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Sample records for tissue drug distribution

  1. Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

    Science.gov (United States)

    Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

    2013-07-01

    Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

  2. Plasma vs heart tissue concentration in humans - literature data analysis of drugs distribution.

    Science.gov (United States)

    Tylutki, Zofia; Polak, Sebastian

    2015-03-12

    Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  3. A hybrid approach to advancing quantitative prediction of tissue distribution of basic drugs in human

    International Nuclear Information System (INIS)

    Poulin, Patrick; Ekins, Sean; Theil, Frank-Peter

    2011-01-01

    A general toxicity of basic drugs is related to phospholipidosis in tissues. Therefore, it is essential to predict the tissue distribution of basic drugs to facilitate an initial estimate of that toxicity. The objective of the present study was to further assess the original prediction method that consisted of using the binding to red blood cells measured in vitro for the unbound drug (RBCu) as a surrogate for tissue distribution, by correlating it to unbound tissue:plasma partition coefficients (Kpu) of several tissues, and finally to predict volume of distribution at steady-state (V ss ) in humans under in vivo conditions. This correlation method demonstrated inaccurate predictions of V ss for particular basic drugs that did not follow the original correlation principle. Therefore, the novelty of this study is to provide clarity on the actual hypotheses to identify i) the impact of pharmacological mode of action on the generic correlation of RBCu-Kpu, ii) additional mechanisms of tissue distribution for the outlier drugs, iii) molecular features and properties that differentiate compounds as outliers in the original correlation analysis in order to facilitate its applicability domain alongside the properties already used so far, and finally iv) to present a novel and refined correlation method that is superior to what has been previously published for the prediction of human V ss of basic drugs. Applying a refined correlation method after identifying outliers would facilitate the prediction of more accurate distribution parameters as key inputs used in physiologically based pharmacokinetic (PBPK) and phospholipidosis models.

  4. Incorporation of lysosomal sequestration in the mechanistic model for prediction of tissue distribution of basic drugs.

    Science.gov (United States)

    Assmus, Frauke; Houston, J Brian; Galetin, Aleksandra

    2017-11-15

    The prediction of tissue-to-plasma water partition coefficients (Kpu) from in vitro and in silico data using the tissue-composition based model (Rodgers & Rowland, J Pharm Sci. 2005, 94(6):1237-48.) is well established. However, distribution of basic drugs, in particular into lysosome-rich lung tissue, tends to be under-predicted by this approach. The aim of this study was to develop an extended mechanistic model for the prediction of Kpu which accounts for lysosomal sequestration and the contribution of different cell types in the tissue of interest. The extended model is based on compound-specific physicochemical properties and tissue composition data to describe drug ionization, distribution into tissue water and drug binding to neutral lipids, neutral phospholipids and acidic phospholipids in tissues, including lysosomes. Physiological data on the types of cells contributing to lung, kidney and liver, their lysosomal content and lysosomal pH were collated from the literature. The predictive power of the extended mechanistic model was evaluated using a dataset of 28 basic drugs (pK a ≥7.8, 17 β-blockers, 11 structurally diverse drugs) for which experimentally determined Kpu data in rat tissue have been reported. Accounting for the lysosomal sequestration in the extended mechanistic model improved the accuracy of Kpu predictions in lung compared to the original Rodgers model (56% drugs within 2-fold or 88% within 3-fold of observed values). Reduction in the extent of Kpu under-prediction was also evident in liver and kidney. However, consideration of lysosomal sequestration increased the occurrence of over-predictions, yielding overall comparable model performances for kidney and liver, with 68% and 54% of Kpu values within 2-fold error, respectively. High lysosomal concentration ratios relative to cytosol (>1000-fold) were predicted for the drugs investigated; the extent differed depending on the lysosomal pH and concentration of acidic phospholipids among

  5. Interspecies comparison of the tissue distribution of WR-2721, a radioprotective drug

    International Nuclear Information System (INIS)

    Washburn, L.C.; Rafter, J.J.; Hayes, R.L.; Yuhas, J.M.

