th1-related cytokines (IFN-γ). These findings suggest that RPM and/or MPA may be promising topical therapeutic candidates for the treatment of AD. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Statistical tools for dose individualization of mycophenolic acid and tacrolimus co-administered during the first month after renal transplantation.

    PubMed

    Musuamba, Flora T; Mourad, Michel; Haufroid, Vincent; De Meyer, Martine; Capron, Arnaud; Delattre, Isabelle K; Verbeeck, Roger K; Wallemacq, Pierre

    2013-05-01

    To predict simultaneously the area under the concentration-time curve during one dosing interval [AUC(0,12 h)] for mycophenolic acid (MPA) and tacrolimus (TAC), when concomitantly used during the first month after transplantation, based on common blood samples. Data were from two different sources, real patient pharmacokinetic (PK) profiles from 65 renal transplant recipients and 9000 PK profiles simulated from previously published models on MPA or TAC in the first month after transplantation. Multiple linear regression (MLR) and Bayesian estimation using optimal samples were performed to predict MPA and TAC AUC(0,12 h) based on two concentrations. The following models were retained: AUC(0,12 h) = 16.5 + 4.9 × C1.5 + 6.7 × C3.5 (r(2) = 0.82, rRMSE = 9%, with simulations and r(2) = 0.66, rRMSE = 24%, with observed data) and AUC(0,12 h) = 24.3 + 5.9 × C1.5 + 12.2 × C3.5 (r(2) = 0.94, rRMSE = 12.3%, with simulations r(2) = 0.74, rRMSE = 15%, with observed data) for MPA and TAC, respectively. In addition, bayesian estimators were developed including parameter values from final models and values of concentrations at 1.5 and 3.5 h after dose. Good agreement was found between predicted and reference AUC(0,12 h) values: r(2) = 0.90, rRMSE = 13% and r(2) = 0.97, rRMSE = 5% with simulations for MPA and TAC, respectively and r(2) = 0.75, rRMSE = 11% and r(2) = 0.83, rRMSE = 7% with observed data for MPA and TAC, respectively. Statistical tools were developed for simultaneous MPA and TAC therapeutic drug monitoring. They can be incorporated in computer programs for patient dose individualization. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

  16. Mycophenolate mofetil in liver transplantation: a review.

    PubMed

    Kaltenborn, Alexander; Schrem, Harald

    2013-12-18

    Liver transplantation is the only live-saving, curative treatment for various end-stage liver diseases, and it has excellent survival rates. Mycophenolate mofetil is widely used as co-medication for immunosuppression after liver transplantation, especially to allow a sparing effect on calcineurin-inhibitors, thus reducing their numerous adverse effects. It improves both graft and patient survival. The properties of its active metabolite, mycophenolic acid, are diverse: inhibition of de novo purine synthesis and selective lymphocyte inhibition, anti-tumoral, antiviral, anti-angioneoplastic, and vasculoprotective mechanisms are described and summarized in this review. The most common adverse effects of mycophenolate mofetil are gastrointestinal complaints such as diarrhea, which often lead to dose-reduction or withdrawal of mycophenolate mofetil. A newer, enteric-coated formulation is available, which is meant to reduce the gastrointestinal adverse effects. Mycophenolate mofetil does not relevantly interact with other common drugs. The question of whether therapeutic drug monitoring allows optimized dosing strategies cannot be satisfyingly answered yet. The optimal partner-immunosuppressant seems to be tacrolimus, especially in low doses. This tutorial review provides an overview of recent studies exploring the role of mycophenolate mofetil in liver transplantation with regards to its development, mechanism of action, and actual controversies such as therapeutic drug monitoring or de novo malignancy after transplantation.

  17. Clinical pharmacokinetics and pharmacodynamics of mycophenolate in patients with autoimmune disease.

    PubMed

    Abd Rahman, Azrin N; Tett, Susan E; Staatz, Christine E

    2013-05-01

    Mycophenolic acid (MPA), the active drug moiety of mycophenolate, is a potent immunosuppressant agent, which is increasingly being used in the treatment of patients with various autoimmune diseases. An understanding of the pharmacokinetics and pharmacodynamics of mycophenolate in this population should assist the clinician with rational dosage decisions. This review aims to provide an overview of the published literature on the clinical pharmacokinetics of mycophenolate in autoimmune disease and a briefer summary of current pharmacodynamic knowledge, and to identify areas of potential future research in this field. A literature search was conducted using PubMed and EMBASE databases as well as bibliographies of relevant articles and 'on-line early' pages of key journals. Twenty-six pharmacokinetic/pharmacodynamic studies of mycophenolate in people with autoimmune disease were identified and appraised. Twenty-two of these studies used non-compartmental analysis techniques and four used population modelling methods to estimate mycophenolate pharmacokinetic parameters. Seven studies linked mycophenolate exposure to treatment outcomes. Only four studies measured free (unbound) as well as total mycophenolate exposure and only two studies characterised MPA disposition following enteric-coated mycophenolate sodium (EC-MPS) administration. Across all studies MPA displayed erratic and complex pharmacokinetics with substantial between-subject variability. Based on total drug measurement, the dose-normalised MPA area under the plasma concentration-time curve (AUC) from 0 to 12 h post-dose (AUC12) varied at least five- to ten-fold between subjects. Typical values for apparent oral clearance (CL/F) of MPA during nonlinear mixed-effects modelling ranged from 8.3 to 25.3 L/h. Patient renal function, serum albumin levels, sex, ethnicity, food intake, concurrent administration of interacting drugs such as antacids, metal-containing medications and proton pump inhibitors and

  18. A limited sampling strategy for the simultaneous estimation of tacrolimus, mycophenolic acid and unbound prednisolone exposure in adult kidney transplant recipients.

    PubMed

    Barraclough, Katherine A; Isbel, Nicole M; Johnson, David W; Hawley, Carmel M; Lee, Katie J; McWhinney, Brett C; Ungerer, Jacobus P; Campbell, Scott B; Leary, Diana R; Staatz, Christine E

    2012-03-01

    The aim of this study was to develop a limited sampling strategy (LSS) for the simultaneous estimation of exposure to tacrolimus, mycophenolic acid and unbound prednisolone in adult kidney transplant recipients. Tacrolimus, mycophenolic acid and unbound prednisolone area under the concentration-time curve profiles from 0 to 12 h post dose (AUC(0-12)) were collected from 20 subjects. Multiple linear regression analyses were performed to develop a LSS enabling the simultaneous estimation of exposure to all three drugs. Median percentage prediction error and median absolute percentage prediction error were calculated via jackknife analysis to evaluate bias and imprecision. LSS showed superior ability to predict exposure compared with single concentration-time points. A LSS incorporating concentration measurements at 0.5 h (C(0.5)), 2 h (C(2)) and 4 h (C(4)) post dose displayed acceptable predictive ability for all three drugs. This LSS may serve as a useful research tool for further investigation of the utility of concentration monitoring of these medications. © 2011 The Authors. Nephrology © 2011 Asian Pacific Society of Nephrology.

  19. Conversion from tacrolimus/mycophenolic acid to tacrolimus/leflunomide to treat cutaneous warts in a series of four pediatric renal allograft recipients.

    PubMed

    Nguyen, Lieuko; McClellan, Robert B; Chaudhuri, Abanti; Alexander, Steven R; Chen, Sharon F; Concepcion, Waldo; Grimm, Paul

    2012-09-15

    The challenge of immunosuppression in pediatric renal transplantation is to balance preventing rejection while avoiding infectious complications. A dermatological complication of immunosuppression is viral warts, which cause significant disfigurement and increase the risk of skin malignancy. We present three pediatric and adolescent renal allograft recipients with multiple, recalcitrant verrucae vulgares lesions and one patient with molluscum contagiosum who were switched from mycophenolate mofetil to leflunomide. Teriflunomide metabolite levels were carefully maintained between 50,000 and 100,000 ng/mL to balance its immunosuppressive and antiviral properties. No adverse events requiring discontinuation of leflunomide were encountered. Switching from mycophenolate mofetil to leflunomide successfully cleared verrucae vulgares and molluscum lesions in all four renal transplant patients. The ability to minimize and even resolve warts can improve quality of life by reducing risk of skin malignancies and emotional distress in solid organ transplant patients. Leflunomide is a potential therapeutic option for posttransplantation patients with skin warts because it serves both as an adjunct to the immunosuppressive regimen and an antiviral agent.

  20. Influence of Proton Pump Inhibitors on Mycophenolic Acid Pharmacokinetics in Patients With Renal Transplantation and the Relationship With Cytochrome 2C19 Gene Polymorphism.

    PubMed

    Ciftci, H S; Karadeniz, M S; Tefik, T; Caliskan, Y; Yazıcı, H; Demir, E; Turkmen, A; Nane, I; Oguz, F S; Aydin, F

    2017-04-01

    Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation. A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively. The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups (P < .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI (P < .05

  1. Nonsteroidal anti-inflammatory drugs may reduce enterohepatic recirculation of mycophenolic acid in patients with childhood-onset systemic lupus erythematosus.

    PubMed

    Fukuda, Tsuyoshi; Brunner, Hermine I; Sagcal-Gironella, Anna Carmela P; Vinks, Alexander A

    2011-10-01

    The large interindividual differences observed in mycophenolic acid (MPA) pharmacokinetics (MPA-PK) are in part attributed to the large variability in enterohepatic recirculation (EHC) of the drug. The main metabolite of MPA, MPA glucuronide is actively secreted into the bile via the multidrug resistance-associated protein 2 (MRP2) transporter. Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to inhibit the MRP2 transporter, which can alter EHC and drug exposure. Here, we evaluated the effects of this potential drug-transporter interaction on MPA-PK in a cohort of patients with childhood-onset systemic lupus erythematosus on mycophenolate mofetil therapy. Full MPA concentration-time profiles and demographics including comedications were available for 19 patients with childhood-onset systemic lupus erythematosus. Concentrations at predose (C(trough)), 9 hour (C₉), and nadir (C(nadir); defined as the lowest concentration between C(max) and C₉), and area under the curve (AUC₀₋₁₂ and AUC₆₋₁₂) were assessed using standard methods (WinNonlin5.1). AUC6-12/AUC₀₋₁₂ and C₉/C(nadir) ratios were used to evaluate the effects of NSAID treatment on MPA-PK. Eleven out of 19 patients were on NSAID treatment and did not show visual evidence of EHC in their PK profile. In contrast, patients not on NSAID therapy showed evidence of EHC-related MPA concentration increase in the later part of their PK profiles, typically after 6 hours. This phenomenon could be well characterized by the C₉/C(nadir) ratio, which was significantly lower in the NSAID-treated cohort (P < 0.01). These preliminary data suggest that the concomitant intake of NSAIDs may lower EHC of MPA possibly through the inhibition of MRP2 transport of MPA-G. Further mechanism-based studies are needed to further elucidate this potential transporter interaction.

  2. UGT1A9, UGT2B7, and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients.

    PubMed

    Fukuda, Tsuyoshi; Goebel, Jens; Cox, Shareen; Maseck, Denise; Zhang, Kejian; Sherbotie, Joseph R; Ellis, Eileen N; James, Laura P; Ward, Robert M; Vinks, Alexander A

    2012-12-01

    Mycophenolic acid (MPA) exposure in pediatric patients with kidney transplant receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyltransferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy. MPA and MPA-glucuronide concentrations from 32 patients were quantified by high-performance liquid chromatography. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (predose/trough and 20 minutes, 1 hour, and 3 hours after dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G, and MRP2-24T>C. Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T or UGT2B7-900A>G (n = 4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n = 5) showed a 2.2 and 1.7 times higher dose-dependent and BSA-normalized MPA-AUC compared with carriers of no or only 1 UGT-SNP (P < 0.001 and P = 0.01, respectively) (n = 7). Dose-dependent and BSA-normalized predose MPA concentrations were 3.0 and 2.4 times higher, respectively (P < 0.001). Interindividual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P < 0.05). Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G, and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population.

  3. UGT1A9, UGT2B7 and MRP2 genotypes can predict mycophenolic acid pharmacokinetic variability in pediatric kidney transplant recipients

    PubMed Central

    Fukuda, Tsuyoshi; Goebel, Jens; Cox, Shareen; Maseck, Denise; Zhang, Kejian; Sherbotie, Joseph R.; Ellis, Eileen N.; James, Laura P.; Ward, Robert M.; Vinks, Alexander A.

    2012-01-01

    Background Mycophenolic acid (MPA) exposure in pediatric kidney transplant patients receiving body surface area (BSA)-based dosing exhibits large variability. Several genetic variants in glucuronosyl transferases (UGTs) and of multidrug resistance-associated protein 2 (MRP2) have independently been suggested to predict MPA exposure in adult patients with varying results. Here, the combined contribution of these genetic variants to MPA pharmacokinetic variability was investigated in pediatric renal transplant recipients who were on mycophenolic mofetil maintenance therapy. Methods MPA and MPA-Glucuronide (MPAG) concentrations from 32 patients were quantified by HPLC. MPA exposure (AUC) was estimated using a 4-point abbreviated sampling strategy (pre-dose/trough and 20min, 1h and 3h post-dose) using a validated pediatric Bayesian estimator. Genotyping was performed for all of the following single nucleotide polymorphisms (SNPs): UGT1A8 830G>A(*3), UGT1A9 98T>C(*3), UGT1A9-440C>T, UGT1A9-2152C>T, UGT1A9-275T>A, UGT2B7-900A>G and MRP2 -24T>C. Results Recipients heterozygous for MRP2-24T>C who also had UGT1A9-440C>T and/or UGT2B7-900A>G (n=4), and MRP2-24T>C-negative recipients having both UGT1A9-440C>T and UGT2B7-900A>G (n=5) showed a 2.2 and 1.7-times higher dose- and BSA-normalized MPA-AUC compared to carriers of no or only one UGT-SNP (P < 0.001 and P=0.01, respectively) (n=7). Dose- and BSA-normalized pre-dose MPA concentrations were 3.0- and 2.4-times higher, respectively (P < 0.001). Inter-individual variability in peak concentrations could be explained by the presence of the UGT1A9-440C>T genotype (P<0.05). Conclusion Our preliminary study demonstrates that combined UGT1A9-440C>T, UGT2B7-900A>G and MRP2-24T>C polymorphisms can be important predictors of interindividual variability in MPA exposure in the pediatric population. PMID:23131697

  4. Pilot conversion trial from mycophenolic acid to everolimus in ABO-incompatible kidney-transplant recipients with BK viruria and/or viremia.

    PubMed

    Belliere, Julie; Kamar, Nassim; Mengelle, Catherine; Allal, Asma; Sallusto, Federico; Doumerc, Nicolas; Game, Xavier; Congy-Jolivet, Nicolas; Esposito, Laure; Debiol, Benedicte; Rostaing, Lionel

    2016-03-01

    Immunosuppression using everolimus (EVR) plus low-dose tacrolimus (Tac) is commonly used in organ transplantation. EVR has potential antiviral effects. Herein, the long-term outcomes and impacts of Tac-EVR on the BK virus are reported in ABO-incompatible kidney-transplant recipients. The initial immunosuppressive regimen combined steroids, Tac, and mycophenolic acid (MPA). At a median of 141 (34-529) days post-transplantation, seven stable ABO-incompatible kidney-transplant recipients were converted from MPA to EVR because of active BK replication, and compared with a reference group of fourteen ABO-incompatible patients receiving classical Tac plus MPA. At 1 month before conversion, at 1, 3 months after, and at last follow-up, clinical and biological parameters were monitored. The median time from conversion to the last follow-up was 784 (398-866) days. Conversion to EVR caused no change to rejection episodes or immunological status (isoagglutinin titers, anti-HLA antibodies). At last follow-up, median eGFR was similar in the Tac-MPA versus Tac-EVR group (40 [range: 14-56] vs. 54.5 ml/min/1.73 m(2) [range: 0-128], P = 0.07). The major adverse event was dyslipidemia. Interestingly, conversion from MPA to EVR decreased BK viral load in five patients. ABO-incompatible kidney-transplant recipients with an active BK virus infection may benefit from conversion to EVR.

  5. Pharmacokinetics and pharmacodynamics of mycophenolic acid in Nagase analbuminemic rats: Evaluation of protein binding effects using the modeling and simulation approach.

    PubMed

    Yoshimura, Kazuaki; Yano, Ikuko; Kawanishi, Misaki; Nakagawa, Shunsaku; Yonezawa, Atsushi; Matsubara, Kazuo

    2015-12-01

    This study aimed to examine the pharmacokinetics and pharmacodynamics of mycophenolic acid (MPA) in Nagase analbuminemic rats (NARs) to evaluate the effect of protein binding on the associated inosine-5'-monophosphate dehydrogenase (IMPDH) activity. Free fractions of MPA in the control rats and NARs were 2.09 and 24.8%, respectively. Pharmacokinetic and pharmacodynamic parameters simultaneously obtained by the nonlinear mixed effects modeling program NONMEM explained reasonably well the concentrations of MPA and MPA glucuronide as well as IMPDH activity in both rats. NARs showed a higher clearance and a smaller volume of distribution based on the free MPA concentration than the controls did, besides the increase in free fraction. The half-maximal inhibitory concentration based on free MPA was estimated as 163 ng/mL for both rats. Simulations based on the obtained pharmacokinetic and pharmacodynamic parameters showed that the area under the IMPDH activity-time curve decreased non-linearly according to the increase in free fraction of MPA. In conclusion, the experimental data obtained from NARs followed by the modeling and simulation approach quantitatively clarified that the free MPA concentration was suitable for the biomarker of immunosuppressive effect of MPA. Dose adjustments based on the total MPA may cause unnecessary overexposure to MPA in patients with hypoalbuminemia.

  6. A novel freeze-dried storage and preparation method for the determination of mycophenolic acid in plasma by high-performance liquid chromatography.

    PubMed

    Wang, Lei; Qiang, Wei; Li, Ying; Cheng, Zeneng; Xie, Mengmeng

    2017-02-15

    Plasma samples were conventionally stored at freezing conditions until the time of detection. Such a technique, when carried out over an extended period, is energy consuming; in addition, preparation and transportation of stored samples is inconvenient. In this study, a freeze-dried storage and preparation method was proposed to determine the presence of mycophenolic acid (MPA) in plasma. Fresh plasma samples were freeze-dried using a device, and then stored at ambient temperature. After the stored samples were soaked with methanol spiked with the internal standard, high-performance liquid chromatography was conducted to detect MPA. The proposed method was demonstrated to be precise and accurate over the linear range of 0.5-50 μg mL(-1) , with both intra- and inter-day precision being <7% and biases <10%. The freeze-dried samples were stable at ambient temperature for at least 40 days. This method was also successfully applied to the pharmacokinetic study of MPA in healthy volunteers. Pharmacokinetic parameters, such as maximum plasma concentration, time point of maximum plasma concentration and elimination half-life, among others, were consistent with the results in the published study. This proposed technique was proved to be simple, reproducible and energy saving. This approach could also simplify the storage and analysis of samples in clinical and scientific drug research.

  7. Mycophenolate mofetil for ocular myasthenia.

    PubMed

    Chan, Jane W

    2008-04-01

    To study the safety and tolerability of mycophenolate mofetil (MM), since this steroid-sparing immunomodulatory agent with less side effects, compared to corticosteroids, may be considered for long-term management of ocular myasthenia (OMG). Consecutive patients with OMG started on MM between December 2000 and December 2002 were followed up to December 2006. All of the 31 patients with OMG were treated with prednisone at 40-60 mg/d while MM was increased up to the target of 1.0 g/d. After symptoms completely resolved, all patients were then tapered off prednisone over a period of 4 weeks. Eighty-seven percent (27/31) of patients continued on MM during the study. Mycophenolate mofetil discontinuation occurred in 4/31 (13%) of patients within the first four months of starting the drug. Of the patients who continued on MM, 93% (25/27) remained at stage I of the disease. The 7% (2/27) of patients on MM who generalized in our study did so by 2 years and were treated with additional prednisone. MM-related adverse events included nausea in 9 of 31 patients, diarrhea in 5 of 31 patients, and vomiting in 1/31 patients. No cases of infections, cytopenias, or malignancies were observed. Eighty-seven percent of OMG patients on corticosteroids who were switched to MM remained at Stage I of the disease over a mean period of 4.2 years. MM at 1.0 g/d was safe and tolerable as a long-term immunosuppressant for OMG.

  8. Simple and Sensitive High-Performance Liquid Chromatography (HPLC) Method with UV Detection for Mycophenolic Acid Assay in Human Plasma. Application to a Bioequivalence Study

    PubMed Central

    Danafar, Hossein; Hamidi, Mehrdad

    2015-01-01

    Purpose: A simple and available reversed-phase high performance liquid chromatography (HPLC) method with UV detection has been developed and validated for mycophenolic acid (MPA) assay in human plasma. Methods: MPA was extracted from plasma with protein precipitation method by acetonitrile: percholeric acid: methanol (75:5:20 v/v/v). The drug separation was achieved using a C8 analytical column and a mobile phase of 0.1M triethylammonium phosphate (pH=5.4)-acetonitril (65:35, v/v), with a flow rate of 1.5 ml/min. The detection wavelength was 304 nm. Limit of detection (LOD) of the method was determined as the lowest MPA concentration producing a signal-to-noise (S/N) ratio of about 3. Limit of quantitation (LOQ) was determined as the lowest MPA concentration capable of being quantitated with enough accuracy and precision. Results: The method showed significant linear response-concentration relationship throughout the MPA concentration range of 0.2-10 µg/ml. A typical linear regression equation of the method was: y = 8.5523 x + 0.094, with x and y representing MPA concentration (in µg/ml) and peak height respectively, and the regression coefficient (r) of 0.9816. The average within-run and between-run variations of 7.81 and 4.78 percent. The average drug recovery from plasma was 95.24 percent throughout the linear concentration range. The limits of detection (LOD) and quantitation (LOQ) of the method were 0.05 and 0.2 µg/ml, respectively. The practical applicability of the method was proven throughout a bioequivalence study. Conclusion: The results showed the acceptable degree of linearity, sensitivity, precision, accuracy and recovery for the method. The method was used successfully for quantitation of MPA in plasma samples of healthy volunteers throughout a bioequivalence study. PMID:26819930

  9. Glutamic acid as anticancer agent: An overview

    PubMed Central

    Dutta, Satyajit; Ray, Supratim; Nagarajan, K.

    2013-01-01

    The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. It also possesses anticancer activity. So the transportation and metabolism of glutamine are also discussed for better understanding the role of glutamic acid. Glutamates are the carboxylate anions and salts of glutamic acid. Here the roles of various enzymes required for the metabolism of glutamates are also discussed. PMID:24227952

  10. Glutamic acid as anticancer agent: An overview.

    PubMed

    Dutta, Satyajit; Ray, Supratim; Nagarajan, K

    2013-10-01

    The objective of the article is to highlight various roles of glutamic acid like endogenic anticancer agent, conjugates to anticancer agents, and derivatives of glutamic acid as possible anticancer agents. Besides these emphases are given especially for two endogenous derivatives of glutamic acid such as glutamine and glutamate. Glutamine is a derivative of glutamic acid and is formed in the body from glutamic acid and ammonia in an energy requiring reaction catalyzed by glutamine synthase. It also possesses anticancer activity. So the transportation and metabolism of glutamine are also discussed for better understanding the role of glutamic acid. Glutamates are the carboxylate anions and salts of glutamic acid. Here the roles of various enzymes required for the metabolism of glutamates are also discussed.

  11. Versatile Enzyme Expression and Characterization System for Aspergillus nidulans, with the Penicillium brevicompactum Polyketide Synthase Gene from the Mycophenolic Acid Gene Cluster as a Test Case▿†

    PubMed Central

    Hansen, Bjarne G.; Salomonsen, Bo; Nielsen, Morten T.; Nielsen, Jakob B.; Hansen, Niels B.; Nielsen, Kristian F.; Regueira, Torsten B.; Nielsen, Jens; Patil, Kiran R.; Mortensen, Uffe H.

    2011-01-01

    Assigning functions to newly discovered genes constitutes one of the major challenges en route to fully exploiting the data becoming available from the genome sequencing initiatives. Heterologous expression in an appropriate host is central in functional genomics studies. In this context, filamentous fungi offer many advantages over bacterial and yeast systems. To facilitate the use of filamentous fungi in functional genomics, we present a versatile cloning system that allows a gene of interest to be expressed from a defined genomic location of Aspergillus nidulans. By a single USER cloning step, genes are easily inserted into a combined targeting-expression cassette ready for rapid integration and analysis. The system comprises a vector set that allows genes to be expressed either from the constitutive PgpdA promoter or from the inducible PalcA promoter. Moreover, by using the vector set, protein variants can easily be made and expressed from the same locus, which is mandatory for proper comparative analyses. Lastly, all individual elements of the vectors can easily be substituted for other similar elements, ensuring the flexibility of the system. We have demonstrated the potential of the system by transferring the 7,745-bp large mpaC gene from Penicillium brevicompactum to A. nidulans. In parallel, we produced defined mutant derivatives of mpaC, and the combined analysis of A. nidulans strains expressing mpaC or mutated mpaC genes unequivocally demonstrated that mpaC indeed encodes a polyketide synthase that produces the first intermediate in the production of the medically important immunosuppressant mycophenolic acid. PMID:21398493

  12. Versatile enzyme expression and characterization system for Aspergillus nidulans, with the Penicillium brevicompactum polyketide synthase gene from the mycophenolic acid gene cluster as a test case.

    PubMed

    Hansen, Bjarne G; Salomonsen, Bo; Nielsen, Morten T; Nielsen, Jakob B; Hansen, Niels B; Nielsen, Kristian F; Regueira, Torsten B; Nielsen, Jens; Patil, Kiran R; Mortensen, Uffe H

    2011-05-01

    Assigning functions to newly discovered genes constitutes one of the major challenges en route to fully exploiting the data becoming available from the genome sequencing initiatives. Heterologous expression in an appropriate host is central in functional genomics studies. In this context, filamentous fungi offer many advantages over bacterial and yeast systems. To facilitate the use of filamentous fungi in functional genomics, we present a versatile cloning system that allows a gene of interest to be expressed from a defined genomic location of Aspergillus nidulans. By a single USER cloning step, genes are easily inserted into a combined targeting-expression cassette ready for rapid integration and analysis. The system comprises a vector set that allows genes to be expressed either from the constitutive PgpdA promoter or from the inducible PalcA promoter. Moreover, by using the vector set, protein variants can easily be made and expressed from the same locus, which is mandatory for proper comparative analyses. Lastly, all individual elements of the vectors can easily be substituted for other similar elements, ensuring the flexibility of the system. We have demonstrated the potential of the system by transferring the 7,745-bp large mpaC gene from Penicillium brevicompactum to A. nidulans. In parallel, we produced defined mutant derivatives of mpaC, and the combined analysis of A. nidulans strains expressing mpaC or mutated mpaC genes unequivocally demonstrated that mpaC indeed encodes a polyketide synthase that produces the first intermediate in the production of the medically important immunosuppressant mycophenolic acid.

  13. Optimization of submerged fermentation conditions for immunosuppressant mycophenolic acid production by Penicillium roqueforti isolated from blue-molded cheeses: enhanced production by ultraviolet and gamma irradiation.

    PubMed

    Ismaiel, Ahmed A; Ahmed, Ashraf S; El-Sayed, El-Sayed R

    2014-10-01

    Mycophenolic acid (MPA) is a promising drug owing to its immunosuppressive and biological activities. In this study, two strains of Penicillium roqueforti designated as AG101 and LG109 were selected among several strains isolated from Roquefort cheese samples on the basis of their activity for MPA-producing ability. The appropriate fermentation conditions necessary for MPA biosynthesis by the two respective fungal strains were investigated. These conditions included selection of the cultivation medium, agitation rate, incubation temperature, fermentation time, pH value, inoculum size, and fermentation medium volume. Maximum MPA productivities were maintained when the fermentation process was carried out using a medium composed of (g l(-1)): Sucrose, 30; peptone, 5.0; KH2PO4, 1.0; MgSO4·7H2O, 0.5 and KCl, 0.5; pH 6.0, inoculated with an inoculum size of 6.0 % (v/v), and incubated at 25 °C for 10 days at 120 rpm. The potentiality of both P. roqueforti strains for further improvement of MPA production was applied by mutagenesis through exposure to irradiation by ultraviolet rays (UV, 254 nm) for different periods of time and gamma rays at various doses (KGy). The dry cell weight of both irradiated fungal strains showed a greater reduction when irradiated either with UV or gamma rays. However, the MPA yield of both strains was increased by 1.27-1.39 fold when irradiated with UV rays and by 2.11-2.33 fold when irradiated with gamma rays, as compared with the respective controls (non-irradiated cultures). These findings indicate the future possibility to reduce the cost of producing fermentation-based drugs.

  14. Pyruvic acid as an etching agent.

    PubMed

    Retief, D H; Bischoff, J; van der Merwe, E H

    1976-07-01

    Phosphoric acid at different concentrations has been extensively used as an etching agent to improve bonding of dental materials to enamel surfaces. Recently attention has been drawn to the possible use of polyfunctional organic acids as conditioning agents. The object of this investigation was to determine the optimal concentration of pyruvic acid as an etching agent. A commercial composite resin with an intermediary bonding system supplied with 37% H3PO4 as an etching agent was used as the control system. In addition, a comparative study was carried out to evaluate 37% H3PO4, 20% lactic acid and the optimal concentration of pyruvic acid as conditioning solutions. Etching enamel surfaces with 10% pyruvic acid resulted in the optimal tensile bond strength of the resin to etched enamel surfaces. The use of 10% pyruvic acid did not adversely affect the bond strength of the resin system when compared to enamel surfaces etched with 37% H3PO4 for the same time period. Significantly lower tensile bond strengths were recorded on enamel surfaces etched with 20% lactic acid. The rate and depth of etching obtained with 37% H3PO4 can be considerably reduced by using 10% pyruvic acid as the conditioning agent.

  15. Refractory linear IgA bullous dermatosis successfully treated with mycophenolate sodium.

    PubMed

    Marzano, Angelo V; Ramoni, Stefano; Spinelli, Diana; Alessi, Elvio; Berti, Emilio

    2008-01-01

    Linear IgA bullous dermatosis (LABD) is a rare, blistering autoimmune disease characterized by linear deposits of IgA at the basement membrane zone (BMZ), with the possible presence of circulating IgA anti-BMZ antibodies. LABD of childhood is usually self-healing, while in adults it follows a more prolonged course and refractory cases may rarely occur. The first-line treatment for LABD is dapsone in monotherapy or in combination with systemic corticosteroids, but various therapeutic approaches have been used in non-responder patients. We report two adult patients with refractory LABD successfully treated with enteric-coated mycophenolate sodium (EC-MPS), a recently introduced formulation of mycophenolic acid (MPA). MPA is an immunosuppressive agent that acts by inhibiting monophosphate dehydrogenase, a key enzyme in the novo synthesis of purines. Based on the present cases, we indicate EC-MPS as being a safe and effective adjuvant therapy in the treatment of LABD when dapsone or the other steroid-sparing drugs fail. It seems to offer an improved gastric side effect profile in comparison with the classic formulation of MPA, namely its ester mycophenolate mofetil (MMF).

  16. A Comparison of the Immunochemical Methods, PETINIA and EMIT, With That of HPLC-UV for the Routine Monitoring of Mycophenolic Acid in Heart Transplant Patients.

    PubMed

    Kunicki, Paweł K; Pawiński, Tomasz; Boczek, Aleksandra; Waś, Joanna; Bodnar-Broniarczyk, Magdalena

    2015-06-01

    The aim of this study was to evaluate particle enhanced turbidimetric inhibition immunoassay (PETINIA) recently developed for mycophenolic acid (MPA) determination in plasma and to compare it with a reference high-performance liquid chromatography (HPLC) method, using samples from heart transplant recipients. The results are presented in the context of PETINIA being compared with enzyme multiplied immunoassay technique (EMIT). PETINIA evaluation was performed using 194 routine trough plasma samples at steady state. EMIT was evaluated using 677 samples from 61 steady-state 12-hour profiles obtained from 35 heart transplant patients. Evaluation was undertaken on a Dimension EXL 200 analyzer (PETINIA) and on a Viva-E analyzer (EMIT). The mean MPA concentration measured by PETINIA was significantly higher than that measured by high-performance liquid chromatography combined with UV detector (2.36 ± 1.30 mcg/mL versus 1.82 ± 1.23 mcg/mL, respectively, P < 0.0001). Bland-Altman analysis revealed a mean bias of 0.54 mcg/mL [95% confidence interval (CI), 0.49-0.59] comprising 33.48% (95% CI, 30.34-36.61). Passing-Bablok regression was: y = 1.100x + 0.38 (95% CI for slope: 1.044-1.154 and for intercept: 0.30-0.47). Regardless of a significant observed correlation (r = 0.9230, P < 0.0001), the statistical analyses showed a significant difference between PETINIA and the reference chromatographic method. The mean MPA concentration measured by EMIT was significantly higher than that measured by HPLC (7.48 ± 8.34 mcg/mL versus 5.57 ± 6.61 mcg/mL, respectively, P < 0.0001) with a mean bias of 1.91 mcg/mL (95% CI, 1.75-2.07) comprising 35.91% (95% CI, 34.37-37.45). The significant difference between EMIT and HPLC was confirmed by Passing-Bablok regression: y = 1.300x + 0.24 (95% CI for slope: 1.279-1.324 and for intercept: 0.18-0.29). The analysis of the determinations, grouped by sampling time, revealed positive bias between EMIT and HPLC ranging from 24.54% to 42.77% and

  17. Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPAR{gamma}-LXR{alpha}-ABCA1 pathway

    SciTech Connect

    Xu, Yanni; Lai, Fangfang; Xu, Yang; Wu, Yexiang; Liu, Qi; Li, Ni; Wei, Yuzhen; Feng, Tingting; Zheng, Zhihui; Jiang, Wei; Yu, Liyan; Hong, Bin; Si, Shuyi

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer Using an ABCA1p-LUC HepG2 cell line, we found that MPA upregulated ABCA1 expression. Black-Right-Pointing-Pointer MPA induced ABCA1 and LXR{alpha} protein expression in HepG2 cells. Black-Right-Pointing-Pointer PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. Black-Right-Pointing-Pointer The effect of MPA upregulating ABCA1 was due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 pathway. -- Abstract: ATP-binding cassette transporter A1 (ABCA1) promotes cholesterol and phospholipid efflux from cells to lipid-poor apolipoprotein A-I and plays an important role in atherosclerosis. In a previous study, we developed a high-throughput screening method using an ABCA1p-LUC HepG2 cell line to find upregulators of ABCA1. Using this method in the present study, we found that mycophenolic acid (MPA) upregulated ABCA1 expression (EC50 = 0.09 {mu}M). MPA upregulation of ABCA1 expression was confirmed by real-time quantitative reverse transcription-PCR and Western blot analysis in HepG2 cells. Previous work has indicated that MPA is a potent agonist of peroxisome proliferator-activated receptor gamma (PPAR{gamma}; EC50 = 5.2-9.3 {mu}M). Liver X receptor {alpha} (LXR{alpha}) is a target gene of PPAR{gamma} and may directly regulate ABCA1 expression. Western blot analysis showed that MPA induced LXR{alpha} protein expression in HepG2 cells. Addition of PPAR{gamma} antagonist GW9662 markedly inhibited MPA-induced ABCA1 and LXR{alpha} protein expression. These data suggest that MPA increased ABCA1 expression mainly through activation of PPAR{gamma}. Thus, the effects of MPA on upregulation of ABCA1 expression were due mainly to activation of the PPAR{gamma}-LXR{alpha}-ABCA1 signaling pathway. This is the first report that the antiatherosclerosis activity of MPA is due to this mechanism.

  18. Influence of uridine diphosphate (UDP)-glucuronosyltransferases and ABCC2 genetic polymorphisms on the pharmacokinetics of mycophenolic acid and its metabolites in Chinese renal transplant recipients.

    PubMed

    Zhang, W-X; Chen, B; Jin, Z; Yu, Z; Wang, X; Chen, H; Mao, A; Cai, W

    2008-11-01

    The aim was to investigate the effect of UGT1A9, UGT1A8, UGT2B7 and ABCC2 polymorphism on the pharmacokinetics of mycophenolic acid (MPA) and its metabolites phenolic glucuronide (MPAG) and acyl glucuronide (AcMPAG) in Chinese renal transplant recipients. Single nucleotide polymorphisms (SNP) in UGT1A9-118(dT)(9)/(10), UGT1A9 T-440C/C-331T, UGT1A8*3, UGT2B7 G211T, UGT2B7 C802T, ABCC2 C-24T, and ABCC2 G1249A were detected. A total of 46 recipients were enrolled in the pharmacokinetics study at day 30 after kidney transplantation. Differences in the MPA pharmacokinetic profiles confirmed large inter-patient variation of MPA exposure. A statistical significant increase in the dose-adjusted AUC(6-12) level of MPA was found in patients bearing the -118(dT)(10) allele of the UGT1A9 gene (T(9) = 7.34 +/- 4.11 mg h ml(-1) g(-1); T(9)/T(10) = 11.54 +/- 7.62 mg h ml(-1) g(-1); and T(10) = 11.89 +/-8.76 mg h ml(-1) g(-1), p = 0.041). A similar trend was also observed for the dose-adjusted AUC(0-12) and AUC(6-12) of MPAG. Patients carrying the heterozygous mutant alleles of ABCC2 G1249A exhibited higher AUC(6-12)/D of AcMPAG than those with wild-type genotype (p = 0.016). The other SNPs that were genotyped did not cause any significant variation in MPA and MPAG pharmacokinetic parameters. In conclusion, the enterohepatic recirculation of MPA in the patients seems to be more extensive in UGT1A9-118(dT)(10) allele carriers, and the exposure of AcMPAG is higher in patients carrying ABCC2 G1249A genotype than those with wild-type genotype.

  19. Nucleic acids as therapeutic agents.

    PubMed

    Alvarez-Salas, Luis M

    2008-01-01

    Therapeutic nucleic acids (TNAs) and its precursors are applied to treat several pathologies and infections. TNA-based therapy has different rationales and mechanisms and can be classified into three main groups: 1) Therapeutic nucleotides and nucleosides; 2) Therapeutic oligonucleotides; and 3) Therapeutic polynucleotides. This review will focus in those TNAs that have reached clinical trials with anticancer and antiviral protocols, the two most common applications of TNAs. Although therapeutic nucleotides and nucleosides that interfere with nucleic acid metabolism and DNA polymerization have been successfully used as anticancer and antiviral drugs, they often produce toxic secondary effects related to dosage and continuous use. The use of oligonucleotides such as ribozyme and antisense oligodeoxynucleotides (AS-ODNs) showed promise as therapeutic moieties but faced several issues such as nuclease sensitivity, off-target effects and efficient delivery. Nevertheless, immunostimulatory oligodeoxynucleotides and AS-ODNs represent the most successful group of therapeutic oligonucleotides in the clinic. A newer group of therapeutic oligonucleotides, the aptamers, is rapidly advancing towards early detection and treatment alternatives the have reached the commercial interest. Despite the very high in vitro efficiency of small interfering RNAs (siRNAs) they present issues with intracellular target accessibility, specificity and delivery. DNA vaccines showed great promise, but they resulted in very poor responses in the clinic and further development is uncertain. Despite their many issues, the exquisite specificity and versatility of therapeutic oligonucleotides attracts a great deal of research and resources that will certainly convert them in the TNA of choice for treating cancer and viral diseases in the near future.

  20. [Duodenal villous atrophy associated with Mycophenolate mofetil: report of one case].

    PubMed

    Tapia, Oscar; Villaseca, Miguel; Sierralta, Armando; Roa, Juan Carlos

    2010-05-01

    Mycophenolate mofetil (MMF) is an immunosupressor agent frequently used in patients after bone marrow or solid organ transplants. The most common adverse reactions of the drug are gastrointestinal, specially diarrhea and vomiting. We report a 53-year-old male, that received a heart transplant receiving immunosuppression with cyclosporine, mycophenolate mofetil and prednisone. Six months after the transplant, the patient started with diarrhea, anorexia and weight loss. A duodenal biopsy showed villous atrophy. Celiac disease and the presence of parasites were discarded. Mycophenolate mofetil was discontinued and one week later, diarrhea subsided. Two months later the patient was asymptomatic and recovered weight. A new duodenal biopsy showed absence of villous atrophy.

  1. Novel cajaninstilbene acid derivatives as antibacterial agents.

    PubMed

    Geng, Zhi-Zhong; Zhang, Jian-Jun; Lin, Jing; Huang, Mei-Yan; An, Lin-Kun; Zhang, Hong-Bin; Sun, Ping-Hua; Ye, Wen-Cai; Chen, Wei-Min

    2015-07-15

    Discovery of novel antibacterial agents with new structural scaffolds that combat drug-resistant pathogens is an urgent task. Cajaninstilbene acid, which is isolated from pigeonpea leaves, has shown antibacterial activity. In this study, a series of cajaninstilbene acid derivatives were designed and synthesized. The antibacterial activities of these compounds against gram-negative and gram-positive bacteria, as well as nine strains of methicillin-resistant staphylococcus aureus (MRSA) bacteria are evaluated,and the related structure-activity relationships are discussed. Assays suggest that some of the synthetic cajaninstilbene acid derivatives exhibit potent antibacterial activity against gram-positive bacterial strains and MRSA. Among these compounds, 5b, 5c, 5j and 5k show better antibacterial activity than the positive control compounds. The results of MTT assays illustrate the low cytotoxicity of the active compounds.

  2. Update on the Teratogenicity of Maternal Mycophenolate Mofetil

    PubMed Central

    Coscia, Lisa A.; Armenti, Dawn P.; King, Ryan W.; Sifontis, Nicole M.; Constantinescu, Serban; Moritz, Michael J.

    2015-01-01

    Mycophenolic acid (MPA) products, namely mycophenolate mofetil and mycophenolate sodium, are immunosuppressive medications used to prevent rejection in solid organ transplant recipients and to treat various autoimmune disorders. Mycophenolate therapy is considered to be teratogenic based on observational studies of pregnancies exposed to MPA, which demonstrated an increased incidence of miscarriages in pregnancies exposed to MPA during their first trimester and a pattern of birth defects in the offspring of some pregnancies exposed to MPA. Herein, we have detailed case and series reports in a comprehensive literature review summarizing what is known to date regarding fetal exposure to MPA. Based on evidence from the literature, results of postmarketing surveillance, and information from registries such as the National Transplantation Pregnancy Registry in the United States, it is advised that pregnancy be avoided by women taking MPA. Preconception planning offers the opportunity to explore the alternatives to protect the mother, her transplanted organ, and minimize fetal risk. How to proceed in cases of unplanned pregnancies exposed to MPA in transplant recipients is a complex issue. Research involving large epidemiological studies is expected to be sparse as women heed the warnings about becoming pregnant on MPA. Published recommendations for managing MPA in women of childbearing potential include discontinuing the medication prior to conception, switching the MPA to another medication, or discontinuing the MPA when the pregnancy is discovered. PMID:27617117

  3. Acetal phosphatidic acids: novel platelet aggregating agents.

    PubMed

    Brammer, J P; Maguire, M H; Walaszek, E J; Wiley, R A

    1983-05-01

    1 Palmitaldehyde, olealdehyde and linolealdehyde acetal phosphatidic acids induced rapid shape change and dose-dependent biphasic aggregation of human platelets in platelet-rich plasma; aggregation was reversible at low doses and irreversible at high doses of the acetal phosphatidic acids. The palmitaldehyde congener elicited monophasic dose-dependent aggregation of sheep platelets in platelet-rich plasma.2 The threshold concentration for palmitaldehyde acetal phosphatidic acid (PGAP)-induced platelet aggregation was 2.5-5 muM for human platelets and 0.25-0.5 muM for sheep platelets. PGAP was 4-5 times as potent versus human platelets as the olealdehyde and linolealdehyde acetal phosphatidic acids, which were equipotent.3 PGAP-induced irreversible aggregation of [(14)C]-5-hydroxytryptamine ([(14)C]-5-HT)-labelled human platelets in platelet-rich plasma was accompanied by release of 44.0+/-2.4% (s.e.) of the platelet [(14)C]-5-HT; reversible aggregation was not associated with release. In contrast, PGAP-induced release of [(14)C]-5-HT-labelled sheep platelets was dose-dependent.4 The adenosine diphosphate (ADP) antagonist, 2-methylthio-AMP, and the cyclo-oxygenase inhibitor, aspirin, abolished PGAP-induced second phase aggregation and release in human platelets but did not affect the first, reversible, phase of aggregation. Both the first and second phases of PGAP-induced aggregation were abolished by chlorpromazine, by the phospholipase A(2) inhibitor, mepacrine, and by nmolar concentrations of prostaglandin E(1) (PGE(1)); these agents abolished the second, but not the first phase of ADP-induced aggregation.5 The related phospholipids, lecithin, lysolecithin and phosphatidic acid, at <100 muM, neither induced aggregation of human platelets in platelet-rich plasma, nor modified PGAP-induced aggregation; 1-palmityl lysophosphatidic acid elicited aggregation of human platelets at a threshold concentration of 100 muM.6 It is concluded that the acetal phosphatidic acids

  4. Mycophenolate mofetil attenuates pulmonary arterial hypertension in rats

    SciTech Connect

    Suzuki, Chihiro; Takahashi, Masafumi . E-mail: masafumi@sch.md.shinshu-u.ac.jp; Morimoto, Hajime; Izawa, Atsushi; Ise, Hirohiko; Hongo, Minoru; Hoshikawa, Yasushi; Ito, Takayuki; Miyashita, Hiroshi; Kobayashi, Eiji; Shimada, Kazuyuki; Ikeda, Uichi

    2006-10-20

    Pulmonary arterial hypertension (PAH) is characterized by abnormal proliferation of smooth muscle cells (SMCs), leading to occlusion of pulmonary arterioles, right ventricular (RV) hypertrophy, and death. We investigated whether mycophenolate mofetil (MMF), a potent immunosuppresssant, prevents the development of monocrotaline (MCT)-induced PAH in rats. MMF effectively decreased RV systolic pressure and RV hypertrophy, and reduced the medial thickness of pulmonary arteries. MMF significantly inhibited the number of proliferating cell nuclear antigen (PCNA)-positive cells, infiltration of macrophages, and expression of P-selectin and interleukin-6 on the endothelium of pulmonary arteries. The infiltration of T cells and mast cells was not affected by MMF. In vitro experiments revealed that mycophenolic acid (MPA), an active metabolite of MMF, dose-dependently inhibited proliferation of human pulmonary arterial SMCs. MMF attenuated the development of PAH through its anti-inflammatory and anti-proliferative properties. These findings provide new insight into the potential role of immunosuppressants in the treatment of PAH.

  5. A preclinical and clinical study of mycophenolate mofetil in pancreatic cancer.

    PubMed

    Rodríguez-Pascual, J; Sha, P; García-García, E; Rajeshkumar, N V; De Vicente, E; Quijano, Y; Cubillo, A; Angulo, B; Hernando, O; Hidalgo, M

    2013-02-01

    A high throughput screening for anticancer activity of FDA approved drugs identified mycophenolic acid (MPA), an inhibitor of inositol monophosphate dehydrogenase (IMPDH) as an active agent with an antiangiogenesis mode of action. Exposure of pancreatic cancer cell lines to MPA resulted in growth inhibition and reduced the expression of VEGF that was reversed by supplementing the media with guanosine supporting and IMPDH-dependant mechanism. In preclinical in vivo study, MPA showed a moderate inhibition of tumor growth in a panel of 6 human derived pancreatic cancer xenografts but reduced the expression of VEGF. To investigate the effects of MPA in human pancreatic cancer, a total of 12 patients with resectable pancreatic cancer (PDA) received increasing doses of mycophenolate mofetil (MMF) in cohorts of 6 patients each from 5-15 days prior to surgical resection. Treatment was well tolerated with one episode of grade 1 muscle pain, one episode of grade 2 lymphopenia (2 gr/day dose) and one episode of grade 2 elevantion in LFT (all in the 2 gr./day dose). Patients recovered from surgery uneventfully with no increased post-operative complications. Assessment of CD31, VEGF, and TUNEL in resected specimens compared to a non treated control of 6 patients showed no significant variations in any of the study endpoints. In conclusion, this study shows the feasibility of translating a preclinical observation to the clinical setting and to explore a drug mechanism of action in patients. MPA, however, did not show any hints of antiangiogenesis of anticancer clinical activity questioning if this agent should be further developed in PDA.

  6. Method of encapsulating polyaminopolycarboxylic acid chelating agents in liposomes

    DOEpatents

    Rahman, Yueh Erh

    1977-11-10

    A method is provided for transferring a polyaminopolycarboxylic acid chelating agent across a cellular membrane by encapsulating the charged chelating agent within liposomes, which liposomes will be taken up by the cells, thereby transferring the chelating agent across the cellular membrane. The chelating agent is encapsulated within liposomes by drying a lipid mixture to form a thin film and wetting the lipid film with a solution containing the chelating agent. Mixing then results in the formation of a suspension of liposomes encapsulating the chelating agent, which liposomes can then be separated.

  7. Salicylic acid as a peeling agent: a comprehensive review

    PubMed Central

    Arif, Tasleem

    2015-01-01

    Salicylic acid has been used to treat various skin disorders for more than 2,000 years. The ability of salicylic acid to exfoliate the stratum corneum makes it a good agent for peeling. In particular, the comedolytic property of salicylic acid makes it a useful peeling agent for patients with acne. Once considered as a keratolytic agent, the role of salicylic acid as a desmolytic agent, because of its ability to disrupt cellular junctions rather than breaking or lysing intercellular keratin filaments, is now recognized and is discussed here. Salicylic acid as a peeling agent has a number of indications, including acne vulgaris, melasma, photodamage, freckles, and lentigines. The efficacy and safety of salicylic acid peeling in Fitzpatrick skin types I–III as well as in skin types V and VI have been well documented in the literature. This paper reviews the available data and literature on salicylic acid as a peeling agent and its possible indications. Its properties, efficacy and safety, the peeling procedure, and possible side effects are discussed in detail. An account of salicylism is also included. PMID:26347269

  8. Salicylic acid as a peeling agent: a comprehensive review.

    PubMed

    Arif, Tasleem

    2015-01-01

    Salicylic acid has been used to treat various skin disorders for more than 2,000 years. The ability of salicylic acid to exfoliate the stratum corneum makes it a good agent for peeling. In particular, the comedolytic property of salicylic acid makes it a useful peeling agent for patients with acne. Once considered as a keratolytic agent, the role of salicylic acid as a desmolytic agent, because of its ability to disrupt cellular junctions rather than breaking or lysing intercellular keratin filaments, is now recognized and is discussed here. Salicylic acid as a peeling agent has a number of indications, including acne vulgaris, melasma, photodamage, freckles, and lentigines. The efficacy and safety of salicylic acid peeling in Fitzpatrick skin types I-III as well as in skin types V and VI have been well documented in the literature. This paper reviews the available data and literature on salicylic acid as a peeling agent and its possible indications. Its properties, efficacy and safety, the peeling procedure, and possible side effects are discussed in detail. An account of salicylism is also included.

  9. Long-acting contraceptive agents: levonorgestrel esters of unsaturated acids.

    PubMed

    Wan, A S; Ngiam, T L; Leung, S L; Go, M L; Francisco, C G; Freire, R; Hernandez, R; Salazar, J A; Suarez, E; García, G A

    1983-03-01

    Esters of levonorgestrel (13 beta-ethyl-17 beta-ethynyl-17 beta-hydroxygon-4-en-3-one) with a variety of unsaturated carboxylic acids have been synthesized for evaluation as potential long-acting, injectable contraceptive agents.

  10. Involvement of carboxylesterase 1 and 2 in the hydrolysis of mycophenolate mofetil.

    PubMed

    Fujiyama, Nobuhiro; Miura, Masatomo; Kato, Shoutaro; Sone, Tomomichi; Isobe, Masakazu; Satoh, Shigeru

    2010-12-01

    Mycophenolate mofetil (MMF) is the ester prodrug of the immunosuppressant agent mycophenolic acid (MPA) and is rapidly activated by esterases after oral administration. However, the role of isoenzymes in MMF hydrolysis remains unclear. Although human plasma, erythrocytes, and whole blood contain MMF hydrolytic activities, the mean half-lives of MMF in vitro were 15.1, 1.58, and 3.20 h, respectively. Thus, blood esterases seemed to contribute little to the rapid MMF disappearance in vivo. In vitro analyses showed that human intestinal microsomes exposed to 5 and 10 μM MMF exhibited hydrolytic activities of 2.38 and 4.62 nmol/(min · mg protein), respectively. Human liver microsomes exhibited hydrolytic activities of 14.0 and 26.1 nmol/(min · mg protein), respectively, approximately 6-fold higher than those observed for intestinal microsomes. MMF hydrolytic activities in human liver cytosols were 1.40 and 3.04 nmol/(min · mg protein), respectively. Because hepatic cytosols generally contain 5-fold more protein than microsomes, MMF hydrolysis in human liver cytosols corresponded to approximately 50% of that observed in microsomes. Fractions obtained by 9000g centrifugation of supernatants from COS-1 cells expressing human carboxylesterase (CES) 1 or 2 exhibited MMF hydrolytic activity, with CES1-containing fractions showing higher catalytic efficiency than CES2-containing fractions. The CES inhibitor bis-p-nitrophenylphosphate inhibited MMF hydrolysis in human liver microsomes and cytosols with IC(50) values of 0.51 and 0.36 μM, respectively. In conclusion, both intestinal and hepatic CESs and in particular CES1 may be involved in MMF hydrolysis and play important roles in MMF bioactivation. Hepatic CES1 activity levels may help explain the between-subject variability observed for MMF usage.

  11. Nucleic acid in-situ hybridization detection of infectious agents

    NASA Astrophysics Data System (ADS)

    Thompson, Curtis T.

    2000-04-01

    Limitations of traditional culture methods and newer polymerase chain reaction (PCR)-based methods for detection and speciation of infectious agents demonstrate the need for more rapid and better diagnostics. Nucleic acid hybridization is a detection technology that has gained wide acceptance in cancer and prenatal cytogenetics. Using a modification of the nucleic acid hybridization technique known as fluorescence in-situ hybridization, infectious agents can be detected in a variety of specimens with high sensitivity and specificity. The specimens derive from all types of human and animal sources including body fluids, tissue aspirates and biopsy material. Nucleic acid hybridization can be performed in less than one hour. The result can be interpreted either using traditional fluorescence microscopy or automated platforms such as micro arrays. This paper demonstrates proof of concept for nucleic acid hybridization detection of different infectious agents. Interpretation within a cytologic and histologic context is possible with fluorescence microscopic analysis, thereby providing confirmatory evidence of hybridization. With careful probe selection, nucleic acid hybridization promises to be a highly sensitive and specific practical diagnostic alternative to culture, traditional staining methods, immunohistochemistry and complicated nucleic acid amplification tests.

  12. Long-acting contraceptive agents: norethisterone esters of polyunsaturated acids.

    PubMed

    Francisco, C G; Freire, R; Hernandez, R; Salazar, J A; Suarez, E; Vlahov, R; Tarpanov, V; Boshkova-Ljapova, M; Milenkov, B; Stoilova, V

    1983-03-01

    Some new derivatives of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) are described in which the 17 beta-hydroxyl group of the steroid is esterified with polyunsaturated aliphatic acids. The potential of these compounds as long-acting contraceptive agents has been evaluated.

  13. Enhancement of commercial antifungal agents by kojic acid

    USDA-ARS?s Scientific Manuscript database

    Kojic acid (KA), a natural by-product of fungal fermentation, is a commonly used food and cosmetic additive. We show that KA increases activity of amphotericin B and strobilurin, medical and agricultural antifungal agents, respectively, possibly targeting the fungal antioxidative system. KA shows pr...

  14. Degradability of fluorapatite-leucite ceramics in naturally acidic agents.

    PubMed

    Kukiattrakoon, Boonlert; Hengtrakool, Chanothai; Kedjarune-Leggat, Ureporn

    2010-10-01

    This study was conducted to evaluate the titratable acidity and effect of naturally acidic agents on the surface microhardness, elemental composition, and surface morphology of fluorapatite-leucite ceramics. One hundred and ten ceramic disks (IPS d.SIGN), 12.0 mm in diameter and 2.0 mm in thickness, were fabricated. Before immersion, the baseline data of Vickers microhardness and elemental composition were recorded. Four groups were immersed in acidic agents (citrate buffer solution, green mango juice, and pineapple juice) and deionized water (control) at 37ºC for 168 hours, whereas one group was immersed in 4% acetic acid at 80ºC for 168 hours. After immersion, specimens were evaluated and data were analyzed using one-way repeated ANOVA and Tukey's test (α=0.05). Microhardness values significantly decreased after immersion (p<0.05). In terms of elemental composition, the weight percentages of silicon, potassium, aluminum, and sodium also decreased after immersion (p<0.05). Results of this study showed that fluorapatite-leucite ceramics were affected by long-term immersion in acidic agents.

  15. Lewis acid-assisted detection of nerve agents in water.

    PubMed

    Butala, Rahul R; Creasy, William R; Fry, Roderick A; McKee, Michael L; Atwood, David A

    2015-06-07

    The five-coordinate compound, Salen((t)Bu)Al(Ac), prepared in situ from Salen((t)Bu)AlBr and NH4Ac, forms Lewis acid-base adducts in aqueous solution with the G-type nerve agents, Sarin and Soman, and the VX hydrolysis product, ethylmethylphosphonate (EMPA). The resulting compounds, [Salen((t)Bu)Al(NA)](+)[Ac] (-) (with NA = Sarin, Soman, and EMPA) are sufficiently stable to be identified by ESI-MS. Molecular ion peaks were detected for every compound with little or no fragmentation. The distinctive MS signatures for the [Salen((t)Bu)Al(NA)](+) compounds provide a new technique for identifying nerve agents from aqueous solution. The energetics of the displacement of Ac(-) by the nerve agents to form [Salen((t)Bu)Al(NA)](+)[Ac](-) were determined computationally.

  16. The use of glycolic acid as a peeling agent.

    PubMed

    Murad, H; Shamban, A T; Premo, P S

    1995-04-01

    Glycolic acid is a member of the AHA family, which occurs naturally in foods and has been used for centuries as a cutaneous rejuvenation treatment. Recently it has proved to be a versatile peeling agent and it is now widely used to treat many defects of the epidermis and papillary dermis in a variety of strengths, ranging from 20% to 70%, depending on the condition being treated. People of almost any skin type and color are candidates, and almost any area of the body can be peeled. Several weeks prior to a peel the skin may be prepared with topical tretinoin or glycolic acid, and immediately prior to the peel the skin may be degreased with a variety of agents. Following the peel the skin is carefully observed for any complications such as hyperpigmentation and infection. Results are maintained with serial peels and at-home use of tretinoin or glycolic acid, as well as sun avoidance. The glycolic acid can be applied simultaneously with TCA and is another technique for a medium-depth peel. Comparison of 35% TCA-treated skin with 70% glycolic acid-treated skin examined histologically at different times reveals similar changes in papillary dermis connective tissue proteins, epidermal necrosis seen only with TCA, and reversion at 2 years postpeel to pretreatment appearance.

  17. Nucleic acid-binding polymers as anti-inflammatory agents

    PubMed Central

    Lee, Jaewoo; Sohn, Jang Wook; Zhang, Ying; Leong, Kam W.; Pisetsky, David; Sullenger, Bruce A.

    2011-01-01

    Dead and dying cells release nucleic acids. These extracellular RNAs and DNAs can be taken up by inflammatory cells and activate multiple nucleic acid-sensing toll-like receptors (TLR3, 7, 8, and 9). The inappropriate activation of these TLRs can engender a variety of inflammatory and autoimmune diseases. The redundancy of the TLR family encouraged us to seek materials that can neutralize the proinflammatory effects of any nucleic acid regardless of its sequence, structure or chemistry. Herein we demonstrate that certain nucleic acid-binding polymers can inhibit activation of all nucleic acid-sensing TLRs irrespective of whether they recognize ssRNA, dsRNA or hypomethylated DNA. Furthermore, systemic administration of such polymers can prevent fatal liver injury engendered by proinflammatory nucleic acids in an acute toxic shock model in mice. Therefore these polymers represent a novel class of anti-inflammatory agent that can act as molecular scavengers to neutralize the proinflammatory effects of various nucleic acids. PMID:21844380

  18. Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil at 12 months post-transplantation.

    PubMed

    Segovia, Javier; Gerosa, Gino; Almenar, Luis; Livi, Ugolino; Viganò, Mario; Arizón, Jose Maria; Yonan, Nizar; Di Salvo, Thomas G; Renlund, Dale G; Kobashigawa, Jon A

    2008-01-01

    Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.

  19. Liquid chromatography tandem mass spectrometry method for the quantitation of mycophenolate mofetil in human plasma: Application to a bioequivalence study and metabolite identification.

    PubMed

    Partani, Pankaj; Verma, Saurabh Manaswita; Monif, Tausif

    2015-10-01

    We established a sensitive, selective, and rapid analytical method for the quantitation and pharmacokinetic investigation of mycophenolate mofetil in human plasma. To our knowledge, this is the first method that characterizes presence of mycophenolate mofetil glucuronide in clinical samples through tandem mass spectrometry detection and resolves mycophenolate mofetil from its glucuronide metabolite. Liquid chromatography coupled to tandem mass spectrometry detection in positive ion mode was selected to provide optimal selectivity and sensitivity. Due to the ionizable characteristics of the mycophenolate mofetil, a mixed-mode cation-exchange disposable extraction cartridge was prudently chosen. The chromatographic separation was achieved on Luna(®) C18(2) (100×4.60 mm) column using mobile phase consisting of a mixture of 1±0.05 mM ammonium formate in water, titrated to pH 3.1±0.1 with formic acid, and methanol (20:80, v/v), at a flow rate of 0.7 mL/min. The detection was led at m/z ratios of 434.4→ 114.2 and 438.4→ 118.3, for mycophenolate mofetil and mycophenolate mofetil-D4, respectively. The developed method was linear between 40.2-4986.0 pg/mL. All validation parameters were within the defined limits. The validated method was then successfully applied for the evaluation of bioequivalence parameters of mycophenolate mofetil after an oral administration of 500 mg mycophenolate mofetil tablet to healthy male Indian volunteers.

  20. [Relative bioavailability study of two oral formulations of mycophenolate mofetil in healthy volunteers].

    PubMed

    Saavedra S, Iván; Sasso A, Jaime; Quiñones S, Luis; Saavedra B, Mónica; Gaete G, Leonardo; Boza T, Ignacio; Carvajal H, Cristóbal; Soto L, Jorge

    2011-07-01

    The bioequivalence of different formulations of a same pharmaceutical product must be tested empirically. To evaluate the relative bioavailability for an oralformulation of mycophenolate mofetil (MMF) (Linfonex™) compared to the reference formulation (Cellcept™) to determine the bioequivalence between both formulations. A randomized, crossover, double-blind trial in 22 healthy male volunteers, who received a single oral dose of 1000 mg of Linfonex and Cellcept with a washout period of 10 days. Plasma levels of the drug were determined by high performance liquid chr ornatography. Plasma concentrations were plotted and maximum concentration, area under the plasma concentration versus time between 0 and 12 hours after administration and área under plasma concentration curve versus time after administration between 0 and infinity, were calculated for both products. The active compound, mycophenolic acid, was similarly absorbed in both formulations. No statistically significant differences were found in calculated pharmacokinetic parameters between both formulations. Linfonex™ 500 mg is bioequivalent to Cellcept™ 500 mg.

  1. Mycophenolate mofetil inducing remission of lupus enteritis.

    PubMed

    Al Balushi, F; Humby, F; Mahto, A; Kelly, C; Jawad, A

    2012-04-01

    We report the case of a young woman with a background history of discoid lupus who presented with abdominal pain, vomiting and intermittent diarrhoea. Physical examination revealed tenderness in the right upper quadrant with a palpable right inguinal lymph node without any other clinical signs of active lupus. Laboratory investigations showed normal inflammatory markers, positive ANA and Anti-Ro antibodies, persistent hypocomplementemia and lymphopenia, CT showed marked bowel oedema involving the small and large bowel (halo sign) with massive ascites and moderate right-sided pleural effusion. Mantoux test, AFB and TB cultures were negative. A diagnosis of lupus enteritis was made and treatment with high-dose steroids was commenced with little improvement. Treatment with cyclophosphamide was discussed but declined by the patient. Mycophenolate mofetil was commenced and resulted in significant clinical and radiological resolution. To the best of the authors' knowledge this is the first report of the successful use of mycophenolate mofetil in inducing and maintaining remission in lupus enteritis.

  2. Enteric coating of mycophenolate reduces dosage adjustments.

    PubMed

    Brister, K; Yau, C L; Slakey, D

    2009-06-01

    Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) are bioequivalent. However, the effectiveness of MMF may be limited by gastrointestinal (GI) side effects. This study assessed the relationship between the number of medication dosage adjustments and posttransplantation side effects. In a review of 109 kidney transplant patients, 65 initially received MMF and 44 initially received EC-MPS. The incidences of patient-reported GI complications were significantly different: MMF 45.5% vs EC-MPS 35.3% (P = .0194). The proportions of patients requiring dosage adjustment due to GI complications were MMF 5.9% and EC-MPS 2.3% (P < .0001). Patients receiving MMF were more likely to experience GI complications resulting in dosage adjustment (odds ratio = 9.9; P = .0306). The incidences of acute rejection, cytomegalovirus (CMV), and leukopenia resulting in dosage adjustment were not significantly different. Patients receiving MMF required more immunosuppressive medication adjustments, which may complicate care and decrease overall compliance.

  3. Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents.

    PubMed

    Nakagawa-Goto, Kyoko; Yamada, Koji; Taniguchi, Masahiko; Tokuda, Harukuni; Lee, Kuo-Hsiung

    2009-07-01

    C-3 esterifications of betulinic acid (BA, 1) and its A-ring homolog, ceanothic acid (CA, 2), were carried out to provide sixteen terpenoids, 4-19, including nine new compounds (4-12). All synthesized compounds were evaluated in an in vitro antitumor-promoting assay using the Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Among them, compounds 4-6, 11-14, 16, and 17 displayed remarkable inhibitory effects of EBV-EA activation. BA analog 6, which contains a prenyl-like group, showed the most potent inhibitory effect (100%, 76%, 37%, and 11% inhibition of EBA activation at 1000, 500, 100, and 10mol ratio/TPA, respectively, with IC(50) value of 285mol ratio/32pmol TPA). Compound 6 merits further development as a cancer preventive agent.

  4. Spectroscopy and Molecular Modeling Study on the Interaction Between Mycophenolate Mofetil and Pepsin.

    PubMed

    Ma, Xiaoli; Guo, Liuqi; Wang, Qing; He, Jiawei; Li, Hui

    2016-03-01

    Mycophenolate mofetil (MMF) is an immunosuppressant used in clinical practice to limit the rejection of transplanted organs. MMF is absorbed and metabolized by the gastrointestinal tract and converted to mycophenolic acid by esterases in the plasma, liver, and kidney. Mycophenolic acid is the resulting active metabolite. The interaction of MMF with pepsin may affect the transfer and distribution of MMF. Given this effect, the present study investigated the interaction behavior between pepsin with MMF using docking simulation and spectroscopy method at different temperatures. The results of spectroscopy revealed that MMF has strong ability to quench the fluorescence of pepsin. The results also show that the acting force for binding was composed of hydrophobic forces. The three-dimensional fluorescence spectra and synchronous spectroscopy employed to determine the conformation showed that the binding of MMF with pepsin could induce MMF conformation and microenvironment changes. Furthermore, the molecular interaction distance and energy-transfer efficiency between pepsin and MMF were determined based on the Förster non-radiative energy-transfer mechanism. Docking simulation showed that MMF entered the hydrophobic cavity of pepsin, and a hydrogen bond was formed between the oxygen atoms of the carbanyl group of MMF and hydrogen atoms of tyrosine 189 of pepsin.

  5. Gradual surface degradation of restorative materials by acidic agents.

    PubMed

    Hengtrakool, Chanothai; Kukiattrakoon, Boonlert; Kedjarune-Leggat, Ureporn

    2011-01-01

    The aim of this study was to investigate the effect of acidic agents on surface roughness and characteristics of four restorative materials. Fifty-two discs were created from each restorative material: metal-reinforced glass ionomer cement (Ketac-S), resin-modified glass ionomer cement (Fuji II LC), resin composite (Filtek Z250), and amalgam (Valiant-PhD); each disc was 12 mm in diameter and 2.5 mm thick. The specimens were divided into four subgroups (n=13) and immersed for 168 hours in four storage media: deionized water (control); citrate buffer solution; green mango juice; and pineapple juice. Surface roughness measurements were performed with a profilometer, both before and after storage media immersion. Surface characteristics were examined using scanning electron microscopy (SEM). Statistical significance among each group was analyzed using two-way repeated ANOVA and Tukey's tests. Ketac-S demonstrated the highest roughness changes after immersion in acidic agents (p<0.05), followed by Fuji II LC. Valiant-PhD and Filtek Z250 illustrated some minor changes over 168 hours. The mango juice produced the greatest degradation effect of all materials tested (p<0.05). SEM photographs demonstrated gradual surface changes of all materials tested after immersions. Of the materials evaluated, amalgam and resin composite may be the most suitable for restorations for patients with tooth surface loss.

  6. Surface characteristic changes of dental ceramics after cyclic immersion in acidic agents and titratable acidity.

    PubMed

    Junpoom, Peerapong; Kukiattrakoon, Boonlert; Hengtrakool, Chanothai

    2010-12-01

    The potential erosive effect of acidic food, sour fruits and drinks on all-ceramic restorations used in dentistry has not been clearly documented. Surface characteristic changes have been evaluated and compared for disc-shaped specimens (diameter 12.0 mm and thickness 2.0 mm) of fluorapatite-leucite and fluorapatite ceramics using various storage agents (deionized water, citrate buffer solution, pineapple juice, green mango juice, cola soft drink and 4% acetic acid). Immersion in pineapple juice, green mango juice, cola soft drink and 4% acetic acid for 16 hours produce significant increases in surface roughness for both types of ceramics investigated.

  7. Theophylline-7-acetic acid derivatives with amino acids as anti-tuberculosis agents.

    PubMed

    Voynikov, Yulian; Valcheva, Violeta; Momekov, Georgi; Peikov, Plamen; Stavrakov, Georgi

    2014-07-15

    A series of amides were synthesized by condensation of theophylline-7-acetic acid and eight commercially available amino acid methyl ester hydrochlorides. Consecutive hydrolysis of six of the amido-esters resulted in the formation of corresponding amido-acids. The newly synthesized compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv. The activity varied depending on the amino acid fragments and in seven cases exerted excellent values with MICs 0.46-0.26 μM. Assessment of the cytotoxicity revealed that the compounds were not cytotoxic against the human embryonal kidney cell line HEK-293T. The theophylline-7-acetamides containing amino acid moieties appear to be promising lead compounds for the development of antimycobacterial agents. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Phytic acid: an alternative root canal chelating agent.

    PubMed

    Nassar, Mohannad; Hiraishi, Noriko; Tamura, Yukihiko; Otsuki, Masayuki; Aoki, Kazuhiro; Tagami, Junji

    2015-02-01

    The objectives of this study were to investigate the effect of phytic acid, inositol hexakisphosphate (IP6), as a final rinse on the surface of instrumented root canals and smear-layered flat dentin surfaces treated with sodium hypochlorite (NaOCl) and to evaluate its effect on the viability and alkaline phosphatase activity of osteoblast-like cells (MC3T3-E1). The universally accepted chelating agent EDTA was used as the control in all conducted experiments. Root canals of human canines were instrumented with rotary files and irrigated with 5% NaOCl, followed by a final rinse of 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. NaOCl-treated flat coronal dentin surfaces were also treated with 17% EDTA (1 minute), 1% IP6 (1 minute or 30 seconds), or distilled water. The presence or absence of smear layer was evaluated with scanning electron microscopy. Cell viability and alkaline phosphatase assays were performed to evaluate the effect of IP6 and EDTA on cultured MC3T3-E1 cells. The results demonstrated the ability of IP6 to remove the smear layer from instrumented root canals and flat coronal dentin surfaces. When compared with EDTA, IP6 was less cytotoxic and did not affect the differentiation of MC3T3-E1 cells. IP6 shows the potential to be an effective and biocompatible chelating agent. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  9. Mycophenolate mofetil in the treatment of systemic lupus erythematosus.

    PubMed

    Sahin, Ali

    2009-12-01

    Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been shown to be effective in transplant patients. It is also efficacious in the management of lupus nephritis and useful in the treatment of autoimmune conditions because its mechanisms of action target T- and B- lymphocytes, leading to suppression of the cell-mediated immune response and antibody formation. MMF has been used successfully to treat immune-mediated conditions like myasthenia gravis, autoimmune hepatitis and immune cytopenias. However, the conditions for its optimal use for non-renal manifestations (e.g., hematological, neuropsychiatric, myocardial, pulmonary or cutaneous symptoms) in lupus patients are unclear. There have yet to be any randomized, controlled trials to guide the optimal dose and duration of MMF treatment in such situations. MMF is well tolerated and safe to use, although there are reports of serious adverse effects including urticaria, myopathy, Epstein-Barr virus-associated B-cell lymphoma, cytomegalovirus infection and disseminated varicella zoster infection. Immunosuppressive treatment with MMF and supportive care over the past few decades have led to improved clinical outcomes in patients with severe lupus nephritis. A favorable long-term prognosis can be ensured provided that effective treatment is instituted early, before irreversible renal parenchymal damage occurs. Another area of concern for patients is the increased cost of long-term MMF use.

  10. Mycophenolate Mofetil Modulates Differentiation of Th1/Th2 and the Secretion of Cytokines in an Active Crohn’s Disease Mouse Model

    PubMed Central

    Lv, Qing-Kang; Liu, Ju-Xiong; Li, Su-Nan; Gao, Ying-Jie; Lv, Yan; Xu, Zi-Peng; Huang, Bing-Xu; Xu, Shi-Yao; Yang, Dong-Xue; Zeng, Ya-Long; Liu, Dian-Feng; Wang, Wei

    2015-01-01

    Mycophenolate mofetil (MMF) is an alternative immunosuppressive agent that has been reported to be effective and well tolerated for the treatment of refractory inflammatory bowel disease (IBD). The aim of this study was to investigate the therapeutic effect of MMF on intestinal injury and tissue inflammation, which were caused by Crohn’s disease (CD). Here, trinitrobenzene sulfonic acid-relapsing (TNBS) colitis was induced in mice; then, we measured the differentiation of Th1/Th2 cells in mouse splenocytes by flow cytometry and the secretion of cytokines in mice with TNBS-induced colitis by real-time polymerase chain reaction and/or enzyme-linked immunosorbent assay (RT-PCR/ELISA). The results show that MMF significantly inhibited mRNA expression of pro-inflammatory cytokines IFN-γ, TNF-α, IL-12, IL-6, and IL-1β in mice with TNBS-induced colitis; however, MMF did not inhibit the expression of IL-10 mRNA. Additionally, ELISA showed that the serum levels of IFN-γ, TNF-α, IL-12, IL-6, and IL-1β were down-regulated in a TNBS model of colitis. Flow cytometric analysis showed MMF markedly reduced the percentages of Th1 and Th2 splenocytes in the CD mouse model. Mycophenolic acid (MPA) also significantly decreased the percentages of splenic Th1 and Th2 cells in vitro. Furthermore, MMF treatment not only significantly ameliorated diarrhea, and loss of body weight but also abrogated the histopathologic severity and inflammatory response of inflammatory colitis, and increased the survival rate of TNBS-induced colitic mice. These results suggest that treatment with MMF may improve experimental colitis and induce inflammatory response remission of CD by down-regulation of pro-inflammatory cytokines via modulation of the differentiation of Th1/Th2 cells. PMID:26561804

  11. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    USDA-ARS?s Scientific Manuscript database

    Several benzoic acid analogs showed antifungal activity against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis. Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids increased by addition of a methyl, methoxyl...

  12. Myasthenia gravis exacerbation after discontinuing mycophenolate

    PubMed Central

    Rocke, David M.; Dengel, Karsten; Richman, David P.

    2016-01-01

    Objective: To determine whether discontinuation or marked reduction of mycophenolate mofetil (MMF) in patients with myasthenia gravis (MG) causes MG exacerbations. Methods: We identified 88 patients with MG who took MMF during the 5-year period 2007–2011 at our MG clinic. We then performed detailed chart reviews and recorded all MG exacerbations and their relationship to MMF and other treatment changes. We also recorded demographic data and disease characteristics (including antibody status and Myasthenia Gravis Foundation of America status). Results: There were 14 patients who had an MG exacerbation during the study period. Of these, 13 had discontinued MMF therapy, with a median time until exacerbation of 16 weeks after discontinuation (9 patients) or marked dose reduction (4 patients) of MMF therapy (exacerbation in the absence of change in any other component of the immunosuppressive regimen). Using the cluster option in a Cox regression analysis, the MMF coefficient was −5.32, with a standard error of 1.05 and a p value of 0.0002, corresponding to an estimated hazard ratio of 204. Conclusions: This retrospective cohort study suggests that discontinuation/marked reduction of MMF therapy may increase the risk of MG exacerbation many fold, supporting the hypothesis that MMF plays a role in the maintenance of MG remission/minimal manifestation status. Classification of evidence: This study provides Class IV evidence that in patients with MG taking MMF, discontinuation or marked reduction of MMF causes MG exacerbation. PMID:26850977

  13. Mycophenolate mofetil therapy for severe immune thrombocytopenia.

    PubMed

    Taylor, Alice; Neave, Lucy; Solanki, Shalini; Westwood, John Paul; Terrinonive, Ilaria; McGuckin, Siobhan; Kothari, Jaimal; Cooper, Nichola; Stasi, Roberto; Scully, Marie

    2015-11-01

    Severe immune thrombocytopenia purpura (ITP) presents a clinical challenge. Second-line treatment options are variable without a precise protocol. We present 46 severe ITP patients treated with mycophenolate mofetil (MMF), retrospectively identified from three London teaching hospitals. Data was collected on patient demographics, co-morbidities and previous treatment strategies. Our key interest was whether there was a sustained response in platelet count to MMF. Patients included 27 males and 19 females whose ages ranged from 19 to 93 years old (median 52·5 years). Twenty-nine had primary ITP and 17 had secondary ITP, a third of whom had viral-associated disease. The standard dose of MMF was 1 g/day. Twenty-four patients (52%) responded with 15 (33%) achieving a complete response. No active viral-associated ITP patients demonstrated a response to MMF, although numbers were small (n = 4). We were not able to demonstrate a difference between responders and non-responders based on gender, age, previous therapies or time since diagnosis of ITP. Three of four previously splenectomized patients responded, two achieving complete response. We conclude that MMF is a useful steroid-sparing immunosuppressant to be considered in the second-line or later treatment of ITP.

  14. Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients.

    PubMed

    Tierce, J C; Porterfield-Baxa, J; Petrilla, A A; Kilburg, A; Ferguson, R M

    2005-12-01

    Mycophenolate mofetil (MMF), a mycophenolic acid prodrug, is a highly effective adjunct immunosuppressive agent in transplant therapy. Although MMF is generally well tolerated, optimal therapy may be limited by adverse effects, in particular gastrointestinal (GI) toxicity, which has been reported to occur in up to 45% of MMF-treated patients. MMF dose changes resulting from these adverse events may lead to sub-therapeutic dosing and impaired clinical outcomes. This retrospective study analyzed clinical records from 772 renal transplant patients from 10 US transplant centers who were initiated on MMF. The analysis revealed that 49.7% (n = 382) of patients experienced at least one GI complication within the first 6 months post-transplant, with 66.8% (n = 255) of these having multiple GI complications. Of the patients with GI complications, 39.0% experienced MMF dose adjustments or discontinuation of MMF therapy. Patients with GI complications who experienced MMF dose adjustments/discontinuation had a significantly increased incidence of acute rejections compared with patients without GI complications (30.2% vs. 19.4%; p = 0.005). Mean treatment costs were higher in patients with GI complications than in those with no GI complications, particularly in those who experienced MMF dose adjustments/discontinuation (p = 0.0001). The mean incremental cost for patients experiencing GI complications was US$3700 per patient during the 6 months post-transplant (p < 0.001), which was mainly attributable to hospitalization costs. In summary, GI complications and MMF dose adjustments/discontinuations are associated with a significant negative impact on transplant outcomes and markedly increase short-term treatment costs.

  15. Three amino acid derivatives of valproic acid: design, synthesis, theoretical and experimental evaluation as anticancer agents.

    PubMed

    Luna-Palencia, Gabriela R; Martinez-Ramos, Federico; Vasquez-Moctezuma, Ismael; Fragoso-Vazquez, Manuel Jonathan; Mendieta-Wejebe, Jessica Elena; Padilla-Martínez, Itzia I; Sixto-Lopez, Yudibeth; Mendez-Luna, David; Trujillo-Ferrara, Jose; Meraz-Rios, Marco A; Fonseca-Sabater, Yadira; Correa-Basurto, Jose

    2014-01-01

    Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.

  16. The use of mycophenolate mofetil suspension in pediatric renal allograft recipients.

    PubMed

    Bunchman, T; Navarro, M; Broyer, M; Sherbotie, J; Chavers, B; Tönshoff, B; Birk, P; Lerner, G; Lirenman, D; Greenbaum, L; Walker, R; Zimmerhackl, L B; Blowey, D; Clark, G; Ettenger, R; Arterburn, S; Klamerus, K; Fong, A; Tang, H; Thomas, S; Ramos, E

    2001-12-01

    Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0-12) of 27.2 microg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.

  17. Synthesis of amino Derivatives of Dithio Acids as Potential Radiation Protective Agents

    DTIC Science & Technology

    1984-08-01

    ation Management S SI ____ K> AD Synthesis of Amino Derivatives of Dithio Acids as Potential Radiation Protective Agents * 0 Annual Report "TIi: o DTIC...Sftcuntiy Clatuftcatio") Synthesis of Amino Derivatives of Dithio Acids as PotentitI- Radiation Protective Agents 12l PERISONAL. Ak.TI4OR(S) * William...methyl- picoline derivatives was accomplished. Use of N-mthyl-2,6-dimethylpyridine also allowed the synthesis of a bis(dithioacetic acid) function not

  18. Augmenting the activity of antifungal agents against aspergilli using structural analogues of benzoic acid as chemosensitizing agents

    USDA-ARS?s Scientific Manuscript database

    Structure-activity analysis revealed that antifungal activities of benzoic and gallic acids were increased against strains of Aspergillus flavus, A. fumigatus and A. terreus, causative agents of human aspergillosis, by addition of a methyl, methoxyl or a chloro group at position 4 of the aromatic ri...

  19. Successful treatment of severe refractory lupus hepatitis with mycophenolate mofetil.

    PubMed

    Tagawa, Y; Saito, T; Takada, K; Kawahata, K; Kohsaka, H

    2016-04-01

    Systemic lupus erythematosus-related hepatitis, known as lupus hepatitis, is a rare manifestation of systemic lupus erythematosus, and is usually subclinical with mild abnormalities of serum liver enzymes. While cases with clinically significant and refractory lupus hepatitis are uncommon, treatment options for lupus hepatitis are to be established. Here, we report the case of a 45-year-old man with progressive lupus hepatitis accompanied by autoimmune haemolytic anaemia. Lupus hepatitis of this patient was refractory to tacrolimus, azathioprine and cyclophosphamide, but was successfully treated by mycophenolate mofetil. Mycophenolate mofetil might be an effective therapeutic option for refractory lupus hepatitis.

  20. Bioconverted Products of Essential Fatty Acids as Potential Antimicrobial Agents

    USDA-ARS?s Scientific Manuscript database

    This review deals with the recent findings on the microbial conversion of essential fatty acids (EFAs) through Pseudomonas aeruginosa PR3 NRRL-B-18602, and the antimicrobial properties of bioconverted essential fatty acids, with particular emphasis on n-3 or n-6 fatty acids. The first section deals...

  1. Spherical Nucleic Acids as Intracellular Agents for Nucleic Acid Based Therapeutics

    NASA Astrophysics Data System (ADS)

    Hao, Liangliang

    Recent functional discoveries on the noncoding sequences of human genome and transcriptome could lead to revolutionary treatment modalities because the noncoding RNAs (ncRNAs) can be applied as therapeutic agents to manipulate disease-causing genes. To date few nucleic acid-based therapeutics have been translated into the clinic due to challenges in the delivery of the oligonucleotide agents in an effective, cell specific, and non-toxic fashion. Unmodified oligonucleotide agents are destroyed rapidly in biological fluids by enzymatic degradation and have difficulty crossing the plasma membrane without the aid of transfection reagents, which often cause inflammatory, cytotoxic, or immunogenic side effects. Spherical nucleic acids (SNAs), nanoparticles consisting of densely organized and highly oriented oligonucleotides, pose one possible solution to circumventing these problems in both the antisense and RNA interference (RNAi) pathways. The unique three dimensional architecture of SNAs protects the bioactive oligonucleotides from unspecific degradation during delivery and supports their targeting of class A scavenger receptors and endocytosis via a lipid-raft-dependent, caveolae-mediated pathway. Owing to their unique structure, SNAs are able to cross cell membranes and regulate target genes expression as a single entity, without triggering the cellular innate immune response. Herein, my thesis has focused on understanding the interactions between SNAs and cellular components and developing SNA-based nanostructures to improve therapeutic capabilities. Specifically, I developed a novel SNA-based, nanoscale agent for delivery of therapeutic oligonucleotides to manipulate microRNAs (miRNAs), the endogenous post-transcriptional gene regulators. I investigated the role of SNAs involving miRNAs in anti-cancer or anti-inflammation responses in cells and in in vivo murine disease models via systemic injection. Furthermore, I explored using different strategies to construct

  2. Effectiveness of mycophenolate mofetil in C3 glomerulonephritis.

    PubMed

    Rabasco, Cristina; Cavero, Teresa; Román, Elena; Rojas-Rivera, Jorge; Olea, Teresa; Espinosa, Mario; Cabello, Virginia; Fernández-Juarez, Gema; González, Fayna; Ávila, Ana; Baltar, José María; Díaz, Montserrat; Alegre, Raquel; Elías, Sandra; Antón, Monserrat; Frutos, Miguel Angel; Pobes, Alfonso; Blasco, Miguel; Martín, Francisco; Bernis, Carmen; Macías, Manuel; Barroso, Sergio; de Lorenzo, Alberto; Ariceta, Gema; López-Mendoza, Manuel; Rivas, Begoña; López-Revuelta, Katia; Campistol, José María; Mendizábal, Santiago; de Córdoba, Santiago Rodríguez; Praga, Manuel

    2015-11-01

    C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing end-stage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.

  3. Long-acting contraceptive agents: testosterone esters of unsaturated acids.

    PubMed

    Francisco, C G; Freire, R; Gawronski, J; Hernández, R; Kielczewski, M; Salazar, J A; Savabi, F; Shafiee, A; Strekowski, L; Suárez, E

    1990-01-01

    The synthesis of 13 new esters of testosterone is described, with the esterifying acids bearing acetylenic, olefinic, or polyunsaturated functions in the chain, for evaluation as long-acting androgens.

  4. Mitigating the antimicrobial activities of selected organic acids and commercial sanitizers with various neutralizing agents.

    PubMed

    Park, Yoen Ju; Chen, Jinru

    2011-05-01

    This study was conducted to evaluate the abilities of five neutralizing agents, Dey-Engley (DE) neutralizing broth (single or double strength), morpholinepropanesulfonic acid (MOPS) buffer, phosphate-buffered saline (PBS), and sodium thiosulfate buffer, in mitigating the activities of acetic or lactic acid (2%) and an alkaline or acidic sanitizer (a manufacturer-recommended concentration) againt the cells of Shiga toxin-producing Escherichia coli (STEC; n = 9). To evaluate the possible toxicity of the neutralizing agents to the STEC cells, each STEC strain was exposed to each of the neutralizing agents at room temperature for 10 min. Neutralizing efficacy was evaluated by placing each STEC strain in a mixture of sanitizer and neutralizer under the same conditions. The neutralizing agents had no detectable toxic effect on the STEC strains. PBS was least effective for neutralizing the activity of selected organic acids and sanitizers. Single-strength DE and sodium thiosulfate neutralized the activity of both acetic and lactic acids. MOPS buffer neutralized the activity of acetic acid and lactic acid against six and five STEC strains, respectively. All neutralizing agents, except double-strength DE broth, had a limited neutralizing effect on the activity of the commercial sanitizers used in the study. The double-strength DE broth effectively neutralized the activity of the two commercial sanitizers with no detectable toxic effects on STEC cells.

  5. Enhancement of Mycophenolate Mofetil Permeation for Topical Use by Eucalyptol and N-Methyl-2-pyrrolidone

    PubMed Central

    Songkram, Chalermkiat

    2016-01-01

    Mycophenolate mofetil (MMF) is a prodrug of mycophenolic acid (MPA) which can be metabolized by esterase. MMF has been approved by the United States Food and Drug Administration (USFDA) for treatment of psoriasis patient with skin symptoms. However, it remains unclear whether MMF is efficiently effective to treat skin symptoms developed from psoriasis. The insufficient amount of MMF penetrating through the skin results in the treatment failure due to the difficulty in MMF penetration through the stratum corneum. Skin permeation enhancers such as eucalyptol (EUL) and N-methyl-2-pyrrolidone (NMP) potentially aid in increasing skin penetration. This study aimed to investigate the effects of a concentration ratio (% w/v) between two enhancers (EUL and NMP). The results showed that EUL enhanced MMF permeation with an enhancement ratio (ER) of 3.44 while NMP was not able to promote the penetration of MMF. Interestingly, the synergistic effect of the two enhancers was observed with a suitable ratio given that the ER was 8.21. EUL and NMP are promising enhancers for the development of MMF based skin product. PMID:27069715

  6. Steroid withdrawal and reduction of cyclosporine A under mycophenolate mofetil after heart transplantation.

    PubMed

    Faulhaber, Marion; Mäding, Ilona; Malehsa, Doris; Raggi, Matthias C; Haverich, Axel; Bara, Christoph L

    2013-04-01

    Survival and quality of life after heart transplantation are limited by a significant incidence of cardiovascular complications. Side effects of immunosuppressives contribute unfavorably. Aim of this study was to determine (1) whether withdrawal of corticosteroids and dose reduction of cyclosporine A can be performed safely under immunosuppressive therapy with mycophenolate mofetil and (2) if this is beneficial for renal function and cardiovascular risk reduction. Long term heart transplant recipients on steroids and cyclosporine A were examined in a monocentric, prospective, single-arm cohort study. Steroids were withdrawn, mycophenolate mofetil introduced and cyclosporine A dose reduced (target level 50-90 ng/ml). Follow up was 24 months. 23 patients were analyzed: Renal parameters (creatinine, urea, uric acid) improved significantly (p<0.01), as did cardiovascular parameters (heart rate [p<0.05], systolic and diastolic blood pressure [p<0.01]), HbA1c (p<0.05) and triglycerides (p<0.05). In contrast, the self-percepted state of health (SF36™) decreased. Drop outs occurred mostly due to steroid withdrawal syndrome [n=7]. The incidence of adverse events reflected the usual course after heart transplantation. We conclude that CS free immunosuppression comprising reduced cyclosporine levels and addition of MMF in long term heart transplant recipients is safe and improves the cardiovascular risk profile, carbohydrate metabolism and renal function. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

    PubMed Central

    Dell'Oglio, Maria Pia; Rossini, Michele; Divella, Chiara; Pontrelli, Paola; Verrienti, Raffaella; Rutigliano, Monica; Ditonno, Pasquale; Stifanelli, Patrizia; Ancona, Nicola; Schena, Francesco Paolo; Grandaliano, Giuseppe

    2010-01-01

    Mycophenolic acid (MPA) appears to have anti-fibrotic effects, but the molecular mechanisms underlying this are unknown. We prospectively studied 35 stable kidney transplant recipients maintained on cyclosporine and azathioprine. We converted 20 patients from azathioprine to enteric-coated mycophenolate sodium (EC-MPS) and continued the remaining 15 patients on azathioprine. Exploratory mRNA expression profiling, performed on five randomly selected EC-MPS patients, revealed significant upregulation of neutral endopeptidase (NEP), which is an enzyme that degrades angiotensin II. We confirmed these microarray data by measuring levels of NEP expression in all subjects; in addition, we found that NEP gene expression correlated inversely with proteinuria. In an additional 33 patients, glomerular and tubular NEP protein levels from renal graft biopsies were significantly higher among the 13 patients receiving cyclosporine + EC-MPS than among the 12 patients receiving cyclosporine + azathioprine or 8 patients receiving cyclosporine alone. Glomerular NEP expression inversely correlated with glomerulosclerosis and proteinuria, and tubular NEP expression inversely correlated with interstitial fibrosis. Incubation of human proximal tubular cells with MPA increased NEP gene expression in a dose- and time-dependent manner. Moreover, MPA reduced angiotensin II–induced expression of the profibrotic factor plasminogen activator inhibitor-1, and a specific NEP inhibitor completely reversed this effect. Taken together, our data suggest that MPA directly induces expression of neutral endopeptidase, which may reduce proteinuria and slow the progression of renal damage in kidney transplant recipients. PMID:20864690

  8. Oleic acid-embedded nanoliposome as a selective tumoricidal agent.

    PubMed

    Jung, Sujin; Lee, Sangah; Lee, Hyejin; Yoon, Jaejin; Lee, E K

    2016-10-01

    HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cell), a molecular complex of human α-lactalbumin and oleic acid, is known to have selective cytotoxic activity against certain types of tumors. This cytotoxicity is known to stem from water-insoluble oleic acid. In this study, we manufactured an alternative complex using liposome as an oleic acid delivery vesicle. We named this nanolipoplex LIMLET (LIposome Made LEthal to Tumor cell). The LIMLET vesicle contained approximately 90,200 oleic acid molecules inserted into its lipophilic phospholipid bilayer and had a nominal mean diameter of 127nm. Using a WST-1 assay, its cytotoxicity against two cancer cell lines, MDA-MB-231 (human breast cancer) and A549 (human lung cancer), were tested. The results were compared with that of a normal cell line, Vero (from monkey kidney). We found that (1) LIMLET showed distinctive cytotoxicity against A549 and MDA-MB-231 cells, whereas bare liposomes (containing no oleic acid) had no toxicity, even at high concentrations, and (2) LIMLET demonstrated selective, concentration-dependent toxicity against the cancer cells: the LD50 values of MDA-MB-231 and A549 cells were 1.3 and 2.2nM LIMLET, respectively, whereas the LD50 of Vero was 5.7nM. The strength of the tumoricidal effect appeared to stem from the number of oleic acid molecules present. Our result suggests that LIMLET, like HAMLET, is an interesting nanolipoplex that can potentially be developed into tumor treatments.

  9. Morroniside cinnamic acid conjugate as an anti-inflammatory agent.

    PubMed

    Takeda, Yoshinori; Tanigawa, Naomi; Sunghwa, Fortunatus; Ninomiya, Masayuki; Hagiwara, Makoto; Matsushita, Kenji; Koketsu, Mamoru

    2010-08-15

    A morroniside cinnamic acid conjugate was prepared and evaluated on E-selectin mediated cell-cell adhesion as an important role in inflammatory processes. 7-O-Cinnamoylmorroniside exhibited excellent anti-inflammatory activity (IC(50)=49.3 microM) by inhibiting the expression of E-selectin; further, it was more active than another cinnamic-acid-conjugated iridoid glycoside (harpagoside; IC(50)=88.2 microM), 7-O-methylmorroniside, and morroniside itself. As a result, 7-O-cinnamoylmorroniside was observed to be a potent inhibitor of TNF-alpha-induced E-selectin expression.

  10. Antitumor Agents 255. Novel Glycyrrhetinic Acid-Dehydrozingerone Conjugates as Cytotoxic Agents

    PubMed Central

    Tatsuzaki, Jin; Taniguchi, Masahiko; Bastow, Kenneth F.; Nakagawa-Goto, Kyoko; Morris-Natschke, Susan L.; Itokawa, Hideji; Baba, Kimiye; Lee, Kuo-Hsiung

    2007-01-01

    Esterification of glycyrrhetinic acid (GA) with dehydrozingerone (DZ) resulted in a novel cytotoxic GA-DZ conjugate. Based on this exciting finding, we conjugated eleven different DZ analogs with GA or other triterpenoids, including oleanoic acid (OA) or ursolic acid (UA). In an in vitro anticancer assay using nine different human tumor cell lines, most of the GA-DZ conjugates showed significant potency. Particularly, compounds 5, 29, and 30 showed significant cytotoxic effects against LN-Cap, 1A9, and KB cells with ED50 values of 0.6, 0.8, and 0.9 μM, respectively. Similar conjugates between DZ and OA or UA were inactive suggesting that the GA component is critical for activity. Notably, although GA-DZ conjugates showed potent cytotoxic activity, the individual components (GA and DZ analogs) were inactive. Thus, GA-DZ conjugates are new chemical entities and represent interesting hits for anticancer drug discovery and development. PMID:17591444

  11. Synthesis of Nucleic Acid and Protein in L Cells Infected with the Agent of Meningopneumonitis

    PubMed Central

    Schechter, Esther M.

    1966-01-01

    Schechter, Esther M. (The University of Chicago, Chicago, Ill.). Synthesis of nucleic acid and protein in L cells infected with the agent of meningopneumonitis. J. Bacteriol. 91:2069–2080. 1966.—Synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein in uninfected L cells and in L cells infected with the meningopneumonitis agent was compared by measuring rates of incorporation of H3-cytidine and C14-lysine into nuclear, cytoplasmic, and agent fractions in successive 5-hr periods during the meningopneumonitis growth cycle. Synthesis of meningopneumonitis DNA, RNA, and protein was first clearly evident in the labeling period 15 to 20 hr after infection, soon after initiation of agent multiplication. The rates of synthesis of agent DNA, RNA, and protein increased logarithmically for a brief period and then declined. However, rates of isotope incorporation into all three meningopneumonitis macromolecules were sustained at near maximal values throughout the remainder of the meningopneumonitis growth cycle. These data are most readily interpreted in terms of multiplication of the meningopneumonitis agent by binary fission. The L cell response to infection was a decreased rate of DNA and RNA synthesis and an accelerated rate of cell death. Host protein synthesis was unaffected. The inhibition of nucleic acid synthesis in infected L cells probably involved competition between host and parasite for nucleic acid precursors. Different sublines of L cells varied greatly in the degree to which their nucleic acid-synthesizing mechanisms were damaged by infection. The cytoplasm of infected L cells contained newly synthesized DNA and RNA that could not be accounted for as intact meningopneumonitis cells. This nucleic acid probably arose from disintegration of the fragile intracellular forms of the meningopneumonitis agent. Images PMID:5937251

  12. Self-resolution of Epstein-Barr virus-associated B-cell lymphoma in a patient with dermatomyositis following withdrawal of mycophenolate mofetil and methotrexate.

    PubMed

    Waldman, Mark A; Callen, Jeffrey P

    2004-08-01

    Self-resolving Epstein-Barr virus (EBV)-associated lymphomas have become more common with the use of immunosuppressive agents in both transplant patients and patients with connective tissue disorders. Immunosuppressive agents are often used for control of dermatomyositis, but their use has not been linked to subsequent malignancy. We present a 46-year-old woman with dermatomyositis, who developed an EBV-associated B-cell lymphoma of the brain while on oral methotrexate, mycophenolate mofetil and low-dose prednisone. The patient's lymphoma gradually resolved "spontaneously" upon discontinuation of the methotrexate and mycophenolate mofetil. The potential for EBV-associated B-cell lymphoma to self-resolve should be recognized by the clinician in order to prevent unnecessary and potentially toxic treatments including radiation therapy or multi-drug chemotherapy.

  13. Mycophenolate mofetil (MMF): firing at the atherosclerotic plaque from different angles?

    PubMed

    van Leuven, Sander I; Kastelein, John J P; Allison, Anthony C; Hayden, Michael R; Stroes, Erik S G

    2006-02-01

    Atherosclerosis is characterized by a persistent, low-grade inflammatory state in which immune cell activation is inseparably linked to plaque formation and destabilization. The T-lymphocyte in particular has emerged as a pivotal player throughout the course of atherogenesis. As a consequence, the concept that immune modulation is a suitable target for cardiovascular prevention is currently an important focus of research. Mycophenolate mofetil (MMF) has emerged as a non-competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) that exerts cytostatic effects, particularly on proliferating T-lymphocytes. In addition, MMF has other immune-modulating effects, such as downregulation of the expression of adhesion molecules and attenuation of monocyte and macrophage responses. Given the added benefit that MMF is well tolerated, this immunosuppressive agent constitutes an attractive candidate for the modulation of inflammatory activation in atherogenesis. The present review provides an overview of the potential anti-atherogenic properties of MMF.

  14. Electrical Properties of Poly-Lactic Acid with Nucleating Agent Added

    NASA Astrophysics Data System (ADS)

    Shinyama, Katsuyoshi; Oi, Toru; Fujita, Shigetaka

    We examined electrical properties of polylactic acid (PLA) with nucleating agent added. At that time, nucleating agent was added to PLA was then heat-treated at 100°C for 30 seconds. The crystallinity of the nucleating agent was added to PLA increased to more than 40%, and its crystallization speed also increased significantly. The temperature dependence of the conductivity (σ) was investigated, the σ of PLA to which nucleating agent had been added showed the tendency to become lower than the σ of PLA to which nucleating agent had not been added in σ at temperatures higher than 60°C. Furthermore, the temperature dependence of the dielectric breakdown strength (EB) was investigated, EB of nucleating agent was added to PLA was around 5.0 MV/cm at a temperature of 25°C. Of particular note was the fact that EB of nucleating agent was added to PLA measured at 100°C was around 4.7 MV/cm, around 3 times greater than the EB value for PLA to which nucleating agent had not been added. The temperature dependence of the relative dielectric constant (εr‧) and the relative dielectric loss factor (εr″) was investigated, the peak dielectric absorption value of εr″ for the PLA to which nucleating agent had been added showed a tendency that lower than that of the PLA to which nucleating agent had not been added.

  15. Anti-tumor agents 255: novel glycyrrhetinic acid-dehydrozingerone conjugates as cytotoxic agents.

    PubMed

    Tatsuzaki, Jin; Taniguchi, Masahiko; Bastow, Kenneth F; Nakagawa-Goto, Kyoko; Morris-Natschke, Susan L; Itokawa, Hideji; Baba, Kimiye; Lee, Kuo-Hsiung

    2007-09-15

    Esterification of glycyrrhetinic acid (GA) with dehydrozingerone (DZ) resulted in a novel cytotoxic GA-DZ conjugate. Based on this exciting finding, we conjugated eleven different DZ analogs with GA or other triterpenoids, including oleanoic acid (OA) or ursolic acid (UA). In an in vitro anti-cancer assay using nine different human tumor cell lines, most of the GA-DZ conjugates showed significant potency. Particularly, compounds 5, 29, and 30 showed significant cytotoxic effects against LN-Cap, 1A9, and KB cells with ED(50) values of 0.6, 0.8, and 0.9 microM, respectively. Similar conjugates between DZ and OA or UA were inactive suggesting that the GA component is critical for activity. Notably, although GA-DZ conjugates showed potent cytotoxic activity, the individual components (GA and DZ analogs) were inactive. Thus, GA-DZ conjugates are new chemical entities and represent interesting hits for anti-cancer drug discovery and development.

  16. Ulcerative cutaneous polyarteritis nodosa treated with mycophenolate mofetil and pentoxifylline.

    PubMed

    Kluger, Nicolas; Guillot, Bernard; Bessis, Didier

    2011-06-01

    Cutaneous polyarteritis nodosa (CPAN) is a self-limited cutaneous vasculitis characterized by painful nodules, affecting mostly the lower limbs, and livedo reticularis. Despite its benign course, CPAN may display a chronic relapsing evolution with repeated exacerbations. Ulcerative CPAN has a more prolonged evolution and is associated with peripheral neuropathy. We report on a patient with a 20-year history of ulcerative and painful CPAN, refractory to multiple immunosuppressive treatments, treated successfully by mycophenolate mofetil and pentoxifylline.

  17. Inhibition of succinic acid production in metabolically engineered Escherichia coli by neutralizing agent, organic acids, and osmolarity.

    PubMed

    Andersson, Christian; Helmerius, Jonas; Hodge, David; Berglund, Kris A; Rova, Ulrika

    2009-01-01

    The economical viability of biochemical succinic acid production is a result of many processing parameters including final succinic acid concentration, recovery of succinate, and the volumetric productivity. Maintaining volumetric productivities >2.5 g L(-1) h(-1) is important if production of succinic acid from renewable resources should be competitive. In this work, the effects of organic acids, osmolarity, and neutralizing agent (NH4OH, KOH, NaOH, K2CO3, and Na2CO3), and Na2CO3) on the fermentative succinic acid production by Escherichia coli AFP184 were investigated. The highest concentration of succinic acid, 77 g L(-1), was obtained with Na2CO3. In general, irrespective of the base used, succinic acid productivity per viable cell was significantly reduced as the concentration of the produced acid increased. Increased osmolarity resulting from base addition during succinate production only marginally affected the productivity per viable cell. Addition of the osmoprotectant glycine betaine to cultures resulted in an increased aerobic growth rate and anaerobic glucose consumption rate, but decreased succinic acid yield. When using NH4OH productivity completely ceased at a succinic acid concentration of approximately 40 g L(-1). Volumetric productivities remained at 2.5 g L(-1) h(-1) for up to 10 h longer when K- or Na-bases where used instead of NH4OH. The decrease in cellular succinic acid productivity observed during the anaerobic phase was found to be due to increased organic acid concentrations rather than medium osmolarity.

  18. A Potent, Versatile Disulfide-Reducing Agent from Aspartic Acid

    PubMed Central

    2013-01-01

    Dithiothreitol (DTT) is the standard reagent for reducing disulfide bonds between and within biological molecules. At neutral pH, however, >99% of DTT thiol groups are protonated and thus unreactive. Herein, we report on (2S)-2-amino-1,4-dimercaptobutane (dithiobutylamine or DTBA), a dithiol that can be synthesized from l-aspartic acid in a few high-yielding steps that are amenable to a large-scale process. DTBA has thiol pKa values that are ∼1 unit lower than those of DTT and forms a disulfide with a similar E°′ value. DTBA reduces disulfide bonds in both small molecules and proteins faster than does DTT. The amino group of DTBA enables its isolation by cation-exchange and facilitates its conjugation. These attributes indicate that DTBA is a superior reagent for reducing disulfide bonds in aqueous solution. PMID:22353145

  19. Pectin functionalized with natural fatty acids as antimicrobial agent.

    PubMed

    Calce, Enrica; Mignogna, Eleonora; Bugatti, Valeria; Galdiero, Massimiliano; Vittoria, Vittoria; De Luca, Stefania

    2014-07-01

    Several pectin derivatives were prepared by chemical modifications of the polysaccharide with natural fatty acids. The obtained biodegradable pectin-based materials, pectin-linoleate, pectin-oleate and pectin-palmitate, were investigated for their antimicrobial activity against several bacterial strains, Staphylococcus aureus and Escherichia coli. Good results were obtained for pectin-oleate and pectin-linoleate, which inhibit the growth of the selected microorganisms by 50-70%. They exert the better antimicrobial activity against S. aureus. Subsequently, the pectin-oleate and the pectin-linoleate samples were coated on polyethylene films and were assessed for their capacity to capture the oxygen molecules, reducing its penetration into the polymeric support. These results confirmed a possible application of the new materials in the field of active food packaging.

  20. Nitrilotriacetic acid: a novel reducing agent for synthesizing colloidal gold.

    PubMed

    Njagi, John I; Goia, Dan V

    2014-05-01

    We report for the first time that nitrilotriacetic acid (NTA) is an effective reductant for the preparation of stable dispersions of uniform gold nanoparticles. The method described is capable of generating stable sols with a metal concentration as high as 1.5×10(-3)moldm(-3). The size of gold nanoparticles can be tuned from 10 to 160 nm by adjusting the stoichiometric excess of NTA. For a constant [Au]/[NTA] ratio the temperature affects the reduction kinetics but has little impact on the size of gold nanoparticles. The mechanisms of the reduction of Au(III) species and the formation and stabilization of gold nanoparticles are discussed. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Selective Extraction of Zinc from Refractory Hemimorphite Using Iminodiacetic Acid as a Complexing Agent

    NASA Astrophysics Data System (ADS)

    Rao, Shuai; Zhang, Duchao; Yang, Tianzu; Liu, Weifeng; Chen, Lin; Ling, Hongbin; Zhang, Xinwang

    2017-10-01

    An environmentally friendly process for the selective extraction of zinc from refractory hemimorphite using iminodiacetic acid (H2Ida) as a complexing agent was investigated. Thermodynamic simulations demonstrated that the partially dissociated protons and amino carboxylate anions synergistically affect the dissolution of hemimorphite. The experimental results were consistent with the theoretical analyses. Under optimal conditions, the leaching extraction of zinc was above 88% and that of iron was below 4%. Furthermore, the complexing agent could be recovered from the leaching solution at the isoelectric point by adding dilute sulfuric acid.

  2. Effect of antibrowning agents on browning and intermediate formation in the glucose-glutamic acid model.

    PubMed

    Lim, Seong-Il; Kwak, Eun-Jung; Lee, Ok-Hwan; Lee, Boo-Yong

    2010-10-01

    In this study, the inhibitory effects of antibrowning agents on browning and the formation of intermediates such as 3-deoxyglucosone (3-DG) and hydroxymethylfurfural (HMF) were evaluated with a glucose-glutamic acid model for soybean paste. The initial antibrowning capacity was measured in the following order: pentasodium tripolyphosphate < citric acid and oxalic acid < cysteine and glutathione < sodium sulfite. Our data showed that antibrowning agents, such as pentasodium tripolyphosphate, citric acid, and oxalic acid, were maintained antibrowning capacities during storage at both 4 and 30 °C, respectively. However, both cysteine and glutathione was reduced with storage time, especially in the air. A marked effect of nitrogen treatment was noted for 3 of the antibrowning agents after storage in air at 30 °C in the following order: sodium sulfite < cysteine < glutathione. The formation ratio of 3-DG and HMF was higher after storage at 30 °C than at 4 °C. These compounds were produced most abundantly in the presence of sodium sulfite, and the yields were not related significantly to the degree of browning. Citric acid and oxalic acid were identified as the most effective in inhibitors of browning and intermediates, even during storage in air at 30 °C.

  3. Thermoresponsive Acidic Microgels as Functional Draw Agents for Forward Osmosis Desalination.

    PubMed

    Hartanto, Yusak; Zargar, Masoumeh; Wang, Haihui; Jin, Bo; Dai, Sheng

    2016-04-19

    Thermoresponsive microgels with carboxylic acid functionalization have been recently introduced as an attractive draw agent for forward osmosis (FO) desalination, where the microgels showed promising water flux and water recovery performance. In this study, various comonomers containing different carboxylic acid and sulfonic acid functional groups were copolymerized with N-isopropylacrylamide (NP) to yield a series of functionalized thermoresponsive microgels possessing different acidic groups and hydrophobicities. The purified microgels were examined as the draw agents for FO application, and the results show the response of water flux and water recovery was significantly affected by various acidic comonomers. The thermoresponsive microgel with itaconic acid shows the best overall performance with an initial water flux of 44.8 LMH, water recovery up to 47.2% and apparent water flux of 3.1 LMH. This study shows that the incorporation of hydrophilic dicarboxylic acid functional groups into the microgels leads to the enhancement on water adsorption and overall performance. Our work elucidates in detail on the structure-property relationship of thermoresponsive microgels in their applications as FO draw agents and would be beneficial for future design and development of high performance FO desalination.

  4. Tranexamic Acid as Antifibrinolytic Agent in Non Traumatic Intracerebral Hemorrhages

    PubMed Central

    ARUMUGAM, Ananda; A RAHMAN, Noor Azman; THEOPHILUS, Sharon Casilda; SHARIFFUDIN, Ashraf; ABDULLAH, Jafri Malin

    2015-01-01

    Background: Mortality and morbidity associated with intracerebral hemorrhage is still high. Up to now, there are no evidence-based effective treatments for acute ICH. This study is to assess the effect of tranexamic acid (TXA) on hematoma growth of patients with spontaneous ICH compared to a placebo. Methods: We performed a single-blinded, randomised placebo-controlled trial of TXA (intravenous 1g bolus, followed by infusion TXA 1 g/hour for 8 hours) in acute (< 8 hours) primary ICH. Strict blood pressure control (target SBP 140-160 mmHg). A repeat Computed Tomography brain was done after 24 hours to reassess hematoma growth. The primary objective is to test the effect of TXA on hematoma growth. Other objective was to test the feasibility, tolerability, and adverse events of TXA in primary ICH. Results: Statistical analysis showed significant hematoma growth in control group after 24 hours compared to baseline (14.3300 vs 17.9940, P = 0.001) whereas the treatment group there is no significant hematoma size expansion between baseline and after 24 hours (P = 0.313). Conclusions: This study showed a significant hematoma volume expansion in the control group compared to the treatment group. PMID:27006639

  5. Remineralizing agents: effects on acid-softened enamel.

    PubMed

    Porcelli, H Bp; Maeda, F A; Silva, B R; Miranda, W G; Cardoso, P Ec

    2015-01-01

    This study sought to evaluate whether remineralizing toothpastes can protect acid-softened enamel against further erosive episodes. Fifty enamel slabs of bovine teeth with preformed erosion-like lesions were randomly assigned to 1 control and 4 experimental groups (n = 10): group 1, nanohydroxyapatite (nanoHAp) dentifrice; group 2, arginine and calcium carbonate (CaCO3) dentifrice; group 3, potassium nitrate (KNO3) and high-fluoride (F) availability dentifrice; group 4, ordinary fluoridated dentifrice (OFD); and group 5, control (deionized water). Initial hardness measurements were taken after the different treatments were applied. Statistically significant mineral gains of 8.0% and 10.0% were exhibited in groups 1 and 4, respectively. Groups 2 and 3 showed mineral gains of 4.5% and 2.1%, respectively; these were not statistically significant. Group 5 showed mineral loss (-11.8%). A 1-way analysis of variance showed no statistically significant differences in the mean microhardness values among groups. However, there are indications that the nanoHAp and OFD toothpastes may decrease erosive lesions after treatment, while the arginine + CaCO3 and KNO3 + F pastes may prevent the progression of erosive lesions.

  6. Synthesis and biological activity of thiazolyl-acetic acid derivatives as possible antimicrobial agents.

    PubMed

    Shirai, Akihiro; Fumoto, Yasuko; Shouno, Tomoaki; Maseda, Hideaki; Omasa, Takeshi

    2013-01-01

    5a-h, a series of (5-substituted-2-methyl-1,3-thiazole-4-yl) acetic acids as heterocyclic acetic acid derivatives, was designed and synthesized from ethyl acetoacetate. The synthesized compounds were screened for their antimicrobial activities against bacterial and fungal strains, and their characteristics were investigated by assays under various temperature and pH conditions. Cytotoxicity was evaluated with the use of sheep erythrocytes and human neonate dermal fibroblasts. Similarly, agents such as lauric acid 6 and parabens 7a-b, which are used as preservative agents for commercial cosmetics and detergents, were assayed for comparison. Although the structure of 5a is simple, comprising a thiazole attached with an octyl group and acetic acid moiety, the compound showed stronger and broader antibacterial and antifungal activities among the 5 series against the tested microbes other than gram-negative bacteria. Interestingly, 5a overcame the weak antifungal activity of parabens 7a-b. Also, the cytotoxicity of 5a was less than that of parabens 7a-b, especially to human dermal fibroblasts. These results suggest that thiazolyl-acetic acid 5a is a potentially effective biocide, and that it could be used as a preservative agent in commercially sold cosmetics and detergents, facilitated by the hydrophilic and charge properties of its carboxylic acid moiety.

  7. Comparison of the tumor-seeking agent Tc-99m(V) dimercaptosuccinic acid and the renal imaging agent Tc-99m dimercaptosuccinic acid in humans

    SciTech Connect

    Ohta, H.; Ishii, M.; Yoshizumi, M.; Endo, K.; Sakahara, H.; Nakajima, T.; Yomoda, I.; Masuda, H.; Horiuchi, K.; Hata, N.

    1985-03-01

    Being aware of the ideal nuclear properties of Tc-99m, interest has been focused on the design of the (+5) oxidation state Tc-99m(V) dimercaptosuccinic acid (Tc(V)-DMSA) as a tumor-seeking agent. Tc-99m(V) DMSA holds a TcO4(3-) core and, like PO4(3-), has excellent characteristics for tumor uptake, but has a different distribution than the well-known renal scanning agent, Tc-99m DMSA. The differences in chemical behavior of Tc-99m(V) DMSA and Tc-99m DMSA are discussed. Three cases in which neoplasms were studied with Tc-99m(V) DMSA and Tc-99m DMSA are presented. Tc-99m DMSA and Tc-99m(V) DMSA, having a common ligand and tracer but, with the metal ion core in a different oxidation state, the uptake characteristics are altered markedly.

  8. Long-acting contraceptive agents: norethisterone esters of monoalkenyl and monoalkynyl acids.

    PubMed

    Francisco, C G; Freire, R; Hernandez, R; Salazar, J A; Suarez, E; García de la Mora, G A; Noguez, J A; Acosta, A; Jimeno, O

    1983-03-01

    The synthesis of nine new esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) is described, with the esterifying acids bearing an acetylenic or olefinic function in a chain of eight or nine carbon atoms, for evaluation as long-acting contraceptive agents.

  9. Influence of polycarboxylic acid chelating agents on the kinetics of the dissolution of metal oxides

    SciTech Connect

    Dyatlova, N.M.; Gorichev, I.G.; Dukhanin, V.S.; Malov, L.V.

    1986-11-01

    The factors influencing the rate of dissolution of metal oxides in aqueous solutions of acids in the presence of polycarboxylic acid chelating agents and other complexing agents have been quantitatively compared in this review, and the decisive role of the gradient of protons and electrons in the realization of this process has been revealed. The main hypotheses of the proposed conceptions of the electron-proton theory for the dissolution of metal oxides have been stated: 1) The rate-limiting step is charge transfer (first hypothesis); 2) The rate limiting step is the desorption of the dissolution products (second hypothesis). The applicability of the proposed electron-proton theory to the theoretical substantiation of all the experimentally observed kinetic features of the influence of various factors has been demonstrated. Practical recommendations for the effective utilization of the chelating agents considered for removing iron oxide surface deposits have been given.

  10. Salicylic acid and some of its derivatives as antibacterial agents for viscose fabric.

    PubMed

    Kantouch, A; El-Sayed, A Atef; Salama, M; El-Kheir, A Abou; Mowafi, S

    2013-11-01

    Salicylic acid and three of its derivatives were used to provide antibacterial properties to viscose fabrics. The four bactericides used were bonded to the viscose fabrics using epichlorohydrin or polymer binders. Optimization of the salicylic acid and its derivatives as well as the concentration of polymers was reported. The ability of the polymer binders to attract and bind the four bactericides was observed. The overall results show that the antibacterial reactivity of salicylic acid and its derivatives are in the following order 5-bromosalicylic acid>salicylic acid>5-chlorosalicylic acid>4-chlorosalicylic acid. Using epichlorohydrin as a binding agent, unfortunately, inhibits the bactericidal activity of the four bactericides. The FTIR study concludes that the reaction between salicylic acid as well as its derivatives with epichlorohydrin takes place through the phenolic group of the acids. The unexpected deterioration in the bactericidal properties of salicylic acid and its derivatives as a result of the treatment with epichlorohydrin could be due to the nature of interaction between the epichlorohydrin molecule and the acids molecules. PVP and PU show superior ability to sustain the four bactericides used even after 10 washing cycles.

  11. New Advances in Fatty Acids as Antimalarial, Antimycobacterial and Antifungal Agents

    PubMed Central

    Carballeira, N.M.

    2008-01-01

    This review deals with the most recent findings on the antimalarial, antimycobacterial, and antifungal properties of fatty acids, with particular emphasis on novel marine fatty acids. The first section deals with the most recent and some background literature on what has been the latest developments with respect to fatty acids as antimalarial agents and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP-reductase (Fab I) of P. falciparum, the principal agent responsible for malaria. This section of the review also emphasizes the latest antimalarial research with the very long-chain Δ5,9 fatty acids from sponges. The second section of the review deals with the recent literature on the antimycobacterial activity of fatty acids and the importance of enzyme inhibition, in particular the inhibition of the enoyl-ACP-reductase (InhA) of M. tuberculosis for antimycobacterial activity. The inhibitory activities of the Δ5,9 fatty acids against InhA as well as that of the α-methoxylated fatty acids are also discussed. The importance of Δ5,9 fatty acids as topoisomerase I inhibitors and its connection to cancer is also reviewed. The last part of the review, the antifungal section, also emphasizes the most recent research with antifungal fatty acids and the importance of enzyme inhibition, in particular N-myristoyltransferase (NMT) inhibition, for antifungal activity. This last section of the review emphasizes the latest research with the α-methoxylated fatty acids but the importance of acetylenic fatty acids is also considered. PMID:18023422

  12. Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients.

    PubMed

    Xie, Xiao-chun; Li, Jun; Wang, Hong-yang; Li, Hong-liang; Liu, Jing; Fu, Qian; Huang, Jia-wen; Zhu, Chen; Zhong, Guo-ping; Wang, Xue-ding; Sun, Ping-ping; Huang, Min; Wang, Chang-xi; Li, Jia-li

    2015-05-01

    To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients. A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 -1818T>C, I399C>T, -118T9/10, -440C>T, -331T>C, UGT2B7 IVS1+985A>G, 211G>T, -900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics. The dose-adjusted MPA AUC0-12 h of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC0-12 h of the patients with the UGT1A7 622CC and UGT1A9 -440CT/-331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and -440C/-331T homozygotes. Furthermore, the genotypes UGT1A9 -1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC0-12 h. The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing.