    1975-01-01

    Pre-irradiation intravenous administration of the radioprotective drug S-2-[3-aminopropylamino]ethylphosphorothioic acid (WR-2721) has potential value in radiotherapy because it doubles the radiation resistance of normal mouse tissues while affording only minimal protection to tumors. Deficient deposition of WR- 2721 in tumor tissue has recently been demonstrated and this is thought to be a major reason for the preferential protection of normal tissues by the drug. Data originally obtained in studies using the mouse and rat indicated that the tissue distribution of WR-2721 was possibly more closely related to dose per unit surface area than to dose per unit weight. To test this hypothesis an interspecies comparison of the tissue distribution of 35 S-labeled WR-2721 was carried out in normal mice, rats, rabbits, and dogs at 15 and 30 minutes after intravenous administration. Results suggest that the surface area and body weight exert equal effects on the tissue concentration of WR-2721. The results further suggest that lower absolute doses of WR-2721 in the human, possibly as low as 20 mg/kg, may provide a radioprotective effect equivalent to that produced from 100 mg/kg in the mouse, i.e., a 50 to 80 percent increase in radiation resistance (CH)

  6. Spatial distribution of theobromine--a low MW drug--in tissues via matrix-free NALDI-MS imaging.

    Science.gov (United States)

    Tata, Alessandra; Montemurro, Chiara; Porcari, Andreia M; Silva, Kamila C; Lopes de Faria, José B; Eberlin, Marcos N

    2014-09-01

    The ability of nano-assisted laser desorption-ionization mass spectrometry imaging (NALDI-IMS) to provide selective chemical monitoring with appropriate spatial distribution of a low molecular drug in a biological tissue was investigated. NALDI-IMS is a matrix-free laser desorption ionization (LDI) protocol based on imprinting of tissue constituents on a nanostructured surface. Using the accumulation of theobromine in rat kidney as a model, NALDI-IMS was found to provide well-resolved images of the special distribution of this low molecular weight (MW) drug in tissue. Copyright © 2014 John Wiley & Sons, Ltd.

  7. Multiscale Modeling of Antibody Drug Conjugates: Connecting tissue and cellular distribution to whole animal pharmacokinetics and potential implications for efficacy

    Science.gov (United States)

    Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M.

    2016-01-01

    Antibody drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from non-specific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody drug conjugate Kadcyla in HER2 positive mouse xenografts. This model is able to capture the impact of the drug antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs. PMID:27287046

  8. Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice.

    Science.gov (United States)

    Chew, Chii Chii; Ng, Salby; Chee, Yun Lee; Koo, Teng Wai; Liew, Ming Hui; Chee, Evelyn Li-Ching; Modamio, Pilar; Fernández, Cecilia; Mariño, Eduardo L; Segarra, Ignacio

    2017-08-01

    Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60 mg/kg PO sunitinib alone (control groups) or with 30 mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC 0→∞ 38% in plasma (p diclofenac increased the liver uptake efficiency in male (27%, p diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.

  9. Vaginal drug distribution modeling.

    Science.gov (United States)

    Katz, David F; Yuan, Andrew; Gao, Yajing

    2015-09-15

    This review presents and applies fundamental mass transport theory describing the diffusion and convection driven mass transport of drugs to the vaginal environment. It considers sources of variability in the predictions of the models. It illustrates use of model predictions of microbicide drug concentration distribution (pharmacokinetics) to gain insights about drug effectiveness in preventing HIV infection (pharmacodynamics). The modeling compares vaginal drug distributions after different gel dosage regimens, and it evaluates consequences of changes in gel viscosity due to aging. It compares vaginal mucosal concentration distributions of drugs delivered by gels vs. intravaginal rings. Finally, the modeling approach is used to compare vaginal drug distributions across species with differing vaginal dimensions. Deterministic models of drug mass transport into and throughout the vaginal environment can provide critical insights about the mechanisms and determinants of such transport. This knowledge, and the methodology that obtains it, can be applied and translated to multiple applications, involving the scientific underpinnings of vaginal drug distribution and the performance evaluation and design of products, and their dosage regimens, that achieve it. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. Comparison of drug distribution images from whole-body thin tissue sections obtained using desorption electrospray ionization tandem mass spectrometry and autoradiography.