  13. Agents.

    PubMed

    Chambers, David W

    2002-01-01

    Although health care is inherently an economic activity, it is inadequately described as a market process. An alternative, grounded in organizational economic theory, is to view professionals and many others as agents, contracted to advance the best interests of their principals (patients). This view untangles some of the ethical conflicts in dentistry. It also helps identify major controllable costs in dentistry and suggests that dentists can act as a group to increase or decrease agency costs, primarily by controlling the bad actors who damage the value of all dentists.

  14. Acid-base properties of 2-phenethyldithiocarbamoylacetic acid, an antitumor agent

    NASA Astrophysics Data System (ADS)

    Novozhilova, N. E.; Kutina, N. N.; Petukhova, O. A.; Kharitonov, Yu. Ya.

    2013-07-01

    The acid-base properties of the 2-phenethyldithiocarbamoylacetic acid (PET) substance belonging to the class of isothiocyanates and capable of inhibiting the development of tumors on many experimental models were studied. The acidity and hydrolysis constants of the PET substance in ethanol, acetone, aqueous ethanol, and aqueous acetone solutions were determined from the data of potentiometric (pH-metric) titration of ethanol and acetone solutions of PET with aqueous solidum hydroxide at room temperature.

  15. In situ gelling properties of chitosan-thioglycolic acid conjugate in the presence of oxidizing agents.

    PubMed

    Sakloetsakun, Duangkamon; Hombach, Juliane M R; Bernkop-Schnürch, Andreas

    2009-10-01

    The rheological behaviour of chitosan-thioglycolic acid conjugate (chitosan-TGA) in the presence of four oxidizing agents was investigated. Chitosan-TGA was synthesized via amide bond formation between the primary amino group of chitosan and the carboxylic acid group of thioglycolic acid. The sol-gel phase transition of the polymer was determined by rheological measurements. Moreover, cytotoxicity of the gel in combination with each oxidizing agent was evaluated utilizing LDH and MTT assay. The modified chitosan displayed 1053+/-44 micromol/g thiol groups. Results of rheological studies showed that 1% (m/v) chitosan-TGA without any oxidizing agents became gel within 40 min. In contrast, when the oxidizing agents hydrogen peroxide, sodium periodate, ammonium persulfate and sodium hypochlorite were added, respectively, gelation took place within a few minutes. Within 20 min, hydrogen peroxide having been added in a final concentration of 25.2 nmol/L increased dynamic viscosity of 1% (m/v) chitosan-TGA up to 16,500-fold. This can be explained by the formation of inter- and/or intramolecular disulfide bonds which were indirectly verified via the decrease in thiol groups. Additionally, evidence of an increase in cross-linking of thiolated chitosan as a function of time was provided by frequency sweep measurements. Furthermore, viability of Caco-2 cells having been incubated with chitosan-TGA/oxidizing agent systems assessed by MTT assay was 70-85% and the percentage of LDH release was only in case of the chitosan-TGA/ammonium persulfate system significantly (p<0.05) raising compared to the negative control. According to these results, chitosan-TGA/oxidizing agent combinations might be a promising novel in situ gelling system for various pharmaceutical applications such as a controlled drug release carrier or for tissue engineering.

  16. Effect of carboxylic acids as compatibilizer agent on mechanical properties of thermoplastic starch and polypropylene blends.

    PubMed

    Martins, Andréa Bercini; Santana, Ruth Marlene Campomanes

    2016-01-01

    In this work, polypropylene/thermoplastic starch (PP/TPS) blends were prepared as an alternative material to use in disposable packaging, reducing the negative polymeric environmental impact. Unfortunately, this material displays morphological characteristics typical of immiscible polymer blends and a compatibilizer agent is needed. Three different carboxyl acids: myristic (C14), palmitic (C16) and stearic acids (C18) were used as natural compatibilizer agent (NCA). The effects of NCA on the mechanical, physical, thermal and morphological properties of PP/TPS blends were investigated and compared against PP/TPS with and without PP-grafted maleic anhydride (PPgMA). When compared to PP/TPS, blends with C18, PPgMA and C14 presented an improvement of 25, 22 and 17% in tensile strength at break and of 180, 194 and 259% in elongation at break, respectively. The highest increase, 54%, in the impact strength was achieved with C14 incorporation. Improvements could be seen, through scanning electron microscopy (SEM) images, in the compatibility between the immiscible components by acids incorporation. These results showed that carboxylic acids, specifically C14, could be used as compatibilizer agent and could substitute PPgMA. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Use of mycophenolate sodium in stable renal transplant recipients in Spain: preliminary results of the MIDATA study.

    PubMed

    Sánchez-Fructuoso, A; Ruiz, J C; Rengel, M; Andrés, A; Morales, J M; Beneyto, I; Guirado, L I; Cantarell, C

    2009-01-01

    The use of mycophenolate mofetil (MMF) is limited by gastrointestinal adverse events (GI-AEs). Enteric-coated mycophenolate sodium (EC-MPS) was developed to avoid these effects. This multicenter prospective study sought to analyze the clinical benefit of EC-MPS among 726 stable renal transplant recipients in Spain. The data collection included: doses and trough levels of mycophenolic acid (MPA) and calcineurin inhibitors (CNI), renal function, routine biochemical parameters (3-6 months preconversion, baseline, and 1, 3, 6, and 12 months of EC-MPS initiation), as well as graft and patient survivals and adverse events. The main indication for EC-MPS introduction was GI-AEs associated with MMF (44.1%). Preliminary data showed that before introduction of EC-MPs there was a progressive deterioration of renal function, as demonstrated by a negative slope of the creatinine clearance (P < .005). However, after EC-MPS conversion, the slope became positive (P < .05), suggesting an improvement in renal function. Only in 4.8%, EC-MPS was stopped due to GI-AEs. There was an increase in MPA serum levels (P < .01) and a reduction in CNI doses. Interestingly, 80% of 85 patients without MMF treatment because of severe GI-AEs tolerated EC-MPS, including 43% who could be treated with adequate doses of EC-MPS (>or=720 mg/d). There was a significant improvement in GI-AEs after conversion from MMF to EC-MPS. The use of lower doses of CNI and the better tolerability of EC-MPS could be the underlying causes of improvement in renal function.

  18. Is mycophenolate more than just an immunosuppressant?--An overview.

    PubMed

    Iyer, Abishek; Brown, Lindsay

    2009-02-01

    The development of immunosuppressant compounds, such as cyclosporine and tacrolimus was crucial to the success of transplant surgery and for treatment of autoimmune diseases. However, immunosuppressant therapy may increase the concentrations of reactive oxygen species (ROS), inducing oxidative damage such as an increased vascular damage. The major source of ROS in the vascular endothelial cells is NADPH oxidase. The subunit structure and function of this enzyme complex in vascular cells differs from that in phagocytic leucocytes. The enzyme subunits Nox1, Nox2 and Nox4 are only found in vascular cells. The GTP-dependent protein subunit Rac 1 needs to be activated for this enzyme to function. Inhibiting this protein subunit should reduce NADPH oxidase-induced oxidative stress. In the cardiovascular system, oxidative stress is observed as hypertension, hypertrophy, fibrosis, conduction abnormalities and endothelial dysfunction, as well as cardiac allograft vasculopathy in transplant patients. In contrast to cyclosporine and tacrolimus, the immunosuppressant mycophenolate inhibits the Rac 1 subunit thus inhibiting NADPH oxidase in the vasculature. This may reduce oxidative stress, prevent the development of cardiac allograft vasculopathy, decrease the deterioration of vascular function and improve cardiovascular function chronically in transplant patients. This overview discusses whether this antioxidant immunosuppressive property could translate into a more general protective role for mycophenolate in the prevention of cardiovascular disease.

  19. Complete Reversion of Familial Adenomatous Polyposis Phenotype Associated with Tacrolimus and Mycophenolate Mofetil Treatment Following Kidney Transplantation.

    PubMed

    Pinsk, Vered; Pinsk, Ilia; Ling, Galina; Yerushalmi, Baruch; Osyntsov, Lidia; Ling, Eduard

    2017-06-01

    Numerous germline mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene are responsible for development of multiple adenomatous colorectal polyps with their inevitable progression to cancer. Multiple attempts at dietary and pharmacological prevention of colorectal carcinoma development in patients with familial adenomatous polyposis (FAP) have provided conflicting results. Immunosuppressive treatment with tacrolimus is known to be associated with an increased risk of malignancy and should be avoided in patients with high propensity for development of neoplasia. We observed a complete reversion of FAP phenotype in a male teenager carrying a germline mutation in APC gene who underwent a kidney transplant due to end-stage kidney disease secondary to congenital dysplastic kidneys. The patient was treated with tacrolimus and mycophenolate mofetil after transplantation. The possible chemopreventative role of these agents should be evaluated and confirmed in a larger cohort. The elucidation of molecular mechanisms underpinning the observed chemopreventative effect of tacrolimus and mycophenolate mofetil might lead to the development of a novel colorectal cancer therapy. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  20. Biological agent identification by nucleic acid base-pair analysis using surface-enhanced Raman spectroscopy

    NASA Astrophysics Data System (ADS)

    Farquharson, Stuart; Smith, Wayne W.; Elliott, Susan; Sperry, Jay F.

    1999-01-01

    Recently, a number of analytical methods have been successfully developed which use nucleic acid sequencing to identify biological warfare agents. However, the effectiveness of these methods, towards the safety and protection of US Armed Forces and their allies are limited by the period required to enumerate the nucleic acid through polymerase chain reactions or culture growth to produce sufficient quantities for analysis. To overcome this limitation, we have been investigating the ability of surface-enhanced Raman spectroscopy to detect nucleic acids with sufficient sensitivity and selectivity to eliminate the need for enumeration. The design of a small volume electrolytic sample cell will be presented along with analysis of the nucleic acid bases and preliminary analysis of model bacteria.

  1. Soil washing of chromium- and cadmium-contaminated sludge using acids and ethylenediaminetetra acetic acid chelating agent.

    PubMed

    Gitipour, Saeid; Ahmadi, Soheil; Madadian, Edris; Ardestani, Mojtaba

    2016-01-01

    In this research, the effect of soil washing in the removal of chromium- and cadmium-contaminated sludge samples collected from Pond 2 of the Tehran Oil Refinery was investigated. These metals are considered as hazardous substances for human health and the environment. The carcinogenicity of chromate dust has been established for a long time. Cadmium is also a potential environmental toxicant. This study was carried out by collecting sludge samples from different locations in Pond 2. Soil washing was conducted to treat the samples. Chemical agents, such as acetic acid, ethylenediaminetetra acetic acid (EDTA) and hydrochloric acid, were used as washing solutions to remove chromium and cadmium from sludge samples. The results of this study indicated that the highest removal efficiencies from the sludge samples were achieved using a 0.3 M HCl solution with 82.69% and 74.47% for chromium and cadmium, respectively. EDTA (0.1 M) in the best condition extracted 66.81% of cadmium and 72.52% of chromium from the sludges. The lowest efficiency values for the samples, however, were achieved using 3 M acetic acid with 41.7% and 46.96% removals for cadmium and chromium, respectively. The analysis of washed sludge indicated that the heavy metals removal decreased in the order of 3 M acetic acid < 0.1 M EDTA<0.3 M HCl, thus hydrochloric acid appears to offer a greater potential as a washing agent in remediating the sludge samples.

  2. Synthesis of palm oil fatty acid as foaming agent for firefighting application

    NASA Astrophysics Data System (ADS)

    Rivai, M.; Hambali, E.; Suryani, A.; Fitria, R.; Firmansyah, S.; Pradesi, J.

    2017-05-01

    Many factors including natural factor, human carelessness, new land clearance or agricultural burning/act of vandalism and ground fire are suspected as the causes of forest fire. Foam, which cools the fire down, covers the burning material/fuel, and avoids contact between burning materials with oxygen, is an effective material used to fight large-scale fires. For this purpose, surfactant which can facilitate foam formation and inhibit the spread of smoke is required. This study was aimed at producing prototype product of foaming agent from palm oil and its formulation as a fire fighting material. Before the formulation stage, the foaming agent was resulted from saponification process of oleic, lauric, and palmitic acids by using NaOH and KOH alkaline. Foam stability was used as the main indicator of foaming agent. Results showed that potassium palmitate had the highest foam stability of 82% until the 3rd day. The best potassium palmitate concentration was 7%.

  3. Solution of Azelaic Acid (20%), Resorcinol (10%) and Phytic Acid (6%) Versus Glycolic Acid (50%) Peeling Agent in the Treatment of Female Patients with Facial Melasma.

    PubMed

    Faghihi, Gita; Taheri, Azam; Shahmoradi, Zabihollah; Nilforoushzadeh, Mohammad Ali

    2017-01-01

    Melasma, a common acquired disorder of hyperpigmentation, especially in women, is often resistant to therapy. This study was aimed to evaluate the efficacy and safety of azelaic acid, resorcinol and phytic acid solution in chemical peeling of melasma in comparison to 50% glycolic acid. This clinical trial was performed, on 42 female patients with bilateral melasma. Severity of melasma was assessed by melasma area and severity index (MASI). Combination of (20% azelaic acid + 10% resorcinol + 6% phytic acid) was used as a new peeling agent on the right side of the face and 50% glycolic acid on the left side every 2 weeks for 6 times. Follow-up was carried out for 3 months after the last session. Any decrease in MASI score and unwanted complications following peeling were evaluated and compared during the trial. Patients showed marked improvement as calculated with MASI score before and after treatment in both sides of the face. The efficacy of combination formula (azelaic acid, resorcinol and phytic acid) was similar to glycolic acid, but with fewer complications. There was no statistically difference in improvement between two groups (P > 0.05). However, the patient's discomfort following procedures was significantly lower with azelaic acid, resorcinol and phytic compared with the glycolic acid peels (P < 0.05) and there was the same duration in the beginning of the therapeutic response in both groups. Results showed that triple-combination was found to be an effective and safe peeling agent in the treatment of melasma and it was as effective as 50% glycolic acid peel.

  4. Solution of Azelaic Acid (20%), Resorcinol (10%) and Phytic Acid (6%) Versus Glycolic Acid (50%) Peeling Agent in the Treatment of Female Patients with Facial Melasma

    PubMed Central

    Faghihi, Gita; Taheri, Azam; Shahmoradi, Zabihollah; Nilforoushzadeh, Mohammad Ali

    2017-01-01

    Background: Melasma, a common acquired disorder of hyperpigmentation, especially in women, is often resistant to therapy. This study was aimed to evaluate the efficacy and safety of azelaic acid, resorcinol and phytic acid solution in chemical peeling of melasma in comparison to 50% glycolic acid. Materials and Methods: This clinical trial was performed, on 42 female patients with bilateral melasma. Severity of melasma was assessed by melasma area and severity index (MASI). Combination of (20% azelaic acid + 10% resorcinol + 6% phytic acid) was used as a new peeling agent on the right side of the face and 50% glycolic acid on the left side every 2 weeks for 6 times. Follow-up was carried out for 3 months after the last session. Any decrease in MASI score and unwanted complications following peeling were evaluated and compared during the trial. Results: Patients showed marked improvement as calculated with MASI score before and after treatment in both sides of the face. The efficacy of combination formula (azelaic acid, resorcinol and phytic acid) was similar to glycolic acid, but with fewer complications. There was no statistically difference in improvement between two groups (P > 0.05). However, the patient's discomfort following procedures was significantly lower with azelaic acid, resorcinol and phytic compared with the glycolic acid peels (P < 0.05) and there was the same duration in the beginning of the therapeutic response in both groups. Conclusion: Results showed that triple-combination was found to be an effective and safe peeling agent in the treatment of melasma and it was as effective as 50% glycolic acid peel. PMID:28299301

  5. Plant-derived antifungal agent poacic acid targets β-1,3-glucan

    SciTech Connect

    Piotrowski, Jeff S.; Okada, Hiroki; Lu, Fachuang; Li, Sheena C.; Hinchman, Li; Ranjan, Ashish; Smith, Damon L.; Higbee, Alan J.; Ulbrich, Arne; Coon, Joshua J.; Deshpande, Raamesh; Bukhman, Yury V.; McIlwain, Sean; Ong, Irene M.; Myers, Chad L.; Boone, Charles; Landick, Robert; Ralph, John; Kabbage, Mehdi; Ohya, Yoshikazu

    2015-03-09

    A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole. The cellular target was identified; poacic acid localized to the cell wall and inhibited β-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding β-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. In conclusion, the discovery of poacic acid as a natural antifungal agent targeting β-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates.

  6. Plant-derived antifungal agent poacic acid targets β-1,3-glucan

    DOE PAGES

    Piotrowski, Jeff S.; Okada, Hiroki; Lu, Fachuang; ...

    2015-03-09

    A rise in resistance to current antifungals necessitates strategies to identify alternative sources of effective fungicides. We report the discovery of poacic acid, a potent antifungal compound found in lignocellulosic hydrolysates of grasses. Chemical genomics using Saccharomyces cerevisiae showed that loss of cell wall synthesis and maintenance genes conferred increased sensitivity to poacic acid. Morphological analysis revealed that cells treated with poacic acid behaved similarly to cells treated with other cell wall-targeting drugs and mutants with deletions in genes involved in processes related to cell wall biogenesis. Poacic acid causes rapid cell lysis and is synergistic with caspofungin and fluconazole.more » The cellular target was identified; poacic acid localized to the cell wall and inhibited β-1,3-glucan synthesis in vivo and in vitro, apparently by directly binding β-1,3-glucan. Through its activity on the glucan layer, poacic acid inhibits growth of the fungi Sclerotinia sclerotiorum and Alternaria solani as well as the oomycete Phytophthora sojae. A single application of poacic acid to leaves infected with the broad-range fungal pathogen S. sclerotiorum substantially reduced lesion development. In conclusion, the discovery of poacic acid as a natural antifungal agent targeting β-1,3-glucan highlights the potential side use of products generated in the processing of renewable biomass toward biofuels as a source of valuable bioactive compounds and further clarifies the nature and mechanism of fermentation inhibitors found in lignocellulosic hydrolysates.« less

  7. Could valproic acid be an effective anticancer agent? The evidence so far.

    PubMed

    Brodie, Seth A; Brandes, Johann C

    2014-10-01

    Valproic acid is an inhibitor of class I histone deacetylases. Epigenetic therapies in cancer have been focus of a keen interest and histone deacetylase inhibitors, in particular, have been approved for certain types of hematologic malignancies. Valproic acid is an attractive candidate for cancer therapy due to its mechanism of action, its low cost and generally good clinical tolerability. In the following editorial, we will review its role as monotherapy for cancer, its place in combination epigenetic therapy, and its role as chemosensitizer, and cancer preventative agent.

  8. Trivalent phosphorus acids amides as phosphorylating agents for alcohols and amines

    NASA Astrophysics Data System (ADS)

    Nifantiev, Edward E.; Grachev, M. K.

    1994-07-01

    The principal results of studies on trivalent phosphorus acid amides (TPAA) as phosphorylating agents for alcohols, phenols, and amines are summarised and discussed. Problems concerning the catalysis and mechanism of the phosphorylation of proton-donating nucleophiles by TPAA are considered and new possibilities for the development of investigations on these lines are analysed. The preparative advantages of TPAA and the specific prospects for their use in fine organic synthesis and macromolecular chemistry are demonstrated. The bibliography includes 560 references.

  9. Combination of amino acid/dipeptide with ligustrazine-betulinic acid as antitumor agents.

    PubMed

    Xu, Bing; Yan, Wen-Qiang; Xu, Xin; Wu, Gao-Rong; Zhang, Chen-Ze; Han, Yao-Tian; Chu, Fu-Hao; Zhao, Rui; Wang, Peng-Long; Lei, Hai-Min

    2017-04-21

    The lead compound TBA, 3β-Hydroxy-lup-20(29)-ene-28-oic acid-3, 5, 6-trimethylpyrazin-2-methyl ester, which exhibited promising antitumor activity and induced tumor cell apoptosis in various cancer cell lines, had previously been reported. Moreover, reports have revealed that the introduction of amino acid to betulinic acid could improve selective cytotoxicity as well as water solubility. Thus, a series of novel TBA amino acid and dipeptide derivatives were designed, synthesized and screened for selective cytotoxic activity against five cancer cell lines (HepG2, HT-29, Hela, BCG-823 and A549) and the not malignant cell line MDCK by standard MTT assay. Most of the tested TBA-amino acid and dipeptide analogues showed stronger anti-proliferative activity against all tested tumor cell lines than TBA. Among them, BA-25 exhibited the greatest cytotoxic activity on tumor cell lines (mean IC50 = 2.31 ± 0.78 μM), that was twofold than the positive drug cisplatin (DDP), while it showed lower cytotoxicity on MDCK cell line than DDP. Further cell apoptosis analyses indicated BA-25-induced apoptosis was associated with loss of mitochondrial membrane potential and increase of intracellular free Ca(2+) concentration.

  10. Potential Novel Treatments for Bipolar Depression: Ketamine, Fatty Acids, Anti-inflammatory Agents, and Probiotics.

    PubMed

    Vázquez, G H; Camino, S; Tondo, L; Baldessarini, Ross J

    2017-07-28

    Treatments for depression in bipolar disorder (BD) are far less well developed than for unipolar major depressive disorder. Several innovative and experimental approaches have been emerging recently, including use of the dissociative anesthetic ketamine and other antagonists of central NMDA glutamate receptors, as well as unsaturated fatty acids, anti-inflammatory agents, and possibly probiotic methods. We reviewed relevant reports from the past decade. Ketamine, a phencyclidine-like NMDA-glutamate receptor antagonist, has emerged as a highly innovative, experimental treatment for treatment-resistant unipolar major depression, possibly in bipolar depression, and with brief antisuicidal effects. Its limitations include poor bioavailability, rapid but short-lived effects, and little information about long-term benefits and safety of repeated administration. Polyunsaturated fatty acids critical for the structure and functioning of neuronal and other cell membranes have some evidence of benefit as experimental treatments for depression including in BD. There also is evidence of altered expression of peptides associated with inflammation in mood disorder patients, encouraging experimental treatment with anti-inflammatory agents; of these, the COX-II inhibitor celecoxib has shown some evidence of benefit. The concept of altering intestinal flora with probiotic treatments to treat mood disorders remains speculative. Ketamine represents an innovative, rapidly acting, experimental treatment for bipolar depression with practical limitations. Unsaturated fatty acids and anti-inflammatory agents have inconsistent support; probiotic treatments lack evidence. These innovative approaches require much more clinical investigation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. [Enhanced phytoextraction of heavy metal contaminated soil by chelating agents and auxin indole-3-acetic acid].

    PubMed

    Zhou, Jian-min; Dang, Zhi; Chen, Neng-chang; Xu, Sheng-guang; Xie, Zhi-yi

    2007-09-01

    The environmental risk of chelating agents such as EDTA application to the heavy metals polluted soils and the stress on plant roots due to the abrupt increase metals concentration limit the wide commercial use of chelate-induced phytoextraction. Chelating agent ethylenediaminetetraacetic acid (EDTA) and nitrilotriacetic acid (NTA) and auxin indole-3-acetic acid (IAA) were used for enhancing heavy metals uptake from soils by Zea mays L. (corn) in pot experiments. The metals content in plant tissues was quantified using an inductively coupled plasma mass spectrometer (ICP-MS). The results showed that the combination of IAA and EDTA increased the biomass by about 40.0% and the contents of Cu, Zn, Cd and Pb in corn shoots by 27.0%, 26.8%, 27.5% and 32.8% respectively, as compared to those in EDTA treatment. While NTA&IAA treatment increased the biomass by about 29.9% and the contents of Cu, Zn, Cd and Pb in corn shoots by 31.8%, 27.6%, 17.0% and 26.9% respectively, as compared to those in NTA treatment. These results indicated that corn growth was promoted, and the biomass and the accumulation of heavy metals in plant shoots were increased significantly with the addition of IAA, which probably helps to change the cell membrane properties and the biomass distribution, resulting in the alleviation of the phytotoxicity of metals and the chelating agents.

  12. Acid-mediated formation of trifluoromethyl sulfonates from sulfonic acids and a hypervalent iodine trifluoromethylating agent.

    PubMed

    Koller, Raffael; Huchet, Quentin; Battaglia, Philip; Welch, Jan M; Togni, Antonio

    2009-10-28

    A variety of sulfonic acids have been trifluoromethylated using 1-trifluoromethyl-1,2-benziodoxol-3(1H)-one under mild conditions in good to excellent yields. Initial mechanistic investigations of this reaction show a clean second-order kinetics and only very weak substrate electronic effects.

  13. Nucleic Acid-directed Self-assembly of Multifunctional Gold Nanoparticle Imaging Agents1

    PubMed Central

    Zhang, Ziyan; Liu, Yongjian; Jarreau, Chad; Welch, Michael J.; Taylor, John-Stephen A.

    2013-01-01

    Gold nanoparticles have attracted much interest as a platform for development of multifunctional imaging and therapeutic agents. Multifunctionalized gold nanoparticles are generally constructed by covalent assembly of a gold core with thiolated ligands. In this study, we have assembled multifunctionalized gold nanoparticles in one step by nucleic acid hybridization of ODN (oligodeoxynucleotide)-derivatized gold nanoparticles with a library of pre-functionalized complementary PNAs (peptide nucleic acids). The PNAs were functionalized by conjugation with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for chelating 64Cu for PET imaging, PEG (polyethylene glycol) for conferring stealth properties, and Cy5 for fluorescent imaging. The resulting nanoparticles showed good stability both in vitro and in vivo showing biodistribution behavior in a mouse that would be expected for a PEGylated gold nanoparticle rather than that for the radiolabelled PNA used in its assembly. PMID:24058728

  14. Pharmacokinetics-based optimal dose prediction of donor source-dependent response to mycophenolate mofetil in unrelated hematopoietic cell transplantation.

    PubMed

    Wakahashi, Kanako; Yamamori, Motohiro; Minagawa, Kentaro; Ishii, Shinichi; Nishikawa, Shinichirou; Shimoyama, Manabu; Kawano, Hiroki; Kawano, Yuko; Kawamori, Yuriko; Sada, Akiko; Matsui, Toshimitsu; Katayama, Yoshio

    2011-08-01

    Mycophenolate mofetil (MMF) has been widely used for prophylaxis against graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-SCT). However, no clear advantage over methotrexate has been reported, other than reduced incidence of mucositis. We speculated that the wide inter-individual variation of plasma mycophenolic acid (MPA) levels veiled the benefits of MMF. Data from 36 unrelated allogeneic bone marrow (allo-BMT) and cord blood transplantation (CBT) were analyzed retrospectively based on MPA area under the curve (AUC(0-24h)). In allo-BMT, high AUC(0-24h) (>30 μg h/ml) resulted in no incidence of grade II-IV acute/extensive chronic GVHD and tended to show higher overall and disease-free survival, lower relapse rates, and non-relapse mortality. In CBT, AUC(0-24h) less than 30 μg h/ml was sufficient for low incidence of acute/chronic GVHD and high survival. Strong correlation between AUC(0-24h) and C(2h), plasma MPA concentration at 2 h after administration was observed. Single point assessment of C(2h) was shown to provide a useful surrogate of AUC(0-24h) to predict GVHD incidence. The results of this study suggest that individualized MMF dosing in a donor source-dependent fashion may be important for maximizing the benefit of MMF in allo-SCT.

  15. Do Asian renal transplant patients need another mycophenolate mofetil dose compared with Caucasian or African American patients?

    PubMed

    Li, Pengmei; Shuker, Nauras; Hesselink, Dennis A; van Schaik, Ron H N; Zhang, Xianglin; van Gelder, Teun

    2014-10-01

    Mycophenolate mofetil (MMF) is used to prevent acute rejection following solid organ transplantation in transplant centers all over the world. Patients from different ethnic backgrounds are treated with this drug, for which therapeutic drug monitoring (TDM) has not become the standard of practice in most centers. Whether or not some ethnic groups require a different MMF dose has been a topic of debate in recent years. In this review, it is shown that Asian patients, compared with Caucasian patients, with a comparable MMF dose reach higher mycophenolic acid (MPA) exposure. Also clinical experience points toward more adverse events in case of treatment with 1 g MMF bid in Asian patients, and therefore, for this ethnic group, a lower maintenance dose seems justified. In contrast, African American patients reach similar drug concentrations as Caucasians patients receiving the same MMF dose, but due to immunological reasons, they require a higher MMF dose to reach comparable acute rejection incidences. When TDM is performed, clinicians can correct the dose and compensate for interethnic differences in drug exposure. Otherwise, it is important to choose the right dose. This optimal dose is 20-46% lower in Asian transplant recipients than in Caucasian or African American patients. © 2014 Steunstichting ESOT.

  16. Pharmacokinetic and pharmacodynamic analysis of inosine monophosphate dehydrogenase activity in hematopoietic cell transplantation recipients treated with mycophenolate mofetil.

    PubMed

    Li, Hong; Mager, Donald E; Sandmaier, Brenda M; Storer, Barry E; Boeckh, Michael J; Bemer, Meagan J; Phillips, Brian R; Risler, Linda J; McCune, Jeannine S

    2014-08-01

    A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplantation (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNCs) at 5 time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic-dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory maximum effect model with an IC50 of 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, nonrelapse mortality, and overall mortality. In conclusion, a pharmacokinetic-dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.

  17. Amino acid derivatives of ligustrazine-oleanolic acid as new cytotoxic agents.

    PubMed

    Chu, Fuhao; Xu, Xin; Li, Guoliang; Gu, Shun; Xu, Kuo; Gong, Yan; Xu, Bing; Wang, Mina; Zhang, Huazheng; Zhang, Yuzhong; Wang, Penglong; Lei, Haimin

    2014-11-07

    A series of novel ligustrazine-oleanolic acid (TOA) derivatives were designed, and synthesized by conjugating amino acids to the 3-hydroxy group of TOA by ester bonds. Their cytotoxicity was evaluated on four cancer cell lines (HepG2, HT-29, Hela and BGC-823) by standard MTT assays. The ClogP values were calculated by means of computer simulation, and logP values of both 3β-glycine ester olean-12-en-28-oic acid-3,5,6-trimethylpyrazin-2-methyl ester (6a) and TOA were determined using a shake flask-ultraviolet spectrophotometry method. It was found that 6a and the 3β-L-lysine ester-6g not only displayed good cytotoxicity (IC50<3.5 μM) but also possessed better hydrophilicity than TOA. Moreover, 6a (IC50=4.884 μM) had lower nephrotoxicity than both 6g (IC50=2.310 μM) and cisplatin (CDDP, IC50=3.691 μM) on MDCK cells. Combining Giemsa and DAPI staining, it was further verified that 6a could induce HepG2 apoptosis via nuclei fragmentation and had lower nephrotoxicity. In addition, the structure-activity relationships of these derivatives are briefly discussed.

  18. A Protocol for the Pharmacokinetics of Enteric Coated Mycophenolate Sodium in Lupus Nephritis (POEMSLUN): an open-label, randomised controlled trial

    PubMed Central

    Ranganathan, Dwarakanathan; John, George T; Healy, Helen; Roberts, Matthew J; Fassett, Robert G; Lipman, Jeffrey; Kubler, Paul; Ungerer, Jacobus; McWhinney, Brett C; Lim, Aaron; Purvey, Megan; Reyaldeen, Reza; Roberts, Jason A

    2013-01-01

    Introduction Mycophenolate sodium, an enteric-coated tablet (EC-MPS), is as effective and safe as mycophenolate mofetil (MMF) in preventing transplant rejection. EC-MPS and MMF improve the outcome of severe lupus nephritis (LN) and have fewer side effects than pulsed intravenous cyclophosphamide. Blood concentrations of mycophenolic acid (MPA), the active metabolite of EC-MPS, vary between participants despite fixed dosing. Interpatient variability has been studied in transplantation, but not well documented in LN. The relationship between MPA concentration and its clinical effect on LN has not been described. Methods and analysis This is a prospective, open-label, randomised controlled trial. –32 participants with LN who meet the inclusion and exclusion criteria will be randomised into two groups: one receiving a fixed dose of EC-MPS and the second, a dosing regimen that is titrated with therapeutic drug monitoring. Included participants will have blood sampled over a period of 8–12 h on three different occasions. Pharmacokinetic parameters will be calculated using non-compartmental methods. Ethics and dissemination The Human Research and Ethics Committee of the Royal Brisbane Women's Hospital have approved this study. The study is registered with Australian and New Zealand Clinical Trials Registry—ACTRN12611000798965 We planned to present the de-identified information at conferences and publish the results in medical journals. Trial Registration ACTRN12611000798965 PMID:23929919

  19. Mycophenolate sodium dosing in combination with tacrolimus: pharmacokinetic evaluation of a novel regimen in de novo tacrolimus-treated kidney transplant patients.

    PubMed

    Pons, Bertrand; Delavenne, Xavier; Mehdi, Manolie; Maillard, Nicolas; Sauron, Catherine; Berthoux, François; Alamartine, Eric; Basset, Thierry; Mariat, Christophe

    2012-06-01

    There are no clear guidelines concerning the appropriate dose of mycophenolate acid (MPA) to be used in association with tacrolimus. When MPA is given at an approved fixed dose in cyclosporine-treated patients, initial systemic under exposure is frequent and associated with the occurrence of acute rejection. We pharmacologically evaluated in tacrolimus-treated recipients a novel dosing regimen of MPA with an initial high dose followed by a gradual decrease over time. 15 de novo tacrolimus-treated kidney transplant patients were administered mycophenolate sodium at the dose of 720 mg b.i.d. for the first week post-transplant, 540 mg b.i.d. until Day 30, and then 360 mg b.i.d. until Day 90. MPA exposure was evaluated by the 12 h area under MPA concentration versus time curve (AUC) determined at Days 2, 7, 15, 30 and 90 post-transplant. Median MPA AUC was constantly within the therapeutic window of 30 - 60 mg/l × h throughout the three months of evaluation. More than 75% of patients had a MPA AUC above 30 mg/l × h at Day 2 and Day 7 post-transplant. This exploratory study suggests that such a dosing regimen of mycophenolate sodium might quickly offer and sustain an optimal exposure to MPA in tacrolimus-treated kidney transplant patients.

  20. Toxoplasmic encephalitis during mycophenolate mofetil immunotherapy of neuromuscular disease

    PubMed Central

    Chahin, Nizar

    2015-01-01

    Objective: To show that immunotherapy with medications such mycophenolate mofetil (MMF) can cause serious complications in patients with neuromuscular disorders. Methods: Two patients with neuromuscular disorders on immunotherapy with long-term MMF who developed toxoplasmic encephalitis (TE) were included in this case series. Results: One patient with myasthenia gravis and one patient with inflammatory myopathy on immunotherapy with long-term MMF developed severe TE. Diagnosis was based on clinical presentation, MRI brain imaging characteristics, and CSF PCR positivity for Toxoplasma gondii. Both patients were treated with pyrimethamine, sulfadiazine, and leucovorin for 2 months without clinical improvement, and both died. Conclusions: Immunotherapy with medications such as MMF can cause devastating TE in non-HIV patients with neuromuscular disorders. Early consideration and recognition of this complication is important to possibly prevent unfavorable outcomes. The utility of screening and prophylaxis against toxoplasmosis in individuals with neuroimmunologic disorders and other autoimmune disorders who receive immunosuppressive therapy requires future study. PMID:25635260

  1. Enteric-coated mycophenolate sodium experience in liver transplant patients.

    PubMed

    Cantisani, G P C; Zanotelli, M L; Gleisner, A L M; de Mello Brandão, A; Marroni, C A

    2006-04-01

    Mycophenolate sodium (EC-MPS) has been shown to be as effective and as safe as mycophenolate mofetil (MMF) in renal transplant patients. Nevertheless, compared to MMF its use in liver transplant patients has been limited. The purpose of this study was to analyze the efficacy of EC-MPS as a primary immunosuppressant or as a replacement for MMF in liver transplant patients. Ninety among 470 liver transplant recipients were receiving or had added an antimetabolite to their immunosuppressant therapy. The most common reason for this change was renal dysfunction (47.8%) or diabetes (32.2%). EC-MPS was started at a median of 30 months after liver transplantation. The mean administered daily dose was 720 mg/d. At least one gastrointestinal symptom was reported by 25 patients. Abdominal pain (16.6%) and diarrhea (14.5%) were the most frequent. EC-MPS had to be discontinued in two patients, while six others required dose reduction to resolve the symptoms. Hematological adverse events were infrequent: three patients had leukopenia and one, anemia, all of which responded to dosage reduction. There was a creatinine reduction within 6 months of drug commencement and maintenance of the lower creatinine levels at 1 year among patients who began EC-MPS for renal dysfunction. Serum low-density lipoprotein cholesterol and triglyceride levels were significantly lower among patients on EC-MPS than on MMF. In conclusion, EC-MPS appears to have a similar efficacy and safety profile as MMF in liver transplant patients. Hematological and gastrointestinal adverse events were infrequent; seldom had the drug to be discontinued.

  2. [Effects of tooth whitening agents and acidic drinks on the surface properties of dental enamel].

    PubMed

    Chen, Xiaoling; Chen, Zhiqun; Lin, Yao; Shao, Jinquan; Yin, Lu

    2013-10-01

    Using tooth whitening agents (bleaching clip) in vitro and acidic drinks, we conducted a comparative study of the changes in enamel surface morphology, Ca/P content, and hardness. Tooth whitening glue pieces, cola, and orange juice were used to soak teeth in artificial saliva in vitro. Physiological saline was used as a control treatment. The morphology of the four groups was observed under a scanning electron microscope (SEM) immediately after the teeth were soaked for 7 and 14 d. The changes in Ca/P content and microhardness were analyzed. The enamel surfaces of the teeth in the three test groups were demineralized. The Ca/P ratio and the average microhardness were significantly lower than those of the control group immediately after the teeth were soaked (P < 0.05). The Ca/P ratio and microhardness gradually increased after 7 d. No significant difference was observed between the control group and the test groups after 14 d (P > 0.05). Bleaching agents caused transient demineralization of human enamel, but these agents could induce re-mineralization and repair of enamel over time. Demineralization caused by bleaching covered a relatively normal range compared with acidic drinks and daily drinking.

  3. MULTIFUNCTIONAL SYNTHETIC POLY(L-GLUTAMIC ACID)-BASED CANCER THERAPEUTIC AND IMAGING AGENTS

    PubMed Central

    Melancon, Marites P.

    2012-01-01

    Modern polymer chemistry has led to the generation of a number of biocompatible synthetic polymers have been increasingly studied as efficient carriers for drugs and imaging agents. Synthetic biocompatible polymers have been used to improve the efficacy of both small-molecular-weight therapeutics and imaging agents. Furthermore, multiple targeted anticancer agents and/or imaging reporters can be attached to a single polymer chain, allowing multifunctional and/or multimodality therapy and molecular imaging. Having both an anticancer drug and an imaging reporter in a single polymer chain allows noninvasive real-time visualization of the pharmacokinetics of polymeric drug delivery systems, which can uncover and explain the complicated mechanisms of in vivo drug delivery and their correlation to pharmacodynamics. This review examines use of the synthetic biocompatible polymer poly(L-glutamic acid) (PG) as an efficient carrier of cancer therapeutics and imaging agents. This review will summarize and update our recent research on use of PG as a platform for drug delivery and molecular imaging, including recent clinical findings with respect to PG-paclitaxel (PG-TXL); the combination of PG-TXL with radiotherapy; mechanisms of action of PG-TXL; and noninvasive visualization of in vivo delivery of polymeric conjugates with contrast-enhanced magnetic resonance imaging (MRI), optical imaging, and multimodality imaging. PMID:21303613

  4. Radioiodinated 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid: a useful new agent to evaluate myocardial fatty acid uptake

    SciTech Connect

    Knapp, F.F. Jr.; Goodman, M.M.; Callahan, A.P.; Kirsch, G.

    1986-04-01

    Radioiodinated 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP) has been prepared as a new terminal iodophenyl-substituted fatty acid containing dimethyl-branching at the beta position. For the synthesis of this new agent, chain homologation was accomplished by fabrication of a 2,5-disubstituted thiophene by successive Friedel-Crafts acylation and Wolff-Kishner reduction reactions, followed by thiophene ring opening. The dimethyl-branching was introduced using the monomethyl ester of dimethylglutaryl chloride. Radioiodination of the 15-phenyl-3,3-dimethylpentadecanoic acid substrate in the para position then gave DMIPP. Iodine-125-labeled DMIPP showed rapid, high myocardial uptake (min, mean % injected dose/g) in fasted rats (5, 4.67; 30, 5.06; 60, 4.79; 120, 4.37), and also exhibited good heart:blood ratios (min, heart:blood: 5, 3:1; 30, 12:1; 60, 12:1; 120, 13:1). To further evaluate the effects of dimethyl-branching, the biodistribution properties of DMIPP were compared with the 3-monomethyl-branched (15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid; BMIPP) and the unbranched (15-(p-iodophenyl)pentadecanoic acid; IPP) analogs. A triple-labeled (/sup 123/I)DMIPP/(/sup 131/I)BMIPP/(/sup 125/I)IPP mixture was administered to groups of fasted rats. These results confirmed the greater myocardial retention and higher heart:blood ratios observed with DMIPP in comparison with both the 3-monomethyl-(BMIPP) and unbranched (IPP) analogs. These data suggest that (/sup 123/3I)DMIPP is an excellent candidate for clinical evaluation of regional energy substrates (fatty acid) uptake.

  5. Mycophenolate mofetil alters the antioxidant status in duodenum of rats: Implication for silymarin usage in mycophenolate mofetil-induced gastrointestinal disorders.

    PubMed

    Sheikhzadeh, Sanaz; Malekinejad, Hassan; Hobbenaghi, Rahim

    2013-01-01

    Mycophenolate mofetil (MMF) as an immunosuppressive agent is used to prevent graft rejection. One of the adverse effects of long time administration of MMF is the gastrointestinal disorder. This study aimed to investigate the gastroprotective effect of silymarin (SMN) on MMF-induced gastrointestinal (GI) disorders. Twenty-four adult female Wistar rats were assigned into three groups including the control and test groups. The control animals received saline (5 mL kg(-1)) and the test animals were treated with MMF (40 mg kg(-1), orally) and saline, MMF and silymarin (SMN, 50 mg kg(-1), orally) for 14 consecutive days, respectively. To evaluate the GI disorders due to the MMF-induced oxidative stress and subsequently the protective effect of SMN, malondialdehyde (MDA), total thiol molecules (TTM) levels and total anti-oxidant capacity (TAC) were determined. Additionally, histopathological examinations in the duodenal region of small intestine were performed. The MMF-increased level of MDA was reduced by SMN administration, while the MMF-reduced level of TTM increased significantly (p < 0.05) by SMN administration. Histopathological examinations showed the goblet cell reduction and congestion in the MMF-received animals; while SMN was able to improve the MMF-induced goblet cell reduction and congestion. Our data suggest that the MMF-induced GI disorders are characterized by changes in antioxidant status, which presented by the elevation of MDA level and reduction of TTM concentration. Moreover, the improved biochemical alterations and histopathologic damages by SMN indicating its gastroprotective and antioxidant effects.

  6. Pilot study of anti-thymocyte globulin plus mycophenolate mofetil in recent-onset diffuse scleroderma.

    PubMed

    Stratton, R J; Wilson, H; Black, C M

    2001-01-01

    To assess the safety and efficacy of anti-thymocyte globulin (ATG) followed by mycophenolate mofetil (MMF) in the treatment of diffuse scleroderma. A pilot study of 13 patients with recent-onset diffuse scleroderma was carried out. Patients received ATG for 5 days, followed by MMF for 12 months. We recorded adverse events, scleroderma skin score, hand contractures, EuroQol score, scleroderma functional assessment, pulmonary function studies, echocardiogram and plasma creatinine concentration. Mean skin score decreased during the study from 28 at baseline to 17 after 12 months of MMF (P<0.01). Hand contractures worsened during the study. Mean measurements of systemic disease remained stable. One patient died after a scleroderma renal crisis. Five patients developed serum sickness after ATG treatment, but this was controlled by corticosteroid therapy. MMF therapy was well tolerated. ATG and MMF appear safe in scleroderma. The improvement in skin score and the apparent stability of systemic disease during the study period suggest that controlled studies of these agents are justified.

  7. Pharmacokinetics and target attainment of mycophenolate in pediatric renal transplant patients.

    PubMed

    Martial, Lisa C; Jacobs, Bart A W; Cornelissen, Elisabeth A M; de Haan, Anton F J; Koch, Birgit C P; Burger, David M; Aarnoutse, Rob E; Schreuder, Michiel F; Brüggemann, Roger J M

    2016-06-01

    MPA is an immunosuppressive agent used to prevent graft rejection after renal transplantation. MPA shows considerable inter- and intraindividual variability in exposure in children and has a defined therapeutic window, and TDM is applied to individualize therapy. We aimed to study the exposure to MPA measured as the AUC in pediatric renal transplant patients, to identify factors influencing exposure and to assess target attainment. Children transplanted between 1998 and 2014 in a single center were included. Two groups were identified: Group 1 (AUC <3 wk post-transplantation) and Group 2 (AUC >18 months post-transplantation). Therapeutic targets were set at: AUC0-12h of 30-60 mg h/L. A total of 39 children were included in Group 1 (median age 13.3 yr) vs. 14 in Group 2 (median age 13.4 yr). AUC0-12h was 29.7 mg h/L in Group 1 and 56.6 mg h/L in Group 2, despite a lower dosage in Group 2 (584 and 426 mg/m(2) , respectively). About 46% of patients reached the target AUC0-12h in Group 1. Time since transplantation and serum creatinine were significantly associated with MPA exposure (p < 0.001), explaining 36% of the variability. Individualization of the mycophenolate dose by more intense and more early TDM could improve target attainment. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. No relevant pharmacokinetic interaction between pantoprazole and mycophenolate in renal transplant patients: a randomized crossover study

    PubMed Central

    Rissling, Olesja; Glander, Petra; Hambach, Pia; Mai, Marco; Brakemeier, Susanne; Klonower, Daniela; Halleck, Fabian; Singer, Eugenia; Schrezenmeier, Eva-Vanessa; Dürr, Michael; Neumayer, Hans-Hellmut; Budde, Klemens

    2015-01-01

    Aims Mycophenolic acid (MPA) suppresses lymphocyte proliferation through inosine monophosphate dehydrogenase (IMPDH) inhibition. Two formulations have been approved: mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS). Pantoprazole (PAN) inhibits gastric acid secretion, which may alter MPA exposure. Data from healthy volunteers suggest a significant drug–drug interaction (DDA) between pantoprazole and MPA. In transplant patients, a decreased MPA area under the concentration–time curve (AUC) may lead to higher IMPDH activity, which may lead to higher acute rejection risk. Therefore this DDA was evaluated in renal transplant patients under maintenance immunosuppressive therapy. Methods In this single-centre, open, randomized, four-sequence, four-treatment crossover study, the influence of PAN 40 mg on MPA pharmacokinetics such as (dose-adjusted) AUC0–12 h (dAUC) was analysed in 20 renal transplant patients (>6 months post-transplantation) receiving MMF (1–2 g day–1) and EC-MPS in combination with ciclosporin. The major metabolite MPA glucuronide (MPAG) and the IMPDH activity were also examined. Results MMF + PAN intake led to a lowest mean dAUC for MPA of 41.46 ng h ml–1 mg–1 [95% confidence interval (CI) 32.38, 50.54], while MPA exposure was highest for EC-MPS + PAN [dAUC: 46.30 ng h ml–1 mg–1 (95% CI 37.11, 55.49)]. Differences in dAUC and dose-adjusted maximum concentration (dCmax) were not significant. Only for MMF [dAUC: 41.46 ng h ml–1 mg–1 (95% CI 32.38, 50.54)] and EC-MPS [dAUC: 43.39 ng h ml–1 mg–1 (95% CI 33.44, 53.34)] bioequivalence was established for dAUC [geometric mean ratio: 101.25% (90% CI 84.60, 121.17)]. Simultaneous EC-MPS + PAN intake led to an earlier time to Cmax (tmax) [median: 2.0 h (min–max: 0.5–10.0)] than EC-MPS intake alone [3 h (1.5–12.0); P = 0.037]. Tmax was not affected for MMF [1.0 h (0.5–5.0)] ± pantoprazole [1.0 h (0.5–6.0), P = 0

  9. Failure of various agents to decrease oleic acid pulmonary albumin leak.

    PubMed

    Sugerman, H J; Blocher, C R; Hirsch, J I; Strash, A M; Tatum, J L

    1983-05-01

    Computerized pulmonary gamma scintigraphy has been shown to be a sensitive technique for the measurement of albumin flux in oleic acid pulmonary microvascular injury. In this technique technetium-99m-tagged human serum albumin is administered intravenously and lung:heart radioactivity ratios are constructed. This ratio remains constant unless there is a net flux of albumin from the vascular space into the lung, when a rising ratio is seen, called the "slope of injury" or SI. Gamma scintigraphy provides a method to rapidly screen the ability of various possible therapeutic agents to reduce the flux of albumin in experimental ARDS. In this study, 0.05 ml/kg oleic acid produced a significant increase in the SI. None of the agents tested (30 mg/kg methylprednisolone, 12.5 mg/kg ibuprofen, 4 mg/kg MK-447, a superoxide radical scavenger, or 140 mg/kg calcium gluconate) were able to alter the scintigraphically measured increased albumin flux produced by 0.05 ml/kg oleic acid.

  10. Treatment of presumptive primary immune-mediated thrombocytopenia with mycophenolate mofetil versus cyclosporine in dogs.

    PubMed

    Cummings, F O; Rizzo, S A

    2017-02-01

    The objective of this study was to compare hospitalisation duration, survival times, adverse events and cost of therapy in dogs with presumptive primary immune-mediated thrombocytopenia undergoing therapy with mycophenolate mofetil and corticosteroids versus cyclosporine and corticosteroids. A retrospective study of medical case records of dogs with presumed primary immune-mediated thrombocytopenia was conducted. Data collected included signalment, presenting complaints, haematologic and biochemical profiles, vector-borne disease testing, thoracic and abdominal radiographs, abdominal ultrasound, medications administered, duration of hospitalisation, 30- and 60-day survival, adverse events and cost of therapy. Variables were compared between dogs treated solely with mycophenolate mofetil and corticosteroids or cyclosporine and corticosteroids. A total of 55 dogs with primary immune-mediated thrombocytopenia were identified. Eighteen were excluded because multiple immunosuppressive medications were used during treatment. Hospitalisation times, 30-day survival and 60-day survival times were similar between both groups. Dogs in the mycophenolate mofetil/corticosteroid group experienced fewer adverse events than the cyclosporine/corticosteroid group. Therapy with mycophenolate mofetil was less expensive than that with cyclosporine. These results suggest that using the combination of mycophenolate mofetil and corticosteroids appears to be as effective as cyclosporine and corticosteroids in the treatment of presumed primary immune-mediated thrombocytopenia in dogs. Adverse events were less common and cost of therapy was lower in the mycophenolate mofetil group. Additional larger prospective, controlled, double-masked, outcome-based, multi-institutional studies are required to substantiate these preliminary findings. © 2017 British Small Animal Veterinary Association.

  11. Phytic acid (IP6), novel broad spectrum anti-neoplastic agent: a systematic review.

    PubMed

    Fox, C H; Eberl, M

    2002-12-01

    Phytic acid or IP6 has been extensively studied in animals and is being promoted as an anti-cancer agent in health food stores. It is naturally found in legumes, wheat bran, and soy foods. It is believed to be the active ingredient that gives these substances their cancer fighting abilities. Proposed mechanisms of action include gene alteration, enhanced immunity, and anti-oxidant properties. A Medline search from 1966 to May 2002 using the keywords phytic acid and cancer, and limiting the search to the subheadings of therapeutic uses, prevention, and adverse effects revealed 28 studies. These studies were included in the review. A great majority of the studies were done in animals and showed that phytic acid had anti-neoplastic properties in breast, colon, liver, leukemia, prostate, sarcomas, and skin cancer. There were no human studies. Side effects included chelation of multivalent cations, and an increase in bladder and renal papillomas. This increase in papilloma formation only occurred with the sodium salt of phytic acid. It did not occur with either the potassium or magnesium salts. There is a large body of animal evidence to show that phytic acid may have a role in both the prevention and treatment of many forms of cancer. There is clearly enough evidence to justify the initiation of Phase I and Phase II clinical trials in humans.

  12. Inhibition of HIV replication in vitro by clinical immunosuppressants and chemotherapeutic agents

    PubMed Central

    2013-01-01

    Background Recent studies have suggested that a functional cure for HIV-1 infection, purportedly resultant from allogeneic bone marrow transplantation, may be possible. Additionally, the first such patient was treated with whole-body irradiation, immunosuppressants, and the chemotherapeutic, cytarabine. However, the precise role of the coinciding medical interventions in diminishing detectable HIV reservoirs remains unstudied. Findings In this article, we demonstrate that the immunosuppressants, mycophenolic acid and cyclosporine, and the chemotherapeutic, cytarabine, are potent antiretroviral agents at clinically relevant dosages. These drugs strongly inhibit HIV-1 replication in a GFP indicator T cell line and peripheral blood mononuclear cells (PBMC). Conclusions Our study suggests that certain clinical immunosuppressants and chemotherapeutic agents may act combinatorially to inhibit HIV infection. Additionally, chemotherapy-mediated cytotoxicity may also affect the stability of viral reservoirs. Thus, further study is needed to examine potential therapeutic value of these interventions in patients. PMID:23672887

  13. Evaluation of unnatural cyclic amino acids as boron delivery agents for treatment of melanomas and gliomas.

    PubMed

    Barth, Rolf F; Kabalka, George W; Yang, Weilian; Huo, Tianyao; Nakkula, Robin J; Shaikh, Aarif L; Haider, Syed A; Chandra, Subhash

    2014-06-01

    Unnatural cyclic amino acids (UNAAs) are a new class of boron delivery agents that are in a pre-clinical stage of evaluation. In the present study, the biodistribution of racemic forms of the cis- and trans-isomers of the boronated UNAA 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) and 1-amino-3-boronocycloheptanecarboxylic acid (ABCHC) were evaluted in B16 melanoma bearing mice and this was compared to l-p-boronophenylalanine (BPA). Boron concentrations were determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES) at 2.5h following intraperitoneal (i.p.) injection of the test agents at a concentration equivalent to 24mg/B/kg. While all compounds attained comparable tumor boron concentrations, the tumor/blood (T/Bl) boron concentration ratios were far superior for both cis-ABCPC and cis-ABCHC compared to BPA (T/Bl=16.4, and 15.1 vs. 5.4). Secondary ion mass spectrometry (SIMS) imaging revealed that the cis-ABCPC delivered boron to the nuclei, as well as the cytoplasm of B16 cells. Next, a biodistribution study of cis-ABCPC and BPA was carried out in F98 glioma bearing rats following i.p. administration. Both compounds attained comparable tumor boron concentrations but the tumor/brain (T/Br) boron ratio was superior for cis-ABCPC compared to BPA (6 vs. 3.3). Since UNAAs are water soluble and cannot be metabolized by tumor cells, they could be potentially more effective boron delivery agents than BPA. Our data suggest that further studies are warranted to evaluate these compounds prior to the initiation of clinical studies.

  14. Reaction of nucleic acids and cis-diamminedichloroplatinum(II) in the presence of intercalating agents.

    PubMed Central

    Malinge, J M; Leng, M

    1986-01-01

    The reaction of cis-diamminedichloroplatinum(II) and several synthetic or natural double-stranded polydeoxyribonucleotides has been carried out in the presence of such intercalating agents as ethidium bromide, proflavine, and acridine. After incubation of the reaction mixtures at 37 degrees C for 24 hr, some ethidium or proflavine, but no acridine, molecules are tightly bound to nucleic acids. Tight binding is defined by resistance to extraction with butanol, assayed by filtration at acid pH or by thin-layer chromatography at basic pH. In the ternary complexes, there is about one tightly bound ethidium (or proflavine) per platinum residue. At 37 degrees C, but not at 4 degrees C, tightly bound ethidium exchanges with free ethidium, whereas platinum residues do not exchange. The binding and the release of tightly bound ethidium are very slow (several hours). It is suggested that in the ternary complexes, nucleic acid-cis-Pt(NH3)2-intercalating agent, a bidentate adduct (guanine-ethidium or -proflavine)-cis-Pt(NH3)2, is formed. No tightly bound ethidium or proflavine is found when cis-diamminedichloroplatinum(II) is replaced by trans-diamminedichloroplatinum(II). Competition experiments between cis-diamminedichloroplatinum(II), poly(dG-dC), and poly(dG)-poly(dC) or poly(dA-dT) show that the presence of ethidium bromide, proflavine, or acridine interferes with the distribution of platinum between the polynucleotides. These results might help to explain the synergism for drugs used in combination with cis-diamminedichloroplatinum(II) and in the design of new chemotherapeutic agents. PMID:3462697

  15. In vivo efficacy of the diuretic agent ethacrynic acid against multiple myeloma.

    PubMed

    Kim, Young; Gast, Sanna-Marie; Endo, Tomoyuki; Lu, Desheng; Carson, Dennis; Schmidt-Wolf, Ingo G H

    2012-05-01

    It was recently confirmed that the diuretic agent ethacrynic acid (EA) inhibits Wnt/beta catenin signaling in myeloma. This study investigated the antitumor effect of EA in vivo in a murine myeloma model. In vivo, tumor growth was significantly reduced and overall survival significantly prolonged in mice treated with EA as compared to untreated mice. Interestingly, this effect was higher as compared to the effect by lenalidomide, a commonly used drug against myeloma. These results reveal a significant in vivo effect by EA against myeloma.

  16. Synthesis and biological evaluation of pseudolaric acid B derivatives as potential immunosuppressive agents.

    PubMed

    Chen, Shou-Qiang; Wang, Jie; Zhao, Chuan; Sun, Qiang-Wen; Wang, Yi-Teng; Ai, Ting; Li, Tan; Gao, Ying; Wang, Huo; Chen, Hong

    2015-01-01

    Pseudolaric acid B (PB) derivatives with immunosuppressive activity were found by our group. In order to find potential immunosuppressive agents with high efficacy and low toxicity, a series of novel PB derivatives were synthesized and evaluated on their immunosuppressive activities. Most of the synthesized compounds were tested in vitro on murine T and B proliferation. In particular, compound 11 exhibited excellent inhibitory activity toward murine T cells (up to 19-fold enhancement compared to that of mycophenolatemofetil) and little cytotoxicity toward normal murine spleen cells. These experimental data demonstrated that some of these PB derivatives have great potential for future immunosuppressive studies.

  17. Investigation of Changing Pore Topology and Porosity During Matrix Acidizing using Different Chelating Agents

    NASA Astrophysics Data System (ADS)

    Umer Shafiq, Mian; Khaled Ben Mahmud, Hisham; Rezaee, Reza; Testamanti, Nadia

    2017-07-01

    Core flooding acidizing experiments on sandstone/carbonate formation are usually performed in the laboratory to observe different physical phenomena and to design acidizing stimulation jobs for the field. During the tests, some key parameters are analyzed such as pore volume required for breakthrough as well as pressure. Hydrochloric acid (HCl) is commonly used in the carbonate matrix acidizing while Mud acid (HF: HCl) is usually applied during the sandstone acidizing to remove damage around the well bore. However, many problems are associated with the application of these acids, such as fast reaction, corrosion and incompatibility of HCl with some minerals (illite). To overcome these problems, chelating agents (HEDTA, EDTA and GLDA) were used in this research. Colton tight sandstone and Guelph Dolomite core samples were used in this study. The experiments usually are defined in terms of porosity, permeability, dissolution and pore topology. Effluent samples were analyzed to determine dissolved iron, sodium, potassium, calcium and other positive ions using Inductively Coupled Plasma (ICP). Meanwhile Nuclear Magnetic Resonance (NMR) was employed to determine porosity and pore structure of the core sample. Core flood experiments on Berea sandstone cores and dolomite samples with dimensions of 1.5 in × 3 in were conducted at a flow rate of 1 cc/min under 150oF temperature. NMR and porosity analysis concluded that applied chemicals are effective in creating fresh pore spaces. ICP analysis concluded that HEDTA showed good ability to chelate calcium, sodium, magnesium, potassium and iron. It can be established from the analysis that HEDTA can increase more amount of permeability as compared to other chelates.

  18. Potential Use of Phenolic Acids as Anti-Candida Agents: A Review

    PubMed Central

    Teodoro, Guilherme R.; Ellepola, Kassapa; Seneviratne, Chaminda J.; Koga-Ito, Cristiane Y.

    2015-01-01

    There has been a sharp rise in the occurrence of Candida infections and associated mortality over the last few years, due to the growing body of immunocompromised population. Limited number of currently available antifungal agents, undesirable side effects and toxicity, as well as emergence of resistant strains pose a considerable clinical challenge for the treatment of candidiasis. Therefore, molecules that derived from natural sources exhibiting considerable antifungal properties are a promising source for the development of novel anti-candidal therapy. Phenolic compounds isolated from natural sources possess antifungal properties of interest. Particularly, phenolic acids have shown promising in vitro and in vivo activity against Candida species. However, studies on their mechanism of action alone or in synergism with known antifungals are still scarce. This review attempts to discuss the potential use, proposed mechanisms of action and limitations of the phenolic acids in anti-candidal therapy. PMID:26733965

  19. Conversion of glucose to fatty acids and methane: roles of two mycoplasmal agents

    SciTech Connect

    Rose, C.S.; Pirt, S.J.

    1981-07-01

    Two species of obligately anaerobic mycoplasmas were the major components of a methanogenic glucose-limited enrichment culture. In pure culture, one of these organisms, tentatively named Anaeroplasma sp. strain London, was shown to be responsible for the fermentation of glucose to fatty acids, hydrogen, and carbon dioxide; the other mycoplasma was shown to produce methane from hydrogen and carbon dioxide and was named Methanoplasma elizabethii. This same methanogenic mycoplasma contained a low-molecular-weight fluorescent cofactor which had a maximum light absorbance at 430 nm. When both species of mycoplasmas were grown together on glucose, fermentation products included fatty acids and methane. For the first time, mycoplasmas are implicated as agents of anaerobic degradation and methanogenesis in a sewage sludge digester.

  20. Antimicrobial peptides incorporating non-natural amino acids as agents for plant protection.

    PubMed

    Ng-Choi, Iteng; Soler, Marta; Güell, Imma; Badosa, Esther; Cabrefiga, Jordi; Bardaji, Eduard; Montesinos, Emilio; Planas, Marta; Feliu, Lidia

    2014-04-01

    The control of plant pathogens is mainly based on copper compounds and antibiotics. However, the use of these compounds has some limitations. They have a high environmental impact and the use of antibiotics is not allowed in several countries. Moreover, resistance has been developed to these pathogens. The identification of new agents able to fight plant pathogenic bacteria and fungi will represent an alternative to currently used antibiotics or pesticides. Antimicrobial peptides are widely recognized as promising candidates, however naturally occurring sequences present drawbacks that limit their development. These include susceptibility to protease degradation and low bioavailability. To overcome these problems, research has focused on the introduction of unnatural amino acids into lead peptide sequences. In particular, we have improved the biological profile of antimicrobial peptides active against plant pathogenic bacteria and fungi by incorporating triazolyl, biaryl and D-amino acids into their sequence. These modifications and their influence on the biological activity are summarized.

  1. Lignosulfonates carboxylated with chloroacetic acid as additives in oil recovery processes involving chemical recovery agents

    SciTech Connect

    Kalfoglou, G.

    1981-05-19

    A process for producing petroleum from subterranean formations is disclosed wherein production from the formation is obtained by driving a fluid from an injection well to a production well. The process involves injecting via the injection well into the formation an aqueous solution of lignosulfonates carboxylated with chloroacetic acid as a sacrificial agent to inhibit the deposition of surfactant and/or polymer on the reservoir matrix. The process may best be carried out by injecting the lignosulfonates carboxylated with chloroacetic acid into the formation through the injection well mixed with either a polymer, a surfactant solution and/or a micellar dispersion. This mixture would then be followed by a drive fluid such as water to push the chemicals to the production well.

  2. Associations of UDP-glucuronosyltransferases polymorphisms with mycophenolate mofetil pharmacokinetics in Chinese renal transplant patients

    PubMed Central

    Xie, Xiao-chun; Li, Jun; Wang, Hong-yang; Li, Hong-liang; Liu, Jing; Fu, Qian; Huang, Jia-wen; Zhu, Chen; Zhong, Guo-ping; Wang, Xue-ding; Sun, Ping-ping; Huang, Min; Wang, Chang-xi; Li, Jia-li

    2015-01-01

    Aim: To evaluate the effects of UDP-glucuronosyltransferases (UGTs) polymorphisms on the pharmacokinetics of the immunosuppressant mycophenolate mofetil (MMF) in Chinese renal transplant recipients. Methods: A total of 127 renal transplant patients receiving MMF were genotyped for polymorphisms in UGT1A9 −1818T>C, I399C>T, −118T9/10, −440C>T, −331T>C, UGT2B7 IVS1+985A>G, 211G>T, −900A>G, UGT1A8 518C>G and UGT1A7 622T>C. The plasma concentrations of the MMF active moiety mycophenolic acid (MPA) and main metabolite 7-O-MPA-glucuronide (MPAG) were analyzed using HPLC. Univariate and multivariate analyses were used to assess the effects of UGT-related gene polymorphisms on MPA pharmacokinetics. Results: The dose-adjusted MPA AUC0–12 h of the patients with the UGT2B7 IVS1+985AG genotype was 48% higher than that of the patients with the IVS1+985AA genotype, which could explain 11.2% of the inter-individual variation in MPA pharmacokinetics. The dose-adjusted MPAG AUC0–12 h of the patients with the UGT1A7 622CC and UGT1A9 −440CT/−331TC genotypes, respectively, was significantly higher than that of the patients with 622T homozygotes and −440C/−331T homozygotes. Furthermore, the genotypes UGT1A9 −1818T>C and UGT1A8 518C>G were associated with a low dose-adjusted MPAG AUC0–12 h. Conclusion: The UGT2B7 11+985A>G genotype is associated with the pharmacokinetics of MPA in Chinese renal transplant patients, which demonstrates the usefulness of this SNP for individualizing MMF dosing. PMID:25864649

  3. An Overview of Structurally Modified Glycyrrhetinic Acid Derivatives as Antitumor Agents.

    PubMed

    Xu, Bing; Wu, Gao-Rong; Zhang, Xin-Yu; Yan, Meng-Meng; Zhao, Rui; Xue, Nan-Nan; Fang, Kang; Wang, Hui; Chen, Meng; Guo, Wen-Bo; Wang, Peng-Long; Lei, Hai-Min

    2017-06-02

    Glycyrrhetinic Acid (GA), a triterpenoid aglycone component of the natural product glycyrrhizinic acid, was found to possess remarkable anti-proliferative and apoptosis-inducing activity in various cancer cell lines. Though GA was not as active as other triterpenes, such as betulinic acid and oleanolic acid, it could trigger apoptosis in tumor cells and it can be obtained easily and cheaply, which has stimulated scientific interest in using GA as a scaffold to synthesize new antitumor agents. The structural modifications of GA reported in recent decades can be divided into four groups, which include structural modifications on ring-A, ring-C, ring-E and multiple ring modifications. The lack of a comprehensive and recent review on this topic prompted us to gather more new information. This overview is dedicated to summarizing and updating the structural modification of GA to improve its antitumor activity published between 2005 and 2016. We reviewed a total of 210 GA derivatives that we encountered and compiled the most active GA derivatives along with their activity profile in different series. Furthermore, the structure activity relationships of these derivatives are briefly discussed. The included information is expected to be of benefit to further studies of structural modifications of GA to enhance its antitumor activity.

  4. Hyaluronic acid and its use as a "rejuvenation" agent in cosmetic dermatology.

    PubMed

    Andre, Pierre

    2004-12-01

    Since 1996, hyaluronic acid (HA) has been launched onto the market in Europe. Since then, different companies proposed their HAs. Biomatrix (NJ, USA) proposes an animal-derived HA (from rooster comb). Q-Med AB (Uppsala, Sweden) and LEA-DERM (Paris, France) are the main companies to have a nonanimal HA. HA is produced by bacterial fermentation from a specific strain of streptococci. HA has no species specificity and theoretically has no risk of allergy. No skin testing is necessary before injecting because HA is a biodegradable agent. To be utilized as a filler agent for improving wrinkles, scars, or increasing volumes, HA must be stabilized to obtain a sufficient half-life. Process of stabilization varies, according to each manufacturer. This explains the differences in longevity and in viscosity of the different products. Several HAs are suitable to fine lines, to deep wrinkles/folds, or to increase volume. A new indication for "rejuvenation" is injection into the superficial dermis and epidermis. The HA (stabilized or not) is not used to fill in but rather to hydrate and finally to rejuvenate the skin. This procedure must be repeated at intervals of a few weeks or months. If HA is the safest filler agent in cosmetic indications today, some rare side effects may appear and must be known to inform patients. Most of these complications are not severe and will disappear when the product is degraded.

  5. Salvianolic acid A as a multifunctional agent ameliorates doxorubicin-induced nephropathy in rats.

    PubMed

    Fan, Hua-Ying; Yang, Ming-Yan; Qi, Dong; Zhang, Zuo-Kai; Zhu, Lin; Shang-Guan, Xiu-Xin; Liu, Ke; Xu, Hui; Che, Xin

    2015-07-21

    Nephrotic syndrome (NS) is still a therapeutic challenge. To date there is no ideal treatment. Evidence suggest that multidrug therapy has more effect than monotherapy in amelioration of renal injury. Salvianolic acid A (SAA) is the major active component of Salviae Miltiorrhizae Bunge. Previous studies have demonstrated that SAA is a multi-target agent and has various pharmacological activities. The pleiotropic properties of SAA predict its potential in the treatment of NS. The study investigated the effect of SAA on doxorubicin-induced nephropathy. The kidney function related-biochemical changes, hemorheological parameters and oxidative stress status were determined, and histological examination using light and transmission electron microcopies and western blot analysis were also performed. Results revealed that treatment with SAA alleviated histological damages, relieved proteinuria, hypoalbuminemia and hyperlipidemia, reduced oxidative stress, as well as improving hemorheology. Furthermore, SAA restored podocin expression, down-regulated the expression of NF-κB p65 and p-IκBα while up-regulating IκBα protein expression. Overall, as a multifunctional agent, SAA has a favorable renoprotection in doxorubicin-induced nephropathy. The anti-inflammation, antioxidant, amelioration of podocyte injury, improvement of hemorheology and hypolipidemic properties may constituent an important part of its therapeutic effects. All these indicate that SAA is likely to be a promising agent for NS.

  6. Salvianolic acid A as a multifunctional agent ameliorates doxorubicin-induced nephropathy in rats

    PubMed Central

    Fan, Hua-Ying; Yang, Ming-Yan; Qi, Dong; Zhang, Zuo-Kai; Zhu, Lin; Shang-Guan, Xiu-Xin; Liu, Ke; Xu, Hui; Che, Xin

    2015-01-01

    Nephrotic syndrome (NS) is still a therapeutic challenge. To date there is no ideal treatment. Evidence suggest that multidrug therapy has more effect than monotherapy in amelioration of renal injury. Salvianolic acid A (SAA) is the major active component of Salviae Miltiorrhizae Bunge. Previous studies have demonstrated that SAA is a multi-target agent and has various pharmacological activities. The pleiotropic properties of SAA predict its potential in the treatment of NS. The study investigated the effect of SAA on doxorubicin-induced nephropathy. The kidney function related-biochemical changes, hemorheological parameters and oxidative stress status were determined, and histological examination using light and transmission electron microcopies and western blot analysis were also performed. Results revealed that treatment with SAA alleviated histological damages, relieved proteinuria, hypoalbuminemia and hyperlipidemia, reduced oxidative stress, as well as improving hemorheology. Furthermore, SAA restored podocin expression, down-regulated the expression of NF-κB p65 and p-IκBα while up-regulating IκBα protein expression. Overall, as a multifunctional agent, SAA has a favorable renoprotection in doxorubicin-induced nephropathy. The anti-inflammation, antioxidant, amelioration of podocyte injury, improvement of hemorheology and hypolipidemic properties may constituent an important part of its therapeutic effects. All these indicate that SAA is likely to be a promising agent for NS. PMID:26194431

  7. Hyaluronic acid as an internal wetting agent in model DMAA/TRIS contact lenses.

    PubMed

    Weeks, Andrea; Luensmann, Doerte; Boone, Adrienne; Jones, Lyndon; Sheardown, Heather

    2012-11-01

    Model silicone hydrogel contact lenses, comprised of N,N-dimethylacrylamide and methacryloxypropyltris (trimethylsiloxy) silane, were fabricated and hyaluronic acid (HA) was incorporated as an internal wetting agent using a dendrimer-based method. HA and dendrimers were loaded into the silicone hydrogels and cross-linked using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide chemistry. The presence and location of HA in the hydrogels was confirmed using X-ray photoelectron spectroscopy and confocal laser scanning microscopy, respectively. The effects of the presence of HA on the silicone hydrogels on hydrophilicity, swelling behavior, transparency, and lysozyme sorption and denaturation were evaluated. The results showed that HA increased the hydrophilicity and the equilibrium water content of the hydrogels without affecting transparency. HA also significantly decreased the amount of lysozyme sorption (p < 0.002). HA had no effect on lysozyme denaturation in hydrogels containing 0% and 1.7% methacrylic acid (MAA) (by weight) but when the amount of MAA was increased to 5%, the level of lysozyme denaturation was significantly lower compared to control materials. These results suggest that HA has great potential to be used as a wetting agent in silicone hydrogel contact lenses to improve wettability and to decrease lysozyme sorption and denaturation.

  8. Lactic acid bacteria from fresh fruit and vegetables as biocontrol agents of phytopathogenic bacteria and fungi.

    PubMed

    Trias, Rosalia; Bañeras, Lluís; Montesinos, Emilio; Badosa, Esther

    2008-12-01

    This study evaluated the efficacy of lactic acid bacteria (LAB) isolated from fresh fruits and vegetables as biocontrol agents against the phytopathogenic and spoilage bacteria and fungi, Xanthomonas campestris, Erwinia carotovora, Penicillium expansum, Monilinia laxa, and Botrytis cinerea. The antagonistic activity of 496 LAB strains was tested in vitro and all tested microorganisms except P. expansum were inhibited by at least one isolate. The 496 isolates were also analyzed for the inhibition of P. expansum infection in wounds of Golden Delicious apples. Four strains (TC97, AC318, TM319, and FF441) reduced the fungal rot diameter of the apples by 20%; only Weissella cibaria strain TM128 decreased infection levels by 50%. Cell-free supernatants of selected antagonistic bacteria were studied to determine the nature of the antimicrobial compounds produced. Organic acids were the preferred mediators of inhibition but hydrogen peroxide was also detected when strains BC48, TM128, PM141 and FF441 were tested against E. carotovora. While previous reports of antifungal activity by LAB are scarce, our results support the potential of LAB as biocontrol agents against postharvest rot.

  9. Clinicopathologic features and outcome of mycophenolate-induced colitis in renal transplant recipients.

    PubMed

    de Andrade, Luis Gustavo M; Rodrigues, Maria Aparecida M; Romeiro, Fernando G; Garcia, Paula D; Contti, Mariana M; de Carvalho, Maria Fernanda C

    2014-11-01

    Reports on the clinical course of mycophenolic acid (MPA)-related colitis in kidney transplant recipients are scarce. This study aimed at assessing MPA-related colitis incidence, risk factors, and progression after kidney transplantation. All kidney transplant patients taking MPA who had colonic biopsies for persistent chronic diarrhea, between 2000 and 2012, at the Kidney Transplantation Unit of Botucatu Medical School Hospital, Brazil, were included. Cytomegalovirus (CMV) immunohistochemistry was performed in all biopsy specimens. Data on presenting symptoms, medications, immunosuppressive drugs, colonoscopic findings, and follow-up were obtained. Of 580 kidney transplant patients on MPA, 34 underwent colonoscopy. Colonoscopic findings were associated with MPA usage in 16 patients. The most frequent histologic patterns were non-specific colitis (31.3%), inflammatory bowel disease (IBD)-like colitis (25%), normal/near normal (18.8%), graft-versus-host disease-like (18.8%), and ischemia-like colitis (12.5%). All patients had persistent acute diarrhea and weight loss. Six of the 16 MPA-related diarrhea patients (37.5%) showed acute dehydration requiring hospitalization. Diarrhea resolved when MPA was switched to sirolimus (50%), discontinued (18.75%), switched to azathioprine (12.5%), or reduced by 50% (18.75%). No graft loss occurred. Four patients died during the study period. Late-onset MPA was more frequent, and no correlation with MPA dose or formulation was found.

  10. Spectrophotometric Determination of Mycophenolate Mofetil as Its Charge-Transfer Complexes with Two π-Acceptors

    PubMed Central

    Vinay, K. B.; Revanasiddappa, H. D.; Raghu, M. S.; Abdulrahman, Sameer. A. M.; Rajendraprasad, N.

    2012-01-01

    Two simple, selective, and rapid spectrophotometric methods are described for the determination of mycophenolate mofetil (MPM) in pure form and in tablets. Both methods are based on charge-transfer complexation reaction of MPM with p-chloranilic acid (p-CA) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in dioxane-acetonitrile medium resulting in coloured product measurable at 520 nm (p-CA) or 580 nm (DDQ). Beer's law is obeyed over the concentration ranges of 40–400 and 12–120 μg mL−1 MPM for p-CA and DDQ, respectively, with correlation coefficients (r) of 0.9995 and 0.9947. The apparent molar absorptivity values are calculated to be 1.06 × 103 and 3.87 × 103 L mol−1 cm−1, respectively, and the corresponding Sandell's sensitivities are 0.4106 and 0.1119 μg cm−1. The limits of detection (LOD) and quantification (LOQ) are also reported for both methods. The described methods were successfully applied to the determination of MPM in tablets. Statistical comparison of the results with those of the reference method showed excellent agreement. No interference was observed from the common excipients present in tablets. Both methods were validated statistically for accuracy and precision. The accuracy and reliability of the methods were further ascertained by recovery studies via standard addition procedure. PMID:22567572

  11. RNA Preservation Agents and Nucleic Acid Extraction Method Bias Perceived Bacterial Community Composition

    PubMed Central

    McCarthy, Ann; Chiang, Edna; Schmidt, Marian L.; Denef, Vincent J.

    2015-01-01

    Bias is a pervasive problem when characterizing microbial communities. An important source is the difference in lysis efficiencies of different populations, which vary depending on the extraction protocol used. To avoid such biases impacting comparisons between gene and transcript abundances in the environment, the use of one protocol that simultaneously extracts both types of nucleic acids from microbial community samples has gained popularity. However, knowledge regarding tradeoffs to combined nucleic acid extraction protocols is limited, particularly regarding yield and biases in the observed community composition. Here, we evaluated a commercially available protocol for simultaneous extraction of DNA and RNA, which we adapted for freshwater microbial community samples that were collected on filters. DNA and RNA yields were comparable to other commonly used, but independent DNA and RNA extraction protocols. RNA protection agents benefited RNA quality, but decreased DNA yields significantly. Choice of extraction protocol influenced the perceived bacterial community composition, with strong method-dependent biases observed for specific phyla such as the Verrucomicrobia. The combined DNA/RNA extraction protocol detected significantly higher levels of Verrucomicrobia than the other protocols, and those higher numbers were confirmed by microscopic analysis. Use of RNA protection agents as well as independent sequencing runs caused a significant shift in community composition as well, albeit smaller than the shift caused by using different extraction protocols. Despite methodological biases, sample origin was the strongest determinant of community composition. However, when the abundance of specific phylogenetic groups is of interest, researchers need to be aware of the biases their methods introduce. This is particularly relevant if different methods are used for DNA and RNA extraction, in addition to using RNA protection agents only for RNA samples. PMID:25798612

  12. RNA preservation agents and nucleic acid extraction method bias perceived bacterial community composition.

    PubMed

    McCarthy, Ann; Chiang, Edna; Schmidt, Marian L; Denef, Vincent J

    2015-01-01

    Bias is a pervasive problem when characterizing microbial communities. An important source is the difference in lysis efficiencies of different populations, which vary depending on the extraction protocol used. To avoid such biases impacting comparisons between gene and transcript abundances in the environment, the use of one protocol that simultaneously extracts both types of nucleic acids from microbial community samples has gained popularity. However, knowledge regarding tradeoffs to combined nucleic acid extraction protocols is limited, particularly regarding yield and biases in the observed community composition. Here, we evaluated a commercially available protocol for simultaneous extraction of DNA and RNA, which we adapted for freshwater microbial community samples that were collected on filters. DNA and RNA yields were comparable to other commonly used, but independent DNA and RNA extraction protocols. RNA protection agents benefited RNA quality, but decreased DNA yields significantly. Choice of extraction protocol influenced the perceived bacterial community composition, with strong method-dependent biases observed for specific phyla such as the Verrucomicrobia. The combined DNA/RNA extraction protocol detected significantly higher levels of Verrucomicrobia than the other protocols, and those higher numbers were confirmed by microscopic analysis. Use of RNA protection agents as well as independent sequencing runs caused a significant shift in community composition as well, albeit smaller than the shift caused by using different extraction protocols. Despite methodological biases, sample origin was the strongest determinant of community composition. However, when the abundance of specific phylogenetic groups is of interest, researchers need to be aware of the biases their methods introduce. This is particularly relevant if different methods are used for DNA and RNA extraction, in addition to using RNA protection agents only for RNA samples.

  13. Mycophenolate mofetil (MMF) for the treatment of steroid-resistant idiopathic thrombocytopenic purpura.

    PubMed

    Hou, Ming; Peng, Jun; Shi, Yan; Zhang, Chunqing; Qin, Ping; Zhao, Chuanli; Ji, Xuebin; Wang, Xueyong; Zhang, Maohong

    2003-06-01

    The treatment of chronic idiopathic thrombocytopenic purpura (ITP) is difficult in those unresponsive to corticosteroids and/or splenectomy. We attempted to induce durable response in 21 patients with refractory ITP by applying mycophenolate mofetil (MMF) (1.5-2.0 g/d), a novel immunosuppressive agent. Overall response rate was 62% (13 of 21), including 24% (five of 21) in complete response (CR), 29% (six of 21) in partial response (PR), and 10% (two of 21) in minor response (MR). The response rates for non-splenectomized and splenectomized ITP patients were 64% (nine of 14) and 57% (four of seven), respectively (P > 0.05). 39% (five of 13) responders relapsed as a result of dose reduction or withdraw of MMF, and 61% (eight of 13) responders maintained their effectiveness for a median of 24 wk. Sustained response was observed in three patients in whom MMF was withdrawn. MMF was well tolerated with only slight nausea and diarrhea recorded in 3 of 21 cases. No premature withdrawal was found in this study. CD3+ peripheral blood mononuclear cells (PBMC) and CD19+ PBMC were significantly reduced 12 wk after MMF administration in the responders. Platelet-associated antibodies against glycoproteins GPIIb/IIIa were detected in 13 of 21 (62%) patients before MMF treatment, and antibody levels were significantly decreased in responders 12 wk after MMF administration. This suggested that MMF might correct the immunologic abnormalities underlying the destruction of circulating platelets in ITP. We conclude that MMF could be used as a second-line agent for the treatment of steroid-resistant ITP before or after splenectomy and thereby is worth of further evaluation in randomized studies.

  14. Nitrilase-catalyzed production of pyrazinoic acid, an antimycobacterial agent, from cyanopyrazine by resting cells of Rhodococcus rhodochrous J1.

    PubMed

    Kobayashi, M; Yanaka, N; Nagasawa, T; Yamada, H

    1990-10-01

    Using resting cells of Rhodococcus rhodochrous J1, in which a large amount of nitrilase is induced, a simple and efficient bioconversion process for the production of pyrazinoic acid, an antimycobacterial agent, through catalysis by a nitrilase was developed. The reaction conditions for production of pyrazinoic acid were optimized. Under optimum conditions, 3.5 M cyanopyrazine was converted to pyrazinoic acid, with a molar conversion yield of 100%. The highest yield achieved corresponded to 434 g of pyrazinoic acid per liter of reaction mixture. The synthesized pyrazinoic acid was isolated and identified physico-chemically.

  15. ATP-dependent uptake of anti-neoplastic agents by acidic organelles.

    PubMed

    Moriyama, Y; Manabe, T; Yoshimori, T; Tashiro, Y; Futai, M

    1994-02-01

    Daunomycin, an anti-neoplastic agent, is known to be sequestered by acidic organelles in normal and multidrug-resistant cells [Willingham, M.C., Cornwell, M.M., Cardarelli, C.O., Gottesman, M.M., & Pastan, I. (1986) Cancer Res. 46, 5941-5946]. We studied the mechanism of accumulation of daunomycin into acidic organelles using chromaffin granule vesicles and proteoliposomes reconstituted with purified F-type H(+)-ATPase as model systems. Radiolabeled daunomycin was taken up by chromaffin vesicles upon addition of ATP. Its ATP-dependent uptake was stimulated about 1.4- to 1.8-fold by valinomycin plus K+, but was inhibited by ammonium chloride (10 mM) and nigericin plus K+. Quinidine (5 microM), verapamil (5 microM), or vanadate (0.5 mM), inhibitors of P-glycoprotein, had no effect on its uptake. Daunomycin was also taken up by liposomes reconstituted with F-type H(+)-ATPase. Furthermore, doxorubicin and vinblastine were taken up by these vesicles, whereas colchicine and rhodamine 123 were not. The accumulations of daunomycin and doxorubicin in acidic organelles of cultured cells were decreased by inhibiting vacuolar ATPase by addition of bafilomycin A1 or concanamycin A, or by increasing the internal pH by addition of nigericin. Melittin and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide dissipated the delta pH and inhibited accumulation of daunomycin in the membrane vesicles and acidic organelles in cultured cells. These results indicate that the delta pH established by vacuolar-type ATPase drives the uptake of daunomycin, doxorubicin or vinblastine into acidic organelles, and that no specific transporters are involved in their uptakes.

  16. Mycophenolate Mofetil (MMF) Efficacy in Glomerulonephritis (GN), a Retrospective Analysis.

    PubMed

    Huraib, Sameer O; Qureshi, Junaid I; Quadri, Khaja Hm; Al Flaiw, Ahmed; Al Ghamdi, Ghormullah; Jumani, Abdulqadir; Al Hejaili, Fayez; Raza, Hammad; Al Johani, Abdulaziz; Al-Katheri, Abdulmalik; Al-Khader, Abdullah A

    2005-01-01

    Mycophenolate Mofetil MMF has been widely used in post-transplant immunosuppression. Its role is emerging in GN. MMF demonstrated promising results compared with cyclosphosphamide in stage IV lupus nephritis, in a recently published trial. It has been found to have a wide safety profile, with mostly gastroinetestinal side effects, which can be avoided through titration. Its action is through inhibition of the enzyme IMDPH (ionosine monophosphate dehydrogenase), leading to purine antagonism and inhibition of lymphocytes. We were aiming to demonstrate the efficacy of MMF in our GN population. In this study, we reviewed 17 patients who received MMF (dose - 1 gm po bid) for the past year. They were only included if it was given for the management of resistant primary glomerulonephritis. Complete remission has been defined as proteinuria of less than 0.5 g/day and partial remission as a reduction of proteinuria 50% of starting MMF therapy; all 17 MMF therapy patients uniformly achieved good BP ((29%) achieved complete remission and this group consisted of 1 membranous GN, 2 lupus GN (type IV and membranous), one FSGS and one with MPGN. Four of 17 (23%) were non-responders to therapy. This group articles.aspx? id=41 to side effects. We conclude that the MMF appears to be an effective alternate treatment modality in resistant membranous GN, lupus nephritis (type IV and V) and possibly MPGN, and to a lesser extent in resistant FSGS. Further prospective data may demonstrate the efficacy of MMF in GN.

  17. Mycophenolate mofetil embryopathy: A newly recognized teratogenic syndrome.

    PubMed

    Perez-Aytes, Antonio; Marin-Reina, Purificacion; Boso, Virginia; Ledo, Ana; Carey, John C; Vento, Maximo

    2017-01-01

    Mycophenolate mofetil (MMF) is probably the most common employed immunosuppressant drug in recipients of solid organ transplant and in many autoimmune diseases. In vitro studies, a significant number of single clinical observations and a recent study from a group of different European teratogen information services, have provided very consistent data supporting the existence of a specific MMF embryopathy. The typical malformative pattern of MMF embryopathy includes external ear anomalies ranging from hypoplastic pinna (microtia) to complete absence of pinna (anotia); cleft lip, with or without cleft palate, and ocular anomalies as iris or chorioretinal coloboma and anophthalmia/microphthalmia. Other less frequent features are congenital heart defects, distal limbs anomalies, esophageal atresia, vertebral malformations, diaphragmatic hernia, and kidney and central nervous system anomalies. Neurodevelopmental outcome seems favorable in the small number of patients where information about this issue is available, but neurological deficits have been documented. Physicians in charge of women under MMF therapy should be aware of the potential risk of this drug to cause a specific embryopathy and the need of interrupting the treatment at least six weeks before becoming pregnant.

  18. [Mycophenolate mofetil in lupus nephritis refractory to intravenous cyclophosphamide].

    PubMed

    Daza, Leonel; Pérez, Salvador; Velasco, Ulises; Hernández, Martha

    2006-09-01

    To evaluate the use of mycophenolate mofetil (MMF) in lupus nephritis (LN) patients with prior failure to intravenous cyclophosphamide over a 12-month follow-up. Eleven patients with LN were included. MMF doses ranged from 1.5-2 grams per day. In all patients, 24-h urinary protein excretion, creatinine clearance, and serum creatinine were evaluated. Treatment-related adverse effects were recorded over the 12-month follow-up. Basal proteinuria decreased from 1.63 g/L (95% CI: 0.78-2.5) to 0.93 (95% CI: 0.1-1.62) g/L at the end of the follow-up period (p = 0.04). Creatinine clearance showed a tendency to improve but no statistically significant differences were found, 69.2 (95% CI 51.4- 87.4) vs. 79.29 (IC 95% 49.2-109.3) ml/min, respectively; p = 0.90). No significant differences were found in the remaining variables. Patients without response to MMF had a higher chronicity index than those with good or average response. MMF doses of 1.5-2 grams per day are a good alternative in LN patients without response to intravenous cyclophosphamide and a low chronicity index. No severe adverse effects were found. Copyright © 2006 Elsevier España S.L. Barcelona. Published by Elsevier Espana. All rights reserved.

  19. Primary CNS lymphoproliferative disease, mycophenolate and calcineurin inhibitor usage

    PubMed Central

    Crane, Genevieve M.; Powell, Helen; Kostadinov, Rumen; Rocafort, Patrick Tim; Rifkin, Dena E.; Burger, Peter C.; Ambinder, Richard F.; Swinnen, Lode J.; Borowitz, Michael J.; Duffield, Amy S.

    2015-01-01

    Immunosuppression for solid organ transplantation increases lymphoproliferative disease risk. While central nervous system (CNS) involvement is more rare, we noticed an increase in primary CNS (PCNS) disease. To investigate a potential association with the immunosuppressive regimen we identified all post-transplant lymphoproliferative disease (PTLD) cases diagnosed over a 28-year period at our institution (174 total, 29 PCNS) and all similar cases recorded in a United Network for Organ Sharing-Organ Procurement and Transplant Network (UNOS-OPTN) data file. While no PCNS cases were diagnosed at our institution between 1986 and 1997, they comprised 37% of PTLD cases diagnosed from 2011–2014. PCNS disease was more often associated with renal vs. other organ transplant, Epstein-Barr virus, large B-cell morphology and mycophenolate mofetil (MMF) as compared to PTLD that did not involve the CNS. Calcineurin inhibitors were protective against PCNS disease when given alone or in combination with MMF. A multivariate analysis of a larger UNOS-OPTN dataset confirmed these findings, where both MMF and lack of calcineurin inhibitor usage were independently associated with risk for development of PCNS PTLD. These findings have significant implications for the transplant community, particularly given the introduction of new regimens lacking calcineurin inhibitors. Further investigation into these associations is warranted. PMID:26460822

  20. Anthranilic acid analogs as diamagnetic CEST MRI contrast agents that feature an intramolecular-bond shifted hydrogen.

    PubMed

    Song, Xiaolei; Yang, Xing; Ray Banerjee, Sangeeta; Pomper, Martin G; McMahon, Michael T

    2015-01-01

    Diamagnetic chemical exchange saturation transfer (diaCEST) agents are a new class of imaging agents, which have unique magnetic resonance (MR) properties similar to agents used for optical imaging. Here we present a series of anthranilic acid analogs as examples of diaCEST agents that feature an exchangeable proton shifted downfield, namely, an intramolecular-bond shifted hydrogen (IM-SHY), which produces significant and tunable contrast at frequencies of 4.8-9.3 ppm from water. Five analogs of N-sulfonyl anthranilic acids are all highly soluble and produced similar CEST contrast at ~6-8 ppm. We also discovered that flufenamic acid, a commercial nonsteroidal anti-inflammatory drug, displayed CEST contrast at 4.8 ppm. For these N-H IM-SHY agents, the contrast produced was insensitive to pH, making them complementary to existing diaCEST probes. This initial IM-SHY library includes the largest reported shifts for N-H protons on small organic diaCEST agents, and should find use as multifrequency MR agents for in vivo applications.

  1. Facile synthesis of graphene from graphite using ascorbic acid as reducing agent

    NASA Astrophysics Data System (ADS)

    Andrijanto, Eko; Shoelarta, Shoerya; Subiyanto, Gatot; Rifki, Sadur

    2016-04-01

    Graphene has attracted a tremendous attention in recent years due to its unique properties such as mechanical, thermal, optical and electrical properties. However, a large scale production of this material is still an issue and subjected to intense research efforts. Here, we show a simple and green approach of the graphene synthesis from graphene oxide using ascorbic acid as reduction agent. A facile synthesis of graphene (rGO) through chemical oxidation of graphite into graphene oxide (GO) was described using modified Hummers method (Improved Tour Method/ITM). The ITM method does not produce toxic gas and the temperature of the oxidation is easily controlled using ice bath. The synthesized of graphene oxide was highly soluble and stable in water. The reduction of graphene oxide into graphene was performed using ascorbic acid (AA) in mild condition. The combined ITM method and green reduction using ascorbic acid open the avenue of replacing hydrazine in the reduction of graphite oxide into graphene and may be very important step for bulk production of graphene.

  2. Targeted delivery of 5-fluorouracil to cholangiocarcinoma cells using folic acid as a targeting agent.

    PubMed

    Ngernyuang, Nipaporn; Seubwai, Wunchana; Daduang, Sakda; Boonsiri, Patcharee; Limpaiboon, Temduang; Daduang, Jureerut

    2016-03-01

    There are limits to the standard treatment for cholangiocarcinoma (CCA) including drug resistance and side effects. The objective of this study was to develop a new technique for carrying drugs by conjugation with gold nanoparticles and using folic acid as a targeting agent in order to increase drug sensitivity. Gold nanoparticles (AuNPs) were functionalized with 5-fluorouracil (5FU) and folic acid (FA) using polyethylene glycol (PEG) shell as a linker (AuNPs-PEG-5FU-FA). Its cytotoxicity was tested in CCA cell lines (M139 and M213) which express folic acid receptor (FA receptor). The results showed that AuNPs-PEG-5FU-FA increased the cytotoxic effects in the M139 and M213 cells by 4.76% and 7.95%, respectively compared to those treated with free 5FU+FA. It is found that the cytotoxicity of the AuNPs-PEG-5FU-FA correlates with FA receptor expression suggested the use of FA as a targeted therapy. The mechanism of cytotoxicity was mediated via mitochondrial apoptotic pathway as determined by apoptosis array. In conclusion, our findings shed some light on the use of gold nanoparticles for conjugation with potential compounds and FA as targeted therapy which contribute to the improvement of anti-cancer drug efficacy. In vivo study should be warranted for its effectiveness of stability, biosafety and side effect reduction.

  3. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    PubMed

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors.

  4. A prospective analysis of the effects of enteric-coated mycophenolate sodium and mycophenolate mofetil co-medicated with a proton pump inhibitor in kidney transplant recipients at a single institute in China.

    PubMed

    Xu, L; Cai, M; Shi, B-Y; Li, Z-L; Li, X; Jin, H-L

    2014-06-01

    Enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF), two prodrugs of mycophenolic acid (MPA), have been used in immunosuppressive regimens. After being taken orally, both of them transform to MPA to achieve immune suppression effects; however, the main site of absorption and metabolism of EC-MPS is different from that of MMF in vivo. Therefore, combined application with related drugs may result in different MPA levels and have different clinical effects in kidney transplant recipients. To evaluate the efficacy of EC-MPS compared with MMF in Chinese renal transplant patients comedicated with a proton pump inhibitor (PPI). Our subjects were 88 patients who received renal transplants at the 309th Hospital of the Chinese PLA from May 2010 to April 2013. These were made up of two groups including 27 patients with EC-MPS and 61 with MMF. The immunosuppression regimen was EC-MPS/MMF + cyclosporine/tacrolimus + steroid hormone, comedicated with a PPI (omeprazole). The patients' levels of exposure of MPA within 1 week after operation were monitored. Clinical indicators such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine hemoglobin, leucocytes, and neutrophils, as well as clinical adverse drug reactions and drug conversion were analyzed retrospectively. The kidney function of patients recovered to normal in both the EC-MPS and MMF groups. The mean concentration to peak (Cmax), the mean half-life (t1/2), and the area under the concentration-time curve (AUC0-12) of MPA in the EC-MPS group were higher than those in the MMF group (P < .05). This indicated that the pharmacokinetic parameters for MPA when EC-MPS is co-administered with a PPI in kidney transplant patients in China is better than for comedication with MMF and a PPI. The MMF group had a higher incidence of drug withdrawal because of higher infection rates, leucocyte decrease, and more gastrointestinal side effects than the EC-MPS group (P

  5. Insights on chronic-relapsing opsoclonus-myoclonus from a pilot study of mycophenolate mofetil.

    PubMed

    Pranzatelli, Michael R; Tate, Elizabeth D; Travelstead, Anna L; Baumgardner, Christine A; Gowda, Narayana V; Halthore, Sri N; Kerstan, Peter; Kossak, Brian D; Mitchell, Wendy G; Taub, Jeffrey W

    2009-03-01

    Opsoclonus-myoclonus syndrome is characterized by abnormal lymphocyte trafficking into brain. The authors hypothesized that mycophenolate mofetil, a lymphocyte proliferation inhibitor, might be therapeutic. The cerebrospinal fluid and blood immunophenotypes of 15 children with predominantly chronic-relapsing opsoclonus-myoclonus syndrome were compared before and after treatment by flow cytometry. Mycophenolate mofetil reduced the cerebrospinal fluid expansion of HLA-DR+ activated T cells (-40%); the frequency of other T-cell or natural killer cell subsets remained unchanged, but cerebrospinal fluid B cells increased significantly. Adrenocorticotropic hormone dose was lowered by 64% over an average of 1.5 years, yet 73% eventually relapsed despite therapeutic drug levels. Prior treatment with rituximab prevented relapse-associated increase in cerebrospinal fluid B cells, without hindering mycophenolate mofetil-induced reduction in T-cell activation. These data demonstrate resistant immunologic problems in chronic-relapsing opsoclonus-myoclonus syndrome. Mycophenolate mofetil did not prevent relapse. The novel effect of mycophenolate mofetil on chronically activated T cells may contribute to its efficacy in T-cell mediated neurological disorders.

  6. Effect of chaotropic agents on reversible unfolding of a soybean (Glycine max) seed acid phosphatase.

    PubMed

    Cavagis, Alexandre Donizeti Martins; Granjeiro, Paulo Afonso; Ferreira, Carmen Veríssima; Aoyama, Hiroshi

    2004-04-01

    In this work we examined the effect of urea and guanidinium chloride on the structural stability of a single isoform of soybean seed acid phosphatase, based on the intensity of tryptophan fluorescence as a function of denaturant concentration. The free energy of unfolding, DeltaGu, was calculated at 25 degrees C as a function of the concentrations of both chaotropic agents; the conformational stability, DeltaG (H2O), was determined to be 2.48 kcal mol(-1). Center of mass, determined from analysis of fluorescence data, was used as a parameter to assess conformational changes. Our results indicate that complete enzyme inactivation occurred before full enzyme unfolding in both cases, and suggest that there are differences between the conformational flexibility of the active-site and that of the macromolecule as a whole.

  7. Evolution in medicinal chemistry of ursolic acid derivatives as anticancer agents.

    PubMed

    Chen, Haijun; Gao, Yu; Wang, Ailan; Zhou, Xiaobin; Zheng, Yunquan; Zhou, Jia

    2015-03-06

    Currently, there is a renewed interest in common dietaries and plant-based traditional medicines for the prevention and treatment of cancer. In the search for potential anticancer agents from natural sources, ursolic acid (UA), a pentacyclic triterpenoid widely found in various medicinal herbs and fruits, exhibits powerful biological effects including its attractive anticancer activity against various types of cancer cells. However, the limited solubility, rapid metabolism and poor bioavailability of UA restricted its further clinical applications. In the past decade, with substantial progress toward the development of new chemical entities for the treatment of cancer, numerous UA derivatives have been designed and prepared to overcome its disadvantages. Despite extensive effort, discovery of effective UA derivatives has so far met with only limited success. This review summarizes the current status of the structural diversity and evolution in medicinal chemistry of UA analogues and provides a detailed discussion of future direction for further research in the chemical modifications of UA.

  8. Evolution in Medicinal Chemistry of Ursolic Acid Derivatives as Anticancer Agents

    PubMed Central

    Chen, Haijun; Gao, Yu; Wang, Ailan; Zhou, Xiaobin; Zheng, Yunquan; Zhou, Jia

    2015-01-01

    Currently, there is a renewed interest in common dietaries and plant-based traditional medicines for the prevention and treatment of cancer. In the search for potential anticancer agents from natural sources, ursolic acid (UA), a pentacyclic triterpenoid widely found in various medicinal herbs and fruits, exhibits powerful biological effects including its attractive anticancer activity against various types of cancer cells. However, the limited solubility, rapid metabolism and poor bioavailability of UA restricted its further clinical applications. In the past decade, with substantial progress toward the development of new chemical entities for the treatment of cancer, numerous UA derivatives have been designed and prepared to overcome its disadvantages. Despite extensive effort, discovery of effective UA derivatives has so far met with only limited success. This review summarizes the current status of the structural diversity and evolution in medicinal chemistry of UA analogues and provides a detailed discussion of future direction for further research in the chemical modifications of UA. PMID:25617694

  9. Trapping of organophosphorus chemical nerve agents in water with amino acid functionalized baskets.

    PubMed

    Ruan, Yian; Dalkiliç, Erdin; Peterson, Paul W; Pandit, Aroh; Dastan, Arif; Brown, Jason D; Polen, Shane M; Hadad, Christopher M; Badjić, Jovica D

    2014-04-07

    We prepared eleven amino-acid functionalized baskets and used (1) H NMR spectroscopy to quantify their affinity for entrapping dimethyl methylphosphonate (DMMP, 118 Å(3) ) in aqueous phosphate buffer at pH=7.0±0.1; note that DMMP guest is akin in size to chemical nerve agent sarin (132 Å(3) ). The binding interaction (Ka ) was found to vary with the size of substituent groups at the basket's rim. In particular, the degree of branching at the first carbon of each substituent had the greatest effect on the host-guest interaction, as described with the Verloop's B1 steric parameter. The branching at the remote carbons, however, did not perturb the encapsulation, which is important for guiding the design of more effective hosts and catalysts in future. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. Synthesis of novel 2'-fluoro-3'-hydroxymethyl-5'-deoxythreosyl phosphonic acid nucleoside analogues as antiviral agents.

    PubMed

    Kim, Kyung Mi; Hong, Joon Hee

    2014-01-01

    A series of purine 5'-deoxyphosphonate analogues were designed and synthesized to mimic naturally occurring purine monophosphate from 1,3-dihydroxyacetone as starting material. The discovery of threosyl phosphonate nucleoside (PMDTA, EC50 = 2.53 μM) as a potent anti-HIV agent has led to the synthesis and biological evaluation of 2',3'-modified 5'-deoxyversions of the threosyl phosphonate nucleosides. The synthesized 2'-fluoro-3'-hydroxymethyl 5'-deoxythreosyl phosphonic acid nucleoside analogues 14, 18, 23, and 27 were tested for anti-HIV activity as well as cytotoxicity. The adenine analogue 18 exhibits weak in vitro anti-HIV-1 activity (EC50 = 19.2 μM).

  11. Environmentally relevant concentrations of aminopolycarboxylate chelating agents mobilize Cd from humic acid.

    PubMed

    North, Ashley E; Sarpong-Kumankomah, Sophia; Bellavie, Andrew R; White, Wade M; Gailer, Jürgen

    2017-07-01

    Although Cd is a pollutant of public health relevance, many dietary sources from which it can be absorbed into human tissues remain unknown. While it is well established that the biogeochemical cycle of Cd involves its complexation with environment-derived ligands (e.g., humic acids, HAs) and anthropogenic ones (e.g., chelating agents, CAs), the interaction of Cd with both of these ligands is less well understood. To gain insight, a HA-Cd complex was injected on a size-exclusion chromatography (SEC) column coupled on-line with a flame atomic absorption spectrometer (FAAS) using 10mmol/L Tris buffer (pH8.0) as the mobile phase. This approach allowed us to observe the intact HA-Cd complex and the retention behavior of Cd as a function of 2-20μmol/L concentrations of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA) or methylglycinediacetic acid (MGDA) that were added to the mobile phase. An increase of the retention time of Cd was indicative of a partial or complete abstraction of Cd from HA. Our results revealed that all CAs abstracted Cd from the HA-Cd complex at concentrations of 5μmol/L, while MGDA and DTPA were effective at 2μmol/L. The bioavailability of some of the on-column formed CA-Cd complexes explains the previously reported increased accumulation of Cd in periphyton in the ecosystem downstream of wastewater treatment plants. In addition, our results imply that the use of effluents which contain CAs and Cd for the irrigation of food crops can introduce Cd into the food supply and compromise food safety. Copyright © 2017. Published by Elsevier B.V.

  12. "On-off" thermoresponsive coating agent containing salicylic acid applied to maize seeds for chilling tolerance.

    PubMed

    Guan, Yajing; Li, Zhan; He, Fei; Huang, Yutao; Song, Wenjian; Hu, Jin

    2015-01-01

    Chilling stress is an important constraint for maize seed establishment in the field. In this study, a type of "on-off" thermoresponsive coating agent containing poly (N-isopropylacrylamide-co-butylmethacrylate) (Abbr. P(NIPAm-co-BMA)) hydrogel was developed to improve the chilling tolerance of coated maize seed. The P(NIPAm-co-BMA) hydrogel was synthesized by free-radical polymerization of N-isopropylacrylamide (NIPAm) and butylmethacrylate (BMA). Salicylic acid (SA) was loaded in the hydrogel as the chilling resistance agent. SA-loaded P(NIPAm-co-BMA) was used for seed film-coating of two maize varieties, Huang C (HC, chilling-tolerant) and Mo17 (chilling-sensitive), to investigate the coated seed germination and seedling growth status under chilling stress. The results showed that the hydrogel obtained a phase transition temperature near 12°C with a NIPAM to MBA weight ratio of 1: 0.1988 (w/w). The temperature of 12°C was considered the "on-off" temperature for chilling-resistant agent release; the SA was released from the hydrogel more rapidly at external temperatures below 12°C than above 12°C. In addition, when seedlings of both maize varieties suffered a short chilling stress (5°C), higher concentrations of SA-loaded hydrogel resulted in increased germination energy, germination percentage, germination index, root length, shoot height, dry weight of roots and shoots and protective enzyme activities and a decreased malondialdehyde content in coated maize seeds compared to single SA treatments. The majority of these physiological and biochemical parameters achieved significant levels compared with the control. Therefore, SA-loaded P(NIPAm-co-BMA), a nontoxic thermoresponsive hydrogel, can be used as an effective material for chilling tolerance in film-coated maize seeds.

  13. Plasma Sterilization of Poly Lactic Acid Ultrasound Contrast Agents: Surface Modification and Implications for Drug Delivery

    PubMed Central

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

    2013-01-01

    Poly lactic acid (PLA) ultrasound contrast agents (CA) have been previously developed 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 minutes) and intensity (low- 10 mA, 6.8 W; medium- 15 mA, 10.5 W; and high- 25 mA, 18W) on the CA’s 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 three minutes 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 minutes, 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 drug. PMID:19766380

  14. Material characterization of poly-lactic acid shelled ultrasound contrast agent and their dynamics

    NASA Astrophysics Data System (ADS)

    Paul, Shirshendu; Russakow, Daniel; Rodgers, Tyler; Sarkar, Kausik; Cochran, Michael; Wheatley, Margaret

    2011-11-01

    Micron-size gas bubbles encapsulated with lipids and proteins are used as contrast enhancing agents for ultrasound imaging. Biodegradable polymer poly-lactic acid (PLA) has recently been suggested as a possible means of encapsulation. Here, we report in vitro measurement of attenuation and scattering of ultrasound through an emulsion of PLA agent as well as theoretical modeling of the encapsulated bubble dynamics. The attenuation measured with three different transducers of central frequencies 2.25, 3.5 and 5 MHz, shows a peak around 2-3 MHz. These bubbles also show themselves to possess excellent scattering characteristics including strong non-linear response that can be used for harmonic and sub-harmonic contrast imaging. Our recently developed interfacial rheological models are applied to describe the dynamics of these bubbles; rheological model properties are estimated using measured attenuation data. The model is then applied to predict nonlinear scattered response, and the prediction is compared against experimental observation. Partially supported by NSF and NIH.

  15. Foam injection molding of poly(lactic acid) with physical blowing agents

    NASA Astrophysics Data System (ADS)

    Pantani, R.; Sorrentino, A.; Volpe, V.; Titomanlio, G.

    2014-05-01

    Foam injection molding uses environmental friendly blowing agents under high pressure and temperature to produce parts having a cellular core and a compact solid skin (the so-called "structural foam"). The addition of a supercritical gas reduces the part weight and at the same time improves some physical properties of the material through the promotion of a faster crystallization; it also leads to the reduction of both the viscosity and the glass transition temperature of the polymer melt, which therefore can be injection molded adopting lower temperatures and pressures. These aspects are of extreme interest for biodegradable polymers, which often present a very narrow processing window, with the suitable processing temperatures close to the degradation conditions. In this work, foam injection molding was carried out by an instrumented molding machine, able to measure the pressure evolution in different positions along the flow-path. The material adopted was a biodegradable polymer, namely the Poly(lactic acid), PLA. The effect of a physical blowing agent (PBA) on the viscosity was measured. The density reduction and the morphology of parts obtained by different molding conditions was assessed.

  16. Photochemical degradation of sunscreen agent 2-phenylbenzimidazole-5-sulfonic acid in different water matrices.

    PubMed

    Ji, Yuefei; Zhou, Lei; Zhang, Ya; Ferronato, Corinne; Brigante, Marcello; Mailhot, Gilles; Yang, Xi; Chovelon, Jean-Marc

    2013-10-01

    The occurrence of sunscreen agents in natural environment is of scientific concern recently due to their potential risk to ecology system and human beings as endocrine disrupting chemicals (EDCs). In this work the photodegradation mechanism and pathways of sunscreen agent 2-phenylbenzimidazole-5-sulfonic acid (PBSA) were investigated under artificial solar irradiation with the goal of assessing the potential of photolysis as a transformation mechanism in aquatic environments. The quantum yield of PBSA direct photolysis in pH 6.8 buffer solution under filtered mercury lamp irradiation was determined as 2.70 × 10(-4). Laser flash photolysis (LFP) experiments confirmed the involvement of PBSA radical cation (PBSA(·+)) during direct photolysis. Acidic or basic condition facilitated PBSA direct photolysis in aqueous solution. Indirect photolysis out-competes direct photolysis as a major process for PBSA attenuation only at higher level of photosensitizers (e.g., NO3(-) > 2 mM). Thus, direct photolysis is likely to be the major loss pathway responsible for the elimination of PBSA in natural sunlit surface waters, while indirect photolysis (e.g., mediated by HO·) appeared to be less important due to a general low level of steady-state concentration of HO· ([HO·]ss) in natural surface waters. Direct photolysis pathways of PBSA includes desulfonation and benzimidazole ring cleavage, which are probably initiated by the excited triplet state ((3)PBSA*) and radical cation (PBSA(·+)). Conversely, hydroxylation products of PBSA and 2-phenyl-1H-benzimidazole as well as their ring opening intermediates were found in nitrate-induced PBSA photolysis, suggesting the indirect photodegradation was primarily mediated by HO and followed a different mechanism.

  17. Treatment of canine idiopathic immune-mediated haemolytic anaemia with mycophenolate mofetil and glucocorticoids: 30 cases (2007 to 2011).

    PubMed

    Wang, A; Smith, J R; Creevy, K E

    2013-08-01

    To compare short-term outcome and frequency of adverse events for dogs with idiopathic immune-mediated haemolytic anaemia treated with glucocorticoids and mycophenolate mofetil vs alternate immunosuppressive protocols. A retrospective study of medical case records of dogs with immune-mediated haemolytic anaemia was conducted. Data collected included signalment, clinicopathological data, medications administered, duration of hospitalization, short-term survival and adverse events. Variables were compared between dogs treated with glucocorticoids and mycophenolate mofetil (mycophenolate mofetil group) vs dogs treated with other two-drug immunosuppressive protocols (combined group). Sixty-four cases of idiopathic immune-mediated haemolytic anaemia were identified. Two dogs were euthanased without treatment, three received glucocorticoids alone, and seven received two additional drugs. Fifty-two dogs received glucocorticoids and additional immunosuppressive medications: 30 mycophenolate mofetil, 15 cyclosporine, 6 azathioprine and 1 human immunoglobulin. There was no significant difference between the discharge rate, 30-day or 60-day survival rates between the mycophenolate mofetil and the combined groups (Fisher's exact; P=0·272, 0·518, 1·000, respectively). The sole adverse event observed in the mycophenolate mofetil group was diarrhoea (n=5). Administration of mycophenolate mofetil appears safe in dogs with idiopathic immune-mediated haemolytic anaemia. The combination of glucocorticoids and mycophenolate mofetil has similar efficacy to alternate immunosuppressive protocols used to treat this disease. © 2013 British Small Animal Veterinary Association.

  18. Inactivation of Matrix-bound MMPs by Cross-linking Agents in Acid Etched Dentin

    PubMed Central

    Scheffel, Débora Lopes Salles; Hebling, Josimeri; Scheffel, Régis Henke; Agee, Kelly A.; Turco, Gianluca; de Souza Costa, Carlos Alberto; Pashley, David H.

    2014-01-01

    Objectives Published TEM analysis of in vivo resin-dentin bonds shows that in 44 months almost 70% of collagen fibrils from the hybrid layer disappear. Matrix metalloproteinases (MMPs) play an important role in that process and are thought to be the main factor responsible for the solubitization of dentin collagen. Therefore, this study aimed to evaluate the inactivation of matrix-bound MMPs by carbodiimide (EDC) or proanthocyanidin (PA) both cross-linking agents, or the MMP-inhibitor, chlorhexidine (CHX), on acid-etched dentin using a simplified MMP assay method. Methods Dentin beams (1×1×6mm) were obtained from mid-coronal dentin of sound third molars and randomly divided into 6 groups (G) according to the dentin treatment: G1: Deionized water (control), G2: 0.1M EDC, G3: 0.5M EDC, G4: 0.5M EDC+35% HEMA, G5: 5% Proanthocyanidin (PA) and G6: 2% CHX. The beams were etched for 15s with 37% phosphoric acid, rinsed and then immersed for 60s in one of the treatment solutions. The total MMP activity of dentin was analyzed for 1 h by colorimetric assay (Sensolyte). Data were submitted to Wilcoxon non-parametric test and Mann-Whitney tests (p>0.05). Results All experimental cross-linking solutions significantly reduced MMP activity compared to control, except 0.1M EDC (53.6% ±16.1). No difference was observed between cross-linking agents and 2% CHX 0.5M EDC + 35% HEMA (92.3% ±8.0) was similar to 0.5M EDC (89.1% ±6.4), 5% PA (100.8% ±10.9) and 2% CHX (83.4% ±10.9). Conclusion Dentin treatment with cross-linking agents is effective to significantly reduce MMP activity. Mixing 0.5M EDC and 35% HEMA did not influence EDC inhibitor potential. PMID:23786610

  19. The efficacy of Mycophenolate mofetil for the treatment of Chinese Takayasu’s arteritis

    PubMed Central

    Li, Jing; Yang, Yunjiao; Zhao, Jiuliang; Li, Mengtao; Tian, Xinping; Zeng, Xiaofeng

    2016-01-01

    To investigate the therapeutic effect of mycophenolate mofetil(MMF) on Chinese Takayasu’s arteritis(TAK) patients. Thirty consecutive TAK outpatients were prospectively enrolled during 2013 to 2015. MMF combined with glucocorticoid was the primary treatment regimen. If clinical stable disease could not be reached, another traditional immunosuppressive agent could be added. All patients were evaluated and followed up every 3 months and vascular image studies by Doppler ultrasonography were repeated every 6 months. The effectiveness of MMF was defined as:(1) ESR < 20 mm/hr;(2) CRP < 10 mg/L or hs-CRP<3 mg/L;(3) stable or improved in vascular image studies;(4) clinical assessment is stable, improved or in remission;(5) the dosage of glucocorticoid could be tapered to less than 15 mg/day. ESR < 40 mm/hr, CRP < 20 mg/L or hs-CRP < 6 mg/L, but meet the other three criteria is defined as partial effectiveness. MMF alone combined with corticosteroid was effective in 12(40.0%) patients. When MMF combined with methotrexate less than 15 mg/week, the effective rate was 30.0%(9/30), including partial effective in 3 patients. When MMF combined with azathioprine 100–150 mg/day, the effective rate was 10.0%(3/30), including partial effective in 1 patient. Four patients withdrew due to side effects. Two patients failed to show response. The overall effective rate of therapy including MMF in treating TAK is 80%. PMID:27924855

  20. Fructooligosaccharide raftilose reduces the mycophenolate mofetil-induced complications: Hematological and biochemical alterations.

    PubMed

    Cheraghi, Hadi; Khaki, Zohreh; Malekinejad, Hassan; Sasani, Farhang

    2015-01-01

    Mycophenolate mofetil (MMF) is a selective inhibitor of Inosine-5'-monophosphate dehydrogenase. Gastrointestinal (GI) disturbances in immature ones are reported for MMF-induced compilations, which in the case of occurrence dose reduction is required. Thus, in the present study, the fructooligosaccharide raftilose(®) (RFT) was co-administrated with MMF to estimate the protective effect of RFT against MMF-induced GI complications. Thirty six immature male Wistar rats were divided into six groups including: Control (normal saline), RFT-treated (100 mg kg(-1)), MMF-treated (20 mg kg(-1)), MMF + LRFT (50 mg kg(-1)), MMF + MRFT (100 mg kg(-1)) and MMF + HRFT (200 mg kg(-1)) groups. The hematocrit (Hct), lymphocyte/total WBC, feces water content and pH were analyzed. Moreover, the hepatic functional tests, kidney-related biomarkers, lipid and protein profiles, total antioxidant capacity (TAC), malondialdehyde (MDA) and nitric oxide (NO) contents were assessed. Co-administration of RFT stabilized the MMF-reduced body weight. The MMF significantly diminished Hct and lymph/total WBC (p < 0.05). Only MRFT enhanced the lymphocyte/total WBC. Increased water content, no changes in feces pH, increased serum ALT and AST, no alteration in urea and mild enhancement in creatinine were demonstrated in MMF-received animals. However, RFT at low dose ameliorated the feces parameters and reduced ALT. No significant changes were demonstrated for serum lipid and protein profiles in MMF- and RFT + MMF-treated groups. The RFT enhanced the serum TAC, reduced MDA and NO contents. In conclusion, our data suggested that RFT could be considered as an effective agent to subsidize the MMF-induced clinical, hematological and biochemical disorders.