    Science.gov (United States)

    Kertesz, Vilmos; Van Berkel, Gary J; Vavrek, Marissa; Koeplinger, Kenneth A; Schneider, Bradley B; Covey, Thomas R

    2008-07-01

    Desorption electrospray ionization tandem mass spectrometry (DESI-MS/MS) and whole-body autoradiography (WBA) were used for chemical imaging of whole-body thin tissue sections of mice intravenously dosed with propranolol (7.5 mg/kg). DESI-MS/MS imaging utilized selected reaction monitoring detection performed on an AB/MDS SCIEX 4000 QTRAP mass spectrometer equipped with a prototype extended length particle discriminator interface. Propranolol images of the tissue sections using DESI-MS/MS were obtained at surface scan rates of 0.1, 0.5, 2, and 7 mm/s. Although signal decreased with increasing scan rate, useful whole-body images for propranolol were obtained from the tissues even at 7 mm/s, which required just 79 min of analysis time. Attempts to detect and image the distribution of the known propranolol metabolites were unsuccessful. Regions of the tissue sections showing the most radioactivity from WBA sections were excised and analyzed by high-performance liquid chromatography (HPLC) with radiochemical detection to determine relative levels of propranolol and metabolites present. Comparison of the DESI-MS/MS signal for propranolol and the radioactivity attributed to propranolol from WBA sections indicated nominal agreement between the two techniques for the amount of propranolol in the brain, lung, and liver. Data from the kidney showed an unexplained disparity between the two techniques. The results of this study show the feasibility of using DESI-MS/MS to obtain useful chemical images of a drug in whole-body thin tissue sections following drug administration at a pharmacologically relevant level. Further optimization to improve sensitivity and enable detection of the drug metabolites will be among the requirements necessary to move DESI-MS/MS chemical imaging forward as a practical tool in drug discovery.

  11. Drugs Approved for Soft Tissue Sarcoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for soft tissue sarcoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  12. Toward a unified model of passive drug permeation II: the physiochemical determinants of unbound tissue distribution with applications to the design of hepatoselective glucokinase activators.

    Science.gov (United States)

    Ghosh, Avijit; Maurer, Tristan S; Litchfield, John; Varma, Manthema V; Rotter, Charles; Scialis, Renato; Feng, Bo; Tu, Meihua; Guimaraes, Cris R W; Scott, Dennis O

    2014-10-01

    In this work, we leverage a mathematical model of the underlying physiochemical properties of tissues and physicochemical properties of molecules to support the development of hepatoselective glucokinase activators. Passive distribution is modeled via a Fick-Nernst-Planck approach, using in vitro experimental data to estimate the permeability of both ionized and neutral species. The model accounts for pH and electrochemical potential across cellular membranes, ionization according to Henderson-Hasselbalch, passive permeation of the neutral species using Fick's law, and passive permeation of the ionized species using the Nernst-Planck equation. The mathematical model of the physiochemical system allows derivation of a single set of parameters governing the distribution of drug molecules across multiple conditions both in vitro and in vivo. A case study using this approach in the development of hepatoselective glucokinase activators via organic anion-transporting polypeptide-mediated hepatic uptake and impaired passive distribution to the pancreas is described. The results for these molecules indicate the permeability penalty of the ionized form is offset by its relative abundance, leading to passive pancreatic exclusion according to the Nernst-Planck extension of Fickian passive permeation. Generally, this model serves as a useful construct for drug discovery scientists to understand subcellular exposure of acids or bases using specific physiochemical properties. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  13. Spatial distribution of soluble insulin in pig subcutaneous tissue

    DEFF Research Database (Denmark)

    Thomsen, Maria; Rasmussen, Christian Hove; Refsgaard, Hanne H F

    2015-01-01

    in the tomographic reconstructions and the amount of drug in each tissue class was quantified. With a scan time of about 45min per sample, and a robust segmentation it was possible to analyze differences in the spatial drug distribution between several similar injections. It was studied how the drug distribution...

  14. Distribution of Podoplanin in Synovial Tissues in Rheumatoid Arthritis Patients Using Biologic or Conventional Disease-Modifying Anti-Rheumatic Drugs.