  1. Fructooligosaccharide raftilose reduces the mycophenolate mofetil-induced complications: Hematological and biochemical alterations

    PubMed Central

    Cheraghi, Hadi; Khaki, Zohreh; Malekinejad, Hassan; Sasani, Farhang

    2015-01-01

    Mycophenolate mofetil (MMF) is a selective inhibitor of Inosine-5′-monophosphate dehydrogenase. Gastrointestinal (GI) disturbances in immature ones are reported for MMF-induced compilations, which in the case of occurrence dose reduction is required. Thus, in the present study, the fructooligosaccharide raftilose® (RFT) was co-administrated with MMF to estimate the protective effect of RFT against MMF-induced GI complications. Thirty six immature male Wistar rats were divided into six groups including: Control (normal saline), RFT-treated (100 mg kg-1), MMF-treated (20 mg kg-1), MMF + LRFT (50 mg kg-1), MMF + MRFT (100 mg kg-1) and MMF + HRFT (200 mg kg-1) groups. The hematocrit (Hct), lymphocyte/total WBC, feces water content and pH were analyzed. Moreover, the hepatic functional tests, kidney-related biomarkers, lipid and protein profiles, total antioxidant capacity (TAC), malondialdehyde (MDA) and nitric oxide (NO) contents were assessed. Co-administration of RFT stabilized the MMF-reduced body weight. The MMF significantly diminished Hct and lymph/total WBC (p < 0.05). Only MRFT enhanced the lymphocyte/total WBC. Increased water content, no changes in feces pH, increased serum ALT and AST, no alteration in urea and mild enhancement in creatinine were demonstrated in MMF-received animals. However, RFT at low dose ameliorated the feces parameters and reduced ALT. No significant changes were demonstrated for serum lipid and protein profiles in MMF- and RFT + MMF-treated groups. The RFT enhanced the serum TAC, reduced MDA and NO contents. In conclusion, our data suggested that RFT could be considered as an effective agent to subsidize the MMF-induced clinical, hematological and biochemical disorders. PMID:26973768

  2. Down-regulation of multiple low dose streptozotocin-induced diabetes by mycophenolate mofetil

    PubMed Central

    MAKSIMOVIC-IVANIC, D; TRAJKOVIC, V; MILJKOVIC, DJ; STOJKOVIC, M MOSTARICA; STOSIC-GRUJICIC, S

    2002-01-01

    The new immunosuppressive agent mycophenolate mofetil (MMF) has been shown recently to exert a protective effects in certain animal models of autoimmunity, including diabetes in diabetes-prone bio-breeding (BB) rats. In the present study, the immunomodulatory potential of MMF was investigated in autoimmune diabetes induced by multiple low doses of streptozotocin (MLD-STZ) in genetically susceptible DA rats 20 mg STZ/kg body weight (b.w.) for 5 days] and CBA/H mice (40 mg STZ/kg b.w. for 5 days). In both species, short time treatment of animals with MMF (25 mg/kg) during the early development of the disease, as well as continuous MMF treatment, prevented the appearance of hyperglycaemia and inflammatory infiltrates in the pancreatic tissue. Moreover, clinical manifestations of diabetes were suppressed by application of the drug after the onset of clinical symptoms. Treatment with guanosine (1 mg/kg) in parallel with MMF completely reversed MMF activity in vivo, indicating that inhibition of inosine monophosphate dehydrogenase (IMPDH) was responsible for the observed suppressive effects. MMF-mediated protection from diabetes correlated with reduced ex vivo spontaneous spleen mononuclear cell (MNC) proliferation and defective adhesive cell interactions. MMF-treated animals also had lower local production of IFN-γ, as well as IL-12 and nitric oxide (NO) production by peripheral tissues (spleen and peritoneal cells), compared to that in control diabetic groups, while IL-10 level was elevated. Together, these data demonstrate that MMF interferes with autoimmune process in streptozotocin-induced diabetes at multiple levels, including lymphocyte proliferation and adhesion, as well as pro/anti-inflammatory cytokine balance. PMID:12165076

  3. Dynamic wettability of wood surface modified by acidic dyestuff and fixing agent

    NASA Astrophysics Data System (ADS)

    Wei, Shuangying; Shi, Junyou; Gu, Jiyou; Wang, Di; Zhang, Yanhua

    2012-01-01

    Acidic dyestuffs can bring brilliant colors to the wood and fixing agents can avoid the color loss. They could change the surface wettability of wood, which impact the gluing process of veneers. In condition of the higher moisture content of wood, the rare veneers, the veneers dyed by acidic dyestuffs and the dyed veneers fixed by Chitosan were glued respectively by one-component wet-curing isocyanate adhesive and the contact angles (θ) of the different gluing interfaces were measured. The dynamic wettability of these gluing interfaces was characterized by both the contact angle θ and the spreading-penetration parameter (K) calculated by θ. The results showed that the θ-values decreased significantly with the extension of time and the initial contact angles (θi) decreased with the moisture contents of veneers increasing, but the variation of the balance contact angles (θe) was reversed with θi. When the moisture contents of veneers were same, the variation of θ of the rare veneers was minimal and the variation of θ of the fixed veneers was maximal. The K-values of these gluing interfaces all decreased significantly with the moisture contents of veneers increasing, but the variations of K were different. The wetting model describing the dynamic wetting process was established on the basis of these variations.

  4. Synthesis and biological evaluation of pyrazolylthiazole carboxylic acids as potent anti-inflammatory-antimicrobial agents.

    PubMed

    Khloya, Poonam; Kumar, Satish; Kaushik, Pawan; Surain, Parveen; Kaushik, Dhirender; Sharma, Pawan K

    2015-03-15

    Current Letter presents design, synthesis and biological evaluation of a novel series of pyrazolylthiazole carboxylates 1a-1p and corresponding acid derivatives 2a-2p. All 32 novel compounds were tested for their in vivo anti-inflammatory activity by carrageenan-induced rat paw edema method as well as for in vitro antimicrobial activity. All the tested compounds exhibited excellent AI activity profile. Three compounds 1p (R=Cl, R(1)=Cl), 2c (R=H, R(1)=F) and 2n (R=Cl, R(1)=OCH3) were identified as potent anti-inflammatory agents exhibiting edema inhibition of 93.06-89.59% which is comparable to the reference drug indomethacin (91.32%) after 3h of carrageenan injection while most of the other compounds displayed inhibition ⩾80%. In addition, pyrazolylthiazole carboxylic acids (2a-2p) also showed good antimicrobial profile. Compound 2h (R=OCH3, R(1)=Cl) showed excellent antimicrobial activity (MIC 6.25μg/mL) against both Gram positive bacteria comparable with the reference drug ciprofloxacin (MIC 6.25μg/mL).

  5. Solubilizing properties of new surface-active agents, products of catalytic oxyethylation of cholic acid.

    PubMed

    Kołodziejczyk, Michał Krzysztof; Nachajski, Michal Jakub; Lukosek, Marek; Zgoda, Marian Mikołaj

    2013-01-01

    Solubilizing properties of aqueous solutions of a series of surface-active agents, products of oxyethylation of cholic acid, were examined in the present study. The content of oxyethylated segments determined by means of the 1H NMR method enabled the verification of the molecular mass of surfactants along with the calculation of the structural hydrophilic-lipophilic balance (HLB), the solubility parameter delta1/2, and the required solubility level of balance HLB(R). Viscosimetric measurements enabled the calculation of the limiting viscosity number, the content-average molecular mass, the effective volume, the hydrodynamic radius of the surfactant micelle and their equilibrium adducts with rutin, diclofenac and loratadine (BCS Class II and III). By means of the spectrophotometric method (UV) the amount of the solubilized diclofenac, loratadine and rutin (rutoside) was determined in the equilibrium system (saturated solution) in the environment of aqueous solutions of cholic acid derivatives of n(TE) = 20-70. The obtained results serve as a basis for determining the solubilization mechanism of lipophilic therapeutic products and indirectly for estimating the influence of the above process on pharmaceutical as well as biological availability of a micellar adduct from model drug forms (Lindbladt lithogenolitic index).

  6. Safety of oral and intravenous mycophenolate mofetil in healthy cats.

    PubMed

    Slovak, Jennifer E; Villarino, Nicolas F

    2017-02-01

    Objectives The aim of this study was to evaluate the safety and clinical effects of intravenous (IV) and oral mycophenolate mofetil (MMF) in healthy cats. Methods A total of 24 healthy adult cats weighing >3.5 kg were either administered IV MMF (over a 2 h infusion) or oral MMF. The dosages used were as follows: 5 mg/kg IV once (n = 2), 10 mg/kg q12h IV for 1 day (n = 1), 20 mg/kg q12h IV for 1 day (n = 6) and 10 mg/kg q12h IV for 3 days (n = 5). Blood was collected from each cat at intervals of up to 12 h from the last dose for analysis purposes. Oral MMF was given at 10 mg/kg q12h for 7 days (n = 3), 15 mg/kg q12h for 7 days (n = 3) and 15 mg/kg q8h for 7 days (n = 4). Results Side effects to MMF were minimal. There was no anorexia or vomiting noted in any of the cats during or after IV medication administration. Only 4/14 cats had diarrhea from 12-48 h after IV administration. There was hyporexia in 1/10 cats given oral MMF and no vomiting noted. In 5/10 cats given oral MMF, there was diarrhea between days 2 and 7 of the study. Conclusions and relevance Cats tolerate MMF at an IV dose of 10 mg/kg q12h for 3 days and an oral dose ⩽15 mg/kg q12h for up to 7 days. There seems to be a dose-dependent incidence of gastrointestinal side effects. MMF may be a useful alternative immunosuppressant to be considered for use in some cats.

  7. Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis

    PubMed Central

    Appel, Gerald B.; Contreras, Gabriel; Dooley, Mary Anne; Ginzler, Ellen M.; Isenberg, David; Jayne, David; Li, Lei-Shi; Mysler, Eduardo; Sánchez-Guerrero, Jorge; Solomons, Neil; Wofsy, David

    2009-01-01

    Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m2 in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis. PMID:19369404

  8. Frailty, Mycophenolate Reduction, and Graft Loss in Kidney Transplant Recipients

    PubMed Central

    McAdams-DeMarco, Mara A.; Law, Andrew; Tan, Jingwen; Delp, Cassandra; King, Elizabeth A.; Orandi, Babak; Salter, Megan; Alachkar, Nada; Desai, Niraj; Grams, Morgan; Walston, Jeremy; Segev, Dorry L.

    2014-01-01

    Background: Mycophenolate mofetil (MMF) side effects often prompt dose reduction or discontinuation, and this MMF dose reduction (MDR) can lead to rejection and possibly graft loss. Unfortunately, little is known about what factors might cause or contribute to MDR. Frailty, a measure of physiologic reserve, is emerging as an important, novel domain of risk in kidney transplantation (KT) recipients. We hypothesized that frailty, an inflammatory phenotype, might be associated with MDR. Methods: We measured frailty (shrinking, weakness, exhaustion, low activity, and slowed walking speed), other patient and donor characteristics, longitudinal MMF doses, and graft loss in 525 KT recipients. Time-to-MDR was quantified using an adjusted Cox proportional hazards model. Results: By 2 years post-transplant, 54% of frail recipients and 45% of non-frail recipients experienced MDR; by 4 years, incidence was 67% and 51%. Frail recipients were 1.29-times (95%CI:1.01-1.66; P=0.04) more likely to experience MDR, as were deceased donor recipients (aHR=1.92, 95%CI:1.44-2.54, P<0.001) and older adults (age≥65 vs. <65; aHR=1.47, 95%CI:1.10-1.96, P=0.01). MDR was independently associated with a substantially increased risk of death-censored graft loss (aHR=5.24, 95%CI:1.97-13.98, P=0.001). Conclusion: A better understanding of risk factors for MMF intolerance might help in planning alternate strategies to maintain adequate immunosuppression and prolong allograft survival. PMID:25393156

  9. Safety evaluation of a potential ablation agent-hydrochloric acid in the rabbits' model.

    PubMed

    Yao, Wang; Gu, Yang-Kui; Wang, Jian; Gao, Fei; Liu, Wan-Li; Huang, Jin-Hua

    2014-10-01

    To evaluate the safety of a potential ablation agent-hydrochloric acid (HCl), which may apply to treat hepatocellular carcinoma (HCC). Eighty adult New Zealand rabbits were divided into five groups of equal size (n=16), i.e., untreated group, normal saline (NS) control group, 10% HCl group, 20% HCl group and 30% HCl group. Each group was divided into two subgroups: ten rabbits for two-week toxicology study at the time points of hours 0, 0.25, 0.5, 1, 3, 6 and days 2, 7, 14 and six rabbits for imaging and histopathology study at the time points of days 2, 7 and 14. In toxicology study we evaluated the safety of HCl from arterial blood gas status, hematology and hepatic and renal functions. In imaging and histopathology study, we observed the relationship between the sizes of lesion and the concentration of HCl, as well as extension of necrosis and concentration of HCl. In this study we also observed the microcosmic and macroscopic lesion that caused by HCl. In general condition, food, water consumption and body weight decreased notablely during the beginning of the experiment. In toxicology study, alanine aminotransferase, aspartate aminotransferase and lactic acid contents were higher in the 30% hydrochloric acid group than in other groups (P<0.005), all test items returned to normal on day 14. Imaging and histopathology study showed that 30% HCl caused larger lesion area than other HCl concentration and the necrosis that caused by HCl was complete. There was also a close relationship between the size of minor damaged area and HCl concentration. The 30% HCl caused larger minor damaged area than other HCl concentration. Because the damaged area was surrounded by a layer of fiber tissue, the lesion area became larger at days 7 and 14 time points. This study also demonstrated that the adjacent organs had no obvious damage, and all the damaged areas were limited in the liver. HCl is a safe ablation agent for local injection in the liver. HCl at a lower concentration is

  10. Monitoring of mycophenolate mofetil metabolites in children with nephrotic syndrome and the proposed novel target values of pharmacokinetic parameters.

    PubMed

    Sobiak, Joanna; Resztak, Matylda; Ostalska-Nowicka, Danuta; Zachwieja, Jacek; Gąsiorowska, Karolina; Piechanowska, Wiktoria; Chrzanowska, Maria

    2015-09-18

    The aim of the study was to estimate target values of mycophenolate mofetil (MMF) pharmacokinetic parameters in children with proteinuric glomerulopathies by calculating the pharmacokinetic parameters of MMF metabolites (mycophenolic acid [MPA], free MPA [fMPA] and MPA glucuronide [MPAG]) and assessing their relation to proteinuria recurrence. One hundred and sixty-eight blood samples were collected from children, aged 3-18 years, diagnosed with nephrotic syndrome or lupus nephritis. MMF metabolites concentrations were examined before drug administration (Ctrough) and up to 12h afterward employing high-performance liquid chromatography. Dose-normalized MPA Ctrough and area under the concentration-time curve from 0 to 12h (AUC12) were within 0.29-6.47 μg/mL/600 mg/m(2) and 9.97-105.52 μg h/mL/600 mg/m(2), respectively. MPA Ctrough was twofold lower (p=0.024) in children with proteinuria recurrence. MPA, fMPA and MPAG concentrations correlated positively to respective AUC12. It may be suggested MMF metabolites monitoring in children with proteinuric glomerulopathies is justified by MPA Ctrough<2 μg/mL in patients at risk of the proteinuria recurrence. Such a recurrence is most probably caused by not sufficient MPA concentration during proteinuric glomerulopathies treatment. MPA Ctrough>3 μg/mL may be considered as an efficient one to avoid proteinuria recurrence. Finally, MPA target AUC12 should exceed 60 μg h/mL to ensure the safe and effective treatment in children with nephrotic syndrome, however, the upper limit is still to be established. Copyright © 2015 Elsevier B.V. All rights reserved.

  11. Development and validation of limited sampling strategy equation for mycophenolate mofetil in children with systemic lupus erythematosus

    PubMed Central

    Prabha, R.; Mathew, B. S.; Jeyaseelan, V.; Kumar, T. S.; Agarwal, I.; Fleming, D. H.

    2016-01-01

    The aim of this study was to establish a limited sample strategy (LSS) to predict the mycophenolic acid (MPA) area under the curve (AUC)(0-12) in children with systemic lupus erythematosus (SLE). Three months after initiation of mycophenolate mofetil (MMF) 26 children with SLE presented for therapeutic drug monitoring of MPA. On the day of the test, 10 specimens were collected, analyzed, and MPA AUC(0-12) was calculated. Using step-wise regression analysis, LSS equations were developed. Using bootstrap validation, the predictive performance was calculated. The measured mean (standard deviation) for the trough concentration and AUC(0-12) were 2.55 (1.57) μg/ml and 62.6 (21.67) mg.h/L, respectively. The range of trough concentrations and AUC(0-12) were 0.7–5.54 μg/ml and 22.1–104.8 mg.h/L, respectively. The interindividual variability (%CV) for dose normalized AUC(0-12) and dose normalized Ctrough was 46.5% and 61.1%, respectively. The correlation between the concentrations at the different time points and MPA AUC(0-12) ranged from 0.05 (1.5 h) to 0.56 (4 h). Two LSS equations that included 4 or 5 time points up to 3 h were developed and validated. The 4 point LSS had a correlation (R2) of 0.88 and the 5 point LSS an R2 of 0.87. With respect to the 4 point and 5 point MPA LSS AUC(0-12), the bias was 1.92% and 1.96%, respectively, and the imprecision was 11.24% and 11.28%, respectively. A 4 point LSS which concludes within 3 h after the administration of the MMF dose was developed and validated, to determine the MPA AUC(0-12) in children with SLE. PMID:27942171

  12. Synthesis of Sugar-Boronic Acid Derivatives: A Class of Potential Agents for Boron Neutron Capture Therapy.

    PubMed

    Imperio, Daniela; Del Grosso, Erika; Fallarini, Silvia; Lombardi, Grazia; Panza, Luigi

    2017-04-07

    To date, sugar analogues that contain boronic acids as substitutes for hydroxyl groups are a class of compounds nearly unknown in the literature. The challenging synthesis of two sugar-boronic acid analogues is described, and data are retrieved on their solution behavior, stability, and toxicity. As these compounds were expected to mimic the behavior of carbohydrates, they were tested in regards to their future development as potential boron neutron capture therapy agents.

  13. Use of Magnetic Bead Resin and Automated Liquid Handler Extraction Methods to Robotically Isolate Nucleic Acids of Biological Agent Simulates

    DTIC Science & Technology

    2003-09-01

    allows the ABATS to use a CORE system to link the Applied Biosystems ABI Prism® 7900HT thermocycler and the ORIGEN ® M8 Analyzer (IGEN, Gaithersburg, MD) to...measures pertaining to nucleic acid extraction of two accepted biological agent simulants in an effort to reduce labor and speed analysis of unknown...sites. As part of the labor reduction effort, we have developed a hybrid protocol for extraction of nucleic acids from environmental samples that can

  14. Clinical Comparison of Two Contrast Agents for Oral Cholecystography: Radiologic Efficacy and Drug Safety of Iopanoic Acid and Iopronic Acid 1

    PubMed Central

    Hedlund, Laurence; Putman, Charles E.; Burrell, Morton

    1979-01-01

    Oral doses of either iopronic acid (4.5 g Oravue, Squibb) or iopanoic acid (3 g Telepaque, Winthrop) were given to 98 patients requiring cholecystography. Radiographs were taken 13 to 16 hours after treatment showed good to excellent gallbladder opacification in 44 percent of patients after the first dose of iopronic acid and in an additional 29 percent after a second dose. Similar opacification occurred in 42 percent of patients after the first dose of iopanoic acid and in 34 percent after a second dose. Drug-related abnormalities in blood and urine tests occurred about equally in both groups and one patient in each group exhibited a clinically adverse reaction (diarrhea). Thus, the performance (radiographic efficacy and drug safety) of the new contrast agent, iopronic acid, was similar to a widely used drug, iopanoic acid. PMID:380184

  15. Dumb and dumber--the potential waste of a useful antistaphylococcal agent: emerging fusidic acid resistance in Staphylococcus aureus.

    PubMed

    Howden, Benjamin P; Grayson, M Lindsay

    2006-02-01

    Fusidic acid has activity against a range of pathogens but has mainly been used to treat staphylococcal infections. Fusidic acid monotherapy, especially topical preparations, has been strongly associated with the emergence of fusidic acid resistance among both methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus. Key resistance determinants include mutations in the fusA gene, which encodes elongation factor G, and plasmid-mediated resistance (i.e., acquisition of resistance gene fusB). Clonal outbreaks of fusidic acid-resistant S. aureus have been noted throughout the United Kingdom and Europe, such that the efficacy of fusidic acid is threatened. Fusidic acid in combination with other agents, such as rifampicin, has proven effective for difficult-to-treat MRSA infections and provides a convenient oral alternative to oxazolidinones. Ensuring that systemic fusidic acid is always used in combination and that the use of topical fusidic acid is either abolished or restricted will be vital if we are to prevent the loss of this potentially useful agent.

  16. Investigating the use of coupling agents to improve the interfacial properties between a resorbable phosphate glass and polylactic acid matrix.

    PubMed

    Hasan, Muhammad Sami; Ahmed, Ifty; Parsons, Andrew J; Rudd, Chris D; Walker, Gavin S; Scotchford, Colin A

    2013-09-01

    Eight different chemicals were investigated as potential candidate coupling agents for phosphate glass fibre reinforced polylactic acid composites. Evidence of reaction of the coupling agents with phosphate glass and their effect on surface wettability and glass degradation were studied along with their principle role of improving the interface between glass reinforcement and polymer matrix. It was found that, with an optimal amount of coupling agent on the surface of the glass/polymer, interfacial shear strength improved by a factor of 5. Evidence of covalent bonding between agent and glass was found for three of the coupling agents investigated, namely: 3-aminopropyltriethoxysilane; etidronic acid and hexamethylene diisocyanate. These three coupling agents also improved the interfacial shear strength and increased the hydrophobicity of the glass surface. It is expected that this would provide an improvement in the macroscopic properties of full-scale composites fabricated from the same materials which may also help to retain these properties for the desired length of time by retarding the breakdown of the fibre/matrix interface within these composites.

  17. Stable renal transplant recipients can be safely converted from MMF to enteric-coated mycophenolate sodium tablets: Interim results of a multicenter Latin American study.

    PubMed

    Abbud-Filho, M; Girón, F; Hernández, E; Juarez, F; Liendo, C; Novoa, P; Toledo, M

    2004-01-01

    Enteric-coated mycophenolate sodium (EC-MPS) is designed to reduce mycophenolate acid (MPA)-related upper gastrointestinal (GI) adverse events (AEs). A multicenter, open-label, Latin American study in stable renal transplant patients is ongoing to assess the safety of the conversion from mycophenolate mofetil (MMF) to EC-MPS. An interim analysis was performed when 93 patients had completed 3 months. Prior to conversion, they had received MMF at a dose of 2 g/d, with the exception of eight adult patients who were receiving an average daily dose of 1.25 g. All adult patients were converted to EC-MPS (1.44 g/d; 0.450 g/m(2) bid for children). After conversion, the reported total incidence of AEs was 40.9%, including 28% infections, 1.1% hematologic, 19.4% GI, including 10.8% upper-GI AE (all mild) and 5.4% diarrhea. No patient discontinued the study medication due to adverse events. Only six patients (6%) required a dose adjustment. There were no episodes of acute rejection, death, or graft loss. During the period of analysis, the conversion from MMF to EC-MPS was safe, the enteric-coated tablet formulation prevented release of MPA in the upper GI tract, and only one patient had to reduce the dose due to an upper GI AE, concomitant with diarrhea. EC-MPS offers transplant physicians and their patients an alternative MPA therapy that is as effective and safe as MMF, but in a formulation that may provide GI tolerability benefits.

  18. In vitro studies on ultrasmall superparamagnetic iron oxide nanoparticles coated with gummic acid for T2 MRI contrast agent

    PubMed Central

    Rabias, I.; Pratsinis, H.; Drossopoulou, G.; Fardis, M.; Maris, T.; Boukos, N.; Tsotakos, N.; Kletsas, D.; Tsilibary, E.; Papavassiliou, G.

    2007-01-01

    Ultrasmall superparamagnetic iron oxide nanoparticles coated with gummic acid have been investigated as possible constituents of aqueous ferrofluids for biomedical applications and especially for MRI contrast agent. The structural characteristics and the size of the nanoparticles have been analyzed as well as the magnetic properties. In order to evaluate any possible capabilities as a contrast agent, the relaxation time, T2, of hydrogen protons in the colloidal solutions of nanoparticles have been measured in order to gain information on the relaxation behavior compared to other MRI contrast agents. The in vitro cytotoxicity of the obtained magnetic nanoparticles of iron oxide coated with gummic acid was investigated by two separate methods (MTT and FACS analysis) and by using three different normal and transformed cell lines. Our results showed that the synthesized nanoparticles had no toxic effect on any of the cell lines used. PMID:19693403

  19. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer

    PubMed Central

    Vasudevan, Anita; Yu, Yingjie; Banerjee, Sanjeev; Woods, James; Farhana, Lulu; Rajendra, Sindhu G.; Patel, Aamil; Dyson, Gregory; Levi, Edi; Maddipati, Krishna Rao; Majumdar, Adhip P.N.; Nangia-Makker, Pratima

    2014-01-01

    Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer (CRC), are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs) underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is un-explored. The primary objectives of this investigation are to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (b) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemo-resistant; CR) colon cancer cells, highly enriched in CSCs, were utilized for this study. While EPA alone was effective, combination of EPA and FuOx was more potent in (a) inhibiting cell growth, colonosphere formation and sphere-forming frequency, (b) increasing sphere disintegration, (c) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (d) decreasing pro-inflammatory metabolites in mice. Additionally, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization and transcriptional activity by EPA suggests a role for PTEN/Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring CRC. PMID:25193342

  20. Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer.

    PubMed

    Vasudevan, Anita; Yu, Yingjie; Banerjee, Sanjeev; Woods, James; Farhana, Lulu; Rajendra, Sindhu G; Patel, Aamil; Dyson, Gregory; Levi, Edi; Maddipati, Krishna Rao; Majumdar, Adhip P N; Nangia-Makker, Pratima

    2014-11-01

    Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer, are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSC/CSLC), underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is unexplored. The primary objectives of this investigation are (i) to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (ii) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemoresistant; CR) colon cancer cells, highly enriched in CSCs, were used for this study. Although EPA alone was effective, combination of EPA and FuOx was more potent in (i) inhibiting cell growth, colonosphere formation, and sphere-forming frequency, (ii) increasing sphere disintegration, (iii) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (iv) decreasing proinflammatory metabolites in mice. In addition, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization, and transcriptional activity by EPA suggests a role for the PTEN-Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring colorectal cancer.

  1. Efficacy and safety of a conversion from the original tacrolimus and mycophenolate mofetil to the generics Tacpan® and Mowel® after liver transplantation

    PubMed Central

    Vollmar, Johanna; Bellmann, Maren Christina; Darstein, Felix; Hoppe-Lotichius, Maria; Mittler, Jens; Heise, Michael; Rüttger, Bernd; Weyer, Veronika; Zimmermann, Anca; Lang, Hauke; Galle, Peter R; Zimmermann, Tim

    2015-01-01

    Background Expensive pharmaceuticals are a major reason for cost intensive health care systems. Long-term immunosuppressive therapy plays a relevant role after organ transplantation. Patents of original drugs have expired and cheaper products are available. Little data are available regarding efficacy and safety of generic immunosuppressive agents. Methods In this prospective study, 25 patients, who were clinically stable for a minimum of 2 years after liver transplantation, were converted from the original formulations of tacrolimus (TAC) and mycophenolate mofetil to the generics Tacpan® (TAP) and Mowel® (MOW). Patients were followed-up for 6 months. Results were compared retrospectively to 25 age- and sex-matched controls treated with the original brands. Results In the matched-pair analysis of TAC trough level/dose ratio, no significant difference was found between TAP/MOW and TAC/mycophenolate mofetil groups. No acute rejection occurred in either group. In total, 17 patients reported mild side effects in the TAP/MOW group. The most common side effects were gastrointestinal symptoms. Intra-individual analysis of costs revealed a considerable cost reduction in the TAP/MOW group (in median 25.03%; P<0.001). Conclusion In summary, the use of the generics TAP/MOW is effective and seems to be safe and cost-efficient in stable liver-transplantation patients. PMID:26604701

  2. Mycophenolate mofetil versus azathioprine for maintenance treatment of lupus nephritis.

    PubMed

    Kaballo, Babikir G; Ahmed, Ahmed Elias; Nur, Musa Mohammed; Khalid, Ismail Osman; Abu-Aisha, Hasan

    2016-01-01

    To compare the efficacy of mycophenolate mofetil (MMF) with that of azathioprine (AZA) drugs in the maintenance therapy of lupus nephritis (LN) patients, we studied 81 Sudanese patients with LN (32 in Class III, 34 in Class IV, and 15 in combined Class V + IV of the ISN/RPS 2003 Classification). All patients received induction therapy consisting of monthly intravenous pulse doses of cyclophosphamide (CYC) (500 mg/m 2 of body-surface area) for six months, plus three consecutive pulses of intravenous methylprednisolone 15 mg/kg/day of body weight (maximum 500 mg). Subsequently, 41 (50.6%) patients were randomized into a group that received oral MMF (22 mg/kg/day), and 40 (49.4%) patients randomized to a group that received oral AZA (2 mg/kg/day). All patients initially received oral prednisone (1 mg/kg of body weight daily) for four weeks. The baseline characteristics of the two groups were similar. Total remission rate was 75.3% (80.5% in MMF and 70% in AZA), complete remission rate of 54.3% (56.1% with MMF and 52.5% with AZA), and a partial remission rate of 21% (24.4% with MMF and 17.5% with AZA) over 29 months. During maintenance therapy, six patients died (four in the AZA group and two in the MMF group), and end-stage renal disease (ESRD) developed in five patients (three in the AZA group and two in the MMF group). During the 36-months of the study, both groups had comparable event-free survival rate for the composite end point of death or ESRD and rate of relapse-free survival. Furthermore, both groups had no significant differences in terms of frequency of hospitalization, amenorrhea, infection, nausea, and vomiting. We conclude that our study showed that short-term therapy with intravenous CYC followed by maintenance therapy with oral MMF or AZA had similar efficacy and safety for the treatment of patients with moderate to severe LN.

  3. Development and Optimization of a Doxorubicin Loaded Poly Lactic Acid Contrast Agent for Ultrasound Directed Drug Delivery

    PubMed Central

    Eisenbrey, J.R.; Burstein, O. Mualem; Kambhampati, R.; Forsberg, F.; Liu, J-B.; Wheatley, M.A.

    2010-01-01

    An echogenic, intravenous drug delivery platform is proposed in which an encapsulated chemotherapeutic can travel to a desired location and drug delivery can be triggered using external, focused ultrasound at the area of interest. Three methods of loading poly lactic acid (PLA) shelled ultrasound contrast agents (UCA) with doxorubicin are presented. Effects on encapsulation efficiency, in vitro enhancement, stability, particle size, morphology and release during UCA rupture are compared by loading method and drug concentration. An agent containing doxorubicin within the shell was selected as an ideal candidate for future hepatocellular carcinoma studies. The agent achieved a maximal drug load of 6.2 mg Dox/g PLA with an encapsulation efficiency of 20.5%, showed a smooth surface morphology and tight size distribution (poly dispersity index = 0.309) with a peak size of 1865 nm. Acoustically, the agent provided 19 dB of enhancement in vitro at a dosage of 10 µg/ml, with a half life of over 15 mins. In vivo, the agent provided ultrasound enhancement of 13.4 ± 1.6 dB within the ascending aorta of New Zealand rabbits at a dose of 0.15 ml/kg. While the drug-incorporated agent is thought to be well suited for future drug delivery experiments, this study has shown that agent properties can be tailored for specific applications based on choice of drug loading method. PMID:20060024

  4. Can we consider zoledronic acid a new antitumor agent? Recent evidence in clinical setting.

    PubMed

    Santini, Daniele; Virzi, Vladimir; Fratto, Maria Elisabetta; Bertoldo, Francesco; Sabbatini, Roberto; Berardi, Rossana; Calipari, Nicola; Ottaviani, Davide; Ibrahim, Toni

    2010-02-01

    New emerging data suggest that bisphosphonates may exert antitumor properties. Preclinical studies have demonstrated that zoledronic acid (ZA) can induce direct and indirect antitumor activities such as inhibition of angiogenesis, invasion and adhesion of tumor cells, and overall tumor progression, stimulation of adoptive and innate immunity and emerging evidence suggests that the use of these agents may prevent the development of skeletal and extra skeletal metastases. This review will critically describe the new growing evidence of antitumor activity exerted by bisphosphonates in cancer patients, both in metastatic disease and in the adjuvant setting. The effects of bisphosphonates on survival in metastatic cancer patients will be described and evidence from retrospective analyses and prospective studies will be critically reported. The early evidence from prospective analyses of survival impact by ZA in the adjuvant setting in breast cancer will be discussed together with the recently published results of the ABCSG-12 study. A new "era" for bisphosphonates in the oncological setting is opening. The clinical data that will be reported in this review represent the first step in a path that will conduct us to explore new horizons in the field of adjuvant and metastatic cancer therapies.

  5. Potassium fulvate as co-interpenetrating agent during graft polymerization of acrylic acid from cellulose.

    PubMed

    Ghazy, Mohamed B M; El-Hai, Farag Abd; Mohamed, Magdy F; Essawy, Hisham A

    2016-10-01

    Grafting polymerization of acrylic acid onto cellulose in presence of potassium fulvate (KF) as a co-interpenetrating agent results enhanced water sorption compared to materials prepared similarly in its absence. The insertion of potassium fulvate (KF) did not affect the grafting process and is thought to proceed in parallel to the graft polymerization via intensive polycondensation reactions of its function groups (-COOH and OH) with COOH of the monomer and OH groups of cellulose. The combination of graft copolymerization and polycondensation reactions is assumed to produce interpenetrating network structure. Fourier transform infrared (FTIR) confirmed successful incorporation within the network structure which is an evidence for formation of interpenetrating network. The obtained structures showed homogeneous uniform surface as revealed by scanning electron microscopy (SEM). The obtained superabsorbent possessed high water absorbency 422 and 48.8g/g in distilled water and saline (0.9wt.% NaCl solution), respectively, and enhanced water retention even at elevated temperatures as revealed by thermogravimetric analysis (TGA). This could be explained by the high content of hydrophilic groups. The new superabsorbents proved to be efficient devices for controlled release of fertilizers which expands their use in agricultural applications.

  6. Hyaluronic acid-functionalized single-walled carbon nanotubes as tumor-targeting MRI contrast agent

    PubMed Central

    Hou, Lin; Zhang, Huijuan; Wang, Yating; Wang, Lili; Yang, Xiaomin; Zhang, Zhenzhong

    2015-01-01

    A tumor-targeting carrier, hyaluronic acid (HA)-functionalized single-walled carbon nanotubes (SWCNTs), was explored to deliver magnetic resonance imaging (MRI) contrast agents (CAs) targeting to the tumor cells specifically. In this system, HA surface modification for SWCNTs was simply accomplished by amidation process and could make this nanomaterial highly hydrophilic. Cellular uptake was performed to evaluate the intracellular transport capabilities of HA-SWCNTs for tumor cells and the uptake rank was HA-SWCNTs> SWCNTs owing to the presence of HA, which was also evidenced by flow cytometry. The safety evaluation of this MRI CAs was investigated in vitro and in vivo. It revealed that HA-SWCNTs could stand as a biocompatible nanocarrier and gadolinium (Gd)/HA-SWCNTs demonstrated almost no toxicity compared with free GdCl3. Moreover, GdCl3 bearing HA-SWCNTs could significantly increase the circulation time for MRI. Finally, to investigate the MRI contrast enhancing capabilities of Gd/HA-SWCNTs, T1-weighted MR images of tumor-bearing mice were acquired. The results suggested Gd/HA-SWCNTs had the highest tumor-targeting efficiency and T1-relaxivity enhancement, indicating HA-SWCNTs could be developed as a tumor-targeting carrier to deliver the CAs, GdCl3, for the identifiable diagnosis of tumor. PMID:26213465

  7. The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections.

    PubMed

    Korde, Amit S; Sullivan, Patrick G; Maragos, William F

    2005-10-01

    It is now generally accepted that excitotoxic cell death involves bioenergetic failure resulting from the cycling of Ca2+ and the generation of reactive oxygen species (ROS) by mitochondria. Both Ca2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Deltapsi(m)) that results from the proton gradient that is generated across the inner membrane. Mitochondrial uncoupling refers to a condition in which protons cross the inner membrane back into the matrix while bypassing the ATP synthase. As a consequence of this "short-circuit," there is a reduction in Deltapsi(m). We have previously demonstrated that animals treated with the classic uncoupling agent 2,4-dinitrophenol (DNP) show significant protection against brain damage following striatal injections of the NMDA agonist quinolinic acid (QA). In an effort to elucidate the mechanism of neuroprotection, we have assessed the effects of DNP on several parameters of mitochondrial function caused by QA. The results presented herein demonstrate that treatment with DNP attenuates QA-induced increases in mitochondrial Ca2+ levels and ROS formation and also improves mitochondrial respiration. Our findings indicate that DNP may confer protection against acute brain injury involving excitotoxic pathways by mechanisms that maintain mitochondrial function.

  8. Evaluating the efficacy of amino acids as CO2 capturing agents: a first principles investigation.

    PubMed

    Hussain, M Althaf; Soujanya, Yarasi; Sastry, G Narahari

    2011-10-01

    Comprehension of the basic concepts for the design of systems for CO2 adsorption is imperative for increasing interest in technology for CO2 capture from the effluents. The efficacy of 20 naturally occurring amino acids (AAs) is demonstrated as the most potent CO2 capturing agents in the process of chemical absorption and physisorption through a systematic computational study using highly parametrized M05-2X/6-311+G(d,p) method. The ability of AAs to bind CO2 both in the noncovalent and covalent fashion and presence of multiple adsorption sites with varying magnitude of binding strengths in all 20 AAs makes them as most promising materials in the process of physisorption. The binding energies (BEs) estimating the strength of noncovalent interaction of AAs and CO2 are calculated and results are interpreted in terms of the nature and strength of the various types of cooperative interactions which are present. The study underlines the possibility to engineer the porous solid materials with extended networks by judiciously employing AA chains as linkers which can substantially augment their efficacy. Results show that a significant increase in the CO2···AA affinity is achieved in the case of AAs with polar neutral side chains. Furthermore, the study proposes AAs as effective alternatives to alkanolamines in chemical dissolution of CO2.

  9. In vitro release of organophosphorus acid anhydrolase from functionalized mesoporous silica against nerve agents

    PubMed Central

    Chen, Baowei; Shah, Saumil S.; Shin, Yongsoon; Lei, Chenghong; Liu, Jun

    2011-01-01

    We report here that under different physiological conditions, biomolecular drugs can be stockpiled in a nanoporous support and afterwards can be instantly released when needed for acute responses, and the biomolecular drug molecules can also be gradually released from the nanoporous support over a long time for a complete recovery. Organophosphorus acid anhydrolase (OPAA) was spontaneously and largely entrapped in functionalized mesoporous silica (FMS) due to the dominant electrostatic interaction. The OPAA-FMS composite exhibited a burst release in pH 9.0, NaHCO3-Na2CO3 buffer system and a gradual release in pH 7.4, simulated body fluid. The binding of OPAA to NH2-FMS can result in less Trp exposure of OPAA molecules to aqueous environment. The bound OPAA in FMS displayed lower activity than the free OPAA in solution prior to the enzyme entrapment. However, the released enzyme still displayed the native conformational structure and the same high enzymatic activity as that prior to the enzyme entrapment. The in vitro results in the rabbit serum demonstrate that both OPAA-FMS and the released OPAA may be used as the medical measures against the organophosphorus nerve agents. PMID:22019765

  10. Competitive FRET-aptamer-based detection of methylphosphonic acid, a common nerve agent metabolite.

    PubMed

    Bruno, John G; Carrillo, Maria P; Phillips, Taylor; Vail, Neal K; Hanson, Douglas

    2008-09-01

    Competitive fluorescence resonance energy transfer (FRET)-aptamer-based assay formats are described for one-step detection of methylphosphonic acid (MPA; a metabolite of several organophosphorus (OP) nerve agents). AminoMPA was attached to tosyl-magnetic beads and used for DNA aptamer selection from which one dominant aptamer sequence emerged. Two different FRET approaches were attempted. In one approach, the complementary DNA sequence was used as a template for labeling the aptamer with Alexa Fluor 546 (AF 546)-14-dUTP by asymmetric PCR. Following 3-dimensional (3-D), molecular modeling of the aptamer-MPA complex, a series of three fluoresceinated aptamers labeled at positions 50, 51, and 52 in the putative optimal binding pocket were synthesized. In both FRET formats, aminoMPA was linked to Black Hole Quencher (BHQ-1 or BHQ-2)-succinimides and allowed to bind the fluorescein or AF 546-labeled MPA aptamer. Following gel filtration to purify the labeled MPA aptamer-BHQ-aminoMPA FRET complexes, the complexes were competed against various concentrations of unlabeled MPA, MPA derivatives, and unrelated compounds in titration and cross-reactivity studies. Both approaches yielded low microgram per milliliter detection limits for MPA with generally low levels of cross-reactivity for unrelated compounds. However, the data suggest a pattern of traits that may effect the direction (lights on or off) and intensity of the FRET.

  11. Salvianolic Acid B, a Potential Chemopreventive Agent, for Head and Neck Squamous Cell Cancer

    PubMed Central

    Zhao, Yuan; Guo, Yinhan; Gu, Xinbin

    2011-01-01

    Head and neck squamous cell cancer (HNSCC) is one of the top ten cancers in the United States. The survival rate of HNSCC has only marginally improved over the last two decades. In addition, African-American men bear a disproportionate burden of this preventable disease. Therefore, a critical challenge of preventive health approaches is warranted. Salvianolic acid B (Sal-B) isolated from Salvia miltiorrhiza Bge, which is a well-know Chinese medicines has been safely used to treat and prevent aging diseases for thousand of years. Recently, the anticancer properties of Sal-B have received more attention. Sal-B significantly inhibits or delays the growth of HNSCC in both cultured HNSCC cells and HNSCC xenograft animal models. The following anticancer mechanisms have been proposed: the inhibition of COX-2/PGE-2 pathway, the promotion of apoptosis, and the modulation of angiogenesis. In conclusion, Sal-B is a potential HNSCC chemopreventive agent working through antioxidation and anti-inflammation mechanisms. PMID:21209716

  12. Cell morphology of extrusion foamed poly(lactic acid) using endothermic chemical foaming agent.

    PubMed

    Matuana, Laurent M; Faruk, Omar; Diaz, Carlos A

    2009-12-01

    Poly(lactic acid) (PLA) was foamed with an endothermic chemical foaming agent (CFA) through an extrusion process. The effects of polymer melt flow index, CFA content, and processing speed on the cellular structures, void fraction, and cell-population density of foamed PLA were investigated. The apparent melt viscosity of PLA was measured to understand the effect of melt index on the cell morphology of foamed PLA samples. The void fraction was strongly dependent on the PLA melt index. It increased with increasing melt index, reaching a maximum value, after which it decreased. Melt index showed no significant effect on the cell-population density of foamed samples within the narrow range studied. A gas containment limit was observed in PLA foamed with CFA. Both the void fraction and cell-population density increased with an initial increase in CFA content, reached a maximum value, and then decreased as CFA content continued to increase. The processing speed also affected the morphology of PLA foams. The void fraction reached a maximum value as the extruder's screw speed increased to 40 rpm and a further increase in the processing speed tended to reduce the void fraction of foamed samples. By contrast, cell-population density increased one order of magnitude by increasing the screw speed from 20 to 120 rpm. The experimental results indicate that a homogeneous and finer cellular morphology could be successfully achieved in PLA foamed in an extrusion process with a proper combination of polymer melt flow index, CFA content, and processing speed.

  13. Protection afforded by sunscreens containing inorganic sunscreening agents against blue light sensitivity induced by aminolevulinic acid.

    PubMed

    Bissonnette, Robert; Nigen, Simon; Bolduc, Chantal; Méry, Sophie; Nocera, Thérèse

    2008-11-01

    Application of aminolevulinic acid (ALA) for photodynamic therapy induces significant sensitivity to visible light. To determine whether sunscreens containing inorganic agents are effective against sensitivity to blue light induced by ALA application. Twenty subjects received application of ALA on the arm. Thirty minutes before blue light exposure, two sun protection factor 50 inorganic-based sunscreens containing iron oxide 3.2% and 0.2% were applied on separate areas where ALA was applied; a third area received no sunscreen. Small areas of skin were exposed to increasing fluences of blue light 3 or 18 hours later, and the minimal phototoxic dose (MPD) was noted. Three hours after ALA application MPD was 29.2 and 22.6 J/cm(2) for skin protected with sunscreen containing iron oxide 3.2% and 0.2%, respectively, and 10.6 J/cm(2) for unprotected skin (p=.003 and .0497 respectively). At 18 hours after ALA application, MPD for sunscreen containing iron oxide 3.2% was 5.78, compared with 0.33 for unprotected skin (p<.001) with a blue light protection factor of 21. The sunscreen containing iron oxide 3.2% afforded significant protection against blue light sensitivity induced by ALA application.

  14. Hypochlorous Acid: an ideal wound care agent with powerful microbicidal, antibiofilm, and wound healing potency.

    PubMed

    Sakarya, Serhan; Gunay, Necati; Karakulak, Meltem; Ozturk, Barcin; Ertugrul, Bulent

    2014-12-01

    Chronic wounds and the infections associated with them are responsible for a considerable escalation in morbidity and the cost of health care. Infection and cellular activation and the relation between cells are 2 critical factors in wound healing. Since chronic wounds offer ideal conditions for infection and biofilm production, good wound care strategies are critical for wound healing. Topical antiseptics in chronic wounds remain in widespread use today. These antiseptics are successful in microbial eradication, but their cytotoxcity is a controversial issue in wound healing. The aim of this study was to investigate the effect of stabilized hypochlorous acid solution (HOCl) on killing rate, biofilm formation, antimicrobial activity within biofilm against frequently isolated microorganisms and migration rate of wounded fibroblasts and keratinocytes. Minimal bactericidal concentration of stabilized HOCl solution for all standard microorganisms was 1/64 dilution and for clinical isolates it ranged from 1/32 to 1/64 dilutions. All microorganisms were killed within 0 minutes and accurate killing time was 12 seconds. The effective dose for biofilm impairment for standard microorganisms and clinical isolates ranged from 1/32 to 1/16. Microbicidal effects within the biofilm and antibiofilm concentration was the same for each microorganism. The stabilized HOCl solution had dose-dependent favorable effects on fibroblast and keratinocyte migration compared to povidone iodine and media alone. These features lead to a stabilized HOCl solution as an ideal wound care agent.

  15. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis.

    PubMed

    Pardi, Darrell S; Loftus, Edward V; Kremers, Walter K; Keach, Jill; Lindor, Keith D

    2003-04-01

    Ursodeoxycholic acid (UDCA) has shown effectiveness as a colon cancer chemopreventive agent in preclinical studies. In addition, a recent report suggests that it also may decrease the risk for developing colorectal dysplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We sought to evaluate the effect of UDCA on colorectal neoplasia in a group of patients with UC and PSC enrolled in a randomized, placebo-controlled trial. From a prior, randomized, placebo-controlled trial of UDCA therapy in PSC at our center, we followed-up patients with concomitant UC to assess the effect of UDCA on the development of colorectal dysplasia and cancer as compared with placebo. Fifty-two subjects were followed-up for a total of 355 person-years. Those originally assigned to receive UDCA had a relative risk of 0.26 for developing colorectal dysplasia or cancer (95% confidence interval, 0.06-0.92; P = 0.034). Many of the patients originally assigned to the placebo group eventually received open-label UDCA. Assigning these patients to the UDCA group from the time they began active therapy did not change the magnitude of the protective effect (relative risk, 0.26; 95% confidence interval, 0.07-0.99; P = 0.049). UDCA significantly decreases the risk for developing colorectal dysplasia or cancer in patients with UC and PSC.

  16. Modulation of biomechanical properties of hyaluronic acid hydrogels by crosslinking agents.

    PubMed

    Choi, Sung Chul; Yoo, Mi Ae; Lee, Su Yeon; Lee, Hyun Ji; Son, Dong Hoon; Jung, Jessica; Noh, Insup; Kim, Chan-Wha

    2015-09-01

    Modulation of both mechanical properties and biocompatibilities of hyaluronic acid (HA) hydrogels is very importance for their applications in biomaterials. Pure HA solution was converted into a hydrogel by using butanediol diglycidyl ether (BDDE) as a crosslinking agent. Mechanical properties of the HA hydrogels have been evaluated by adding up different amount of BDDEs. While the mechanical properties of the obtained HA hydrogels were evaluated by measuring their crosslinking degrees, elastic modulus and viscosity, their in vitro biocompatibilities were done by measuring the degrees of anti-inflammatory reactions, cell viabilities and cytotoxicity. The degrees of anti-inflammatory reactions were determined by measuring the amount of nitric oxides (NOs) released from lipopolysaccharide(LPS)(+)-induced macrophages; cell viability was evaluated by observing differences in the behaviors of fibroblasts covered with the HA hydrogels, compared with those covered with the films of Teflon and Latex. Cytotoxicity of the HA hydrogels was also evaluated by measuring the degrees of viability of the cells exposed on the extracts of the HA hydrogels over those of Teflon, Latex and pure HA solutions by the assays of thiazoly blue tetrazolium bromide (MTT), neutral reds, and bromodeoxyuridine (BrdU). The results showed that employment of BDDEs beyond critical amounts showed lower biocompatibility of the crosslinked HA hydrogels but higher crosslinking degrees and mechanical properties, indicating the importance of controlling the HA concentrations, BDDE amounts and their reaction times for the synthesis of the crosslinked HA hydrogels for their clinical applications as biomaterials. © 2015 Wiley Periodicals, Inc.

  17. In vitro release of organophosphorus acid anhydrolase from functionalized mesoporous silica against nerve agents.

    SciTech Connect

    Chen, Baowei; Shah, Saumil S.; Shin, Yongsoon; Lei, Chenghong; Liu, Jun

    2011-10-02

    We report here that under different physiological conditions, biomolecular drugs can be stockpiled in a nanoporous support and afterward can be instantly released when needed for acute responses, and the biomolecular drug molecules can also be gradually released from the nanoporous support over a long time for a complete recovery. Organophosphorus acid anhydrolase (OPAA) was spontaneously and largely entrapped in functionalized mesoporous silica (FMS) due to the dominant electrostatic interaction. The OPAA-FMS composite exhibited a burst release in a pH 9.0 NaHCO(3)-Na(2)CO(3) buffer system and a gradual release in pH 7.4 simulated body fluid. The binding of OPAA to NH(2)-FMS can result in less tyrosinyl and tryptophanyl exposure OPAA molecules to aqueous environment. The bound OPAA in FMS displayed lower activity than the free OPAA in solution prior to the enzyme entrapment. However, the released enzyme maintained the native conformational structure and the same high enzymatic activity as that prior to the enzyme entrapment. The in vitro results in the rabbit serum demonstrate that both OPAA-FMS and the released OPAA may be used as a medical countermeasure against the organophosphorus nerve agents.

  18. Nicotinic acid (niacin) receptor agonists: will they be useful therapeutic agents?

    PubMed

    Kamanna, Vaijinath S; Kashyap, Moti L

    2007-12-03

    niacin receptor agonists as therapeutic agents. Several niacin receptor agonists have been developed and patented, but their clinical effects have not been described. Future research is needed to determine whether niacin receptor agonists will demonstrate all the beneficial properties of nicotinic acid on atherosclerosis and without significant adverse effects.

  19. Linear IgA/IgG bullous dermatosis: successful treatment with dapsone and mycophenolate mofetil.

    PubMed

    Passos, Leny; Rabelo, Renata Fernandes; Matsuo, Christiane; Santos, Mônica; Talhari, Sinesio; Talhari, Carolina

    2011-01-01

    A 21-year-old female presenting linear IgA and IgG disease initially responded well to dapsone therapy. However, the treatment with dapsone was withdrawn due to severe anemia induced by malaria, which led to worsening of the clinical picture. Although prednisone and methylprednisolone were tried, the patient responded only to the association of dapsone and mycophenolate mofetil.

  20. [Effects of peeling agents (resorcinol, crystalline sulfur, salicylic acid) on the epidermis of guinea pig (author's transl)].

    PubMed

    Windhager, K; Plewig, G

    1977-08-22

    The mode of action of "classical peeling agents" such as resorcinol, crystalline sulfur, and salicylic acid on the epidermis is almost unknown. There are only a few experimental data available. Therefore the effects of resorcinol, crystalline sulfur, and salicylic acid were studied. A 1% and 3% concentration of these chemicals in vaselinum flavum or Unguentum Cordes was applied to the ears and flanks of adult male guinea pigs up to 14 days. Prior to biopsies at various time intervals, 3H-thymidine was injected intradermally. Specimens were paraffin embedded and routinely processed for autoradiographical analysis. The following parameters were assessed: Labelling index (L.I. in %); number of labelled basal cells per unit length of basement membrane; papillomatosis-index; and acanthosis-factor (projection histoplanimetry). The data were statistically analysed. The peeling agents induced a concentration-dependent increase of the L.I., acanthosis, and papillomatosis. Crystalline sulfur caused the most pronounced effect, followed by resorcinol. In contrast salicylic acid caused only a minute acanthosis factor and a slight increase in labelling. The correlation coefficient r of epidermal thickness to the L.I. for all concentrations and peeling agents used reaches the high figure of 0.978 for the ear. The 1% and 3% salicylic acid has a lower acanthosis factor than vaselinum flavum by itself. Preliminary autoradiographical studies in humans with 1% and 10% salicylic acid confirm these data. Salicylic acid counteracts acanthosis. These experiments show that crystalline sulfur and resorcinol have a potent effect on cell proliferation and acanthosis. They peel via proliferation hyperkeratosis. The mode of peeling by salicylic acid must be different, as cell proliferation and acanthosis are barely enhanced. The clinically known "keratolytic" effect of salicylic acid may be due to a direct action on the intercellular cement substance of the horny cells.

  1. Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters: Cross-sectional study.

    PubMed

    Noreikaitė, Aurelija; Saint-Marcoux, Franck; Marquet, Pierre; Kaduševičius, Edmundas; Stankevičius, Edgaras

    2017-03-01

    The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR).Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) were evaluated.The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0-12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ± 10.97 vs 28.08 ± 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ± 6.27 vs 28.85 ± 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ± 16.78 vs 36.20 ± 3.70 h mg/L; rs = 0.608, P < 0.05).A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ± 10.82 vs 12.08 ± 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ± 8.86 vs 13.00 ± 6.82 mg/L; rs = 0.414, P < 0.01).The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0-12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA.The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0-12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0-12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the likelihood of adverse events.

  2. Influence of cyclosporine and everolimus on the main mycophenolate mofetil pharmacokinetic parameters

    PubMed Central

    Noreikaitė, Aurelija; Saint-Marcoux, Franck; Marquet, Pierre; Kaduševičius, Edmundas; Stankevičius, Edgaras

    2017-01-01

    Abstract The objective of the present study was to assess the effect of cyclosporine (CsA) on the pharmacokinetic parameters of mycophenolic acid (MPA), an active mycophenolate mofetil (MMF) metabolite, and to compare with the effect of everolimus (EVR). Anonymized medical records of 404 kidney recipients were reviewed. The main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) were evaluated. The patients treated with a higher mean dose of CsA displayed higher MPA AUC(0–12) exposure in the low-dose MMF group (1000 mg/day) (40.50 ± 10.97 vs 28.08 ± 11.03 h mg/L; rs = 0.497, P < 0.05), medium-dose MMF group (2000 mg/day) (43.00 ± 6.27 vs 28.85 ± 11.08 h mg/L; rs = 0.437, P < 0.01), and high-dose MMF group (3000 mg/day) (56.75 ± 16.78 vs 36.20 ± 3.70 h mg/L; rs = 0.608, P < 0.05). A positive correlation was also observed between the mean CsA dose and the MPA Cmax in the low-dose MMF group (Cmax 22.83 ± 10.82 vs 12.08 ± 5.59 mg/L; rs = 0.507, P < 0.05) and in the medium-dose MMF group (22.77 ± 8.86 vs 13.00 ± 6.82 mg/L; rs = 0.414, P < 0.01). The comparative analysis between 2 treatment arms (MMF + CsA and MMF + EVR) showed that MPA AUC(0–12) exposure was by 43% higher in the patients treated with a medium dose of MMF and EVR than in the patients treated with a medium dose of MMF and CsA. The data of the present study suggest a possible CsA versus EVR influence on MMF pharmacokinetics. Study results show that CsA has an impact on the main MPA pharmacokinetic parameters (AUC(0–12) and Cmax) in a CsA dose-related manner, while EVR mildly influence or does not affect MPA pharmacokinetic parameters. Low-dose CsA (lower than 180 mg/day) reduces MPA AUC(0–12) exposure under the therapeutic window and may lead to ineffective therapy, while a high-dose CsA (>240 mg/day) is related to greater than 10 mg/L MPA Cmax and increases the

  3. GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner

    SciTech Connect

    Lin, Tao; Meng, Lingjun; Tsai, Robert Y.L.

    2011-10-22

    Highlights: {yields} Strong synergy between mycophenolic acid (MPA) and 5-FU in MDA-MB-231 cells. {yields} Cell type-dependent synergy between MPA and anti-proliferative agents. {yields} The synergy of MPA on 5-FU is recapitulated by RNA polymerase-I inhibition. {yields} The synergy of MPA on 5-FU requires the expression of nucleostemin. -- Abstract: Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors.

  4. Increase in the ozone decay time in acidic ozone water and its effects on sterilization of biological warfare agents.

    PubMed

    Uhm, Han S; Hong, Yi F; Lee, Han Y; Park, Yun H

    2009-09-15

    The sterilization properties of ozone in acidic water are investigated in this study. Acidification of water increases the ozone decay time by several times compared to the decay time in neutral water, thereby enhancing the sterilization strength of ozone in acidic water. A simple analytical model involving the viable microbial counts after contact with acidic ozone water was derived, and a sterilization experiment was conducted on bacterial cells using the acidic ozone water. The acidic ozone water was found to kill very effectively endospores of Bacillus atrophaeus ATCC 9372, thereby demonstrating the potential for disinfection of a large surface area in a very short time and for reinstating the contaminated environment as free from toxic biological agents.

  5. Caffeic acid: potential applications in nanotechnology as a green reducing agent for sustainable synthesis of gold nanoparticles.

    PubMed

    Seo, Yu Seon; Cha, Song-Hyun; Yoon, Hye-Ran; Kang, Young-Hwa; Park, Youmie

    2015-04-01

    The sustainable synthesis of gold nanoparticles from gold ions was conducted with caffeic acid as a green reducing agent. The formation of gold nanoparticles was confirmed by spectroscopic and microscopic methods. Spherical nanoparticles with an average diameter of 29.99 ± 7.43 nm were observed in high- resolution transmission electron microscopy and atomic force microscopy images. The newly prepared gold nanoparticles exhibited catalytic activity toward the reduction of 4-nitrophenol to 4-aminophenol in the presence of sodium borohydride. This system enables the preparation of green catalysts using plant natural products as reducing agents, which fulfills the growing need for sustainability initiatives.

  6. Microwave Treated Rapid Hydrothermal Synthesis Of Zno Nano-Flakes Array: The Effect Of Citric Acid As Capping Agent

    NASA Astrophysics Data System (ADS)

    Gopal Ram, S. D.; Ravi, G.; Kulandainathan, M. Anbu

    2010-10-01

    Microwave assisted hydrothermal synthesis of ZnO nanostructures with improved surface area by the addition of Citric Acid (CA) as a metal capping agent is reported. Citric acid is added to the mother precursor in three different concentrations for the preparation of ZnO nanostructure. The influence of the citric acid as a capping agent has been studied both in the preparation of ZnO nanopowders and in the ordered array formation on the precoated ZnO seed layer over glass substrates. The addition of this capping agent has shown up clearly in the morphology of the nanostructures. The X-ray diffraction patterns has shown a diminished crystallinity and a increased full width half maximum (FWHM) in the preferred oriented diffraction peak. The peak broadening is an indication of the reduced crystallite size. This cause of the inhibition in growth is realized to be the effect of capping action of citric acid. The optical property of the ZnO nanostructure was characterized by UV-vis-NIR spectroscopy.

  7. Lactic Acid as a New Therapeutic Peeling Agent in the Treatment of Lifa Disease (Frictional Dermal Melanosis)

    PubMed Central

    Sharquie, Khalifa E; Al-Dhalimi, Muhsin A; Noaimi, Adil A; Al-Sultany, Hussein A

    2012-01-01

    Background: Lifa disease (frictional dermal melanosis) is a common dermatological problem. Full strength lactic acid has been proved to be effective and safe peeling agent in the treatment of melasma. Objective: To assess the effectiveness and the safety of lactic acid chemical peeling in the treatment of lifa disease. Materials and Methods: This open label therapeutic trial was conducted in Department of Dermatology in Najaf and Baghdad Teaching Hospitals, from March 2007-October 2008. Full strength lactic acid (92%, pH 3.5) was used as a peeling agent. The treatment sessions were done every 2 weeks until the desired response was achieved (but not more than 6 sessions). The response to therapy was evaluated by objective and subjective methods. All patients were followed monthly for 3 months after the last treatment session. Results: 52 patients with typical clinical features of lifa disease were included. All patients were slim with prominent bones and low body mass index, and gave history of using the lifa (washing agent) during bathing. The number of sessions ranged from 2-6 sessions. The pigmentation was improved in all patients as revealed by objective and subjective methods, and this response was statistically highly significant. No significant side effects were recorded in all treated patients. The improvement has been sustained without any obvious relapse throughout the follow-up period. Conclusion: Lactic acid peel is a new, non-costly mode of therapy in treating dermal melanosis in patients with lifa disease. PMID:23248362

  8. Acetic Acid as a Sclerosing Agent for Renal Cysts: Comparison with Ethanol in Follow-Up Results

    SciTech Connect

    Seo, Tae-Seok; Oh, Joo Hyeong; Yoon, Yup; Lim, Joo Won; Park, Seong Jin; Chang, Sung-Goo; Jeon, Yang Hyeon

    2000-03-15

    Purpose: To compare follow-up results of sclerotherapy for renal cyst using 50% acetic acid with those using 99% ethanol as sclerosing agents.Methods: Eighty-one patients underwent sclerotherapy and 58 patients, 23 males, 35 females, aged 6-76 years, having a total of 60 cysts, were included in this study; the others were lost to follow-up. The renal cysts were diagnosed by sonography, computed tomography (CT), or magnetic resonance imaging (MRI). Sclerotherapy was performed using 50% acetic acid for 32 cysts in 31 patients and 99% ethanol for 28 cysts in 27 patients. Under fluoroscopic guidance, cystic fluid was aspirated as completely as possible. After instillation of a sclerosing agent corresponding to 11.7%-25% (4-100 ml) of the aspirated volume, the patient changed position for 20 min and then the agent was removed. Patients were followed up by sonography for a period of 1-49 months. The volume of the renal cyst after sclerotherapy was compared with that of the renal cyst calculated before sclerotherapy. Medical records were reviewed to analyze complications.Results: The mean volume after sclerotherapy of the 17 cysts followed for 3-4 months in the acetic acid group was 5.1% of the initial volume, and for the 14 cysts in the ethanol group it was 10.2%. Complete regression during follow-up was shown in 21 cysts (66%) in the acetic acid group; the mean volume of these cysts before the procedure was 245 ml. The mean volume of the nine (32%) completely regressed cysts in the ethanol group was 184 ml. Mild flank pain, which occurred in three patients in each group, was the only complication and resolved the next day.Conclusion: Acetic acid was an effective and safe sclerosing agent for renal cysts, tending to induce faster and more complete regression than ethanol.

  9. Ultrasound triggered cell death in vitro with doxorubicin loaded poly lactic-acid contrast agents.

    PubMed

    Eisenbrey, J R; Huang, P; Hsu, J; Wheatley, M A

    2009-12-01

    Traditional chemotherapy generally results in systemic toxicity, which also limits drug levels at the area of need. Two ultrasound contrast agents (UCA), with diameters between 1-2 microm in diameter and shell thicknesses of 100-200 nm, composed of poly lactic-acid (PLA), one loaded by surface adsorption and the other loaded by drug incorporation in the shell, were compared in vitro for potential use in cancer therapy. These poly lactic-acid (PLA) UCA platforms contain a gas core that in an ultrasound (US) field can cause the UCA to oscillate or rupture. Following a systemic injection of drug loaded UCA with external application of US focused at the area of interest, this platform could potentially increase drug toxicity at the area of need, while protecting healthy tissue through microencapsulation of the drug. In vitro toxicity in MDA-MB-231 breast cancer cells of the surface-adsorbed and shell-incorporated doxorubicin (Dox) loaded UCA were examined at 5 MHz insonation using a pulse repetition frequency of 100 Hz at varying pressure amplitudes. Both platforms resulted in equivalent cell death compared to free Dox and US when insonated at peak positive pressure amplitudes of 1.26 MPa and above. While no significant changes in cell death were seen for surface adsorbed Dox-UCA with or without insonation, cell death using the platform with Dox incorporated within the shell increased from 16.12% to 25.78% (p=0.0272), approaching double the potency of the platform when insonated at peak positive pressure amplitudes of 1.26 MPa and above. This mechanism is believed to be the result of UCA rupture at higher insonation pressure amplitudes, resulting in more exposed drug and shell surface area as well as increased cellular uptake of Dox containing polymer shell fragments. This study has shown that a polymer UCA with drug housed within the shell may be used for US-triggered cell death. US activation can be used to make a carrier significantly more potent once in the area of

  10. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model.

    PubMed

    Nagy, Zoltán; Baghy, Kornélia; Hunyadi-Gulyás, Éva; Micsik, Tamás; Nyírő, Gábor; Rácz, Gergely; Butz, Henriett; Perge, Pál; Kovalszky, Ilona; Medzihradszky, Katalin F; Rácz, Károly; Patócs, Attila; Igaz, Peter

    2015-01-01

    The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology.

  11. Evaluation of 9-cis retinoic acid and mitotane as antitumoral agents in an adrenocortical xenograft model

    PubMed Central

    Nagy, Zoltán; Baghy, Kornélia; Hunyadi-Gulyás, Éva; Micsik, Tamás; Nyírő, Gábor; Rácz, Gergely; Butz, Henriett; Perge, Pál; Kovalszky, Ilona; Medzihradszky, Katalin F; Rácz, Károly; Patócs, Attila; Igaz, Peter

    2015-01-01

    The available drug treatment options for adrenocortical carcinoma (ACC) are limited. In our previous studies, the in vitro activity of 9-cis retinoic acid (9-cisRA) on adrenocortical NCI-H295R cells was shown along with its antitumoral effects in a small pilot xenograft study. Our aim was to dissect the antitumoral effects of 9-cisRA on ACC in a large-scale xenograft study involving mitotane, 9-cisRA and their combination. 43 male SCID mice inoculated with NCI-H295R cells were treated in four groups (i. control, ii. 9-cisRA, iii. mitotane, iv. 9-cisRA + mitotane) for 28 days. Tumor size follow-up, histological and immunohistochemical (Ki-67) analysis, tissue gene expression microarray, quantitative real-time-PCR for the validation of microarray results and to detect circulating microRNAs were performed. Protein expression was studied by proteomics and Western-blot validation. Only mitotane alone and the combination of 9-cisRA and mitotane resulted in significant tumor size reduction. The Ki-67 index was significantly reduced in both 9-cisRA and 9-cisRA+mitotane groups. Only modest changes at the mRNA level were found: the 9-cisRA-induced overexpression of apolipoprotein A4 and down-regulation of phosphodiesterase 4A was validated. The expression of circulating hsa-miR-483-5p was significantly reduced in the combined treatment group. The SET protein was validated as being significantly down-regulated in the combined mitotane+9-cisRA group. 9-cisRA might be a helpful additive agent in the treatment of ACC in combination with mitotane. Circulating hsa-miR-483-5p could be utilized for monitoring the treatment efficacy in ACC patients, and the treatment-induced reduction in protein SET expression might raise its relevance in ACC biology. PMID:26885453

  12. Pharmacokinetics of chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent, in rats.

    PubMed

    Jung, Ji Won; Kim, Ju Myung; Jeong, Jin Seok; Son, Miwon; Lee, Hye Suk; Lee, Myung Gull; Kang, Hee Eun

    2014-07-01

    1.Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1-8 mg/kg) or CRD (1.1-4.5 mg/kg) and their equivalent dose of DA-9701 to rats. 2.  Dose-proportional AUC and dose-independent clearance (10.3-12.1 ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478-0.899%). 3.  CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5 mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.

  13. Susceptibility of lactic acid bacteria, bifidobacteria and other bacteria of intestinal origin to chemotherapeutic agents.

    PubMed

    Flórez, Ana B; Sierra, Marta; Ruas-Madiedo, Patricia; Mayo, Baltasar

    2016-11-01

    Chemotherapy is a cornerstone of cancer treatment but it can have serious side effects, such as intestinal mucositis. This work reports the susceptibility/resistance profiles of 34 species of lactic acid bacteria (LAB), bifidobacteria and other intestinal bacteria from different collections to various chemotherapeutic agents (CAs) currently used in cancer treatments in an attempt to identify microorganisms that could prevent or treat mucositis symptoms. The highest concentrations of the CAs tested were equal to or higher than those reached in plasma during anticancer treatments. All 34 species proved to be resistant at the highest concentrations assayed [minimum inhibitory concentrations (MICs) > 128 µg/mL] to capecitabine, cyclophosphamide, docetaxel, erlotinib, gefitinib, irinotecan and paclitaxel. For doxorubicin, 5-fluorouracil, gemcitabine and, especially, afatinib and pemetrexed, interspecies variation in the MIC was observed. In further work to assess the interspecies and intraspecies variability, MICs of the CAs pemetrexed and afatinib were determined for 32 strains belonging to four Bifidobacterium spp. of intestinal origin. For pemetrexed, a bimodal MIC curve was obtained (modes <2-8 µg/mL and >256 µg/mL), whilst a normal unimodal curve was obtained for afatinib (mode 128 µg/mL). Altogether, these results suggest that the majority of CAs should not, by themselves, perturb the microbial populations of the gut microbiota (but considering that they could be transformed in vivo into more toxic compounds). However, LAB and bifidobacteria, which are key players in the intestinal microbial balance of the healthy state, might be particularly inhibited by CAs such as gemcitabine or doxorubicin. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  14. Synthesis and biological relationships of 3',6-substituted 2-phenyl-4-quinolone-3-carboxylic acid derivatives as antimitotic agents.

    PubMed

    Lai, Ya-Yun; Huang, Li-Jiau; Lee, Kuo-Hsiung; Xiao, Zhiyan; Bastow, Kenneth F; Yamori, Takao; Kuo, Sheng-Chu

    2005-01-03

    As part of a continuing search for potential anticancer drug candidates in the 2-phenyl-4-quinolone series, 3',6-substituted 2-phenyl-4-quinolone-3-carboxylic acid derivatives and their salts were synthesized and evaluated. Preliminary screening showed that carboxylic acid analogs containing a m-fluoro substituted 2-phenyl group displayed the highest in vitro anticancer activity. Activity decreased significantly if a chlorine or methoxy group replaced the fluorine atom. 3'-Fluoro-6-methoxy-2-phenyl-4-quinolone-3-carboxylic acid (68) had the highest in vitro cytotoxic activity among all tested carboxylic acid derivatives and their salts. The mechanism of action may be similar, but not identical, to that of tubulin binding drugs, such as navelbine and taxol. Compound 68 merits further investigation as a novel hydrophilic antimitotic agent.

  15. Gallic Acid as a Complexing Agent for Copper Chemical Mechanical Polishing Slurries at Neutral pH

    NASA Astrophysics Data System (ADS)

    Kim, Yung Jun; Kang, Min Cheol; Kwon, Oh Joong; Kim, Jae Jeong

    2011-05-01

    Gallic acid was investigated as a new complexing agent for copper (Cu) chemical mechanical polishing slurries at neutral pH. Addition of 0.03 M gallic acid and 1.12 M H2O2 at pH 7 resulted in a Cu removal rate of 560.73±17.49 nm/min, and the ratio of the Cu removal rate to the Cu dissolution rate was 14.8. Addition of gallic acid improved the slurry performance compared to glycine addition. X-ray photoelectron spectroscopy analysis and contact angle measurements showed that addition of gallic acid enhanced the Cu polishing behavior by suppressing the formation of surface Cu oxide.

  16. Curcumin Targeted, Polymalic Acid-Based MRI Contrast Agent for the Detection of Aβ Plaques in Alzheimer's Disease.

    PubMed

    Patil, Rameshwar; Gangalum, Pallavi R; Wagner, Shawn; Portilla-Arias, Jose; Ding, Hui; Rekechenetskiy, Arthur; Konda, Bindu; Inoue, Satoshi; Black, Keith L; Ljubimova, Julia Y; Holler, Eggehard

    2015-09-01

    Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Aβ) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Aβ plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(β-l-malic acid) (PMLA) containing covalently attached gadolinium-DOTA(Gd-DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Aβ plaques and is detected by MRI. It efficiently detected Aβ plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD.

  17. Effects of Citric Acid and Desensitizing Agent Application on Nonfluorosed and Fluorosed Dentin: An In Vitro Sem Study

    PubMed Central

    Neha, Mahajan; Vandana, Laxman K

    2015-01-01

    Fluorosis is one of the factors which bring about mineralisation changes in a dentinal structure leading to dentin. The purpose of the present study was to compare and evaluate the dentinal tubular changes in fluorosed and nonfluorosed teeth subsequent to the application of citric acid,strontium acetate based sodium fluoride (SAF) using scanning electron microscopy (SEM). Dentin specimens from healthy fluorosed and nonfluorosed teeth were included in the study. Each of them was grouped into acid treated and SAF treatment groups. Using SEM, the photomicrographs (3500x) of dentin specimens were evaluated. Results showed while there was a significant difference in tubular width of partial occlusion ≤ 25%, being more in fluorosed group compared to nonfluorosed group after application SAF. Application of desensitising agents demonstrated higher number of dentinal tubular occlusion and diameter reduction in nonfluorosed dentin compared to fluorosed dentin. Summary: Root biomodification and desensitising agent procedure brings in definite difference between fluorosed and non-fluorosed dentin specimens. PMID:25870716

  18. Data of thermal degradation and dynamic mechanical properties of starch-glycerol based films with citric acid as crosslinking agent.

    PubMed

    González Seligra, Paula; Medina Jaramillo, Carolina; Famá, Lucía; Goyanes, Silvia

    2016-06-01

    Interest in biodegradable edible films as packaging or coating has increased because their beneficial effects on foods. In particular, food products are highly dependents on thermal stability, integrity and transition process temperatures of the packaging. The present work describes a complete data of the thermal degradation and dynamic mechanical properties of starch-glycerol based films with citric acid (CA) as crosslinking agent described in the article titled: "Biodegradable and non-retrogradable eco-films based on starch-glycerol with citric acid as crosslinking agent" González Seligra et al. (2016) [1]. Data describes thermogravimetric and dynamical mechanical experiences and provides the figures of weight loss and loss tangent of the films as a function of the temperature.

  19. Quinolone antimicrobial agents. 1. Versatile new synthesis of 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids.

    PubMed

    Mitscher, L A; Gracey, H E; Clark, G W; Suzuki, T

    1978-05-01

    A flexible reaction sequence has been developed which starts with readily available anthranilic acids or isatoic anhydrides and leads regiospecifically to 1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids after reaction with 1,3-dicarbonyl compounds. The sequence is superior to earlier published methods by allowing electron-releasing and -withdrawing groups in any position on the aro;atic ring, by allowing convenient substitution at C2, and better overall yield. A number of new and known antimicrobial agents were prepared and tested in vitro, demonstrating, inter alia, that substitution of the H at C2 abolished antibacterial activity.

  20. [Effects of mycophenolate mofetil in ischemic acute renal failure in rats].

    PubMed

    Chávez-Velásquez, M; Pons, H; Medina, M; Quiroz, Y; Parra, G; Herrera, J

    2007-01-01

    Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsies shown that the histologic damage was 54 +/- 28% in post-MMF group vs 34+/- 22% in pre-MMF group and 61 +/- 25% in control group (pre-MMF vs post-MMF, p NS). On the 5th day post-ischemic, MMF-rats showed more severe tubulointerstitial necrosis (pre-MMF group: 17 +/- 20 %, post-MMF group: 33 +/- 27%) than controls (4 +/- 5%). The severity of ATN was significantly higher in post-MMF group compared with controls (p=0.01). Tubulointersticial T-lymphocyte (T CD 5) and monocyte (ED 1) infiltration evaluated on the 2nd post-ischemic day was less intense in group I (T CD5: 3 +/- 3, ED 1: 10 +/- 9, cel/mm2) compared to post-MMF group (T CD 5: 10 +/- 4, ED 1: 55 +/- 40) and to control group (T CD 5: 10+/- 4, ED 1: 64 +/- 46). However, on the 5th post-ischemia day, ED 1 infiltration was significantly higher in post-MMF group (24 +/- 18%) compared to pre-MMF group (5 +/- 5, p NS) and also in pre-MMF group vs control group (31 +/- 33, p< 0.05). Our results suggest that MMF given before a renal ischemic

  1. Suberoylanilide hydroxamic acid as a potential therapeutic agent for human breast cancer treatment.

    PubMed Central

    Huang, L.; Pardee, A. B.

    2000-01-01

    BACKGROUND: Suberoylanilide hydroxamic acid (SAHA) is a prototype of the newly developed, second-generation, hybrid polar compounds. It is a novel histone deacetylase inhibitor with high potency for inducing cell differentiation of cultured murine erythroleukemia cells. Studies with SAHA have primarily been performed with hematopoietic tumor cells. Here we extent these studies with SAHA to human breast cancer cell lines in an attempt to find better therapeutic agents for breast cancer treatment. MATERIALS AND METHODS: Human breast cancer cell lines, MCF7, MDA-MB-231, and MDA-MB-435, as well as normal cells, including the normal breast epithelial cell line MCF-10A, and fibroblasts, were treated with SAHA. Cells assayed for cell survival by using trypan blue exclusion assay, colony formation assay, and cell cycle and apoptosis analysis. The effects of SAHA on cell cycle and apoptosis regulatory proteins were examined by Western blots analysis. The identification of additional target genes was carried out by differential display (DD) and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: SAHA inhibited clonogenic growth of MCF7, MDA-MB-231, and MDA-MB-435 breast cancer cells. These cells were more sensitive to SAHA-mediated cytotoxic effects than normal breast epithelial cells and fibroblasts. The cytotoxic effects of SAHA on breast cancer cells were manifested by G1 and G2/M cell cycle arrest and eventual apoptosis. The pan-caspase inhibitor, Z-VAD.fmk, blocked SAHA-induced cell death, DNA laddering, and cleavage of poly(ADP-ribose) polymerase, indicating the involvement of caspases in SAHA-mediated apoptosis. In addition, SAHA modulated cell cycle and apoptosis regulatory proteins. For example, cyclin-dependent kinase (CDK) inhibitors p21WAF1/Cip1 and p27Kip1 were induced, and retinoblastoma protein pRb was hypophosphorylated. Moreover, SAHA induced several genes associated with differentiation and/ or growth inhibition. These genes encode gelsolin

  2. A short synthetic route to biologically active (+/-)-daurichromenic acid as highly potent anti-HIV agent.

    PubMed

    Lee, Yong Rok; Wang, Xue

    2005-11-07

    The efficient total synthesis of biologically interesting (+/-)-daurichromenic acid is accomplished starting from 2,4-dihydroxy-6-methylbenzoic acid or 2,4-dihydroxy-6-methylbenzaldehyde in one or two steps.

  3. Application of chiral derivatizing agents in the high-performance liquid chromatographic separation of amino acid enantiomers: a review.

    PubMed

    Ilisz, István; Berkecz, Robert; Péter, Antal

    2008-05-12

    The past 20 years has seen an explosive growth in the field of chirality, as illustrated by the rapid progress in the various facets of this intriguing field. The impetus for advances in chiral separation has been highest in the past decade and this still continues to be an area of high focus. This paper reviews indirect separation approaches, i.e. derivatization reactions aimed at creating the basis for the chromatographic resolution of biologically and pharmaceutically important enantiomers, with emphasis on the literature published in the last 12 years. The main aspects of the chiral derivatization of amino acids are discussed, i.e. derivatization on the amino group, transforming the molecules into covalently bonded diastereomeric derivatives through the use of homochiral derivatizing agents. The diastereomers formed (amides, urethanes, urea, thiourea derivatives, etc.) can be separated on achiral stationary phases. The applications are considered, and in some cases different derivatizing agents for the resolution of complex mixtures of proteinogenic d,l-amino acids, non-proteinogenic amino acids and peptides/amino acids from peptide syntheses or microorganisms are compared.

  4. Comparison of natural humic substances and synthetic ethylenediaminetetraacetic acid and nitrilotriacetic acid as washing agents of a heavy metal-polluted soil.

    PubMed

    Soleimani, Mohsen; Hajabbasi, Mohammad A; Afyuni, Majid; Akbar, Samira; Jensen, Julie K; Holm, Peter E; Borggaard, Ole K

    2010-01-01

    Ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), and other synthetic polycarboxylic acids have been shown to possess substantial capacity as washing agents of heavy metal-polluted soils, but they are environmentally problematic. Therefore, a sample of natural soluble humic substances (HS) was tested as a possible substitute. The efficiency of HS to extract cadmium (Cd), copper (Cu), and lead (Pb) from a strongly polluted calcareous urban soil was compared with that of EDTA and NTA. The influence of extractant concentration (25-100 mmol L(-1) C), solution/soil ratio (5-100 L kg(-1)), and single-step vs. multistep extraction on heavy metal removal from the soil was investigated. The extracted pools were assessed by sequential extraction. Ethylenediaminetetraacetic acid and NTA extracted up to 86, 77, and 30% of total soil Cd, Cu, and Pb, respectively, whereas HS extracted 44, 53, and 4%. Extracted amounts of Cd, Cu, and Pb increased with increasing extractant concentration and solution/soil ratio in the range 5 to 100 L kg(-1). Single-step extraction removed about the same amounts of the three metals as multiple-step extraction. The metal-extracted pools of the soil depended on the metal and on the extractant. The overall conclusion is that soluble HS can replace synthetic EDTA and NTA as washing agents for Cd- and Cu-polluted soils, whereas HS is not a promising substitute of EDTA or NTA for cleaning Pb-polluted, calcareous soils.

  5. Synthesis of novel oleanolic acid and ursolic acid in C-28 position derivatives as potential anticancer agents.

    PubMed

    Tian, Tian; Liu, Xinyu; Lee, Eung-Seok; Sun, Jingyang; Feng, Zhonghua; Zhao, Longxuan; Zhao, Chunhui

    2017-04-01

    A series of nitrogen-containing derivatives of oleanolic acid and ursolic acid were prepared by a modification at C-28 position via esterification with 2-hydroxyacetic acid followed by amidation with amines, such as piperazine, N-methylpiperazine, and alkane-1, 2-diamines, alkane-1, 4-diamines, alkane-1, 6-diamines. In vitro antiproliferative activities of the compounds prepared towards MCF-7, Hela and A549 cell lines were evaluated by a MTT method to show that OA-5a, OA-5b, OA-5c and UA-5a showed somewhat improved antiproliferative activities against MCF-7, Hela and A549 cells comparing to that of the positive control, gefitinib.

  6. Autoimmune myelofibrosis with pancytopenia as a presenting manifestation of systemic lupus erythematosus responsive to mycophenolate mofetil.

    PubMed

    Ungprasert, P; Chowdhary, V R; Davis, M D; Makol, A

    2016-04-01

    Hematological abnormalities, such as anemia, leucopenia, and thrombocytopenia, secondary to peripheral destruction, are common in systemic lupus erythematosus (SLE). However, cytopenias from autoimmune myelofibrosis (AIMF) are extremely uncommon in SLE, with less than 40 reported cases in the literature. We report the case of a 33-year-old female who presented with bullous skin lesions and pancytopenia as the presenting manifestation of what was ultimately diagnosed as SLE with AIMF. She responded well to glucocorticoids and mycophenolate mofetil.

  7. A Pilot Study of Continuous Infusion of Mycophenolate Mofetil for Prophylaxis of Graft-versus-Host-Disease in Pediatric Patients.

    PubMed

    Windreich, Randy M; Goyal, Rakesh K; Joshi, Rujuta; Kenkre, Tanya S; Howrie, Denise; Venkataramanan, Raman

    2016-04-01

    Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used increasingly for graft-versus-host disease (GVHD) prophylaxis. Empiric fixed-dose-escalation strategies in pediatric hematopoietic cell transplantation (HCT) recipients have failed to achieve target MPA exposure. We evaluated the safety and feasibility of a pharmacokinetics-based dosing approach using a novel continuous infusion (CI) method of administration of MMF in pediatric HCT recipients. All patients received a myeloablative conditioning with cyclosporine A and MMF for GVHD prophylaxis. MMF was initiated on day 0 at a dose of 15 mg/kg every 8 hours. Based on steady-state pharmacokinetics, MMF was converted to CI to target a total MPA AUC(0-24) of 40 to 80 μg·hour/mL. The MMF dose was adjusted to maintain a total MPA steady-state concentration (Css) of 1.7 to 3.3 μg/mL. During the CI schedule, MPA AUC(0-24) was maintained at a mean of 40.1 μg·hour/mL (range, 20.6 to 63.8), and 17 of 19 patients (89%) achieved MPA Css within target of 1.7 to 3.3 μg/mL. Eighteen of 19 patients (95%) achieved neutrophil engraftment at a median of 13 days (range, 8 to 41) post-transplant and platelet engraftment at 39 days (range, 17 to 298) days post-transplant. Six of 18 assessable patients (33%) developed stages II to IV acute GVHD and 2 of 15 (13%) developed chronic GVHD. The MMF dose was reduced in 9 patients due to gastrointestinal symptoms (n = 6), low blood counts (n = 4), and viral infection (n = 3). Five patients with acute lymphoblastic leukemia relapsed, of whom 4 have died. Fifteen of 19 patients are alive with a median follow-up of 2.4 years (range, .4 to 4.9), with 3-year event-free and overall survival rates of 68% and 79%, respectively. In this pilot study of pharmacokinetically directed MMF dosing, we observed no toxic deaths, excellent engraftment, and low rates of grades III to IV acute and chronic GVHD. We found significantly lower half-life and higher drug clearance in

  8. Incorporation of Exogenous Fatty Acids Protects Enterococcus faecalis from Membrane-Damaging Agents

    PubMed Central

    Saito, Holly E.; Harp, John R.

    2014-01-01

    Enterococcus faecalis is a commensal bacterium of the mammalian intestine that can persist in soil and aquatic systems and can be a nosocomial pathogen to humans. It employs multiple stress adaptation strategies in order to survive such a wide range of environments. Within this study, we sought to elucidate whether membrane fatty acid composition changes are an important component for stress adaptation. We noted that E. faecalis OG1RF was capable of changing its membrane composition depending upon growth phase and temperature. The organism also readily incorporated fatty acids from bile, serum, and medium supplemented with individual fatty acids, often dramatically changing the membrane composition such that a single fatty acid was predominant. Growth in either low levels of bile or specific individual fatty acids was found to protect the organism from membrane challenges such as high bile exposure. In particular, we observed that when grown in low levels of bile, serum, or the host-derived fatty acids oleic acid and linoleic acid, E. faecalis was better able to survive the antibiotic daptomycin. Interestingly, the degree of membrane saturation did not appear to be important for protection from the stressors examined here; instead, it appears that a specific fatty acid or combination of fatty acids is critical for stress resistance. PMID:25128342

  9. Chiral discrimination of α-hydroxy acids and N-Ts-α-amino acids induced by tetraaza macrocyclic chiral solvating agents by using (1)H NMR spectroscopy.

    PubMed

    Lv, Caixia; Feng, Lei; Zhao, Hongmei; Wang, Guo; Stavropoulos, Pericles; Ai, Lin

    2017-02-21

    In the field of chiral recognition, reported chiral discrimination by (1)H NMR spectroscopy has mainly focused on various chiral analytes with a single chiral center, regarded as standard chiral substrates to evaluate the chiral discriminating abilities of a chiral auxiliary. Among them, chiral α-hydroxy acids, α-amino acids and their derivatives are chiral organic molecules involved in a wide variety of biological processes, and also play an important role in the area of preparation of pharmaceuticals, as they are part of the synthetic process in the production of chiral drug intermediates and protein-based drugs. In this paper, several α-hydroxy acids and N-Ts-α-amino acids were used to evaluate the chiral discriminating abilities of tetraaza macrocyclic chiral solvating agents (TAMCSAs) 1a-1d by (1)H NMR spectroscopy. The results indicate that α-hydroxy acids and N-Ts-α-amino acids were successfully discriminated in the presence of TAMCSAs 1a-1d by (1)H NMR spectroscopy in most cases. The enantiomers of the α-hydroxy acids and N-Ts-α-amino acids were assigned based on the change of integration of the (1)H NMR signals of the corresponding protons. The enantiomeric excesses (ee) of N-Ts-α-amino acids 11 with different optical compositions were calculated based on the integration of the (1)H NMR signals of the CH3 protons (Ts group) of the enantiomers of (R)- and (S)-11 in the presence of TAMCSA 1b. At the same time, the possible chiral discriminating behaviors have been discussed by means of the Job plots of (±)-2 with TAMCSAs 1b and proposed theoretical models of the enantiomers of 2 and 6 with TAMCSA 1a, respectively.

  10. Determination of methyl-, 2-hydroxyethyl- and 2-cyanoethylmercapturic acids as biomarkers of exposure to alkylating agents in cigarette smoke.

    PubMed

    Scherer, Gerhard; Urban, Michael; Hagedorn, Heinz-Werner; Serafin, Richard; Feng, Shixia; Kapur, Sunil; Muhammad, Raheema; Jin, Yan; Sarkar, Mohamadi; Roethig, Hans-Juergen

    2010-10-01

    Alkylating agents occur in the environment and are formed endogenously. Tobacco smoke contains a variety of alkylating agents or precursors including, among others, N-nitrosodimethylamine (NDMA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), acrylonitrile and ethylene oxide. We developed and validated a method for the simultaneous determination of methylmercapturic acid (MMA, biomarker for methylating agents such as NDMA and NNK), 2-hydroxyethylmercapturic acid (HEMA, biomarker for ethylene oxide) and 2-cyanoethylmercapturic acid (CEMA, biomarker for acrylonitrile) in human urine using deuterated internal standards of each compound. The method involves liquid/liquid extraction of the urine sample, solid phase extraction on anion exchange cartridges, derivatization with pentafluorobenzyl bromide (PFBBr), liquid/liquid extraction of the reaction mixture and LC-MS/MS analysis with positive electrospray ionization. The method was linear in the ranges of 5.00-600, 1.00-50.0 and 1.50-900 ng/ml for MMA, HEMA and CEMA, respectively. The method was applied to two clinical studies in adult smokers of conventional cigarettes who either continued smoking conventional cigarettes, were switched to test cigarettes consisting of either an electrically heated cigarette smoking system (EHCSS) or having a highly activated carbon granule filter that were shown to have reduced exposure to specific smoke constituents, or stopped smoking. Urinary excretion of MMA was found to be unaffected by switching to the test cigarettes or stop smoking. Urinary HEMA excretion decreased by 46 to 54% after switching to test cigarettes and by approximately 74% when stopping smoking. Urinary CEMA excretion decreased by 74-77% when switching to test cigarettes and by approximately 90% when stopping smoking. This validated method for urinary alkylmercapturic acids is suitable to distinguish differences in exposure not only between smokers and nonsmokers but also between smoking of conventional and

  11. Improved gastrointestinal symptoms and quality of life after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients receiving tacrolimus.

    PubMed

    Hwang, Hyeon Seok; Hyoung, Bok Jin; Kim, Sol; Oh, Ha Young; Kim, Yon Su; Kim, Jung Kyung; Kim, Yeong Hoon; Kim, Yong Lim; Kim, Chan Duck; Shin, Gyu Tae; Yang, Chul Woo

    2010-12-01

    It is reported that a conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) relieves gastrointestinal (GI) symptom burden and improves health-related quality of life (HRQoL). However, it is unclear whether renal transplant recipients using tacrolimus receive the same benefit from the conversion. In this prospective, multi-center, open-label trial, patients were categorized into two groups by their GI symptom screening. Equimolar EC-MPS (n=175) was prescribed for patients with GI burdens; those with no complaints remained on MMF (n=83). Gastrointestinal Symptom Rating Scale (GSRS) and Gastrointestinal Quality of Life Index (GIQLI) were evaluated at baseline and after one month. Patients and physicians completed Overall Treatment Effect (OTE) at one month. EC-MPS-converted patients had worse GSRS and GIQLI scores at baseline than MMF-continued patients (all P<0.001). Significant improvements in GSRS and GIQLI scores were observed for EC-MPS-converted patients at one month, but MMF-continued patients showed worsened GSRS scores (all P<0.05). OTE scale indicated that EC-MPS patients improved in overall GI symptoms and HRQoL more than MMF patients did (P<0.001). In tacrolimus-treated renal transplant recipients with GI burdens, a conversion from MMF to EC-MPS improves GI-related symptoms and HRQoL.

  12. Development and in-vitro characterization of fish oil oleogels containing benzoyl peroxide and salicylic acid as keratolytic agents.

    PubMed

    Rehman, K; Tan, C M; Zulfakar, M H

    2014-03-01

    Topical keratolytic agents such as benzoyl peroxide (BP) and salicylic acid (SA) are one of the common treatments for inflammatory skin diseases. However, the amount of drug delivery through the skin is limited due to the stratum corneum. The purposes of this study were to investigate the ability of fish oil to act as penetration enhancer for topical keratolytic agents and to determine the suitable gelator for formulating stable fish oil oleogels. 2 types of gelling agents, beeswax and sorbitan monostearate (Span 60), were used to formulate oleogels. To investigate the efficacy of fish oil oleogel permeation, commercial hydrogels of benzoyl peroxide (BP) and salicylic acid (SA) were used as control, and comparative analysis was performed using Franz diffusion cell. Stability of oleogels was determined by physical assessments at 20°C and 40°C storage. Benzoyl peroxide (BP) fish oil oleogels containing beeswax were considered as better formulations in terms of drug permeation and cumulative drug release. All the results were found to be statistically significant (p<0.05, ANOVA) and it was concluded that the beeswax-fish oil combination in oleogel can prove to be beneficial in terms of permeation across the skin and stability.

  13. Cytocompatibility and Mechanical Properties of Short Phosphate Glass Fibre Reinforced Polylactic Acid (PLA) Composites: Effect of Coupling Agent Mediated Interface

    PubMed Central

    Hasan, Muhammad Sami; Ahmed, Ifty; Parsons, Andrew; Walker, Gavin; Scotchford, Colin

    2012-01-01

    In this study three chemical agents Amino-propyl-triethoxy-silane (APS), sorbitol ended PLA oligomer (SPLA) and Hexamethylene diisocyanate (HDI) were identified to be used as coupling agents to react with the phosphate glass fibre (PGF) reinforcement and the polylactic acid (PLA) polymer matrix of the composite. Composites were prepared with short chopped strand fibres (l = 20 mm, ϕ = 20 µm) in a random arrangement within PLA matrix. Improved, initial composite flexural strength (~20 MPa) was observed for APS treated fibres, which was suggested to be due to enhanced bonding between the fibres and polymer matrix. Both APS and HDI treated fibres were suggested to be covalently linked with the PLA matrix. The hydrophobicity induced by these coupling agents (HDI, APS) helped to resist hydrolysis of the interface and thus retained their mechanical properties for an extended period of time as compared to non-treated control. Approximately 70% of initial strength and 65% of initial modulus was retained by HDI treated fibre composites in contrast to the control, where only ~50% of strength and modulus was retained after 28 days of immersion in PBS at 37 °C. All coupling agent treated and control composites demonstrated good cytocompatibility which was comparable to the tissue culture polystyrene (TCP) control, supporting the use of these materials as coupling agent’s within medical implant devices. PMID:24955744

  14. Inhibition of Thymidine Kinase Activity and Deoxyribonucleic Acid Synthesis in L Cells Infected with the Meningopneumonitis Agent

    PubMed Central

    Lin, Hsiu-San

    1968-01-01

    The activities of enzymes related to deoxyribonucleic acid (DNA) synthesis were studied in uninfected L cells and in L cells infected with Chlamydia psittaci (strain meningopneumonitis). The meningopneumonitis agent multiplied normally but failed to induce the synthesis of thymidine kinase in LM (TK−) cells which contain no thymidine kinase in the uninfected state. It was concluded that this microorganism has no thymidine kinase of its own and that it does not depend on the functioning of the host enzyme for synthesizing its DNA. Exposure of clone 5b L cells to the meningopneumonitis agent was followed by a decline in their thymidine kinase activity to nearly zero levels, whereas the levels of uridine kinase and thymidylate synthetase remained unchanged. Inhibition of thymidine kinase activity in L cells occurred soon after infection and required new protein synthesis by the meningopneumonitis agent. This inhibition occurred before inhibition of host DNA synthesis, but it was not an essential prelude to the latter inhibition. On the basis of this and previous investigations and in light of present knowledge of the mammalian cell cycle, it was postulated that the meningopneumonitis agent inhibits macromolecular synthesis in L cells by preventing the initiation of a new cell cycle. PMID:5724972

  15. Heritable and cancer risks of exposures to anticancer drugs: inter-species comparisons of covalent deoxyribonucleic acid-binding agents.

    PubMed

    Vogel, E W; Barbin, A; Nivard, M J; Stack, H F; Waters, M D; Lohman, P H

    1998-05-25

    In the past years, several methodologies were developed for potency ranking of genotoxic carcinogens and germ cell mutagens. In this paper, we analyzed six sub-classes of covalent deoxyribonucleic acid (DNA) binding antineoplastic drugs comprising a total of 37 chemicals and, in addition, four alkyl-epoxides, using four approaches for the ranking of genotoxic agents on a potency scale: the EPA/IARC genetic activity profile (GAP) database, the ICPEMC agent score system, and the analysis of qualitative and quantitative structure-activity and activity-activity relationships (SARs, AARs) between types of DNA modifications and genotoxic endpoints. Considerations of SARs and AARs focused entirely on in vivo data for mutagenicity in male germ cells (mouse, Drosophila), carcinogenicity (TD50s) and acute toxicity (LD50s) in rodents, whereas the former two approaches combined the entire database on in vivo and in vitro mutagenicity tests. The analysis shows that the understanding and prediction of rank positions of individual genotoxic agents requires information on their mechanism of action. Based on SARs and AARs, the covalent DNA binding antineoplastic drugs can be divided into three categories. Category 1 comprises mono-functional alkylating agents that primarily react with N7 and N3 moieties of purines in DNA. Efficient DNA repair is the major protective mechanism for their low and often not measurable genotoxic effects in repair-competent germ cells, and the need of high exposure doses for tumor induction in rodents. Due to cell type related differences in the efficiency of DNA repair, a strong target cell specificity in various species regarding the potency of these agents for adverse effects is found. Three of the four evaluation systems rank category 1 agents lower than those of the other two categories. Category 2 type mutagens produce O-alkyl adducts in DNA in addition to N-alkyl adducts. In general, certain O-alkyl DNA adducts appear to be slowly repaired, or

  16. [Experimental model for the study of the teratogenic interaction of chemical agents and drugs (toluene and acetylsalicylic acid)].

    PubMed

    Tátrai, E; Hudák, A; Ungváry, G

    1979-10-01

    On the 10th-13th days of pregnancy toluene (3600 mg/m3) by inhalation) and on 12th day acetylsalicylic acid (500 mg/kg of body weight per os) were administered to CFY rats and the common effect of these agents was studied. It was established that: 1. the maternal toxicity increased, i.e. increased the mortality rate, decreased the consumption of the food and the gain of weight, increased the relative weight of the liver; 2. the foetal toxicity increased, i.e. increased the mortality rate of foetuses, the rate of the loss of the body weight, the number of the anomalies of the sternum and the incidence of the supernumerary ribs. It is believed, that the non-teratogenic toluene rises the utilization of the glycine and the level of the free salicylic-acid, consequently the embryotoxic effect of the acetylsalicylic-acid. The danger of the occurrence of malformations as an effect of interaction of chemical agents and drugs taken in therapeutic doses is stressed.

  17. Recent advances in inhibitors of bacterial fatty acid synthesis type II (FASII) system enzymes as potential antibacterial agents.

    PubMed

    Wang, Yi; Ma, Shutao

    2013-10-01

    Bacterial infections are a constant and serious threat to human health. With the increase of multidrug resistance of clinically pathogenic bacteria, common antibiotic therapies have been less effective. Fatty acid synthesis type II (FASII) system enzymes are essential for bacterial membrane lipid biosynthesis and represent increasingly promising targets for the discovery of antibacterial agents with new mechanisms of action. This review highlights recent advances in inhibitors of bacterial FASII as potential antibacterial agents, paying special attention to the activities, mechanisms, and structure-activity relationships of those inhibitors that mainly target β-ketoacyl-ACP synthase, β-ketoacyl-ACP reductase, β-hydroxyacyl-ACP dehydratase, and enoyl-ACP reductase. Although inhibitors with low nanomolar and selective activity against various bacterial FASII have entered clinical trials, further research is needed to expand upon both available and yet unknown scaffolds to identify new FASII inhibitors that may have antibacterial potential, particularly against resistant bacterial strains.

  18. Synthesis, characterization and application of a novel chemical sand-fixing agent-poly(aspartic acid) and its composites.

    PubMed

    Yang, Jun; Wang, Fang; Fang, Li; Tan, Tianwei

    2007-09-01

    A novel sand-fixing agent-poly(aspartic acid) and its composites were synthesized to improve sand particles compressive strength and anti-wind erosion properties. The relationship between the concentration of sand-fixing agent and the sand-fixing properties was studied by three kinds of aging tests. Some composites were choose to improve the sand-fixing property and the composition of 40% xanthan gum and 60% ethyl cellulose were chosen to compare sand-fixing property with lignosulfonate. The results showed that the sand-fixing and water-retaining properties of xanthan gum and ethyl cellulose composites were better than that of lignosulfonate. The biodegradability experiment showed that the PASP and its composites were environment-friendly products and the field test showed that the PASP composites could improve wind erosion disturbance.

  19. Design, synthesis and molecular docking of salicylic acid derivatives containing metronidazole as a new class of antimicrobial agents.

    PubMed

    Guo, Zhi-Hua; Yin, Yong; Wang, Cong; Wang, Peng-Fei; Zhang, Xing-Tao; Wang, Zhong-Chang; Zhu, Hai-Liang

    2015-09-15

    A series of novel salicylic acid derivatives containing metronidazole as Staphylococcus aureus Tyrosyl-tRNA synthetase (TyrRS) inhibitors have been synthesized and evaluated their biology activities as potential antibacterial agents. Among these compounds, compound 5r exhibited the most potent antibacterial activity against Gram-positive (S. aureus ATCC 6538 and Bacillus subtilis ATCC 6633) and Gram-negative (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525) with MICs of 0.39-1.57 μg/mL and showed the most potent S. aureus Tyrosyl-tRNA synthetase inhibitory with 2.3 μM. Docking simulation was performed to insert compound 5r into the crystal structure of S. aureus Tyrosyl-tRNA synthetase active site to determine the probable binding model. These results suggested that compound 5r may be a promising antibacterial agent.

  20. Copolymer of methacrylic acid with its diethylammonium salt: Effective waterproofing agent for oil wells

    SciTech Connect

    Kuznetsova, O.N.; Avvakumova, N.I.

    1992-08-10

    In the development of technology for the copolymerization of methacrylic acid with its diethylammonium salt (MAA-MAA{center_dot}DEA), the polymer-like reaction of polymethacrylic acid (PMAA) with diethylamine (DEA) and the polymerization of MAA in the presence of DEA have been studied. 13 refs., 3 figs., 4 tabs.

  1. Synthesis and Biological Evaluation of Novel Phosphatidylcholine Analogues Containing Monoterpene Acids as Potent Antiproliferative Agents

    PubMed Central

    Gliszczyńska, Anna; Niezgoda, Natalia; Gładkowski, Witold; Czarnecka, Marta; Świtalska, Marta; Wietrzyk, Joanna

    2016-01-01

    The synthesis of novel phosphatidylcholines with geranic and citronellic acids in sn-1 and sn-2 positions is described. The structured phospholipids were obtained in high yields (59–87%) and evaluated in vitro for their cytotoxic activity against several cancer cell lines of different origin: MV4-11, A-549, MCF-7, LOVO, LOVO/DX, HepG2 and also towards non-cancer cell line BALB/3T3 (normal mice fibroblasts). The phosphatidylcholines modified with monoterpene acid showed a significantly higher antiproliferative activity than free monoterpene acids. The highest activity was observed for the terpene-phospholipids containing the isoprenoid acids in sn-1 position of phosphatidylcholine and palmitic acid in sn-2. PMID:27310666

  2. Enteric-coated tablet of risedronate sodium in combination with phytic acid, a natural chelating agent, for improved oral bioavailability.

    PubMed

    Kim, Jeong S; Jang, Sun W; Son, Miwon; Kim, Byoung M; Kang, Myung J

    2016-01-20

    The oral bioavailability (BA) of risedronate sodium (RS), an antiresorptive agent, is less than 1% due to its low membrane permeability as well as the formation of non-absorbable complexes with multivalent cations such as calcium ion (Ca(2+)) in the gastrointestinal tract. In the present study, to increase oral BA of the bisphosphonate, a novel enteric-coated tablet (ECT) dosage form of RS in combination with phytic acid (IP6), a natural chelating agent recognized as safe, was formulated. The chelating behavior of IP6 against Ca(2+), including a stability constant for complex formulation was characterized using the continuous variation method. Subsequently, in vitro dissolution profile and in vivo pharmacokinetic profile of the novel ECT were evaluated comparatively with that of the marketed product (Altevia, Sanofi, US), an ECT containing ethylenediaminetetraacetic acid (EDTA) as a chelating agent, in beagle dogs. The logarithm of stability constant for Ca(2+)-IP6 complex, an equilibrium constant approximating the strength of the interaction between two chemicals to form complex, was 19.05, which was 3.9-fold (p<0.05) and 1.7-fold (p<0.05) higher than those of Ca(2+)-RS and Ca(2+)-EDTA complexes. The release profile of RS from both enteric-coated dosage forms was equivalent, regardless of the type of chelating agent. An in vivo absorption study in beagle dogs revealed that the maximum plasma concentration and area under the curve of RS after oral administration of IP6-containing ECT were approximately 7.9- (p<0.05) and 5.0-fold (p<0.05) higher than those of the marketed product at the same dose (35mg as RS). Therefore, our study demonstrates the potential usefulness of the ECT system in combination with IP6 for an oral therapy with the bisphosphonate for improved BA.

  3. Nucleic acid approaches for detection and identification of biological warfare and infectious disease agents.

    PubMed

    Ivnitski, Dmitri; O'Neil, Daniel J; Gattuso, Anthony; Schlicht, Roger; Calidonna, Michael; Fisher, Rodney

    2003-10-01

    Biological warfare agents are the most problematic of the weapons of mass destruction and terror. Both civilian and military sources predict that over the next decade the threat from proliferation of these agents will increase significantly. In this review we summarize the state of the art in detection and identification of biological threat agents based on PCR technology with emphasis on the new technology of microarrays. The advantages and limitations of real-time PCR technology and a review of the literature as it applies to pathogen and virus detection are presented. The paper covers a number of issues related to the challenges facing biological threat agent detection technologies and identifies critical components that must be overcome for the emergence of reliable PCR-based DNA technologies as bioterrorism countermeasures and for environmental applications. The review evaluates various system components developed for an integrated DNA microchip and the potential applications of the next generation of fully automated DNA analyzers with integrated sample preparation and biosensing elements. The article also reviews promising devices and technologies that are near to being, or have been, commercialized.

  4. Poly(Lactic-co-Glycolic) Acid as a Carrier for Imaging Contrast Agents

    PubMed Central

    Doiron, Amber L.; Homan, Kimberly A.; Emelianov, Stanislav; Brannon-Peppas, Lisa

    2010-01-01

    Purpose With the broadening field of nanomedicine poised for future molecular level therapeutics, nano-and microparticles intended for the augmentation of either single- or multimodal imaging are created with PLGA as the chief constituent and carrier. Methods Emulsion techniques were used to encapsulate hydrophilic and hydrophobic imaging contrast agents in PLGA particles. The imaging contrast properties of these PLGA particles were further enhanced by reducing silver onto the PLGA surface, creating a silver cage around the polymeric core. Results The MRI contrast agent Gd-DTPA and the exogenous dye rhodamine 6G were both encapsulated in PLGA and shown to enhance MR and fluorescence contrast, respectively. The silver nanocage built around PLGA nanoparticles exhibited strong near infrared light absorbance properties, making it a suitable contrast agent for optical imaging strategies such as photoacoustic imaging. Conclusions The biodegradable polymer PLGA is an extremely versatile nano- and micro-carrier for several imaging contrast agents with the possibility of targeting diseased states at a molecular level. PMID:19034628

  5. Removal of heavy metals from polluted soil using the citric acid fermentation broth: a promising washing agent.

    PubMed

    Zhang, Hongjiao; Gao, Yuntao; Xiong, Huabin

    2017-04-01

    The citric acid fermentation broth was prepared and it was employed to washing remediation of heavy metal-polluted soil. A well-defined washing effect was obtained, the removal percentages using citric acid fermentation broth are that 48.2% for Pb, 30.6% for Cu, 43.7% for Cr, and 58.4% for Cd and higher than that using citric acid solution. The kinetics of heavy metals desorption can be described by the double constant equation and Elovich equation and is a heterogeneous diffusion process. The speciation analysis shows that the citric acid fermentation broth can effectively reduce bioavailability and environmental risk of heavy metals. Spectroscopy characteristics analysis suggests that the washing method has only a small effect on the mineral composition and does not destroy the framework of soil system. Therefore, the citric acid fermentation broth is a promising washing agent and possesses a potential practical application value in the field of remediation of soils with a good washing performance.

  6. Synthesis and antitussive evaluation of verticinone-cholic acid salt, a novel and potential cough therapeutic agent.

    PubMed

    Xu, Fang-Zhou; Chen, Chang; Zhang, Yong-Hui; Ruan, Han-Li; Pi, Hui-Fang; Zhang, Pong; Wu, Ji-Zhou

    2007-10-01

    To seek a novel and potent antitussive drug based on Shedan-Chuanbei powder, a complex of traditional Chinese medicine preparation for cough therapy. Verticinone-cholic acid (Ver-CA) salt, a novel, salifying derivative of verticinone and cholic acid, both of which are the major bioactive components in Shedan-Chuanbei powder, was synthesized. We then evaluated the antitussive activity and the acute toxicity of the salt. The new compound, with good solubility in water, has much more potent antitussive activity in comparison with the same dose of single verticinone and single cholic acid. The administration 3 mg/kg of Ver-CA could result in over 50% reduction of a citric acid-induced cough. Pretreatment with naloxone (0.8 mg/kg, ip) can only partially antagonize its antitussive effect. On the other hand, glybenclamide (3 mg/kg, ip), an ATP-sensitive K+ channel blocker, can also significantly reduce the antitussive effect of Ver-CA. A further acute toxicity study showed that the LD(50) values of Ver-CA were 3 times that of verticinone. Based on the studies of pharmacology and acute toxicity, the salt has a synergic and attenuated toxicity compared with single verticinone and cholic acid. Moreover, the present study also suggests that Ver-CA, a potential novel antitussive agent, may exert its antitussive effect via both the peripheral (modulated by ATP-sensitive K+ channels) and central mechanisms (modulated by the opioid receptor).

  7. Improved Cycling Performance of a Si Nanoparticle Anode Utilizing Citric Acid as a Surface-Modifying Agent.

    PubMed

    Nguyen, Cao Cuong; Seo, Daniel M; Chandrasiri, K W D K; Lucht, Brett L

    2017-09-19

    Citric acid and its analogues have been investigated as surface-modifying agents for Si nanoparticle anodes using electrochemical cycling, attenuated total reflectance infrared (ATR IR), and X-ray photoelectron spectroscopy (XPS). A Si nanoparticle anode prepared with citric acid (CA) has better capacity retention than one containing 1,2,3,4-butanetetracarboxylic acid (BA), but both electrodes outperform Si-PVDF. The Si-CA anode has an initial specific capacity of 3530 mA h/g and a first cycle efficiency of 82%. Surprisingly, the Si-CA electrode maintains a high specific capacity of ∼2200 mA h/g after 250 cycles, corresponding to 64% capacity retention, which is similar to the Si prepared with long-chain poly(acrylic acid) (PAA). On the contrary, the silicon electrode prepared with PVDF has a fast capacity fade and retains only 980 mA h/g after 50 cycles. The IR and XPS data show that the Si-CA electrode has an SEI composed primarily of lithium citrate during the first 50 cycles, resulting from the electrochemical reduction of citric acid. Only low concentrations of electrolyte reduction products are observed. The lithium citrate layer derived from CA stabilizes the silicon surface and suppresses electrolyte reduction, which likely contributes to the enhanced cycling performance of the Si nanoparticle anode.

  8. Noncovalent modification of carbon nanotubes with ferrocene-amino acid conjugates for electrochemical sensing of chemical warfare agent mimics.

    PubMed

    Khan, Mohammad A K; Kerman, Kagan; Petryk, Michael; Kraatz, Heinz-Bernhard

    2008-04-01

    The electrochemical detection of chemical warfare agent (CWA) mimics was explored using multiwalled carbon nanotubes (MWCNTs) on indium tin oxide (ITO) surfaces in connection with ferrocene-amino acid conjugates. Various ferrocene-amino acid conjugates were synthesized and utilized as the recognition layer for the detection of CWA mimics. The ferrocene-amino acid conjugates were noncovalently attached to the pretreated MWCNTs on the ITO surface and reacted with CWA mimics, upon which the electrical properties of the MWCNTs and the Fc group were affected significantly. Alternating current voltammetry and capacitance-based detection offered large dynamic ranges for the detection of methylphosphonic acid, diethyl cyanophosphonate, ethylmethylphosphonate, and pinacolyl methylphosphonate in water. Electrochemical measurements showed dramatic changes upon the electrostatic interaction between the CWA mimics and the ferrocene-amino acid conjugates immobilized on MWCNTs on ITO surfaces. Electrochemical sensing in connection with MWCNTs is shown to be a promising analytical tool for the trace-level detection of CWA mimics in aqueous solutions.

  9. Delivery of selective agents via time-delayed release tablets improves recovery of Listeria monocytogenes injured by acid and nitrite.

    PubMed

    Nyarko, Esmond; D'Amico, Dennis; Mach, Patrick; Xia, Wensheng; Donnelly, Catherine

    2014-05-01

    Listeria selective enrichment media are designed to enhance the isolation of the organism and increase the chances of detection. Drawbacks include the requirements for prolonged sample incubation (48 to 72 h) and manual addition of selective agents, which may be a source of contamination. Modified Listeria recovery broth (mLRB) is a proprietary enrichment medium formulated to facilitate the recovery of injured cells; its selective agents are incorporated into a format that allows delayed release until 6 h of incubation. We evaluated the change in cell populations over time for acid- and nitrite-injured Listeria monocytogenes in mLRB with the selective agents added manually at 0 h (mLRBS0) and 6 h (mLRBS6). Recovery of injured cells in mLRB plus time-delayed tablets (mLRBTD) was also compared with that in enrichment media recommended by the U.S. Department of Agriculture (University of Vermont broth), the U.S. Food and Drug Administration (buffered Listeria enrichment broth), and the International Organization for Standardization (demi-Fraser broth). Nitrite- or acid-injured Listeria at approximately 10 CFU/ml were inoculated into each broth medium, and Listeria populations were enumerated at various times from 12 to 48 h of incubation at 37°C. Analysis of variance revealed that acid-injured Listeria populations in mLRBS6 at 24 h were significantly higher (P < 0.05) than those in mLRBS0; however, the differences in populations on these two media were not significant for nitrite-injured cells. Cell populations of four strains of Listeria inoculated into mLRBTD were significantly higher at 24 h than when those strains were enriched in buffered Listeria enrichment broth, demi-Fraser broth, and University of Vermont broth. Comparison between artificially contaminated milk and meat samples with a four-strain cocktail of Listeria resulted in cell populations that were significantly higher (P < 0.05) at 24 h on mLRBTD for contaminated meat than on mLRB for contaminated

  10. 4-Hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester derivatives as potent anti-tumor agents.

    PubMed

    Hayakawa, Ichiro; Shioya, Rieko; Agatsuma, Toshinori; Furukawa, Hidehiko; Naruto, Shunji; Sugano, Yuichi

    2004-01-19

    Based on the structure of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester (1), which exhibits selective cytotoxicity against a tumorigenic cell line, (2,4-dimethoxyphenyl)-(4-hydroxy-3-methyl-6-phenylbenzofuran-2-yl)-methanone (18m) was designed and synthesized as a biologically stable derivative containing no ester group. Although the potency of 18m was almost the same as our initial hit compound 1, 18m is expected to last longer in the human body as an anticancer agent.

  11. Novel conjugates of aspirin with phenolic acid as anti-inflammatory agents having significantly reduced gastrointestinal toxicity.

    PubMed

    Jiang, Shan; Ding, Ning; Zhang, Wei; Zhang, Yichun; Geng, Meiyu; Li, Yingxia

    2010-04-01

    A series of novel conjugates of aspirin with natural phenolic acid antioxidants connected through a diol linker were designed and synthesized as potential bifunctional agents combining antioxidant and anti-inflammatory activity for reducing gastrointestinal toxicity. In general, the conjugates were found to be efficient antioxidants and many of them demonstrated much more potent anti-inflammatory activity than aspirin. Among them, 5a and 5b which bear the best anti-inflammatory activity exhibited significantly reduced ulcerogenic potency and toxicity compared to aspirin. However, it is evident that the anti-inflammatory activity of these dual-acting molecules in vivo, was not simply consistent with their antioxidant ability in vitro.

  12. Synthesis and evaluation of novel 6',6'-difluoro 5'-deoxycarbocyclic phosphonic acid nucleosides as antiviral agents.

    PubMed

    Kim, Eunae; Shen, Guang Huan; Kang, Lien; Hong, Joon Hee

    2013-01-01

    The authors describe highly efficient synthetic routes for the preparation of novel 6',6'-difluoro 5'-deoxycarbocyclic phosphonic acid nucleosides from 1,4-dihydroxy-2-butene. The discovery that the 6'-fluorinated carbocyclic nucleoside (2, EC₅₀ = 0.16 μM) is a potent anti-HSV-1 agent led to the syntheses and biological evaluations of 6'-modified 5'-deoxyversions of carbocyclic phosphonate nucleosides. The synthesized nucleoside analogues 15, 18, 22, and 25 were tested for anti-HIV activity and for cytotoxicity. However, none of them showed significant anti-HIV-1 activity or cytotoxicity at concentrations up to 100 μM.

  13. Synthesis of Novel 4'-Trifluoromethyl-5'-Norcarbocyclic C-Nucleoside Phosphonic Acids as Potent Anti-Leukemic Agents.

    PubMed

    Kim, Seyeon; Hong, Joon Hee

    2015-01-01

    The syntheses of novel C-nucleoside phosphonic acids as potential antiviral agents are described. The sugar moiety that served as the nucleoside skeleton was produced starting from commercially available 1,3-dihydroxy cyclopentane. The key C-C bond formation from sugar to base precursor was performed using the Knoevenagel-type condensation. The synthesized compounds exhibited anti-HIV activity and cytotoxicity. Also, the synthesized compounds were screened in vitro for tumor growth inhibitory activity against mouse leukemia cell lines (L-1210, P-815).

  14. Synthesis and antiviral evaluation of novel 2',2'-difluoro 5'-norcarbocyclic phosphonic acid nucleosides as antiviral agents.

    PubMed

    Shen, Guang Huan; Hong, Joon Hee

    2014-01-01

    A very efficient synthetic route to novel 2',2'-difluoro 5'-norcarbocyclic phosphonic acid nucleosides from but-3-en-1-ol 5 is described. The discovery of 2'-fluorinated furanose nucleoside 1 as a potent anti-HIV-1 agent has led to the synthesis and biological evaluation of 2'-modified 5'-norversions of the carbocyclic phosphonate nucleosides. The synthesized nucleoside analogues 18, 19, 23a, 23b, and 24 were tested for anti-HIV activity as well as cytotoxicity. Adenine analogue 19 shows significant anti-HIV-1 activity (EC(50) = 13 μM).

  15. [Amino acid chloramines and chlorimines as antiplatelet agents: reactive properties and mechanism of action].

    PubMed

    Murina, M A; Roshchupkin, D I; Petrova, A O; Sergienko, V I

    2009-01-01

    Oxidative modifications of thiols, disulfide, and thioester atomic groups in proteins, peptides, and amino acids induced by chloramines or chloramine derivatives of amino acids and other reactive oxidants are considered. In the case of disulfide and thiol groups, production of sulfur-reactive groups may take place, such as disulphide S-oxides and sulphenic groups. Various chloramines and chloramines differently modify sulfur-containing groups. For example, N,N-dichlorotaurine rapidly modifies the thiolgroup in reduced glutathione and N-chloroglycine readily oxidizes the thioester group in methionine. Amino acid chloramines inhibit platelet aggregation by modifying S-containing centres. Autodecay of amino acid chloramines does not affect aggregation as follows from the absence of positive correlation between chloramines decay rate and antiplatelet activity. N,N-dichlorotaurine and its chlorimine derivatives are characterized by high stability and have good prospects as potential antiaggregants.

  16. Poly (amido amine) and nano-calcium phosphate bonding agent to remineralize tooth dentin in cyclic artificial saliva/lactic acid.

    PubMed

    Liang, Kunneng; Weir, Michael D; Reynolds, Mark A; Zhou, Xuedong; Li, Jiyao; Xu, Hockin H K

    2017-03-01

    The objectives of this study were to develop a novel method to remineralize dentin lesions, and investigate the remineralization effects of poly (amido amine) (PAMAM) dendrimer plus a bonding agent with nanoparticles of amorphous calcium phosphate (NACP) in a cyclic artificial saliva/lactic acid environment for the first time. Dentin lesions were produced via phosphoric acid. Four groups were tested: (1) dentin control, (2) dentin with PAMAM, (3) dentin with NACP bonding agent, and (4) dentin with PAMAM plus NACP bonding agent. Specimens were treated with cyclic artificial saliva/lactic acid. The remineralized dentin was examined using scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), hardness and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). NACP bonding agent yielded a dentin shear bond strength similar to commercial controls (Prime & Bond NT, Dentsply; Scotchbond Multi-purpose, 3M) (p>0.1). Increasing NACP in bonding agent from 0 to 40% did not affect bond strength. NACP bonding agent neutralized the acid and released Ca ions with concentrations of 4 to 20mmol/L, and P ions of 2 to 9mmol/L. PAMAM or NACP bonding agent alone achieved slight remineralization. The PAMAM+NACP group achieved the greatest dentin remineralization p<0.05). At 20days, PAMAM+NACP increased the hardness of pre-demineralized dentin to reach the normal dentin hardness (p>0.1). In conclusion, superior remineralization of PAMAM+NACP bonding agent was demonstrated for the first time. PAMAM+NACP bonding agent induced dentin remineralization under acid challenge, when conventional remineralization methods such as PAMAM alone did not work well. The novel PAMAM+NACP bonding agent method is promising to improve the longevity of resin-dentin bonds, inhibit caries, and protect teeth.

  17. Biodegradable DNA-brush Block Copolymer Spherical Nucleic Acids Enable Transfection Agent-Free Intracellular Gene Regulation

    PubMed Central

    Zhang, Chuan; Hao, Liangliang; Calabrese, Colin M.; Zhou, Yu; Choi, Chung Hang J.; Xing, Hang; Mirkin, Chad A.