    Science.gov (United States)

    Takakubo, Yuya; Oki, Hiroharu; Naganuma, Yasushi; Saski, Kan; Sasaki, Akiko; Tamaki, Yasunobu; Suran, Yang; Konta, Tsuneo; Takagi, Michiaki

    2017-01-01

    Podoplanin (PDPN) mediates tumor cell migration and invasion, which phenomena might also play a role in severe rheumatoid arthritis (RA). Therefore, the precise cellular distribution of PDPN and it's relationships with inflammation was studied in RA treated with biologic disease-modifying anti-rheumatic drugs (DMARD) or conventional DMARDs (cDMARD). PDPN+ cells were immunostained by NZ-1 mAb, and scored (3+; >50%/ area, 2+; 20%- 50%, 1+; 5%-20%, 0: <5%) in synovial tissues from RA treated with biologic DMARDs (BIO, n=20) or cDMARD (n=20) for comparison with osteoarthritis (OA, n=5), followed by cell grading of inflammation and cell-typing. Inflammatory synovitis score was 1.4 in both BIO and cDMARD, compared to only 0.2 in OA. PDPN+ cells were found in the lining layer (BIO 1.6, cDMARD 1.3, OA 0.2) and lymphoid aggregates (BIO 0.6, cDMRD 0.7, OA 0.2), and correlated with RA-inflammation in BIO- and cDMARD-groups in both area (r=0.7/0.9, r=0.6/0.7, respectively p<0.05). PDPN was expressed in CD68+ type A macrophage-like and 5B5+ type B fibroblast-like cells in the lining layer, and in IL- 17+ cells in lymphoid aggregates in RA. PDPN was markedly increased in the immunologically inflamed RA synovitis, which was surgically treated due to BIO- and cDMARD-resistant RA. PDPN may have potential of a new marker of residual arthritis in local joints for inflammation-associated severe RA. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  15. Effect of vitamin D3, other drugs altering serum calcium or phosphorus concentrations, and desoxycorticosterone on the distribution of Tc-99m pyrophosphate between target and nontarget tissues

    International Nuclear Information System (INIS)

    Carr, E.A. Jr.; Carroll, M.; Montes, M.

    1981-01-01

    Radioactive imaging agents are chemically designed for selective distribution. Another approach to selectivity is to find stable compounds that favorably influence this distribution. Using a rat model of myocardial necrosis, we studied effects of various stable compounds (as a single, large dose or fractionated into short series) on the ratio, uptake of Tc-99m pyrophosphate (PPi) by the target lesion/uptake by the principal nontarget, bone (L/B). Vitamin D3s ability to increase L/B was mediated by the hypercalcemia and hyperphosphatemia that it caused. The hypercalcemia was accompanied by increased [Ca] in the lesion. In contrast, pulse doses of desoxycorticosterone acetate (DOCA) at 7 and 6 hr before killing increased uptake by lesion, increasing L/B from 0.19 +/- 0.03 to 0.45 +/- 0.08 (p less than 0.01), with no change in serum [Ca] and minimal changes in serum [P], [Na], and [K]. DOCA also increased the lesion-to-blood ratio from 6.5 +/- 0.07 to 15.4 +/- 3.9 (p less than 0.05). These results encourage further study of DOCA's effect and investigation of other stable drugs that may influence distribution of other imaging agents

  16. Controlled drug release for tissue engineering.

    Science.gov (United States)

    Rambhia, Kunal J; Ma, Peter X

    2015-12-10

    Tissue engineering is often referred to as a three-pronged discipline, with each prong corresponding to 1) a 3D material matrix (scaffold), 2) drugs that act on molecular signaling, and 3) regenerative living cells. Herein we focus on reviewing advances in controlled release of drugs from tissue engineering platforms. This review addresses advances in hydrogels and porous scaffolds that are synthesized from natural materials and synthetic polymers for the purposes of controlled release in tissue engineering. We pay special attention to efforts to reduce the burst release effect and to provide sustained and long-term release. Finally, novel approaches to controlled release are described, including devices that allow for pulsatile and sequential delivery. In addition to recent advances, limitations of current approaches and areas of further research are discussed. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Anal submucosal injection: a new route for drug administration in pelvic malignancies. Part I. Experimental study of misonidazole distribution in serum and tissues, with special reference to urinary bladder. Preliminary report

    International Nuclear Information System (INIS)

    Shafik, A.; el-Merzabani, M.M.; el-Aaser, A.A.; el-Desouky, G.H.