    2015-01-01

    A new strategy for synthesizing spherical nucleic acid (SNA) nanostructures from biodegradable DNA block copolymers is reported. Multiple DNA strands are grafted to one end of a polyester chain (poly-caprolactone) to generate an amphiphilic DNA brush block copolymer (DBBC) structure capable of assembling into spherical micelles in aqueous solution. These novel DBBC-based micelle-SNAs exhibit a higher surface density of nucleic acids compared to micelle structures assembled from an analogous linear DNA block copolymer (DBC), which endows them with the ability to more efficiently enter cells without the need for transfection agents. Importantly, the new SNAs show effective gene regulation without observable cellular toxicity in mammalian cell culture. PMID:26297167

  18. Data of thermal degradation and dynamic mechanical properties of starch–glycerol based films with citric acid as crosslinking agent

    PubMed Central

    González Seligra, Paula; Medina Jaramillo, Carolina; Famá, Lucía; Goyanes, Silvia

    2016-01-01

    Interest in biodegradable edible films as packaging or coating has increased because their beneficial effects on foods. In particular, food products are highly dependents on thermal stability, integrity and transition process temperatures of the packaging. The present work describes a complete data of the thermal degradation and dynamic mechanical properties of starch–glycerol based films with citric acid (CA) as crosslinking agent described in the article titled: “Biodegradable and non-retrogradable eco-films based on starch–glycerol with citric acid as crosslinking agent” González Seligra et al. (2016) [1]. Data describes thermogravimetric and dynamical mechanical experiences and provides the figures of weight loss and loss tangent of the films as a function of the temperature. PMID:27158645

  19. Formic acid as an alternative reducing agent for the catalytic nitrate reduction in aqueous media.

    PubMed

    Choi, Eun-Kyoung; Park, Kuy-Hyun; Lee, Ho-Bin; Cho, Misun; Ahn, Samyoung

    2013-08-01

    Formic acid was used for the nitrate reduction as a reductant in the presence of Pd:Cu/gamma-alumina catalysts. The surface characteristics of the bimetallic catalyst synthesized by wet impregnation were investigated by SEM, TEM-EDS. The metals were not distributed homogeneously on the surface of catalyst, although the total contents of both metals in particles agreed well with the theoretical values. Formic acid decomposition on the catalyst surface, its influence on solution pH and nitrate removal efficacy was investigated. The best removal of nitrate (50 ppm) was obtained under the condition of 0.75 g/L catalyst with Pd:Cu ratio (4:1) and two fold excess of formic acid. Formic acid decay patterns resembled those of nitrate removal, showing a linear relationship between k(f) (formic acid decay) and k (nitrate removal). Negligible amount of ammonia was detected, and no nitrite was detected, possibly due to buffering effect of bicarbonate that is in situ produced by the decomposition of formic acid, and due to the sustained release of H2 gas.

  20. Real-time monitoring of matrix acidizing including the effects of diverting agents

    SciTech Connect

    Hill, A.D.; Zhu, D.

    1996-05-01

    Real-time monitoring of the injection rate and pressure during matrix acidizing provides operators with a way to determine the changing skin factor as stimulation proceeds. Current methods are based either on the assumption of steady-state flow in the region around the wellbore affected by acid injection or on computer solution of the transient flow equations describing the unsteady reservoir flow process occurring during acidizing. In this paper, a new method for real-time monitoring of matrix acidizing, the inverse injectivity vs. superposition time function plot, is presented. This new method can be applied with a spreadsheet computer program or a programmable calculator and accounts for the transient flow effects occurring during matrix acidizing at multiple rates and injection pressures. The evolving skin factor during a matrix treatment is readily obtained from the diagnostic plot. Hypothetical examples show how the inverse injectivity plot can be used to assess the efficiency of stimulation and diversion. Comparisons with previously presented field cases show the new method to be a simple and accurate means of monitoring the evolving skin factor during matrix acidizing.

  1. Design, Synthesis and Biological Evaluation of Sulfur-Containing 1,1-Bisphosphonic Acids as Antiparasitic Agents

    PubMed Central

    Recher, Marion; Barboza, Alejandro P.; Li, Zhu-Hong; Galizzi, Melina; Ferrer-Casal, Mariana; Szajnman, Sergio H.; Docampo, Roberto; Moreno, Silvia N. J.

    2013-01-01

    As part of our efforts aimed at searching for new antiparasitic agents, 2-alkylmercaptoethyl-1,1-bisphosphonate derivatives were synthesized and evaluated against Trypanosoma cruzi, the etiologic agent of Chagas disease, and Toxoplasma gondii, the responsible agent for toxoplasmosis. Many of these sulfur-containing bisphosphonates were potent inhibitors against the intracellular form of T. cruzi, the clinically more relevant replicative form of this parasite, and tachyzoites of T. gondii targeting T. cruzi or T. gondii farnesyl diphosphate synthases (FPPSs), which constitute valid targets for the chemotherapy of these parasitic diseases. Interestingly, long chain length sulfur-containing bisphosphonates emerged as relevant antiparasitic agents. Taking compounds 37, 38, and 39 as representative members of this class of drugs, they exhibited ED50 values of 15.8 μM, 12.8 μM, and 22.4 μM, respectively, against amastigotes of T. cruzi. These cellular activities matched the inhibition of the enzymatic activity of the target enzyme (TcFPPS) having IC50 values of 6.4 μM, 1.7 μM, and 0.097 μM, respectively. In addition, these compounds were potent anti-Toxoplasma agents. They had ED50 values of 2.6 μM, 1.2 μM, and 1.8 μM, respectively, against T. gondii tachyzoites, while they exhibited a very potent inhibitory action against the target enzyme (TgFPPS) showing IC50 values of 0.024 μM, 0.025 μM, and 0.021 μM, respectively. Bisphosphonates bearing a sulfoxide unit at C-3 were also potent anti-Toxoplasma agents, particularly those bearing long aliphatic chains such as 43–45, which were also potent antiproliferative drugs against tachyzoites of T. gondii. These compounds inhibited the enzymatic activity of the target enzyme (TgFPPS) at the very low nanomolar range. These bisphosphonic acids have very good prospective not only as lead drugs but also as potential chemotherapeutic agents. PMID:23318904

  2. Multivalent Protein Polymer MRI Contrast Agents: Controlling Relaxivity via Modulation of Amino Acid Sequence

    PubMed Central

    Karfeld-Sulzer, Lindsay S.; Waters, Emily A.; Davis, Nicolynn E.; Meade, Thomas J.; Barron, Annelise E.

    2010-01-01

    Magnetic Resonance Imaging (MRI) is a noninvasive imaging modality with high spatial and temporal resolution. Contrast agents (CAs) are frequently used to increase the contrast between tissues of interest. To increase the effectiveness of MR agents, small molecule CAs have been attached to macromolecules. We have created a family of biodegradable, macromolecular CAs based on protein polymers, allowing control over the CA properties. The protein polymers are monodisperse, random coil, and contain evenly spaced lysines that serve as reactive sites for Gd(III) chelates. The exact sequence and length of the protein can be specified, enabling controlled variation in lysine spacing and molecular weight. Relaxivity could be modulated by changing protein polymer length and lysine spacing. Relaxivities of up to ∼14 mM-1s-1 per Gd(III) and ∼461 mM-1s-1 per conjugate were observed. These CAs are biodegradable by incubation with plasmin, such that they can be easily excreted after use. They do not reduce cell viability, a prerequisite for future in vivo studies. The protein polymer CAs can be customized for different clinical diagnostic applications, including biomaterial tracking, as a balanced agent with high relaxivity and appropriate molar mass. PMID:20420441

  3. Research on the interaction of hydrogen-bond acidic polymer sensitive sensor materials with chemical warfare agents simulants by inverse gas chromatography.

    PubMed

    Yang, Liu; Han, Qiang; Cao, Shuya; Huang, Feng; Qin, Molin; Guo, Chenghai; Ding, Mingyu

    2015-06-02

    Hydrogen-bond acidic polymers are important high affinity materials sensitive to organophosphates in the chemical warfare agent sensor detection process. Interactions between the sensor sensitive materials and chemical warfare agent simulants were studied by inverse gas chromatography. Hydrogen bonded acidic polymers, i.e., BSP3, were prepared for micro-packed columns to examine the interaction. DMMP (a nerve gas simulant) and 2-CEES (a blister agent simulant) were used as probes. Chemical and physical parameters such as heats of absorption and Henry constants of the polymers to DMMP and 2-CEES were determined by inverse gas chromatography. Details concerning absorption performance are also discussed in this paper.

  4. Research on the Interaction of Hydrogen-Bond Acidic Polymer Sensitive Sensor Materials with Chemical Warfare Agents Simulants by Inverse Gas Chromatography

    PubMed Central

    Yang, Liu; Han, Qiang; Cao, Shuya; Huang, Feng; Qin, Molin; Guo, Chenghai; Ding, Mingyu

    2015-01-01

    Hydrogen-bond acidic polymers are important high affinity materials sensitive to organophosphates in the chemical warfare agent sensor detection process. Interactions between the sensor sensitive materials and chemical warfare agent simulants were studied by inverse gas chromatography. Hydrogen bonded acidic polymers, i.e., BSP3, were prepared for micro-packed columns to examine the interaction. DMMP (a nerve gas simulant) and 2-CEES (a blister agent simulant) were used as probes. Chemical and physical parameters such as heats of absorption and Henry constants of the polymers to DMMP and 2-CEES were determined by inverse gas chromatography. Details concerning absorption performance are also discussed in this paper. PMID:26043177

  5. Study of photo-oxidative reactivity of sunscreening agents based on photo-oxidation of uric acid by kinetic Monte Carlo simulation.

    PubMed

    Moradmand Jalali, Hamed; Bashiri, Hadis; Rasa, Hossein

    2015-05-01

    In the present study, the mechanism of free radical production by light-reflective agents in sunscreens (TiO2, ZnO and ZrO2) was obtained by applying kinetic Monte Carlo simulation. The values of the rate constants for each step of the suggested mechanism have been obtained by simulation. The effect of the initial concentration of mineral oxides and uric acid on the rate of uric acid photo-oxidation by irradiation of some sun care agents has been studied. The kinetic Monte Carlo simulation results agree qualitatively with the existing experimental data for the production of free radicals by sun care agents.

  6. Structural characterization of 1,3-propanedithiols that feature carboxylic acids: Homologues of mercury chelating agents.

    PubMed

    Sattler, Wesley; Palmer, Joshua H; Bridges, Christy C; Joshee, Lucy; Zalups, Rudolfs K; Parkin, Gerard

    2013-11-12

    The molecular structures of a series of 1,3-propanedithiols that contain carboxylic acid groups, namely rac- and meso-2,4-dimercaptoglutaric acid (H4DMGA) and 2-carboxy-1,3-propanedithiol (H3DMCP), have been determined by X-ray diffraction. Each compound exhibits two centrosymmetric intermolecular hydrogen bonding interactions between pairs of carboxylic acid groups, which result in a dimeric structure for H3DMCP and a polymeric tape-like structure for rac- and meso-H4DMGA. Significantly, the hydrogen bonding motifs observed for rac- and meso-H4DMGA are very different to those observed for the 1,2-dithiol, rac-2,3-dimercaptosuccinic acid (rac-H4DMSA), in which the two oxygen atoms of each carboxylic acid group hydrogen bond to two different carboxylic acid groups, thereby resulting in a hydrogen bonded sheet-like structure rather than a tape. Density functional theory calculations indicate that 1,3-dithiolate coordination to mercury results in larger S-Hg-S bond angles than does 1,2-dithiolate coordination, but these angles are far from linear. As such, κ(2)-S2 coordination of these dithiolate ligands is expected to be associated with mercury coordination numbers of greater than two. In vivo studies demonstrate that both rac-H 4 DMGA and H3DMCP reduce the renal burden of mercury in rats, although the compounds are not as effective as either 2,3-dimercaptopropane-1-sulfonic acid (H3DMPS) or meso-H4DMSA.

  7. Acid reducing agents to neonates – lack of evidence and guidelines

    PubMed Central

    Paulsson, Stina; Eksborg, Staffan; Andersson, Åsa; Nydert, Per; Grahnquist, Lena

    2012-01-01

    Objective The aim of this retrospective study was to investigate the clinical practice, i.e. the frequency of use and the treatment strategies, for acid reducing drugs to neonates in a Swedish hospital. Methods Retrospective reviews of charts and interviews with nurses at the neonatal wards of Karolinska University Hospital were performed to identify difficulties that might occur with drug administration. All patients admitted over a 2-month period were included. Main outcome measure were the number of patients treated with acid reducing drugs and the dosages. Results Nine out of 215 patients (4.2%) received an acid reducing drug. Patients treated with acid reducing drugs had significantly lower birth weight, lower gestational age and longer duration of hospitalization. Eight of the patients were treated with omeprazole. One of these patients started treatment with omeprazole but continued later on with ranitidine. One patient was exclusively treated with ranitidine. The doses of omeprazole (intravenous or oral administration) were within the range 0.16–1.26 mg/kg/day. Conclusions A wide variation in treatment regimens of acid reducing drugs is given to newborn infants. The percentage of treated children was much lower than earlier reports from the US and UK. No conclusions can be drawn as to whether the doses and dosing intervals used give sufficient acid suppression, since the effect of the therapy was not recorded. The present study is only retrospective and data are not truly comparable with other studies. Further studies are therefore warranted to evaluate effective doses and pharmacokinetics of acid reducing drugs in newborn infants. PMID:27536424

  8. The antiepileptic and anticancer agent, valproic acid, induces P-glycoprotein in human tumour cell lines and in rat liver

    PubMed Central

    Eyal, S; Lamb, J G; Smith-Yockman, M; Yagen, B; Fibach, E; Altschuler, Y; White, H S; Bialer, M

    2006-01-01

    Background and purpose: The antiepileptic drug valproic acid, a histone deacetylase (HDAC) inhibitor, is currently being tested as an anticancer agent. However, HDAC inhibitors may interact with anticancer drugs through induction of P-glycoprotein (P-gp, MDR1) expression. In this study we assessed whether valproic acid induces P-gp function in tumour cells. We also investigated effects of valproic acid on the mRNA for P-gp and the cytochrome P450, CYP3A, in rat livers. >Experimental approach: Effects of valproic acid on P-gp were assessed in three tumour cell lines, SW620, KG1a and H4IIE. Accumulation of acetylated histone H3 in rats' livers treated for two or seven days with valproic acid was evaluated using a specific antibody. Hepatic expression of the P-gp genes, mdr1a, mdr1b and mdr2, was determined by real-time polymerase chain reaction. The effects of valproic acid on CYP3A were assessed by Northern blot analysis and CYP3A activity assays. Key results: Valproic acid (0.5–2.0 mM) induced P-gp expression and function up to 4-fold in vitro. The effect of a series of valproic acid derivatives on P-gp expression in SW620 and KG1a cells correlated with their HDAC inhibition potencies. Treatment of rats with 1 mmol kg−1 valproic acid for two and seven days increased hepatic histone acetylation (1.3- and 3.5-fold, respectively) and the expression of mdr1a and mdr2 (2.2–4.1-fold). Valpromide (0.5–2.0 mM) did not increase histone acetylation or P-gp expression in rat livers, but induced CYP3A expression. Conclusions: Valproic acid increased P-gp expression and function in human tumour cell lines and in rat liver. The clinical significance of this increase merits further investigation. PMID:16894351

  9. Therapeutic drug monitoring of enteric-coated mycophenolate sodium by limited sampling strategies is associated with a high rate of failure

    PubMed Central

    Hougardy, Jean-Michel; Maufort, Laurette; Cotton, Frédéric; Coussement, Julien; Mikhalski, Dimitri; Wissing, Karl M.; Le Moine, Alain; Broeders, Nilufer; Abramowicz, Daniel

    2016-01-01

    Background Therapeutic drug monitoring of mycophenolic acid (MPA) is usually performed with a limited sampling strategy (LSS), which relies on a limited number of blood samples and subsequent extrapolation of the global exposure to MPA. LSS is usually performed successfully with mycophenolate mofetil (MMF), but data on enteric-coated mycophenolate sodium (EC-MPS) are scarce. Here, we evaluated the feasibility of 6-h LSS therapeutic drug monitoring with EC-MPS compared with MMF monitoring among kidney transplant recipients. Methods Sixty-two patients who received EC-MPS during the first 6 months of transplantation were compared with a matched group of 64 MMF-treated kidney transplant recipients. The area under the curve (AUC) was computed by LSS using multiple concentration time points (0, 1, 2, 3 and 6 h post-dose) and a trapezoidal rule. Patients had MPA therapeutic drug monitoring performed on two occasions, one within 2 weeks and the second after 3–4 months of transplantation. Results EC-MPS monitoring and MMF therapeutic drug monitoring were not interpretable in 34.5% (n = 40/116) and 1.8% (n = 2/112) of patients, respectively {relative risk [RR] 19.3 [95% confidence interval (CI) 4.8–78.0]; P < 0.0001}. The main cause of abnormal EC-MPS therapeutic drug monitoring was delayed absorption of both the previous evening and the morning dose, resulting in MPA plasma levels before the next morning dose being higher than MPA plasma levels measured at 1, 2 and 3 h after taking EC-MPS. Cyclosporin in association with MMF significantly increased the risk of low AUC values (<30 mg h/L) in comparison with tacrolimus [55% (n = 11/20) and 10% (n = 9/88), respectively; RR 5.4 (95% CI 2.6–11.2); P < 0.0001]. Conclusions The risk of therapeutic drug monitoring failure with EC-MPS is >30% during the first 6 months of renal transplantation. Delayed pharmacokinetics was the main reason. In contrast, the risk of therapeutic drug monitoring failure was substantially lower with

  10. Development and Evaluation of a Nanoemulsion Containing Ursolic Acid: a Promising Trypanocidal Agent : Nanoemulsion with Ursolic Acid Against T. cruzi.

    PubMed

    Vargas de Oliveira, Erika Cristina; Carneiro, Zumira Aparecida; de Albuquerque, Sérgio; Marchetti, Juliana Maldonado

    2017-02-21

    Over a hundred years after the discovery of Chagas disease, this ailment continues to affect thousands of people. For more than 40 years, only two drugs have been available to treat it. Ursolic acid is a naturally occurring terpene that has shown a good trypanocidal action. However, the hydrophobicity of this compound presents a challenge for the development of proper delivery systems. Nanostructured systems are a prominent in delivering lipophilic drugs. Thus, a nanoemulsion containing ursolic acid was developed and had its trypanocidal activity and cytotoxicity evaluated. Pseudo-ternary phase diagrams and hydrophilic-lipophilic balance (HLB) system were used in the development. The system was stable throughout 90 days of testing, as evidenced by turbidimetry analysis and measurements of the droplet size (57.3 nm) and polydispersity index (0.24). Fourier transform infrared spectroscopy and mass spectrometry evidenced drug's integrity in the formulation. An in vitro dissolution profile showed 75% of ursolic acid release after 5 min from the nanoemulsion into the alkaline dissolution medium, while only 20% could be released from a physical mixture after 2 h. Trypanocidal activity and cytotoxicity were evaluated on the CL Brener strain and LLC-MK2 (monkey kidney) fibroblast by chlorophenol red-β-D-galactoside (CPRG) method. Biological studies showed that the developed formulation was nontoxic and effective against replicant forms of the parasite. A stable and efficient nanoemulsion could be developed to improve the delivery of a promising drug to treat a threatening illness such as Chagas disease.

  11. Novel cytotoxic agents from an unexpected source: bile acids and ovarian tumor apoptosis.

    PubMed

    Horowitz, Neil S; Hua, Jun; Powell, Matthew A; Gibb, Randall K; Mutch, David G; Herzog, Thomas J

    2007-11-01

    Unique biologic activities have been identified for the 4 different bile acids: cholic acid (CA, chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), and ursodeoxycholic acid (UDCA). The aim of this study was to examine and compare the effects of these 4 bile acids on the human ovarian cancer cell lines A2780 and A2780-CP-R(cisplatin-resistant) and to evaluate mechanisms of action. Antiproliferative effects were determined by the cytotoxic MTT assay. Cells undergoing apoptosis were identified by morphologic analysis of cells stained using Diff-Quick and nuclear staining with DAPI and by quantitative nucleosome ELISA assay. Cells were lysed in buffer after 24 h of exposure to three different concentrations of bile acid (50 mM, 200 mM, and 400 mM) and protein concentrations were determined. Cell extracts containing 25 mg of protein were assayed for protein kinase C (PKC) enzyme activity. None of the bile acids stimulated proliferation of ovarian cancer cells. CA and UDCA had only minimal cytotoxic effect even at maximum concentrations. In contrast, DCA and CDCA administration resulted in statistically significant dose-dependent cytotoxicity in both platinum sensitive and platinum-resistant cell lines (p<0.05). Cells incubated with DCA and CDCA exhibited morphologic features characteristic of apoptosis. The quantitative nucleosome ELISA assay demonstrated over 10 times increased nucleosome levels after cells were treated for 24 h by DCA and CDCA at 200 mM and 400 mM as compared to CA or UDCA treatment and to untreated controls (p<0.01). All 4 bile acids reduced PKC activity at concentrations of 200 and 400 mM (p<0.01). CDCA and DCA have significant cytotoxic activity in ovarian cancer cells via induction of apoptosis. The mechanism of apoptosis appears to be mediated by alternative kinases distinct from PKC. CDCA and DCA may have clinical utility in the treatment of ovarian cancer pending in vivo confirmation of activity especially in cisplatin-resistant disease.

  12. Augmenting the antifungal activity of an oxidizing agent with kojic Acid: control of penicillium strains infecting crops.

    PubMed

    Kim, Jong H; Chan, Kathleen L

    2014-11-12

    Oxidative treatment is one of the strategies for preventing Penicillium contamination in crops/foods. The antifungal efficacy of hydrogen peroxide (H2O2; oxidant) was investigated in Penicillium strains by using kojic acid (KA) as a chemosensitizing agent, which can enhance the susceptibility of pathogens to antifungal agents. Co-application of KA with H2O2 (chemosensitization) resulted in the enhancement of antifungal activity of either compound, when compared to the independent application of each agent alone. Of note, heat enhanced the activity of H2O2 to a greater extent during chemosensitization, whereby the minimum inhibitory or minimum fungicidal concentrations of H2O2 was decreased up to 4 or 13 fold, respectively, at 35-45 °C (heat), when compared to that at 28 °C (normal growth temperature). However, heat didn't increase the antifungal activity of KA, indicating specificity exists between heat and types of antifungals applied. The effect of chemosensitization was also strain-specific, where P. expansum (both parental and fludioxonil-resistant mutants) or P. italicum 983 exhibited relatively higher susceptibility to the chemosensitization, comparing to other Penicillium strains tested. Collectively, chemosensitization can serve as a potent antifungal strategy to lower effective dosages of toxic antifungal substances, such as H2O2. This can lead to coincidental lowering of environmental and health risks.

  13. A new facile route for synthesizing of graphene oxide using mixture of sulfuric-nitric-phosphoric acids as intercalating agent

    NASA Astrophysics Data System (ADS)

    Panwar, Vinay; Chattree, Ananya; Pal, Kaushik

    2015-09-01

    In this work, graphene oxide (GO) has been prepared through three different processes namely, eco-friendly Hummers method, modification in improved Hummers method and a new approach. This new approach has been designed by changing some processing parameters and intercalating agent for significant reduction in processing time and to improve the quantity of GO in comparison to the other two methods. This has been achieved through better oxidization of graphite using nitric-sulfuric acid (HNO3-H2SO4) as intercalating agent. X-ray diffraction (XRD), Field Emission Scanning Electron Microscopy (FESEM), Energy-dispersive X-ray spectroscopy (EDX), Raman spectroscopy, Atomic Force Microscopy (AFM), X-ray photoelectron spectroscopy (XPS), UV-visible spectroscopy, and Thermogravimetric analysis (TGA) are used to characterize the GO prepared through different processes. These characterizations have confirmed an improved exfoliation of graphite, using addition of HNO3 in intercalating agent, in a short processing time and bring on higher yield of GO via this new process.

  14. Synthesis of Tryptoline-3-Carboxylic Acid Derivatives A Novel Antidiabetic Agent

    PubMed Central

    Choudhary, AN; Kohli, MS; Kumar, A; Joshi, A

    2011-01-01

    The compounds, 2-(methylsulfonyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid (DM3), 2-(phenylsulfonyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid (DM4), and 2-(p-toluenesulfonyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid (DM5) were synthesized by coupling of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylic acid (DM2) with methanesulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyl chloride, which in turn, was synthesized by dissolving dilute aqueous ammonia with 2-(N-hydroxy methyl amino)-indol-3-yl-propanoic acid (DM1) which is the reaction product of l-tryptophan and formalin. All the intermediates and title compounds were characterized by physical, chemical, analytical, and spectral data. All the title compounds have been screened for in vivo antidiabetic activity in streptozotocin-induced diabetic rats, and serum glucose was estimated spectrophotometrically at 505 nm by glucose oxidase/peroxidase method. Compound DM5 showed potent antidiabetic activity. PMID:21731359

  15. Citrus Flavanones Affect Hepatic Fatty Acid Oxidation in Rats by Acting as Prooxidant Agents

    PubMed Central

    Constantin, Rodrigo Polimeni; do Nascimento, Gilson Soares; Constantin, Renato Polimeni; Salgueiro, Clairce Luzia; Bracht, Adelar; Ishii-Iwamoto, Emy Luiza; Yamamoto, Nair Seiko

    2013-01-01

    Citrus flavonoids have a wide range of biological activities and positive health effects on mammalian cells because of their antioxidant properties. However, they also act as prooxidants and thus may interfere with metabolic pathways. The purpose of this work was to evaluate the effects of three citrus flavanones, hesperidin, hesperetin, and naringenin, on several parameters linked to fatty acid oxidation in mitochondria, peroxisomes, and perfused livers of rats. When exogenous octanoate was used as substrate, hesperetin and naringenin reduced the mitochondrial NADH/NAD+ ratio and stimulated the citric acid cycle without significant changes on oxygen uptake or ketogenesis. When fatty acid oxidation from endogenous sources was evaluated, hesperetin and naringenin strongly reduced the mitochondrial NADH/NAD+ ratio. They also inhibited both oxygen uptake and ketogenesis and stimulated the citric acid cycle. Hesperidin, on the other hand, had little to no effect on these parameters. These results confirm the hypothesis that citrus flavanones are able to induce a more oxidised state in liver cells, altering parameters related to hepatic fatty acid oxidation. The prooxidant effect is most likely a consequence of the ability of these substances to oxidise NADH upon production of phenoxyl radicals in the presence of peroxidases and hydrogen peroxide. PMID:24288675

  16. Synthesis of Ba 2YCu 3O 7 by the SCD method using amino acid salt reducing agents

    NASA Astrophysics Data System (ADS)

    Kourtakis, K.; Robbins, M.; Gallagher, P. K.

    1990-01-01

    The anionic oxidation-reduction or SCD method relies on an internal oxidation-reduction reaction which converts spray-dried precursors into intimately mixed and highly reactive metal oxide powders. Earlier studies focused on precursor mixtures containing oxidizing components such as NO -3 salts with reducing salts (RCOO -, where R is H, CH 3, or CH 2CH 3) which react to form Ba 2YCu 3O 7 powder. In this work, amino acid reducing agents are used. The impact of the functional group change, in the reducing agent of the {NO -3}/{amino acid} precursors, is shown by DSC to result in sharp (and therefore rapid) oxidation-reduction reactions which occur at lower temperatures. The trend in reaction temperature correlates inversely with the expected basicity of the amino group in the series (numbers in parentheses represent mole ratios): {CH 3CH(NH 2)COO -}/{NO -3} ( {4}/{9}) = 206° C > {NH 2CH 2COO -}/{NO -3} ( {4}/{9}) = 195° C > {NH 2CH 2CH 2COO -}/{NO -3} ( {4}/{9}) = 191° C. The mixed oxide product is highly reactive and can be converted to single-phase Ba 2YCu 3O x when fired at 900-910°C for 10 min in flowing oxygen.

  17. Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection.

    PubMed

    Zhou, Kun; Chen, Dongdong; Li, Bin; Zhang, Bingyu; Miao, Fang; Zhou, Le

    2017-01-01

    A series of cinnamic acid esters and their derivatives were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method. Structure-activity relationship was derived also. Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 mM. Eight compounds showed the higher average activity with average EC50 values of 17.4-28.6 μg/mL for the fungi than kresoxim-methyl, a commercial fungicide standard, and ten compounds were much more active than commercial fungicide standards carbendazim against P. grisea or kresoxim-methyl against both P. grisea and Valsa mali. Compounds C1 and C2 showed the higher activity with average EC50 values of 17.4 and 18.5 μg/mL and great potential for development of new plant antifungal agents. The structure-activity relationship analysis showed that both the substitution pattern of the phenyl ring and the alkyl group in the alcohol moiety significantly influences the activity. There exists complexly comprehensive effect between the substituents on the phenyl ring and the alkyl group in the alcohol moiety on the activity. Thus, cinnamic acid esters showed great potential the development of new antifungal agents for plant protection due to high activity, natural compounds or natural compound framework, simple structure, easy preparation, low-cost and environmentally friendly.

  18. Bioactivity and structure-activity relationship of cinnamic acid esters and their derivatives as potential antifungal agents for plant protection

    PubMed Central

    Li, Bin; Zhang, Bingyu; Miao, Fang

    2017-01-01

    A series of cinnamic acid esters and their derivatives were synthesized and evaluated for antifungal activities in vitro against four plant pathogenic fungi by using the mycelium growth rate method. Structure−activity relationship was derived also. Almost all of the compounds showed some inhibition activity on each of the fungi at 0.5 mM. Eight compounds showed the higher average activity with average EC50 values of 17.4–28.6 μg/mL for the fungi than kresoxim-methyl, a commercial fungicide standard, and ten compounds were much more active than commercial fungicide standards carbendazim against P. grisea or kresoxim-methyl against both P. grisea and Valsa mali. Compounds C1 and C2 showed the higher activity with average EC50 values of 17.4 and 18.5 μg/mL and great potential for development of new plant antifungal agents. The structure−activity relationship analysis showed that both the substitution pattern of the phenyl ring and the alkyl group in the alcohol moiety significantly influences the activity. There exists complexly comprehensive effect between the substituents on the phenyl ring and the alkyl group in the alcohol moiety on the activity. Thus, cinnamic acid esters showed great potential the development of new antifungal agents for plant protection due to high activity, natural compounds or natural compound framework, simple structure, easy preparation, low-cost and environmentally friendly. PMID:28423022

  19. Influence of Glacial Acetic Acid and Nitric Acid as a Chelating Agent in Sol-gel Process to the Nanostructured Titanium Dioxide Thin Films

    NASA Astrophysics Data System (ADS)

    Ahmad, M. K.; Rusop, M.

    2009-06-01

    The comparison between different chelating agents in sol-gel process for deposition of nanostructured Titanium Dioxide (TiO2) thin film has been studied. Glacial Acetic Acid (GA) and Nitric Acid (NA) were used in 0.2 M of concentration. The effects to the structural, electrical and optical properties have been studied. The effects of these properties were characterized using X-Ray Diffractometer (XRD), 2-point probe I-V measurement and UV-Vis-NIR Spectrophotometer. For electrical properties, it showed that nanostructured TiO2 thin film that using GA (TF-GA) as chelating agent gives better low sheet resistance compare to nanostructured TiO2 thin film using NA (TF-NA). From XRD results, it indicates that no significantly different between both TiO2 thin film. Both of thin films have crystalline anatase phase at 2θ degree 25.8° which corresponded to (101) orientation. For optical properties, sol-gel using GA has slightly higher in transmittance spectra properties but both of films fully absorbed UV light at 300 nm of wavelength. As for optical band gap, both sol-gels using GA and NA has similar optical band gap which is 3.27 eV.

  20. Quantification of phosphatidylserine, phosphatidic acid and free fatty acids in an ultrasound contrast agent by normal-phase high-performance liquid chromatography with evaporative light scattering detection.

    PubMed

    Hvattum, Erlend; Uran, Steinar; Sandbaek, Anne Gunvor; Karlsson, Anders A; Skotland, Tore

    2006-10-11

    Sonazoid is a new contrast agent for ultrasound imaging. The product is an aqueous suspension of perfluorobutane microbubbles coated with phospholipids obtained from hydrogenated egg phosphatidylserine (H-EPS). A normal-phase high-performance liquid chromatographic (HPLC) method with evaporative light scattering detection was developed for quantification of free fatty acids, phosphatidylserine and phosphatidic acid in H-EPS and Sonazoid. Separation of the lipids was carried out on an HPLC diol column and a gradient of chloroform and methanol with 0.2% formic acid titrated to pH 7.5 with ammonia. The calibration standards contained stearic acid, distearoyl-phosphatidic acid (DSPA) and distearoyl-phosphatidylserine (DSPS) in the concentration range of 0.016-1.0mg/ml (0.4-25microg injected). The method was validated with a limit of quantification of the three lipids set to 0.4microg (approximately 20-60microM). The best fit of the three calibration curves were obtained when the logarithmic transformed theoretical lipid concentration was plotted against the logarithmic transformed area under the peak and fitted to a second order polynomial equation. Stearic acid, DSPA and DSPS were analysed with an intermediate precision ranging from 4.4% to 5.3% R.S.D. and they were extracted from an aqueous suspension with a recovery ranging from 103.3% to 113.3%. The sum of total phospholipid concentration determined in H-EPS ranged from 96.4% to 103.2% of the theoretical values. The lipids in the ultrasound product were quantitated with a repeatability ranging from 6.2% to 11.7% R.S.D.

  1. Effect of sweetening agents in acidic beverages on associated erosion lesions.

    PubMed

    Bassiouny, Mohamed A

    2012-01-01

    Accurate diagnosis of erosion defects caused by acidic beverages is essential when designing a comprehensive management strategy that includes combating possible recurrence. The manifestations of erosion lesions associated with acidic beverages are diverse, as seen in the differences and similarities of lesions associated with various regular and diet varieties of beverages. Erosion lesions caused by regular sugar-sweetened beverages display signs similar to dental caries, while lesions resulting from diet, non-sugar-sweetened soft drinks have defects similar to mechanical wear of the dentition. Aggravating factors such as toothbrushing or compromised oral home care could influence the features of erosion lesions. These diverse characteristics of erosion lesions could make identification difficult. This article describes pertinent signs of erosion defects associated with the regular and diet varieties of acidic beverages and discusses their causative factors. This information is designed to avert an improper diagnosis that would derail any restorative intervention and alter a proper preventive management course.

  2. Label-free functional nucleic acid sensors for detecting target agents

    DOEpatents

    Lu, Yi; Xiang, Yu

    2015-01-13

    A general methodology to design label-free fluorescent functional nucleic acid sensors using a vacant site approach and an abasic site approach is described. In one example, a method for designing label-free fluorescent functional nucleic acid sensors (e.g., those that include a DNAzyme, aptamer or aptazyme) that have a tunable dynamic range through the introduction of an abasic site (e.g., dSpacer) or a vacant site into the functional nucleic acids. Also provided is a general method for designing label-free fluorescent aptamer sensors based on the regulation of malachite green (MG) fluorescence. A general method for designing label-free fluorescent catalytic and molecular beacons (CAMBs) is also provided. The methods demonstrated here can be used to design many other label-free fluorescent sensors to detect a wide range of analytes. Sensors and methods of using the disclosed sensors are also provided.

  3. Citric acid and ethylene diamine tetra-acetic acid as effective washing agents to treat sewage sludge for agricultural reuse.

    PubMed

    Ren, Xianghao; Yan, Rui; Wang, Hong-Cheng; Kou, Ying-Ying; Chae, Kyu-Jung; Kim, In S; Park, Yong-Jin; Wang, Ai-Jie

    2015-12-01

    This paper presents the effects of different concentrations of citric acid (CA) and ethylene diamine tetra-acetic acid (EDTA) when used as additive reagents for the treatment of sewage sludge for agricultural use. Herein, both the retention of nutrients and removal of metals from the sewage sludge are examined. The average removal rate for the metals after treatment by CA decreased in the order Cu>Pb>Cd>Cr>Zn, while the rates after treatment by EDTA decreased in the order of Pb>Cu>Cr>Cd>Zn. After treatment with CA and EDTA, total nitrogen and total phosphorus concentrations in the sludge decreased, while the content of available nitrogen and Olsen-P increased. In addition, a multi-criteria analysis model-fuzzy analytic network process method (with 3 main factors and 12 assessment sub-factors) was adopted to evaluate the effectiveness of different treatment methods. The results showed that the optimal CA and EDTA concentrations for sewage sludge treatment were 0.60 and 0.125 mol/L, respectively.

  4. Boronated Unnatural Cyclic Amino Acids as Potential Delivery Agents for Neutron Capture Therapy

    PubMed Central

    Kabalka, George W.; Shaikh, Aarif L.; Barth, Rolf F.; Huo, Tianyao; Yang, Weilian; Gordnier, Pamela M.; Chandra, Subhash

    2011-01-01

    Boron delivery characteristics of cis and trans isomers of a boronated unnatural amino acid, 1-amino-3-boronocyclopentanecarboxylic acid (ABCPC) were tested in B16 mouse model for human melanoma. Both ABCPC isomers delivered comparable boron to B16 melanoma tumor cells as L-p-boronophenylalanine (BPA). Secondary ion mass spectrometry (SIMS) analysis revealed the presence of boron throughout the tumor from these compounds, and a near homogeneous distribution between the nucleus and cytoplasm of B16 cells grown in vitro. These encouraging observations support further studies of these new boron carriers in BNCT. PMID:21481596

  5. Synthesis and biological evaluation of new heteroaryl carboxylic acid derivatives as anti-inflammatory-analgesic agents.

    PubMed

    Abouzid, Khaled Abouzid Mohamed; Khalil, Nadia Abdalla; Ahmed, Eman Mohamed; Zaitone, Sawsan Abo-Bakr

    2013-01-01

    A series of nicotinic acid derivatives structurally related to niflumic acid and certain pyridazine-containing compounds have been synthesized and characterized by analytical and spectral data. All compounds were screened for their potential analgesic and anti-inflammatory activities. The compounds which displayed analgesic and anti-inflammatory activities were tested for ulcerogenicity and screened for in vivo inhibition of certain inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Compounds 1c, 2a, 2b, and 5a have shown potent analgesic and anti-inflammatory activities.

  6. Development of primary central nervous system lymphoma in a systemic lupus erythematosus patient after treatment with mycophenolate mofetil and review of the literature.

    PubMed

    Balci, M A; Pamuk, G E; Unlu, E; Usta, U; Pamuk, O N

    2017-01-01

    Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin lymphoma and four cases of PCNSL have previously been described in association with mycophenolate mofetil. We report the fifth case of PCNSL in a patient with lupus nephropathy while on mycophenolate mofetil treatment.

  7. New tuberculostatic agents targeting nucleic acid biosynthesis: drug design using QSAR approaches.

    PubMed

    Bueno, Renata V; Braga, Rodolpho C; Segretti, Natanael D; Ferreira, Elizabeth I; Trossini, Gustavo H G; Andrade, Carolina H

    2014-01-01

    Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB is a growing global health concern and there is an urgent need for new anti-TB drugs. Enzymes involved in DNA and ATP biosynthesis are potential targets for tuberculostatic drug design, since these enzymes are essential for Mycobacterium tuberculosis growth. This review presents the current progress and applications of structure-activity relationship analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design.

  8. Effects of six anaesthetic agents on UDP-glucuronic acid and other nucleotides in rat liver.

    PubMed

    Christensson, P I; Eriksson, G

    1985-08-01

    Anaesthesia affects the liver nucleotide pool. It was the aim of the present study to examine how anaesthesia for 60 min with pentobarbital, ketamin + diazepam, halothane, enflurane and isoflurane may influence the nucleotide pool in the rat liver, studied with isotachophoresis. It was found that none of the agents gave both safe and reproducible anaesthesia without affecting the nucleotide pools or affecting the experiments in some other way. Halothane and isoflurane were the two best alternatives with respect to both efficiency and safety. Isoflurane may be preferable since it gives a higher energy charge.

  9. Synthesis and characteristics of (Hydrogenated) ferulic acid derivatives as potential antiviral agents with insecticidal activity

    PubMed Central

    2013-01-01

    Background Plant viruses cause many serious plant diseases and are currently suppressed with the simultaneous use of virucides and insecticides. The use of such materials, however, increases the amounts of pollutants in the environment. To reduce environmental contaminants, virucides with insecticidal activity is an attractive option. Results A series of substituted ferulic acid amide derivatives 7 and the corresponding hydrogenated ferulic acid amide derivatives 13 were synthesized and evaluated for their antiviral and insecticidal activities. The majority of the synthesized compounds exhibited good levels of antiviral activity against the tobacco mosaic virus (TMW), with compounds 7a, 7b and 7d in particular providing higher levels of protective and curative activities against TMV at 500 μg/mL than the control compound ribavirin. Furthermore, these compounds displayed good insecticidal activities against insects with piercing-sucking mouthparts, which can spread plant viruses between and within crops. Conclusions Two series of ferulic acid derivatives have been synthesized efficiently. The bioassay showed title compounds not only inhibit the plant viral infection, but also prevented the spread of plant virus by insect vectors. These findings therefore demonstrate that the ferulic acid amides represent a new template for future antiviral studies. PMID:23409923

  10. Long-acting contraceptive agents: esters of norethisterone with alkoxy- and halogeno-substituted carboxylic acids.

    PubMed

    Shafiee, A; Vossoghi, M; Francisco, C G; Freire, R; Hernandez, R; Salazar, J A; Suarez, E; Sotheeswaran, S

    1983-03-01

    The chemical synthesis and physical data of several new esters of norethisterone (17 alpha-ethynyl-17 beta-hydroxyestr-4-en-3-one) are reported, which contain either a chloro- or an alkoxy-group as a substituent in the acid side-chain.

  11. Wood ants produce a potent antimicrobial agent by applying formic acid on tree-collected resin.

    PubMed

    Brütsch, Timothée; Jaffuel, Geoffrey; Vallat, Armelle; Turlings, Ted C J; Chapuisat, Michel

    2017-04-01

    Wood ants fight pathogens by incorporating tree resin with antimicrobial properties into their nests. They also produce large quantities of formic acid in their venom gland, which they readily spray to defend or disinfect their nest. Mixing chemicals to produce powerful antibiotics is common practice in human medicine, yet evidence for the use of such "defensive cocktails" by animals remains scant. Here, we test the hypothesis that wood ants enhance the antifungal activity of tree resin by treating it with formic acid. In a series of experiments, we document that (i) tree resin had much higher inhibitory activity against the common entomopathogenic fungus Metarhizium brunneum after having been in contact with ants, while no such effect was detected for other nest materials; (ii) wood ants applied significant amounts of endogenous formic and succinic acid on resin and other nest materials; and (iii) the application of synthetic formic acid greatly increased the antifungal activity of resin, but had no such effect when applied to inert glass material. Together, these results demonstrate that wood ants obtain an effective protection against a detrimental microorganism by mixing endogenous and plant-acquired chemical defenses. In conclusion, the ability to synergistically combine antimicrobial substances of diverse origins is not restricted to humans and may play an important role in insect societies.

  12. Barbituric acid-based magnetic N-halamine nanoparticles as recyclable antibacterial agents.

    PubMed

    Dong, Alideertu; Sun, Yue; Lan, Shi; Wang, Qin; Cai, Qian; Qi, Xiuzhen; Zhang, Yanling; Gao, Ge; Liu, Fengqi; Harnoode, Chokto

    2013-08-28

    Novel recyclable bactericidal materials, barbituric acid-based magnetic N-halamine nanoparticles (BAMNH NPs), were fabricated by coating of magnetic silica nanoparticles (MS NPs) with barbituric acid-based N-halamine by the aid of the radical polymerization. The sterilizing effect on the bacterial strain is investigated by incubating Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis). The as-prepared BAMNH NPs exhibit higher biocidal activity than the bulk powder barbituric acid-based N-halamine due to the high activated surface area. The structural effect of N-halamine on antimicrobial performance was fully clarified through the comparison between BAMNH NPs and hydantoin-based magnetic N-halamine nanoparticles (HMNH NPs). BAMNH NPs exhibited promising stability toward repeated washing and long-term storage. BAMNH NPs with different chlorine content were comparatively chosen to investigate the influence of chlorine content on the antimicrobial activity. An antibacterial recycle experiment revealed that no significant change occurred in the structure and antibacterial efficiency of BAMNH NPs after five recycle experiments. The combination of barbituric acid-based N-halamine with magnetic component results in an obvious synergistic effect and facilitates the repeated antibacterial applications, providing potential and ideal candidates for sterilization or even for the control of disease.

  13. Sugar beet pulp and poly(lactic acid) composites using methylene diphenyl diisocyanate as coupling agent

    USDA-ARS?s Scientific Manuscript database

    Composites from sugar beet pulp (SBP) and poly(lactic acid) (PLA) were extruded in the presence of polymeric methylene diphenyl diisocyanate (pMDI). SBP particles were evenly distributed within the PLA matrix phase as revealed by confocal fluorescence microscopic analysis. The resultant composites w...

  14. Lignin-coated cellulose nanocrystals as promising nucleating agent for poly(lactic acid)

    Treesearch

    Anju Gupta; William Simmons; Gregory T. Schueneman; Eric A. Mintz

    2016-01-01

    We report the effect of lignin-coated cellulose nanocrystals (L-CNCs) on the crystallization behavior of poly(lactic acid) (PLA). PLA/L-CNC nanocomposites were prepared by melt mixing, and the crystallization behavior of PLA was investigated using differential scanning calorimetry. Isothermal crystallization data were analyzed using Avrami and Lauritzen–Hoffman...

  15. The iron-chelating agent picolinic acid enhances transferrin receptors expression in human erythroleukaemic cell lines.

    PubMed

    Testa, U; Louache, F; Titeux, M; Thomopoulos, P; Rochant, H

    1985-07-01

    Picolinic acid, a metal chelating molecule, was administered to human erythroleukaemic cell lines (K 562 and HEL) that were grown in serum-containing media. Picolinic acid inhibited both iron uptake and cell growth. Furthermore, picolinic acid was shown to markedly decrease the level of ferritin in the cells. In spite of the inhibition of cell growth, picolinic acid induced a marked increase in the transferrin-binding capacity of the cells. This phenomenon was due to a two-five-fold enhancement of the rate of transferrin receptor biosynthesis. Other iron-chelating compounds, capable of reducing the level of intracellular iron, also elicited a marked enhancement of the transferrin-binding capacity of the cells. However, the addition of iron, as ferric ammonium citrate, in the culture medium elicited a marked increase in the level of ferritin and a strong decrease in the transferrin-binding capacity of the cells. On the basis of these data we propose that a feed-back mechanism is involved in the regulation of transferrin receptors: when the cells accumulate iron they decrease the number of transferrin receptors in order to prevent further accumulation of iron; when no or low iron is available to the cells, the number of transferrin receptors markedly increases as a compensatory mechanism.

  16. Augmenting antifungal activity of oxidizing agent with kojic acid: Control of Penicillium strains infecting crops

    USDA-ARS?s Scientific Manuscript database

    Oxidative treatment is a strategy for preventing Penicillium contamination in foods or crops. Antifungal efficacy of oxidant [hydrogen peroxide (H2O2)], biotic effector [kojic acid (KA)] and abiotic stress (heat), alone or in combination, was investigated in Penicillium. The levels of antifungal int...

  17. Boric acid: a potential chemoprotective agent against aflatoxin b1 toxicity in human blood

    PubMed Central

    Geyikoglu, Fatime

    2010-01-01

    Aflatoxin B1 is the most potent pulmonary and hepatic carcinogen. Since the eradication of Aflatoxin B1 contamination in agricultural products has been difficult, the use of natural or synthetic free radical scavengers could be a potential chemopreventive strategy. Boric acid is the major component of industry and its antioxidant role has recently been reported. The present study assessed, for the first time, the effectiveness of boric acid following exposure to Aflatoxin B1 on human whole blood cultures. The biochemical characterizations of glutathione and some enzymes have been carried out in erythrocytes. Alterations in malondialdehyde level were determined as an index of oxidative stress. The sister-chromatid exchange and micronucleus tests were performed to assess DNA damages in lymphocytes. Aflatoxin B1 treatment significantly reduced the activities of antioxidants by increasing malondialdehyde level (30.53 and 51.43%) of blood, whereas, the boric acid led to an increased resistance of DNA to oxidative damage induced by Aflatoxin B1 in comparison with control values (P < 0.05). In conclusion, the support of boric acid was especially useful in Aflatoxin-toxicated blood. Thus the risk on tissue targeting of Aflatoxin B1 could be reduced ensuring early recovery from its toxicity. PMID:20431944

  18. Influence of root-surface conditioning with acid and chelating agents on clot stabilization.

    PubMed

    Leite, Fábio Renato Manzolli; Sampaio, José Eduardo Cezar; Zandim, Daniela Leal; Dantas, Andréa Abi Rached; Leite, Elza Regina Manzolli; Leite, Amauri Antiquera

    2010-04-01

    To compare the adhesion and maturation of blood components on chemically conditioned root surfaces. Clinical root samples of human teeth were obtained (n = 150) and manually scaled. Five groups of 30 samples were treated as follows: (1) saline solution irrigation (control); (2) 24% EDTA gel; (3) 25% citric acid solution; (4) tetracycline solution (50 mg/mL); and (5) 30% sodium citrate solution. After these treatments, 15 samples of each group received a blood drop and were analyzed by SEM. The remaining 15 had their surface morphology evaluated for collagen fibrils exposure by SEM. Photomicrographs were analyzed according to the score of adhesion of blood components. Kruskal-Wallis and Dunn multiple comparison tests were employed. The control group was characterized by the absence of blood elements on the surface. The best result was observed in the citric acid group, which had a dense fibrin network with blood elements adhered. The EDTA group showed a moderate fibrin network formation. In contrast, a scarce fibrin network and a few cells were present in the tetracycline samples, and an absence of blood elements was found on sodium citrate specimens. The citric acid group was statistically different from the control group (P < .01). No differences were found among the control, EDTA, tetracycline, and sodium citrate groups (P > .05). Under these experimental conditions, citric acid is indicated to stabilize clots on the root surface, which act as a scaffold for connective tissue cell development.

  19. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report.

    PubMed

    Kobashigawa, J A; Miller, L W; Russell, S D; Ewald, G A; Zucker, M J; Goldberg, L R; Eisen, H J; Salm, K; Tolzman, D; Gao, J; Fitzsimmons, W; First, R

    2006-06-01

    The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.

  20. Magnesium hydroxide as the neutralizing agent for radioactive hydrochloric acid solutions

    SciTech Connect

    Palmer, M.J.; Fife, K.W.

    1995-10-01

    The current technology at Los Alamos for removing actinides from acidic chloride waste streams is precipitation with approximately 10 M potassium hydroxide. Although successful, there are many inherent drawbacks to this precipitation technique which will be detailed in this paper. Magnesium hydroxide (K{sub sp} = 1.3 x 10{sup -11}) has limited solubility in water and as a result of the common ion effect, cannot generate a filtrate with a pH greater than 9. At a pH of 9, calcium (K{sub sp} = 5.5 x 10{sup -6}) will not coprecipitate as the hydroxide. This is an important factor since many acidic chloride feeds to hydroxide precipitation contain significant amounts of calcium. In addition, neutralization with Mg(OH){sub 2} produces a more filterable precipitate because neutralization occurs as the Mg(OH){sub 2} is dissolved by the acid rather than as a result of the much faster liquid/liquid reaction of KOH with the waste acid. This slower solid/liquid reaction allows time for crystal growth to occur and produces more easily filterable precipitates. On the other hand, neutralization of spent acid with strong KOH that yields numerous hydroxide ions in solution almost instantaneously forming a much larger volume of small crystallites that result in gelatinous, slow-filtering precipitates. Magnesium hydroxide also offers a safety advantage. Although mildly irritating, it is a weak base and safe and easy to handle. From a waste minimization perspective, Mg(OH){sub 2} offers many advantages. First, the magnesium hydroxide is added as a solid. This step eliminates the diluent water used in KOH neutralizations. Secondly, because the particle size of the precipitate is larger, more actinides are caught on the filter paper resulting in a smaller amount of actinide being transferred to the TA-50 Liquid Waste Treatment Facility. Third, the amount of solids that must be reprocessed is significantly smaller resulting in less waste generation from the downstream processes.

  1. Oral ulcers produced by mycophenolate mofetil in two liver transplant patients.

    PubMed

    Naranjo, J; Poniachik, J; Cisco, D; Contreras, J; Oksenberg, D; Valera, J M; Díaz, J C; Rojas, J; Cardemil, G; Mena, S; Castillo, J; Rencoret, G; Godoy, J; Escobar, J; Rodríguez, J; Leyton, P; Fica, A; Toledo, C

    2007-04-01

    Oral ulcers are a frequent problem in transplant medicine. It is important to consider infectious etiologies, exacerbated by the immunosuppressive treatment, but other etiologies are also possible, like adverse drug reactions. Mycophenolate mofetil (MMF) is an immunosuppressive medication that has been used in combination with calcineurin inhibitors and steroids. Reports of renal transplant patients with oral ulcers related to MMF have appeared lately and herein we have described 2 cases in liver transplant patients. Their oral ulcers resolved quickly after suspension of the medication. Our 2 cases in liver transplant patients represented a unique setting for this type of complication.

  2. A-ring modified betulinic acid derivatives as potent cancer preventive agents.

    PubMed

    Hung, Hsin-Yi; Nakagawa-Goto, Kyoko; Tokuda, Harukuni; Iida, Akira; Suzuki, Nobutaka; Bori, Ibrahim D; Qian, Keduo; Lee, Kuo-Hsiung

    2014-02-01

    Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.

  3. Battery acid--an agent of attempted suicide in black South Africans.

    PubMed

    Wilson, D A; Wormald, P J

    1995-06-01

    Over a 36-month period 27 black adults, who had taken battery acid in apparent suicide attempts, were admitted to a major South African general hospital for assessment and treatment. There were no deaths. Patient features included limited schooling, unemployment and a male/female ratio of 2.4:1. Triggers were minor to moderate stressors (mainly domestic arguments) in 23 patients. Nine had a diagnosable psychiatric disorder and 5 required further psychiatric hospitalisation following discharge from the general hospital. The reported high mortality rate from acid ingestion was not observed; however, 4 patients required surgical intervention to deal with stricture formation. The average duration of stay was 7.6 days. There were no repeat suicide attempts during the study period.

  4. Potential cerebral perfusion agents: synthesis and evaluation of a radioiodinated vinylalkylbarbituric acid analogue

    SciTech Connect

    Srivastava, P.C.; Callahan, A.P.; Cunningham, E.B.; Knapp, F.F. Jr.

    1983-05-01

    A new iodinated barbiturate has been prepared. Treatment of 5-chloropentyne and propargyl bromide with diethyl 2-ethyl-2-sodiomalonate (DESM) provided diethyl 2-ethyl-2-(1-pentyn-5-yl)malonate (3) and diethyl 2-ethyl-2-propargylmalonate (4), respectively. Similar condensation of DESM with (E)-(5-iodo-1-penten-1-yl)boronic acid (9) or the reaction of catecholborane with 3 provided diethyl (E)-2-ethyl-2-(1-borono-1-penten-5-yl)malonate (8). The direct sodium iodide-chloramine-T iodination of 8 or the treatment of (E)-1,5-diiodo-1-pentene (10) with DESM provided diethyl (E)-2-ethyl-2-(1-iodo-1-penten-5-yl)malonate (11). The condensation of functionalized malonates 3, 4, and 11 with urea in the presence of a base provided the corresponding barbiturates, 5-ethyl-5-(1-pentyn-5-yl)-(5), 5-ethyl-5-propargyl- (6), and (E)-5-ethyl-5-(1-iodo-1-penten-5-yl)barbituric acid (12), respectively. (E)-6-(Ethoxycarbonyl)-1-iodo-1-octene-6-carboxylic acid (13) was isolated as the hydrolytic byproduct of 11. Compound 13 decarboxylated under vacuum to provide ethyl (E)-1-iodo-1-octene-6-carboxylate (14). The /sup 125/I-labeled congeners of 12 and 13 were synthesized in the same manner and evaluated in rats. The barbiturate 12 exhibited significant brain uptake (approximately 1% dose after 5 min), demonstrating that iodinated barbiturates freely cross the intact blood-brain barrier.

  5. Molecular level interaction of the human acidic fibroblast growth factor with the antiangiogenic agent, inositol hexaphosphate .

    PubMed

    Kumar, Sriramoju M; Wang, Han-Min; Mohan, Sepuru K; Chou, Ruey-Hwang; Yu, Chin

    2010-12-21

    Acidic fibroblast growth factor (FGF1) regulates a wide array of important biological phenomena such as angiogenesis, cell differentiation, tumor growth, and neurogenesis. Generally, FGFs are known for their strong affinity for the glycosaminoglycan heparin, as a prerequisite for recognition of a specific tyrosine kinase on the cell surface and are responsible for the cell signal transduction cascade. Inositol hexaphosphate (IP6) is a natural antioxidant and is known for its antiangiogenic role, in addition to its ability to control tumor growth. In the present study, we investigated the interaction of IP6 with the acidic fibroblast growth factor (FGF1) using various biophysical techniques including isothermal calorimetry, circular dichroism, and multidimensional NMR spectroscopy. Herein, we have reported the three-dimensional solution structure of the FGF1-IP6 complex. These data show that IP6 binds FGF1 and enhances its thermal stability. In addition, we also demonstrate that IP6 acts as an antagonist to acidic fibroblast growth factor by inhibiting its receptor binding and subsequently decreasing the mitogenic activity. The inhibition likely results in the ability of IP6 to antagonize the angiogenic and mitogenic activity of FGF1.

  6. Xyloglucan from Hymenaea courbaril var. courbaril seeds as encapsulating agent of L-ascorbic acid.

    PubMed

    Farias, Mirla D P; Albuquerque, Priscilla B S; Soares, Paulo A G; de Sá, Daniele M A T; Vicente, António A; Carneiro-da-Cunha, Maria G

    2017-10-05

    This study evaluated the L-ascorbic acid (AA) encapsulation in microparticles of xyloglucan (XAA) extracted from Hymenaea courbaril seeds by spray drying (SD) and its application in tilapia fish burgers. The encapsulation efficiency was 96.34±1.6% and the retention of the antioxidant activity was of 89.48±0.88% after 60days at 25°C. SEM images showed microspheres with diameters ranging from 4.4 to 34.0μm. FTIR spectrum confirmed the presence of AA in xyloglucan microparticles, which was corroborated by DSC and TGA. The release of ascorbic acid was found to be pH-dependent. The application of XAA in tilapia fish burger did not change the pH after heating and the ascorbic acid retention was greater compared to its free form. The results indicate that xyloglucan can be used to encapsulate AA by SD and suggest that XAA was able to reduce undesirable organoleptic changes in fish burgers. Copyright © 2017. Published by Elsevier B.V.

  7. Graphene oxide as a nanocarrier for controlled release and targeted delivery of an anticancer active agent, chlorogenic acid.

    PubMed

    Barahuie, Farahnaz; Saifullah, Bullo; Dorniani, Dena; Fakurazi, Sharida; Karthivashan, Govindarajan; Hussein, Mohd Zobir; Elfghi, Fawzi M

    2017-05-01

    We have synthesized graphene oxide using improved Hummer's method in order to explore the potential use of the resulting graphene oxide as a nanocarrier for an active anticancer agent, chlorogenic acid (CA). The synthesized graphene oxide and chlorogenic acid-graphene oxide nanocomposite (CAGO) were characterized using Fourier transform infrared (FTIR) spectroscopy, thermogravimetry and differential thermogravimetry analysis, Raman spectroscopy, powder X-ray diffraction (PXRD), UV-vis spectroscopy and high resolution transmission electron microscopy (HRTEM) techniques. The successful conjugation of chlorogenic acid onto graphene oxide through hydrogen bonding and π-π interaction was confirmed by Raman spectroscopy, FTIR analysis and X-ray diffraction patterns. The loading of CA in the nanohybrid was estimated to be around 13.1% by UV-vis spectroscopy. The release profiles showed favourable, sustained and pH-dependent release of CA from CAGO nanocomposite and conformed well to the pseudo-second order kinetic model. Furthermore, the designed anticancer nanohybrid was thermally more stable than its counterpart. The in vitro cytotoxicity results revealed insignificant toxicity effect towards normal cell line, with a viability of >80% even at higher concentration of 50μg/mL. Contrarily, CAGO nanocomposite revealed enhanced toxic effect towards evaluated cancer cell lines (HepG2 human liver hepatocellular carcinoma cell line, A549 human lung adenocarcinoma epithelial cell line, and HeLa human cervical cancer cell line) compared to its free form. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Bioprospecting the Curculigoside-Cinnamic Acid-Rich Fraction from Molineria latifolia Rhizome as a Potential Antioxidant Therapeutic Agent.