    1986-01-01

    The anal and oral administration routes were compared in 30 rats to study the distribution of misonidazole, a radiation sensitizer, in the serum and tissues with special reference to the urinary bladder. 14C-labelled misonidazole was administered in a dose of 0.2 ml water/100 gm body weight containing 1 mu Ci misonidazole. The dose was given orally by stomach tube in 15 rats, and was injected in the submucosa of the anal canal in another 15. Animals were then killed after 15, 30, 60, or 120 minutes or after 24 hours. Organs were dissected, and radioactivity was determined in each by the internal standard method. The study has shown that the highest drug concentration in the bladder tissue relative to the serum was achieved with the anal submucosal route. Its level was eight and five times that of the serum 15 and 30 minutes after administration, respectively, in contrast to the oral route in which the drug concentration was one-quarter and equal to the serum level at the same time intervals. The anal route would thus provide the adequate channel required for misonidazole to promote radiation responsiveness in bladder carcinoma

  18. On the search for new anticancer drugs 14: the plasma pharmacokinetics and tissue distribution of spin-labeled thio-TEPA (SL-O-TT).

    Science.gov (United States)

    Gutierrez, P L; Cohen, B E; Sosnovsky, G; Davis, T A; Egorin, M J

    1985-01-01

    We defined the plasma and tissue concentrations and pharmacokinetics of SL-O-TT, a spin-labeled analog of thio-TEPA, in 35-44-g male Swiss Webster mice that had received spin-labeled thio-TEPA at a dosage of 10 mg/kg. Concentrations of spin-labeled thio-TEPA in ethyl acetate extracts of tissue and plasma were determined by gas-liquid chromatography and electron spin resonance spectroscopy. Plasma concentrations of spin-labeled thio-TEPA declined in a biexponential fashion that was well described by the equation: Ct = 21.5e-0.276t + 2.30e-0.026t indicating a half-life alpha of 2.5 min and a half-life beta of 26.6 min. After 2 h there was still spin-labeled thio-TE-PA in plasma, but not in tissues. In tissues, no spin-labeled thio-TEPA was detected with gas-liquid chromatography 15 min after injection, but with electron-spin resonance label was found in lung and skeletal muscle. The main metabolite of spin-labeled thio-TEPA is spin-labeled TEPA, where oxidative desulfurization is invoked as the main metabolic mechanism. Reduction of the spin label to the hydroxylamine was also observed with time.

  19. Tissue distribution, disposition, and metabolism of cyclosporine in rats

    International Nuclear Information System (INIS)

    Wagner, O.; Schreier, E.; Heitz, F.; Maurer, G.

    1987-01-01

    Tissue distribution, disposition, and metabolism of 3 H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak 3 H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. 3 H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile

  20. Distribution of Eight QT-Prolonging Drugs and Their Main Metabolites Between Postmortem Cardiac Tissue and Blood Reveals Potential Pitfalls in Toxicological Interpretation

    DEFF Research Database (Denmark)

    Mikkelsen, Christian R; Jornil, Jakob R; Andersen, Ljubica V

    2018-01-01

    significantly higher compared to femoral and cardiac blood concentrations, with two exceptions. The median cardiac tissue-to-femoral blood concentration ratio (Kb) ranged from 2.2 (venlafaxine) to 15 (nortriptyline). The inter-individual fold difference between the minimum and maximum Kb ranged from 2.6-fold (Z......-hydroxynortriptyline) to 61 (venlafaxine). For 12 compounds, postmortem redistribution appeared to be minimal, whereas four compounds displayed some degree of postmortem redistribution. Citalopram and quetiapine were selected for in-depth analysis of the relation between the toxicological interpretation and femoral blood...

  1. Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

    Science.gov (United States)

    Lau, Christine Li Ling; Chan, Sook Tyng; Selvaratanam, Manimegahlai; Khoo, Hui Wen; Lim, Adeline Yi Ling; Modamio, Pilar; Mariño, Eduardo L; Segarra, Ignacio

    2015-08-01

    Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P brain (P male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P brain, liver, and kidney (all P male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P female mice and in kidney (male and female mice) but decreased 55% in brain (P differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences. © 2015 Société Française de Pharmacologie et de Thérapeutique.

  2. Autoradiographic and biochemical observations on the distribution of non-steroid anti-inflammatory drugs.

    Science.gov (United States)

    Rainsford, K D; Schweitzer, A; Brune, K

    1981-04-01

    A comparison has been made of the distribution of some new radioactively-labelled non-steroid anti-inflammatory (NSAI) drugs or pro-drugs with their respective progenitors and/or standard acidic NSAI drugs (i.e. aspirin, indomethacin and phenylbutazone), using whole body autoradiography and scintillation counting. The object of this study was to establish if the distribution of these new NSAI drugs may contribute to changes in their side-, or therapeutic effects compared with the older drugs. All the NSAI drugs accumulated in those tissues wherein the principle therapeutic and side-effects are manifest. The accumulation in inflamed tissues occurs regardless of the structural type of NSAI drugs, i.e. with specific accumulation occurring in this tissue of the acidic drugs or their acidic metabolites. New aspects of the distribution of the acetyl moiety of aspirin are reported which may be significant in relation to the side-effects induced by this drug.

  3. Methadone Recycling Sustains Drug Reservoir in Tissue.

    Science.gov (United States)

    Linares, Oscar A; Fudin, Jeffrey; Daly, Annemarie; Schiesser, William E; Boston, Raymond C

    2015-09-01

    We hypothesize that there is a tissue store of methadone content in humans that is not directly accessible, but is quantifiable. Further, we hypothesize the mechanism by which methadone content is sustained in tissue stores involves methadone uptake, storage, and release from tissue depots in the body (recycling). Accordingly, we hypothesize that such tissue stores, in part, determine plasma methadone levels. We studied a random sample of six opioid-naïve healthy subjects. We performed a clinical trial simulation in silico using pharmacokinetic modeling. We found a large tissue store of methadone content whose size was much larger than methadone's size in plasma in response to a single oral dose of methadone 10 mg. The tissue store measured 13-17 mg. This finding could only be explained by the contemporaneous storage of methadone in tissue with dose recycling. We found that methadone recycles 2-5 times through an inaccessible extravascular compartment (IAC), from an accessible plasma-containing compartment (AC), before exiting irreversibly. We estimate the rate of accumulation (or storage) of methadone in tissue was 0.029-7.29 mg/h. We predict 39 ± 13% to 83 ± 6% of methadone's tissue stores "spillover" into the circulation. Our results indicate that there exists a large quantifiable tissue store of methadone in humans. Our results support the notion that methadone in humans undergoes tissue uptake, storage, release into the circulation, reuptake from the circulation, and re-release into the circulation, and that spillover of methadone from tissue stores, in part, maintain plasma methadone levels in humans.

  4. Tissue distribution of radiolabeled phosphatidylserine-containing liposome in mice

    Energy Technology Data Exchange (ETDEWEB)

    Borborema, Samanta E.T.; Nascimento, Nanci do [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Biotecnologia], e-mail: samanta@usp.br, e-mail: nnascime@ipen.br; Andrade Junior, Heitor F. de [Instituto de Medicina Tropical de Sao Paulo (IMTSP), Sao Paulo, SP (Brazil)], e-mail: hfandrad@usp.br; Osso Junior, Joao A. [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil). Centro de Radiofarmacia], e-mail: jaosso@ipen.br

    2009-07-01

    Liposomes are used as drug delivery systems to modify pharmacokinetic of drugs and also to improve their action in target cells. Liposomes containing phosphatidylserine are efficiently eliminated from the blood by cells of the mononuclear phagocytic system (MPS), predominantly Kupffer cells in the liver. In this way, this is a valuable approach to treat infectious diseases involving MPS, especially leishmaniasis. Leishmaniasis is a severe parasitic disease, caused by intramacrophage protozoa Leishmania sp., and is fatal if left untreated. Leishmania resides mainly in the liver and the spleen. Antileishmanial agents containing-liposomes showed more effective therapies with reduction of toxicity and adverse side effects. The purpose of this study was to investigate the tissue distribution of radioactive meglumine antimoniate encapsulated in phosphatidylserine-containing liposome. Meglumine antimoniate was neutron irradiated inside the IEA-R1 nuclear reactor to produce antimony radiotracers, {sup 122}Sb and {sup 124}Sb, and encapsulated in liposome. Healthy mice received a single intraperitoneal dose of the radiolabeled drug. Analysis of the mean radioactive tissue concentration-time data curves showed that liver and spleen had the highest levels of radioactivity. In addition these levels of drug remained for more than 48 hours. The dominant route of elimination was via biliary excretion with slow rate. Small fraction of the drug was found in the kidneys with very fast elimination. In conclusion, the phosphatidylserine-containing liposome showed to be a very useful tool to target antileishmanial agents to MPS and to sustain the drug levels for longer times. Besides, radiolabeled liposome is the easiest approach to perform biodistribution evaluation. (author)

  5. Tissue distribution of radiolabeled phosphatidylserine-containing liposome in mice

    International Nuclear Information System (INIS)

    Borborema, Samanta E.T.; Nascimento, Nanci do; Osso Junior, Joao A.