    PubMed

    Ooi, Der Jiun; Chan, Kim Wei; Sarega, Nadarajan; Alitheen, Noorjahan Banu; Ithnin, Hairuszah; Ismail, Maznah

    2016-06-17

    Increasing evidence from both experimental and clinical studies depicts the involvement of oxidative stress in the pathogenesis of various diseases. Specifically, disruption of homeostatic redox balance in accumulated body fat mass leads to obesity-associated metabolic syndrome. Strategies for the restoration of redox balance, potentially by exploring potent plant bioactives, have thus become the focus of therapeutic intervention. The present study aimed to bioprospect the potential use of the curculigoside-cinnamic acid-rich fraction from Molineria latifolia rhizome as an antioxidant therapeutic agent. The ethyl acetate fraction (EAF) isolated from M. latifolia rhizome methanolic extract (RME) contained the highest amount of phenolic compounds, particularly curculigoside and cinnamic acid. EAF demonstrated glycation inhibitory activities in both glucose- and fructose-mediated glycation models. In addition, in vitro chemical-based and cellular-based antioxidant assays showed that EAF exhibited high antioxidant activities and a protective effect against oxidative damage in 3T3-L1 preadipocytes. Although the efficacies of individual phenolics differed depending on the structure and concentration, a correlational study revealed strong correlations between total phenolic contents and antioxidant capacities. The results concluded that enriched phenolic contents in EAF (curculigoside-cinnamic acid-rich fraction) contributed to the overall better reactivity. Our data suggest that this bioactive-rich fraction warrants therapeutic potential against oxidative stress-related disorders.

  9. Evaluation of physicochemical properties, skin permeation and accumulation profiles of salicylic acid amide prodrugs as sunscreen agent.

    PubMed

    Yan, Yi-Dong; Sung, Jun Ho; Lee, Dong Won; Kim, Jung Sun; Jeon, Eun-Mi; Kim, Dae-Duk; Kim, Dong Wuk; Kim, Jong Oh; Piao, Ming Guan; Li, Dong Xun; Yong, Chul Soon; Choi, Han Gon

    2011-10-31

    Various amide prodrugs of salicylic acid were synthesised, and their physicochemical properties including lipophilicity, chemical stability and enzymatic hydrolysis were investigated. In vivo skin permeation and accumulation profiles were also evaluated using a combination of common permeation enhancing techniques such as the use of a supersaturated solution of permeants in an enhancer vehicle, a lipophilic receptor solution, removal of the stratum corneum and delipidisation of skin. Their capacity factor values were proportional to the degree of carbon-carbon saturation in the side chain. All these amides were highly stable in acetonitrile and glycerine. Amide prodrugs were converted to salicylic acid both in hairless mouse liver and skin homogenates. N-dodecyl salicylamide (C12SM) showed the lowest permeation of salicylic acid in skin compared to the other prodrugs, probably due to its low aqueous solubility. It had a high affinity for the stratum corneum and its accumulation was restricted to only the uppermost layer of skin. Thus, this amide prodrug could be a safer topical sunscreen agent with minimum potential for systemic absorption.

  10. Carboxylic Acid-Functionalized Conducting-Polymer Nanotubes as Highly Sensitive Nerve-Agent Chemiresistors

    NASA Astrophysics Data System (ADS)

    Kwon, Oh Seok; Park, Chul Soon; Park, Seon Joo; Noh, Seonmyeong; Kim, Saerona; Kong, Hye Jeong; Bae, Joonwon; Lee, Chang-Soo; Yoon, Hyeonseok

    2016-09-01

    Organophosphates are powerful inhibitors of acetylcholinesterase, which is critical to nerve function. Despite continuous research for detecting the highly toxic organophosphates, a new and improved methodology is still needed. Herein we demonstrate simple-to-fabricate chemiresistive gas sensors using conducting-polymer polypyrrole (PPy) nanotube transducers, which are chemically specific and capable of recognizing sub-ppb concentrations (ca. 0.5 ppb) of dimethyl methylphosphonate (DMMP), a simulant of nerve agent sarin. Interestingly, the introduction of carboxylic groups on the surface of PPy nanotube transistors resulted in enhanced sensitivity to DMMP via intermolecular hydrogen bonding. Furthermore, it was found that the sensitivity of the nanotube transducer depended on the degree of the carboxylic group introduced. Finally, a sensor array composed of 5 different transducers including the carboxylated nanotubes exhibited excellent selectivity to DMMP in 16 vapor species.

  11. Carboxylic Acid-Functionalized Conducting-Polymer Nanotubes as Highly Sensitive Nerve-Agent Chemiresistors

    PubMed Central

    Kwon, Oh Seok; Park, Chul Soon; Park, Seon Joo; Noh, Seonmyeong; Kim, Saerona; Kong, Hye Jeong; Bae, Joonwon; Lee, Chang-Soo; Yoon, Hyeonseok

    2016-01-01

    Organophosphates are powerful inhibitors of acetylcholinesterase, which is critical to nerve function. Despite continuous research for detecting the highly toxic organophosphates, a new and improved methodology is still needed. Herein we demonstrate simple-to-fabricate chemiresistive gas sensors using conducting-polymer polypyrrole (PPy) nanotube transducers, which are chemically specific and capable of recognizing sub-ppb concentrations (ca. 0.5 ppb) of dimethyl methylphosphonate (DMMP), a simulant of nerve agent sarin. Interestingly, the introduction of carboxylic groups on the surface of PPy nanotube transistors resulted in enhanced sensitivity to DMMP via intermolecular hydrogen bonding. Furthermore, it was found that the sensitivity of the nanotube transducer depended on the degree of the carboxylic group introduced. Finally, a sensor array composed of 5 different transducers including the carboxylated nanotubes exhibited excellent selectivity to DMMP in 16 vapor species. PMID:27650635

  12. Refractory optic perineuritis due to granulomatosis with polyangiitis successfully treated with methotrexate and mycophenolate mofetil combination therapy

    PubMed Central

    Kimura, Yoshitaka; Asako, Kurumi; Kikuchi, Hirotoshi; Kono, Hajime

    2017-01-01

    Optic perineuritis is an uncommon inflammatory disorder of the optic sheath that causes visual loss or eye pain. There are few case reports of optic perineuritis associated with granulomatosis with polyangiitis. Herein we report the case of a 37-year-old male with granulomatosis with polyangiitis and who presented with headache, blurred vision in the right eye, diplopia, and numbness in the right forehead. Brain magnetic resonance images (MRI) findings revealed hypertrophic pachymeningitis and refractory optic perineuritis. These were manageable only by means of weekly methotrexate and mycophenolate mofetil combination therapy but not with methotrexate, mycophenolate mofetil, intravenous cyclophosphamide, rituximab, azathioprine, or cyclosporine individually. PMID:28293459

  13. Selection of a biocontrol agent based on a potential mechanism of action: degradation of nicotinic acid, a growth factor essential for Erwinia amylovora.

    PubMed

    Paternoster, Thomas; Défago, Geneviève; Duffy, Brion; Gessler, Cesare; Pertot, Ilaria

    2010-12-01

    This work describes a medium-based screening method for selecting microbial biocontrol agents against Erwinia amylovora based on the degradation of a specific growth factor. Erwinia amylovora, the causal agent of the devastating fire blight disease, requires nicotinic acid or nicotinamide as an essential growth factor. Potential biocontrol agents are either selected for antimicrobial production in plate or directly on immature pears or apple blossoms. In this work, we have attempted to streamline the selection of a new potential biocontrol agent with a lower risk of non-target effects by isolation based on the ability to degrade nicotinic acid in vitro, using therefore few plant materials. A total of 735 bacteria and 1237 yeast were isolated from apple blossoms and pre-screened for nicotinic acid-degradation. Pseudomonas rhizosphaerae strain JAN was able to degrade both nicotinic acid and nicotinamide. Mutants deficient in this ability were constructed. JAN, but not the mutants, controlled E. amylovora on pear slices. On detached apple blossoms, JAN colonized apple hypanthia and strongly suppressed E. amylovora growth. Under greenhouse conditions, JAN was more effective in controlling blossom blight than P. fluorescens A506, a commercial biocontrol agent of fire blight unable to degrade nicotinic acid and nicotinamide.

  14. α-Linolenic acid (ALA) is an anti-inflammatory agent in inflammatory bowel disease.

    PubMed

    Reifen, Ram; Karlinsky, Anna; Stark, Aliza H; Berkovich, Zipi; Nyska, Abraham

    2015-12-01

    Studies suggest that consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFA) plays a protective role in inflammatory bowel disease; however, the use of plant-derived oils rich in α-linolenic acid (ALA) has not been widely investigated. The aims of this study were to test the effects of two different sources of (n-3) PUFA, fish and plant-derived oils, in two animal models of experimental colitis and to determine whether the (n-3) PUFA-enriched diets could ameliorate the inflammatory status. Rats were fed diets rich in corn, fish or sage oil with or without vitamin A supplementation for 3weeks then colitis was induced by adding dextran sodium sulfate to the drinking water or by injecting 2,4,6-trinitrobenzene sulfonic acid. We show that colitic rats fed the sage oil diets had a lower inflammatory response, improved histological repair and had less necrotic damage in the mucosa when compared to the corn and fish oil groups. Colonic damage and myeloperoxidase activity were significantly lower. Colonic mRNA levels of pro-inflammatory genes including interleukin IL-6, cyclooxygenase 2 and tumor necrosis factor α were markedly down-regulated in rats fed fish and sage oils compared to control. These results were supported by experiments in the human colonic epithelial cell line Caco-2, where ALA supplementation was shown to be effective in inhibiting inflammation induced by IL-1β by down-regulating mRNA levels of pro-inflammatory genes including IL-8, COX2 and inducible nitric oxide synthase. Taken together, these results suggest that plant-derived oil rich in ALA could ameliorate the inflammatory damage in colitis.

  15. Synthesis of novel 2',3'-difluorinated 5'-deoxythreosyl phosphonic acid nucleosides as antiviral agents.

    PubMed

    Kim, Eunae; Kim, Seyeon; Hong, Joon Hee

    2015-01-01

    A novel route for the synthesis of 2',3'-difluorinated 5'-deoxythreosyl phosphonic acid nucleosides from glyceraldehyde using the Horner-Emmons reaction in the presence of triethyl α-fluorophosphonoacetate is described. The second fluorination at the 2'-position was an electrophilic reaction performed using N-fluorodibenzenesulfonimide. Glycosylation reactions between the nucleosidic bases and glycosyl donor 9 generated nucleosides that were further phosphonated and hydrolyzed to produce the desired nucleoside analogues. The synthesized nucleoside analogues 13, 16, 20, and 23 were tested for anti- human immunodeficiency virus (HIV) activity as well as cytotoxicity. Adenine derivative 16 showed significant anti-HIV activity up to 100 μM.

  16. [Determination of antidangdruff agent salicylic acid, zinc pyrithione, octopirox, climbazole and ketoconazole in shampoo by high performance liquid chromatography].

    PubMed

    Yang, Yan-Wei; Zhu, Ying; Su, Xiao-Qing

    2005-09-01

    A high performance liquid chromatography method was established for determination of antidangdruff agent salicylic acid,zinc pyrithione, octopirox, climbazole and ketoconazole in shampoo on a C18 column using acetonitrile-metholaqueous solution (10 mmol/L KH2 PO4 and 5 mmol/L EDTANa2, pH is adjusted to 4.0 with H3 PO4) (50:10:40) as mobile phase at a flow rate of 1.0 ml/min, with the column temperature 25 degrees C and detection wave 230nm. The precision was less than 3.8% and recovery varied from 92.7% to 104.9%. The experimental results showed that the method was simple, precise and accurate.

  17. Design, synthesis and evaluation of PEGylated lipoic acid derivatives with functionality as potent anti-melanogenic agents.

    PubMed

    Lu, Chichong; Kim, Bo-Mi; Chai, Kyu Yun

    2011-10-01

    The novel PEGylated lipoic acid (LA) derivatives with functionality were synthesized in satisfactory yield by simple procedures and evaluated about its anti-melanogenic activity on the B16F10 melanoma cells. Grafting a PEG moiety onto the carboxyl group of LA has reduced the cell cytotoxicity and provided the water solubility and functionality to incorporate the other bioactive moieties. We have found that derivatives showed inhibition of melanin formation by up to 36.5% at 0.1 mM, whereas LA decreased the melanin formation by 8.6%. In addition, it also inhibits at least 86.4% UV-induced MMP-1 expression at 0.1 mM which is higher than LA. These data suggest that the novel PEGylated LA derivatives with functionality may thus serve as a potentially effective anti-melanogenic and anti-aging agent.

  18. The sensitization of near-ultraviolet radiation killing of mammalian cells by the sunscreen agent para-aminobenzoic acid

    SciTech Connect

    Osgood, P.J.; Moss, S.H.; Davies, D.J.

    1982-12-01

    The wavelengths of sunlight considered to be responsible for erythema and skin cancer formation are in the range 290-340 nm. Formulated sunscreens usually contain an agent that absorbs in this wavelength region, and one of the most widely used is para-aminobenzoic acid (PABA). Previous work has demonstrated the sensitization by PABA of the lethal and mutagenic effects of near-ultraviolet (UV) radiation in a model bacterial system. Experiments with the mouse lymphoma L5178Y cell line have now demonstrated sensitization by PABA of the lethal effect of near-UV radiation, the extent of which, after correction for absorption of UV radiation by PABA, bears a direct relationship to PABA concentration. The limitations of these results in predicting the response of human skin to the presence of PABA during exposure to UV radiation is emphasized.

  19. Screening of nerve agent markers with hollow fiber-chemosorption of phosphonic acids.

    PubMed

    Holmgren, Karin Höjer; Gustafsson, Tomas; Östin, Anders

    2016-10-15

    This report describes a method developed for extracting nerve gas markers such as phosphonic acids from urine and other aqueous samples. It involves single-step microextraction with chemosorption to hollow fibers that have been pre-soaked in a solution containing a derivatization reagent (3,5 triflouro methyl benzene diazomethane). The derivatives it forms with phosphonic acids can be sensitively detected by mass spectrometric detectors operating in negative chemical ionization (NCI) mode. Limits of quantification obtained in analyses of water and urine extracts by GC/MS in negative chemical ionization and selected ion monitoring mode were 0.1-10 and 0.5-10ng/mL, respectively. Pentaflourophenyl diazomethane can also be used as a derivatization reagent, and the micro-extracts (which generate low background signals) can be sensitively analyzed by GC-MS/MS in NCI selected reaction monitoring (SRM) mode, using two specific transitions for both reagents. Thus, this sensitive approach can be flexibly modified to obtain confirmatory information, or address potential problems caused by interferences in some samples. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Radiolabelling of ascorbic acid: a new clue to clarify its action as an anticancer agent?

    PubMed

    Mamede, A C; Abrantes, A M; Pires, A S; Tavares, S D; Serra, M E; Maia, J M; Botelho, M F

    2012-04-01

    Vitamin C exists in two forms: the reduced (ascorbic acid--AA) and oxidized form (dehydroascorbic acid--DHA). This is a nutrient whose benefits are long known and widely publicized, being most of them related to its antioxidant action. As an antioxidant, the main role of vitamin C is to neutralize free radicals, reducing oxidative stress. However, some controversial studies suggest that this nutrient may have a preventive and therapeutic role in cancer disease due to their possible pro-oxidant activity, promoting the formation of reactive oxygen species that can induce cell death in cancer cells. This factor, coupled with the decrease of antioxidant enzymes and increase of decompartmentalized transition metals in tumor cells may result in the selective cytotoxicity of vitamin C and the subsequent revelation of its therapeutic potential. In this way the first purpose of this work was radioactively label the reduced form of vitamin C with Tc-99m, its quality control by HPLC and the time stability. The second purpose was to use the radioactive complex 99mTc-AA in in vitro and in vivo studies in order to evaluate its uptake by colorectal cancer cells and biodistribution in mices, respectively. The results suggest that the pharmaceutical formulation developed, which was reproducible and stable over time, was residually taken up by colorectal cancer cells. Future studies are needed to deepen our understanding about the radioactive complex 99mTc-AA and clarify the mechanisms of action of vitamin C in oncologic disease.

  1. Synthesis and biological evaluation of quinic acid derivatives as anti-inflammatory agents.

    PubMed

    Zeng, Kui; Thompson, Karin Emmons; Yates, Charles R; Miller, Duane D

    2009-09-15

    Quinic acid (QA) esters found in hot water extracts of Uncaria tomentosa (a.k.a. cat's claw) exert anti-inflammatory activity through mechanisms involving inhibition of the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB). Herein, we describe the synthesis and biological testing of novel QA derivatives. Inhibition of NF-kappaB was assessed using A549 (Type II alveolar epithelial-like) cells that stably express a secreted alkaline phosphatase (SEAP) reporter driven by an NF-kappaB response element. A549-NF-kappaB cells were stimulated with TNF-alpha (10 ng/mL) in the presence or absence of QA derivative for 18 hours followed by measurement of SEAP activity. Amide substitution at the carboxylic acid position yielded potent inhibitors of NF-kappaB. A variety of modifications to the amide substitution were tolerated with the N-propyl amide derivative being the most potent. Further examination of the SAR demonstrated that acetylation of the hydroxyl groups reduced NF-kappaB inhibitory activity. QA amide derivatives lacked anti-oxidant activity and were found to be neither anti-proliferative nor cytotoxic at concentrations up to 100 microM. In conclusion, we have discovered a novel series of non-toxic QA amides that potently inhibit NF-kappaB, despite their lack of anti-oxidant activity. Mechanistic studies and pre-clinical efficacy studies in various inflammatory animal models are on-going.

  2. “On-Off” Thermoresponsive Coating Agent Containing Salicylic Acid Applied to Maize Seeds for Chilling Tolerance

    PubMed Central

    He, Fei; Huang, Yutao; Song, Wenjian; Hu, Jin

    2015-01-01

    Chilling stress is an important constraint for maize seed establishment in the field. In this study, a type of “on-off” thermoresponsive coating agent containing poly (N-isopropylacrylamide-co-butylmethacrylate) (Abbr. P(NIPAm-co-BMA)) hydrogel was developed to improve the chilling tolerance of coated maize seed. The P(NIPAm-co-BMA) hydrogel was synthesized by free-radical polymerization of N-isopropylacrylamide (NIPAm) and butylmethacrylate (BMA). Salicylic acid (SA) was loaded in the hydrogel as the chilling resistance agent. SA-loaded P(NIPAm-co-BMA) was used for seed film-coating of two maize varieties, Huang C (HC, chilling-tolerant) and Mo17 (chilling-sensitive), to investigate the coated seed germination and seedling growth status under chilling stress. The results showed that the hydrogel obtained a phase transition temperature near 12°C with a NIPAM to MBA weight ratio of 1: 0.1988 (w/w). The temperature of 12°C was considered the “on-off” temperature for chilling-resistant agent release; the SA was released from the hydrogel more rapidly at external temperatures below 12°C than above 12°C. In addition, when seedlings of both maize varieties suffered a short chilling stress (5°C), higher concentrations of SA-loaded hydrogel resulted in increased germination energy, germination percentage, germination index, root length, shoot height, dry weight of roots and shoots and protective enzyme activities and a decreased malondialdehyde content in coated maize seeds compared to single SA treatments. The majority of these physiological and biochemical parameters achieved significant levels compared with the control. Therefore, SA-loaded P(NIPAm-co-BMA), a nontoxic thermoresponsive hydrogel, can be used as an effective material for chilling tolerance in film-coated maize seeds. PMID:25807522

  3. Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents.

    PubMed

    Koto, Kazutaka; Murata, Hiroaki; Kimura, Shinya; Horie, Naoyuki; Matsui, Takaaki; Nishigaki, Yasunori; Ryu, Kazuteru; Sakabe, Tomoya; Itoi, Megumi; Ashihara, Eishi; Maekawa, Taira; Fushiki, Shinji; Kubo, Toshikazu

    2010-07-01

    Third-generation bisphosphonates are known to inhibit bone resorption and also appear to exhibit direct anti-tumour activity. We previously reported that third-generation bisphosphonates such as zoledronic acid (ZOL) have a direct antitumour effect, and synergistically augment the effects of antitumor agents in osteosarcoma cells. There has been no report on the antitumor effect of ZOL against soft tissue sarcoma. The aim of this study was to evaluate the antitumor effect of this drug on a human fibrosarcoma cell line, in terms of proliferation and apoptosis, and, moreover, to evaluate the combined effects of ZOL with other antitumor drugs against the human fibrosarcoma cell line. HT1080 cells were treated with ZOL at various concentrations up to 10 microM, and then cell proliferation, cell cycle, nuclear morphology, and Western blot analyses were performed to study the antitumor effects of ZOL alone, and, moreover, HT1080 cells were treated with ZOL and other anticancer drugs such as paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, cisplatin, or methotrexate to investigate the combined effects using proliferation and cell cycle analyses. We found that ZOL strongly inhibited in vitro proliferation, arrested the cell cycle between S and G2/M phases, and induced the apoptosis of human fibrosarcoma cells. Moreover, ZOL augmented the effect of antitumor agents when administered concurrently with paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, and cisplatin in human fibrosarcoma cells. The treatment of fibrosarcoma with ordinary antitumor drugs is not fully effective. These findings suggest that ZOL directly affects the proliferation and survival of fibrosarcoma cells, and that the combined administration of ZOL with other antitumor agents may improve the efficacy of fibrosarcoma treatment. These results support the possibility that their combined use could be beneficial in the treatment of patients not only with

  4. Using poly-glutamic acid as soil-washing agent to remediate heavy metal-contaminated soils.

    PubMed

    Yang, Zong-Han; Dong, Cheng-Di; Chen, Chiu-Wen; Sheu, Yih-Terng; Kao, Chih-Ming

    2017-05-20

    The extraction efficiency of heavy metals from soils using three forms of gamma poly-glutamic acid (γ-PGA) as the washing agents was investigated. Controlling factors including agent concentrations, extraction time, pH, and liquid to soil ratio were evaluated to determine the optimum operational conditions. The distribution of heavy metal species in soils before and after extraction processes was analyzed. Up to 46 and 74% of heavy metal removal efficiencies were achieved with one round and a sequential extraction process using H-bonding form of γ-PGA (200 mM) with washing time of 40 min, liquid to solid ratio of 10 to 1, and pH of 6. Major heavy metal removal mechanisms were (1) γ-PGA-promoted dissolution and (2) complexation of heavy metal with free carboxyl groups in γ-PGA, which resulted in heavy metal desorption from soils. Metal species on soils were redistributed after washing, and soils were remediated without destruction of soil structures and productivity.

  5. Potential of the chlorogenic acid as multitarget agent: Insulin-secretagogue and PPAR α/γ dual agonist.

    PubMed

    Sanchez, Maetzin Becerra; Miranda-Perez, Elizabeth; Verjan, Juan Carlos Gomez; de Los Angeles Fortis Barrera, Maria; Perez-Ramos, Julia; Alarcon-Aguilar, Francisco Javier

    2017-10-01

    The chlorogenic acid (CGA) is a natural product isolated from Cecropia obtusifolia, which possesses several pharmacological properties, such as: anti-carcinogenic, neuroprotective, antioxidant, anti-inflammatory, hypoglycemic, and hypolipidemic. In relation to its effects on the hyperglycemia and hypertriglyceridemia, few is known about the mechanisms in which this compound may be acting, therefore, the aim of the present study was to determine if CGA acts as an insulin secretagogue increasing intracellular calcium concentrations ([Ca(2+)]i) in RINm5F cells; or as an insulin sensitizer and lipid-lowering agent stimulating the expression of PPARγ and PPARα, respectively, in 3T3-L1 adipocytes. As results, RINm5F cells treated with 200μM of CGA showed an increase in [Ca(2+)]i of 9-times versus control and 4-times as compared to positive control; in addition, an increase in insulin secretion was observed similarly to those of positive control. CGA also significantly increased the mRNA expression of PPARγ (150%) and GLUT4 (220%), as well PPARα (40%) and FATP (25%) as it was appreciated by RT-PCR. Additionally, a chemoinformatic analysis suggested that CGA has suitable physicochemical properties to be considered as leader bioactive molecule for the development of novel agents with similar properties. Together, our results indicate that CGA possesses multiple mechanisms of action for the development of highly effective therapeutics in the treatment of metabolic diseases such as type 2 diabetes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Nucleic acid-binding molecules with high affinity and base sequence specificity: intercalating agents covalently linked to oligodeoxynucleotides.

    PubMed Central

    Asseline, U; Delarue, M; Lancelot, G; Toulmé, F; Thuong, N T; Montenay-Garestier, T; Hélène, C

    1984-01-01

    Oligodeoxyribonucleotides covalently linked to an intercalating agent via a polymethylene linker were synthesized. Oligothymidylates attached to an acridine dye (Acr) through the 3'-phosphate group [(Tp)n(CH2) mAcr ] specifically interact with the complementary sequence. The interaction is strongly stabilized by the intercalating agent. By using absorption and fluorescence spectroscopies, it is shown that complex formation between (Tp)n(CH2) mAcr and poly(rA) involves the formation of n A X T base pairs, where n is the number of thymines in the oligonucleotide. The acridine ring intercalates between A X T base pairs. Fluorescence excitation spectra reveal the existence of two environments for the acridine ring, whose relative contributions depend on the linker length (m). The binding of (Tp)4(CH2) mAcr to poly(rA) is analyzed in terms of site binding and cooperative interactions between oligonucleotides along the polynucleotide lattice. Thermodynamic parameters show that the covalent attachment of the acridine ring strongly stabilizes the binding of the oligonucleotide to its complementary sequence. The stabilization depends on the linker length; the compound with m = 5 gives a more stable complex than that with m = 3. These results open the way to the synthesis of a family of molecules exhibiting both high-affinity and high-specificity for a nucleic acid base sequence. PMID:6587350

  7. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer.

    PubMed

    Sadowski, Martin C; Pouwer, Rebecca H; Gunter, Jennifer H; Lubik, Amy A; Quinn, Ronald J; Nelson, Colleen C

    2014-10-15

    Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer.

  8. The fatty acid synthase inhibitor triclosan: repurposing an anti-microbial agent for targeting prostate cancer

    PubMed Central

    Sadowski, Martin C.; Pouwer, Rebecca H.; Gunter, Jennifer H.; Lubik, Amy A.; Quinn, Ronald J.; Nelson, Colleen C.

    2014-01-01

    Inhibition of FASN has emerged as a promising therapeutic target in cancer, and numerous inhibitors have been investigated. However, severe pharmacological limitations have challenged their clinical testing. The synthetic FASN inhibitor triclosan, which was initially developed as a topical antibacterial agent, is merely affected by these pharmacological limitations. Yet, little is known about its mechanism in inhibiting the growth of cancer cells. Here we compared the cellular and molecular effects of triclosan in a panel of eight malignant and non-malignant prostate cell lines to the well-known FASN inhibitors C75 and orlistat, which target different partial catalytic activities of FASN. Triclosan displayed a superior cytotoxic profile with a several-fold lower IC50 than C75 or orlistat. Structure-function analysis revealed that alcohol functionality of the parent phenol is critical for inhibitory action. Rescue experiments confirmed that end product starvation was a major cause of cytotoxicity. Importantly, triclosan, C75 and orlistat induced distinct changes to morphology, cell cycle, lipid content and the expression of key enzymes of lipid metabolism, demonstrating that inhibition of different partial catalytic activities of FASN activates different metabolic pathways. These finding combined with its well-documented pharmacological safety profile make triclosan a promising drug candidate for the treatment of prostate cancer. PMID:25313139

  9. Outcomes in ethnic minority renal transplant recipients receiving everolimus versus mycophenolate: comparative risk assessment results from a pooled analysis.

    PubMed

    Melancon, Keith; Mulgaonkar, Shamkant P; Delcoro, Carlos; Wiland, Anne; McCague, Kevin; Shihab, Fuad S

    2013-12-27

    Everolimus (EVR) has demonstrated good efficacy after renal transplantation. Racial disparities in clinical outcomes after de novo renal transplantation are well documented; whether the efficacy of EVR varies based on recipient ethnicity is unknown. We conducted a comparative risk assessment of EVR by ethnicity. Data on 2004 renal transplant recipients from three EVR studies were pooled to identify the impact of ethnicity on efficacy outcomes across EVR dosing groups and control groups. Ethnic groups compared were African Americans, non-U.S. blacks, Asians, Hispanics, and Caucasians. EVR groups received either 1.5 or 3 mg per day, with either standard-dose cyclosporine or reduced-dose cyclosporine. Control groups received mycophenolic acid (MPA) with standard-dose cyclosporine. Composite efficacy failure endpoint was graft loss, death, biopsy-proven acute rejection, or lost to follow-up. Adjusted odds ratios were calculated using a logistic regression model. The proportion of renal transplant recipients who met the composite endpoint was African Americans (46%), non-U.S. black (35%), Caucasian (31%), Hispanic (28%), and Asian (25%). The odds of meeting the composite endpoint were significantly (P=0.0001) greater for African Americans versus Caucasians but did not differ among the other ethnic groups (ethnic groups were only compared with Caucasians). EVR and MPA were associated with similar efficacy among each of the ethnic groups. In this pooled data analysis in more than 2000 renal transplant recipients, EVR versus MPA resulted in similar composite endpoint incidence events across ethnicities. Consistent with previously published data, African Americans had poorer clinical outcomes. EVR is efficacious regardless of ethnicity.

  10. Outcomes in Ethnic Minority Renal Transplant Recipients Receiving Everolimus versus Mycophenolate: Comparative Risk Assessment Results From a Pooled Analysis

    PubMed Central

    Melancon, Keith; Mulgaonkar, Shamkant P.; Delcoro, Carlos; Wiland, Anne; McCague, Kevin; Shihab, Fuad S.

    2013-01-01

    Background Everolimus (EVR) has demonstrated good efficacy after renal transplantation. Racial disparities in clinical outcomes after de novo renal transplantation are well documented; whether the efficacy of EVR varies based on recipient ethnicity is unknown. We conducted a comparative risk assessment of EVR by ethnicity. Methods Data on 2004 renal transplant recipients from three EVR studies were pooled to identify the impact of ethnicity on efficacy outcomes across EVR dosing groups and control groups. Ethnic groups compared were African Americans, non-U.S. blacks, Asians, Hispanics, and Caucasians. EVR groups received either 1.5 or 3 mg per day, with either standard-dose cyclosporine or reduced-dose cyclosporine. Control groups received mycophenolic acid (MPA) with standard-dose cyclosporine. Composite efficacy failure endpoint was graft loss, death, biopsy-proven acute rejection, or lost to follow-up. Adjusted odds ratios were calculated using a logistic regression model. Results The proportion of renal transplant recipients who met the composite endpoint was African Americans (46%), non-U.S. black (35%), Caucasian (31%), Hispanic (28%), and Asian (25%). The odds of meeting the composite endpoint were significantly (P=0.0001) greater for African Americans versus Caucasians but did not differ among the other ethnic groups (ethnic groups were only compared with Caucasians). EVR and MPA were associated with similar efficacy among each of the ethnic groups. Conclusion In this pooled data analysis in more than 2000 renal transplant recipients, EVR versus MPA resulted in similar composite endpoint incidence events across ethnicities. Consistent with previously published data, African Americans had poorer clinical outcomes. EVR is efficacious regardless of ethnicity. PMID:24345868

  11. Synthesis and biological evaluation of strained unusual amino acid containing tetrapeptides as potential antidepressant agents.

    PubMed

    Mainkar, Prathama S; Chakravarty, Sumana; Srujana, Takkallapally; Vishwanathan, Libi Anandi; Prajapti, Santosh Kumar; Chandra, Karisetty Bhanu; Veeraval, Lenin; Babu, Bathini Nagendra

    2015-12-01

    Strained unusual amino acid derived tetrapeptides were synthesized as mimics of GLYX-13, a clinical candidate for neuroprotective and anti-depressant properties, were studied. The synthesized compounds were screened for neurite growth and anti-depressant properties in vitro and in vivo respectively comparing with the parent GLYX-13 compound. Neurite growth property was assessed by neurite length and anti-depressant property by percentage of immobility in forced swim test, a behavioural assay. Mechanistic insights about protein-ligand interactions were obtained using molecular docking study. Based on the in vitro and in vivo screening data and molecular docking study, a new analogue of GLYX-13, Compound 11a has been found to be as good as the parent compound in all respects.

  12. Concentrated Phosphatidic Acid in Cereal Brans as Potential Protective Agents against Indomethacin-Induced Stomach Ulcer.

    PubMed

    Afroz, Sheuli; Ikoma, Teru; Yagi, Ayano; Kogure, Kentaro; Tokumura, Akira; Tanaka, Tamotsu

    2016-09-21

    One of complications associated with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is peptic ulcer. Recently, we found that orally administered phosphatidic acid (PA) ameliorated aspirin-induced stomach lesions in mice. In this study, we identified PA-rich food sources and examined the effects of the food materials on indomethacin-induced stomach ulcer. Among examined, buckwheat (Fagopyrum esculentum) bran contained the highest level of PA (188 mg/100 g). PA was the richest phospholipid (25%) in the lipid fraction of the buckwheat bran. Administration of the lipid extracts of buckwheat bran significantly ameliorated indomethacin-induced stomach lesions in mice. In contrast, wheat (Triticum durum) bran lipids (PA, 4%) and soybean (Glycine max) lipids (PA, 3%) were not associated with ameliorative effects. These results indicated that PA-rich lipids can be used as an effective supplement for prevention of NSAID-induced stomach ulcer.

  13. Synthesis, evaluation and molecular docking studies of amino acid derived N-glycoconjugates as antibacterial agents.

    PubMed

    Baig, Noorullah; Singh, Rajnish Prakash; Chander, Subhash; Jha, Prabhat Nath; Murugesan, Sankaranarayanan; Sah, Ajay K

    2015-12-01

    Six amino acid derived N-glycoconjugates of d-glucose were synthesized, characterized and tested for antibacterial activity against G(+)ve (Bacillus cereus) as well as G(-)ve (Escherichia coli and Klebsiella pneumoniae) bacterial strains. All the tested compounds exhibited moderate to good antibacterial activity against these bacterial strains. The results were compared with the antibacterial activity of standard drug Chloramphenicol, where results of A5 (Tryptophan derived glycoconjugates) against E. coli and A4 (Isoleucine derived glycoconjugates) against K. pneumoniae bacterial strains are comparable with the standard drug molecule. In silico docking studies were also performed in order to understand the mode of action and binding interactions of these molecules. The docking studies revealed that, occupation of compound A5 at the ATP binding site of subunit GyrB (DNA gyrase, PDB ID: 3TTZ) via hydrophobic and hydrogen bonding interactions may be the reason for its significant in vitro antibacterial activity.

  14. Synthesis of conjugated bile acids/azastilbenes as potential antioxidant and photoprotective agents.

    PubMed

    dos Santos, Juliana Alves; Polonini, Hudson Caetano; Suzuki, Érika Yoko; Raposo, Nádia R B; da Silva, Adilson David

    2015-06-01

    A series of 14 bile acids/azastilbenes conjugates (1a-g and 2a-g) was prepared through the condensation of bile amides (1 and 2) and aromatic aldehydes. The newly synthesized conjugates were evaluated in vitro for their antioxidant and photoprotective activities. Six compounds (1, 1a, 1b, 2, 2a and 2b) showed promising antioxidant activity with IC50 values of 19.60-31.83 μg mL(-1). The synthesized compounds presented a varied photoprotection profile, with the SPF ranging from 2 to 9. Among the 16 compounds tested for the protection against UVB sunrays, 3 compounds (2c, 2e and 2g) presented more significant protection than resveratrol and the free azastilbene 3; while the UVAPF increased from 2 in resveratrol and 5 in 3 to 5-11 in the majority of the conjugates.

  15. Design and synthesis of gambogic acid analogs as potent cytotoxic and anti-inflammatory agents

    PubMed Central

    Yen, Chiao-Ting; Nakagawa-Goto, Kyoko; Hwang, Tsong-Long; Morris-Natschke, Susan L.; Bastow, Kenneth F.; Wu, Yang-Chang; Lee, Kuo-Hsiung

    2012-01-01

    Prenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four human cancer cell lines (KB, KBvin, A549, and DU-145) and anti-inflammatory activity toward superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, prenylxanthones 7-13 were generally less active than pyranoxanthones 14-21 in both anticancer and anti-inflammatory assays. Furthermore, two angular 3,3-dimethypyranoxanthones (16 and 20) showed the greatest and selective activity against the KBvin multidrug resistant (MDR) cell line with IC50 values of 0.9 and 0.8 μ g/mL, respectively. An angular 3-methyl-3-prenylpyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than phenylmethylsulfonyl fluoride (PMSF), the positive control. PMID:22595179

  16. Oleic Acid Produced by a Marine Vibrio spp. Acts as an Anti-Vibrio parahaemolyticus Agent

    PubMed Central

    Leyton, Yanett; Borquez, Jorge; Darias, José; Cueto, Mercedes; Díaz-Marrero, Ana R.; Riquelme, Carlos

    2011-01-01

    It is known that some strains of Vibrio parahaemolyticus are responsible for gastroenteric diseases caused by the ingestion of marine organisms contaminated with these bacterial strains. Organic products that show inhibitory activity on the growth of the pathogenic V. parahaemolyticus were extracted from a Vibrio native in the north of Chile. The inhibitory organic products were isolated by reverse phase chromatography and permeation by Sephadex LH20, and were characterized by spectroscopic and spectrometric techniques. The results showed that the prevailing active product is oleic acid, which was compared with standards by gas chromatography and high-performance liquid chromatography (HPLC). These active products might be useful for controlling the proliferation of pathogenic clones of V. parahaemolyticus. PMID:22073014

  17. Influence of pH, bleaching agents, and acid etching on surface wear of bovine enamel.

    PubMed

    Soares, Ana Flávia; Bombonatti, Juliana Fraga Soares; Alencar, Marina Studart; Consolmagno, Elaine Cristina; Honório, Heitor Marques; Mondelli, Rafael Francisco Lia

    2016-01-01

    Development of new materials for tooth bleaching justifies the need for studies to evaluate the changes in the enamel surface caused by different bleaching protocols. The aim of this study was to evaluate the bovine dental enamel wear in function of different bleaching gel protocols, acid etching and pH variation. Sixty fragments of bovine teeth were cut, obtaining a control and test areas. In the test area, one half received etching followed by a bleaching gel application, and the other half, only the bleaching gel. The fragments were randomly divided into six groups (n=10), each one received one bleaching session with five hydrogen peroxide gel applications of 8 min, activated with hybrid light, diode laser/blue LED (HL) or diode laser/violet LED (VHL) (experimental): Control (C); 35% Total Blanc Office (TBO35HL); 35% Lase Peroxide Sensy (LPS35HL); 25% Lase Peroxide Sensy II (LPS25HL); 15% Lase Peroxide Lite (LPL15HL); and 10% hydrogen peroxide (experimental) (EXP10VHL). pH values were determined by a pHmeter at the initial and final time periods. Specimens were stored, subjected to simulated brushing cycles, and the superficial wear was determined (μm). ANOVA and Tukey´s tests were applied (α=0.05). The pH showed a slight decrease, except for Group LPL15HL. Group LPS25HL showed the highest degree of wear, with and without etching. There was a decrease from the initial to the final pH. Different bleaching gels were able to increase the surface wear values after simulated brushing. Acid etching before bleaching increased surface wear values in all groups.

  18. Influence of pH, bleaching agents, and acid etching on surface wear of bovine enamel

    PubMed Central

    Soares, Ana Flávia; Bombonatti, Juliana Fraga Soares; Alencar, Marina Studart; Consolmagno, Elaine Cristina; Honório, Heitor Marques; Mondelli, Rafael Francisco Lia

    2016-01-01

    ABSTRACT Development of new materials for tooth bleaching justifies the need for studies to evaluate the changes in the enamel surface caused by different bleaching protocols. Objective The aim of this study was to evaluate the bovine dental enamel wear in function of different bleaching gel protocols, acid etching and pH variation. Material and Methods Sixty fragments of bovine teeth were cut, obtaining a control and test areas. In the test area, one half received etching followed by a bleaching gel application, and the other half, only the bleaching gel. The fragments were randomly divided into six groups (n=10), each one received one bleaching session with five hydrogen peroxide gel applications of 8 min, activated with hybrid light, diode laser/blue LED (HL) or diode laser/violet LED (VHL) (experimental): Control (C); 35% Total Blanc Office (TBO35HL); 35% Lase Peroxide Sensy (LPS35HL); 25% Lase Peroxide Sensy II (LPS25HL); 15% Lase Peroxide Lite (LPL15HL); and 10% hydrogen peroxide (experimental) (EXP10VHL). pH values were determined by a pHmeter at the initial and final time periods. Specimens were stored, subjected to simulated brushing cycles, and the superficial wear was determined (μm). ANOVA and Tukey´s tests were applied (α=0.05). Results The pH showed a slight decrease, except for Group LPL15HL. Group LPS25HL showed the highest degree of wear, with and without etching. Conclusion There was a decrease from the initial to the final pH. Different bleaching gels were able to increase the surface wear values after simulated brushing. Acid etching before bleaching increased surface wear values in all groups. PMID:27008254

  19. Acridone acetic acid, sodium salt, as an agent to stop vitiligo progression: a pilot study.

    PubMed

    Korobko, Igor V; Lomonosov, Konstantin M

    2014-01-01

    Vitiligo progression is attributed to immune system malfunctioning, thus immunomodulating compounds might be beneficial in stopping vitiligo progression which is a prerequisite for successful repigmentation. The goal of this study was to assess efficacy of acridone acetic acid, sodium salt (Na-AAA), an immunomodulating compound with favorable safety profile, in stabilizing active vitiligo, and to reveal prognostic factors of treatment outcome. Sixty consecutive patients with progressing nonsegmental vitiligo were treated with 10 i.m. injections of Na-AAA every other day. Disease stability was assessed in 1, 3, 6, and 12 months post-treatment. Statistical analysis was applied to correlate treatment outcome and available clinical parameters. Of the 60 patients treated, vitiligo stopped progression in 44 patients (73.3%). Older age (p = 0.0219), age of 35 and older (p = 0.0189, odds ratio (OR) = 5.2, 95% confidence interval (CI) 1.30-20.84) or age of 40 and older (p = 0.0039, OR = 6.48, 95% CI 1.86-22.61), longer disease duration (p = 0.0234), pre-treatment interleukin-6 level over 2 pg/mL (p = 0.0005, OR = 13.7, 95% CI 2.97-63), and over the reference threshold value 5.9 pg/mL (p = 0.0009, OR = 25.8, 95% CI 2.8-239) as well as presence of other autoimmune diseases (p = 0.038, OR = 7.0, 95% CI 1.14-42.97) were negative prognostic factors of treatment success. In conclusion, acridone acetic acid, sodium salt, emerges as an efficient option for stopping vitiligo progression.

  20. Production of L-lactic acid by a thermophilic Bacillus mutant using sodium hydroxide as neutralizing agent.

    PubMed

    Qin, Jiayang; Wang, Xiuwen; Zheng, Zhaojuan; Ma, Cuiqing; Tang, Hongzhi; Xu, Ping

    2010-10-01

    A sodium lactate tolerant mutant strain named Bacillus sp. Na-2 was obtained and applied to sodium hydroxide-based L-lactic acid (LA) production process. The influences of aeration and pH were investigated to further improve the resistance of strain Na-2 against sodium lactate stress and to obtain the most efficient L-LA production process. Although mild aeration was favorable for cell growth and L-LA production, vigorous aeration resulted in a metabolic shift from homolactic to mixed-acid/acetoin fermentation. Therefore, a two-stage aeration control strategy was employed. Optimum pH was found to be 6.0. A total of 106.0 g/l L-LA was produced in 30 h by Bacillus sp. Na-2 using sodium hydroxide as neutralizing agent. Productivity, conversion rate and optical purity were 3.53 g/l/h, 94% and 99.5%, respectively. The remarkable fermentation traits of Bacillus sp. Na-2 and the environment-friendly characteristics of NaOH-based process represent new insight for industrial scale production of L-LA. Copyright 2010 Elsevier Ltd. All rights reserved.

  1. Biodegradable and non-retrogradable eco-films based on starch-glycerol with citric acid as crosslinking agent.

    PubMed

    Seligra, Paula González; Medina Jaramillo, Carolina; Famá, Lucía; Goyanes, Silvia

    2016-03-15

    Biodegradable and non-retrogradable starch-glycerol based films were obtained using citric acid (CA) as crosslinking agent at 75°C. This material allowed decreasing water vapor permeability (WVP) more than 35%, remained amorphous for at least 45 days as a result of the network formed by the CA that avoided starch retrogradation and maintained the degradability in compost, occurring only six days after the films without citric acid. A simulation of the gelatinization process of starch-glycerol with and without CA, using a differential thermal analysis device, showed that the system with CA completed the gelatinization 5°C before than the other and, CA first reacted with glycerol and then starch-glycerol-CA reaction occurred. The temperature at which the gelatinization process was carried out was critical to obtain the best results. An increase of gelatinization process temperature at 85°C in system with CA, led to a worsening on WVP and its integrity after a swelling process with dimethylsulphoxide (DMSO), compared to the films processed at 75°C. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Short-chain fatty acids and poly-beta-hydroxyalkanoates: (New) Biocontrol agents for a sustainable animal production.

    PubMed

    Defoirdt, Tom; Boon, Nico; Sorgeloos, Patrick; Verstraete, Willy; Bossier, Peter

    2009-01-01

    Because of the risk of antibiotic resistance development, there is a growing awareness that antibiotics should be used more carefully in animal production. However, a decreased use of antibiotics could result in a higher frequency of pathogenic bacteria, which in its turn could lead to a higher incidence of infections. Short-chain fatty acids (SCFAs) have long been known to exhibit bacteriostatic activity. These compounds also specifically downregulate virulence factor expression and positively influence the gastrointestinal health of the host. As a consequence, there is currently considerable interest in SCFAs as biocontrol agents in animal production. Polyhydroxyalkanoates (PHAs) are polymers of beta-hydroxy short-chain fatty acids. Currently, PHAs are applied as replacements for synthetic polymers. These biopolymers can be depolymerised by many different microorganisms that produce extracellular PHA depolymerases. Interestingly, different studies provided some evidence that PHAs can also be degraded upon passage through the gastrointestinal tract of animals and consequently, adding these compounds to the feed might result in biocontrol effects similar to those described for SCFAs.

  3. Versatile methods for synthesizing organic acid salts of quaternary berberine-type alkaloids as anti-ulcerative colitis agents.

    PubMed

    Zhang, Zhi-Hui; Li, Jing; Zhang, Hai-Jing; Deng, An-Jun; Wu, Lian-Qiu; Li, Zhi-Hong; Song, Hong-Rui; Wang, Wen-Jie; Qin, Hai-Lin

    2016-06-01

    Two versatile methods to synthesize kinds of organic acid salts of quaternary berberine-type alkaloids were investigated in order to determine which is more efficient to improve the liposolubility of the target compounds and to explore the efficacy of the target compounds as anti-ulcerative colitis (UC) agents. Overall evaluation according to the reaction results and yields of the final products indicated that the synthetic method using tertiary (±)-8-acylmethyldihydroberberine-type alkaloids as key intermediates is superior to that of using tertiary dihydroberberine-type alkaloids as intermediates. Ten target compounds were synthesized using quaternary berberine chloride and quaternary coptisine chloride as starting materials, respectively, and the anti-UC activity of some target compounds was evaluated in an in vitro x-box-binding protein 1 (XBP1) transcriptional activity assay using dual luciferase reporter detection. At 10 μM, the tested compounds were found to activate the transcription of XBP1 target at almost the same level as that of quaternary coptisine chloride. The synthesized target compounds were also found to share higher liposolubility than the inorganic acid salts of quaternary berberine-type alkaloid.

  4. Biocontrol agents-mediated suppression of oxalic acid induced cell death during Sclerotinia sclerotiorum-pea interaction.

    PubMed

    Jain, Akansha; Singh, Akanksha; Singh, Surendra; Sarma, Birinchi Kumar; Singh, Harikesh Bahadur

    2015-05-01

    Oxalic acid (OA) is an important pathogenic factor during early Sclerotinia sclerotiorum-host interaction and might work by reducing hydrogen peroxide production (H2 O2 ). In the present investigation, oxalic acid-induced cell death in pea was studied. Pea plants treated with biocontrol agents (BCAs) viz., Pseudomonas aeruginosa PJHU15, Bacillus subtilis BHHU100, and Trichoderma harzianum TNHU27 either singly and/or in consortium acted on S. sclerotiorum indirectly by enabling plants to inhibit the OA-mediated suppression of oxidative burst via induction of H2 O2 . Our results showed that BCA treated plants upon treatment with culture filtrate of the pathogen, conferred the resistance via. significantly decreasing relative cell death of pea against S. sclerotiorum compared to control plants without BCA treatment but treated with the culture filtrate of the pathogen. The results obtained from the present study indicate that the microbes especially in consortia play significant role in protection against S. sclerotiorum by modulating oxidative burst and partially enhancing tolerance by increasing the H2 O2 generation, which is otherwise suppressed by OA produced by the pathogen. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells.

    PubMed

    Bommagani, Shobanbabu; Ponder, Jessica; Penthala, Narsimha R; Janganati, Venumadhav; Jordan, Craig T; Borrelli, Michael J; Crooks, Peter A

    2017-08-18

    A series of novel, heteroaryl carboxylic acid conjugates of the sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 human hematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03-0.30 μM and 0.04-0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0.05-0.40 μM and 0.04-0.61 μM, respectively, against 90% of the solid tumor cell lines in the NCI panel. Compound 7a was particularly effective against the sub-panel of breast cancer cell lines with GI50 values in the range <0.01-0.30 μM. Compounds 7j, 7a and its water soluble analog 7p also exhibited potent anticancer activity against rat 9L-SF gliosarcoma cells in culture. Compound 7j was the most potent compound in the series in the M9-ENL1 AML cell assay with a lethal dose concentration EC50 value of 720 nM, and exhibited the greatest cytotoxicity against a collection of primary AML stem cell specimens, which included a specimen that was unresponsive to PTL, affording EC50 values in the range 0.33-1.0 μM in three out of four specimens. The results from this study provide further evidence that analogs of the sesquiterpene MMB can be designed to afford molecules with significantly improved anticancer activity. Thus, both 7j and 7k are considered potential lead molecules in the search for new anticancer agents that can be used as treatments for both hematopoetic and solid tumors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  6. Derivatives of caffeic acid, a natural antioxidant, as the basis for the discovery of novel nonpeptidic neurotrophic agents.

    PubMed

    Moosavi, Fatemeh; Hosseini, Razieh; Rajaian, Hamid; Silva, Tiago; Magalhães E Silva, Diogo; Saso, Luciano; Edraki, Najmeh; Miri, Ramin; Borges, Fernanda; Firuzi, Omidreza

    2017-06-15

    Neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, threaten the lives of millions of people and the number of affected patients is constantly growing with the increase of the aging population. Small molecule neurotrophic agents represent promising therapeutics for the pharmacological management of neurodegenerative diseases. In this study, a series of caffeic acid amide analogues with variable alkyl chain lengths, including ACAF3 (C3), ACAF4 (C4), ACAF6 (C6), ACAF8 (C8) and ACAF12 (C12) were synthesized and their neurotrophic activity was examined by different methods in PC12 neuronal cells. We found that all caffeic acid amide derivatives significantly increased survival in PC12 neuronal cells in serum-deprived conditions at 25μM, as measured by the MTT assay. ACAF4, ACAF6 and ACAF8 at 5µM also significantly enhanced the effect of nerve growth factor (NGF) in inducing neurite outgrowth, a sign of neuronal differentiation. The neurotrophic effects of amide derivatives did not seem to be mediated by direct activation of tropomyosin receptor kinase A (TrkA) receptor, since K252a, a potent TrkA antagonist, did not block the neuronal survival enhancement effect. Similarly, the active compounds did not activate TrkA as measured by immunoblotting with anti-phosphoTrkA antibody. We also examined the effect of amide derivatives on signaling pathways involved in survival and differentiation by immunoblotting. ACAF4 and ACAF12 induced ERK1/2 phosphorylation in PC12 cells at 5 and 25µM, while ACAF12 was also able to significantly increase AKT phosphorylation at 5 and 25µM. Molecular docking studies indicated that compared to the parental compound caffeic acid, ACAF12 exhibited higher binding energy with phosphoinositide 3-kinase (PI3K) as a putative molecular target. Based on Lipinski's rule of five, all of the compounds obeyed three molecular descriptors (HBD, HBA and MM) in drug-likeness test. Taken together, these findings show for the

  7. Hemolysis of human erythrocytes by hypochlorous acid is modulated by amino acids, antioxidants, oxidants, membrane-perforating agents and by divalent metals.

    PubMed

    Ginsburg, Isaac; Sadovnic, Milu; Yedgar, Shaul; Kohen, Ron; Hrbac, Jan

    2002-06-01

    The optimal conditions under which hypochlorous acid (NaOCl) either hemolyzes human RBC or kills monkey kidney epithelial cells (BGM) in culture had been investigated. While in Hank's balanced salt solution (HBSS), micromolar amounts of NaOCl caused full hemolysis and also killed BGM cells, in D-MEM or RPMI media rich in amino acids, 25-40 mM of hypochlorite were needed to induce cell injury. Cells exposed to high amounts of NaOCl became highly refractory to strong detergents. Hemolysis by NaOCl was strongly inhibited by a large variety of antioxidants. RBC treated by subtoxic concentrations either of peroxide, peroxyl radical, NO, cholesterol, PLA2, PLC as well as by N2, argon or by mixture of CO2 (10%) and O2 (90%) became much more susceptible to lysis by NaOCl. On the other hand, while RBC treated by Fe2+, Co2+, and V2+ and to a lesser extent with Cu2+ became highly resistant to NaOCl hemolysis presumably due to NaOCl decomposition, no such effect was found either with Co2+ or by Mn2+. RBC treated by azide to destroy catalase and then incubated with peroxide and with NaOCl failed to undergo hemolysis due to the ability of peroxide to decompose NaOCl. The inhibitory effects of the divalent metals on NaOCl-induced hemolysis were also substantiated by measuring the decrease in pH and by cyclic voltammetry. The findings that like peroxide, NaOCl also synergizes with membrane-perforating agents and with a protease to kill epithelial cells further implicate such "cocktails" in cell injury in inflammatory conditions. Taken together, because of the capacity of many agents to scavenge NaOCl, tissue damage by NaOCl-generated neutrophils can take place primarily if activated neutrophils closely adhere to target cells to avoid the scavenging effects of amino acids and of antioxidants. Therefore, the significance of the data which had tested the cytotoxic effects of NaOCl using cells suspended only in salt solutions, should be reconsidered.

  8. Long-term mycophenolate monotherapy in human leukocyte antigen (HLA)-identical living-donor kidney transplantation

    PubMed Central

    2014-01-01

    Methods We analyzed all PRA-negative patients who received a first kidney transplant from an HLA-identical living donor. The patients received no antibody induction. An intraoperative bolus of 500 mg of methylprednisolone was administered. Then, steroid therapy was withdrawn within one week. Tacrolimus and mycophenolate treatment were started 3 days before transplantation with tacrolimus target levels of 4 to 8 ng/mL. In the absence of rejection, tacrolimus was withdrawn between 3 and 12 months post-transplant to reach mycophenolate mofetil monotherapy of 2 g/day or equivalent. Results Six patients were treated with the above protocol. At last follow-up, graft and patient survival were 100%. MDRD glomerular filtration rates were 54, 60, and 62 mL/min at 3 months, 12 months and last follow-up, respectively. None of the patients developed PRA post-transplant. One episode of acute rejection Banff IA occurred 9 years after transplantation due to non-adherence with good outcome after treatment. The mean number of concomitant drugs given with mycophenolate was 2.6. Four patients needed antihypertensive drugs. Conclusion Steroid-free de novo treatment and calcineurin-inhibitor weaning with mycophenolate monotherapy is feasible in first HLA-identical kidney transplantation from a living sibling. Although recipients of a first HLA-identical living-donor kidney transplant seem to need less immunosuppression, there are no guideline recommendations for these patients, and few prospective trials are available. PMID:24491040

  9. (-)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects.

    PubMed

    Makowski, Kamil; Mir, Joan Francesc; Mera, Paula; Ariza, Xavier; Asins, Guillermina; Hegardt, Fausto G; Herrero, Laura; García, Jordi; Serra, Dolors

    2017-05-05

    C75 is a synthetic anticancer drug that inhibits fatty acid synthase (FAS) and shows a potent anorexigenic side effect. In order to find new cytotoxic compounds that do not impact food intake, we synthesized a new family of C75 derivatives. The most promising anticancer compound among them was UB006 ((4SR,5SR)-4-(hydroxymethyl)-3-methylene-5-octyldihydrofuran-2(3H)-one). The effects of this compound on cytotoxicity, food intake and body weight were studied in UB006 racemic mixture and in both its enantiomers separately. The results showed that both enantiomers inhibit FAS activity and have potent cytotoxic effects in several tumour cell lines, such as the ovarian cell cancer line OVCAR-3. The (-)-UB006 enantiomer's cytotoxic effect on OVCAR-3 was 40-fold higher than that of racemic C75, and 2- and 38-fold higher than that of the racemic mixture and its opposite enantiomer, respectively. This cytotoxic effect on the OVCAR-3 cell line involves mechanisms that reduce mitochondrial respiratory capacity and ATP production, DDIT4/REDD1 upregulation, mTOR activity inhibition, and caspase-3 activation, resulting in apoptosis. In addition, central and peripheral administration of (+)-UB006 or (-)-UB006 into rats and mice did not affect food intake or body weight. Altogether, our data support the discovery of a new potential anticancer compound (-)-UB006 that has no anorexigenic side effects.

  10. Peracetic acid: a practical agent for sterilizing heat-labile polymeric tissue-engineering scaffolds.

    PubMed

    Yoganarasimha, Suyog; Trahan, William R; Best, Al M; Bowlin, Gary L; Kitten, Todd O; Moon, Peter C; Madurantakam, Parthasarathy A

    2014-09-01

    Advanced biomaterials and sophisticated processing technologies aim at fabricating tissue-engineering scaffolds that can predictably interact within a biological environment at the cellular level. Sterilization of such scaffolds is at the core of patient safety and is an important regulatory issue that needs to be addressed before clinical translation. In addition, it is crucial that meticulously engineered micro- and nano- structures are preserved after sterilization. Conventional sterilization methods involving heat, steam, and radiation are not compatible with engineered polymeric systems because of scaffold degradation and loss of architecture. Using electrospun scaffolds made from polycaprolactone, a low melting polymer, and employing spores of Bacillus atrophaeus as biological indicators, we compared ethylene oxide, autoclaving and 80% ethanol to a known chemical sterilant, peracetic acid (PAA), for their ability to sterilize as well as their effects on scaffold properties. PAA diluted in 20% ethanol to 1000 ppm or above sterilized electrospun scaffolds in 15 min at room temperature while maintaining nano-architecture and mechanical properties. Scaffolds treated with PAA at 5000 ppm were rendered hydrophilic, with contact angles reduced to 0°. Therefore, PAA can provide economical, rapid, and effective sterilization of heat-sensitive polymeric electrospun scaffolds that are used in tissue engineering.

  11. Synthesis and Evaluation of Novel Triterpene Analogues of Ursolic Acid as Potential Antidiabetic Agent

    PubMed Central

    Wu, Panpan; Zheng, Jie; Huang, Tianming; Li, Dianmeng; Hu, Qingqing; Cheng, Anming; Jiang, Zhengyun; Jiao, Luoying; Zhao, Suqing; Zhang, Kun

    2015-01-01

    Ursolic acid (UA) is a naturally bioactive compound that possesses potential anti-diabetic activity. The relatively safe and effective molecule intrigued us to further explore and to improve its anti-diabetic activity. In the present study, a series of novel UA analogues was synthesized and their structures were characterized. Their bioactivities against the α-glucosidase from baker's yeast were determined in vitro. The results suggested that most of the analogues exhibited significant inhibitory activity, especially analogues 8b and 9b with the IC50 values of 1.27 ± 0.27 μM (8b) and 1.28 ± 0.27 μM (9b), which were lower than the other analogues and the positive control. The molecular docking and 2D-QSAR studies were carried out to prove that the C-3 hydroxyl could interact with the hydrophobic region of the active pocket and form hydrogen bonds to increase the binding affinity of ligand and the homology modelling protein. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from UA analogues. PMID:26406581

  12. Caffeic Acid Phenethyl Ester Is a Potential Therapeutic Agent for Oral Cancer

    PubMed Central

    Kuo, Ying-Yu; Jim, Wai-Tim; Su, Liang-Cheng; Chung, Chi-Jung; Lin, Ching-Yu; Huo, Chieh; Tseng, Jen-Chih; Huang, Shih-Han; Lai, Chih-Jen; Chen, Bo-Chih; Wang, Bi-Juan; Chan, Tzu-Min; Lin, Hui-Ping; Chang, Wun-Shaing Wayne; Chang, Chuang-Rung; Chuu, Chih-Pin

    2015-01-01

    Head and neck cancers, which affect 650,000 people and cause 350,000 deaths per year, is the sixth leading cancer by cancer incidence and eighth by cancer-related death worldwide. Oral cancer is the most common type of head and neck cancer. More than 90% of oral cancers are oral and oropharyngeal squamous cell carcinoma (OSCC). The overall five-year survival rate of OSCC patients is approximately 63%, which is due to the low response rate to current therapeutic drugs. In this review we discuss the possibility of using caffe