    2009-01-01

    Liposomes are used as drug delivery systems to modify pharmacokinetic of drugs and also to improve their action in target cells. Liposomes containing phosphatidylserine are efficiently eliminated from the blood by cells of the mononuclear phagocytic system (MPS), predominantly Kupffer cells in the liver. In this way, this is a valuable approach to treat infectious diseases involving MPS, especially leishmaniasis. Leishmaniasis is a severe parasitic disease, caused by intramacrophage protozoa Leishmania sp., and is fatal if left untreated. Leishmania resides mainly in the liver and the spleen. Antileishmanial agents containing-liposomes showed more effective therapies with reduction of toxicity and adverse side effects. The purpose of this study was to investigate the tissue distribution of radioactive meglumine antimoniate encapsulated in phosphatidylserine-containing liposome. Meglumine antimoniate was neutron irradiated inside the IEA-R1 nuclear reactor to produce antimony radiotracers, 122 Sb and 124 Sb, and encapsulated in liposome. Healthy mice received a single intraperitoneal dose of the radiolabeled drug. Analysis of the mean radioactive tissue concentration-time data curves showed that liver and spleen had the highest levels of radioactivity. In addition these levels of drug remained for more than 48 hours. The dominant route of elimination was via biliary excretion with slow rate. Small fraction of the drug was found in the kidneys with very fast elimination. In conclusion, the phosphatidylserine-containing liposome showed to be a very useful tool to target antileishmanial agents to MPS and to sustain the drug levels for longer times. Besides, radiolabeled liposome is the easiest approach to perform biodistribution evaluation. (author)

  6. Drug perfusion enhancement in tissue model by steady streaming induced by oscillating microbubbles.

    Science.gov (United States)

    Oh, Jin Sun; Kwon, Yong Seok; Lee, Kyung Ho; Jeong, Woowon; Chung, Sang Kug; Rhee, Kyehan

    2014-01-01

    Drug delivery into neurological tissue is challenging because of the low tissue permeability. Ultrasound incorporating microbubbles has been applied to enhance drug delivery into these tissues, but the effects of a streaming flow by microbubble oscillation on drug perfusion have not been elucidated. In order to clarify the physical effects of steady streaming on drug delivery, an experimental study on dye perfusion into a tissue model was performed using microbubbles excited by acoustic waves. The surface concentration and penetration length of the drug were increased by 12% and 13%, respectively, with streaming flow. The mass of dye perfused into a tissue phantom for 30s was increased by about 20% in the phantom with oscillating bubbles. A computational model that considers fluid structure interaction for streaming flow fields induced by oscillating bubbles was developed, and mass transfer of the drug into the porous tissue model was analyzed. The computed flow fields agreed with the theoretical solutions, and the dye concentration distribution in the tissue agreed well with the experimental data. The computational results showed that steady streaming with a streaming velocity of a few millimeters per second promotes mass transfer into a tissue. © 2013 Published by Elsevier Ltd.

  7. Tissue distribution of 14C-diazepam and its metabolites in rats

    International Nuclear Information System (INIS)

    Igari, Y.; Sugiyama, Y.; Sawada, Y.; Iga, T.; Hanano, M.

    1982-01-01

    We have kinetically investigated the tissue distribution of 14 C-diazepam and described the appearance and disappearance of its metabolites (3-hydroxydiazepam, desmethyldiazepam, and oxazepam) following a single iv injection of 14 C-diazepam into rats. Significant amounts of oxazepam were detected in plasma and various tissues in the rat, contrary to previous reports. Concentration-time profiles of diazepam in the main disposing organs (liver, kidney, and lung) and the other organs (brain, heart, and small intestine) indicated that diazepam was distributed rapidly to these organs. Concentration-time profiles of diazepam in the main tissues for drug distribution (skin and adipose) indicated that diazepam was slowly distributed to these tissues, whereas that in muscle, which is also responsible for drug distribution, indicated that diazepam was less rapidly distributed to this tissue. Metabolites appeared in plasma and various tissues or organs immediately after iv injection of diazepam. Metabolites levels in plasma and various tissues or organs were significantly lower than that of diazepam except for liver and small intestine, where metabolites levels were higher compared to that of diazepam and metabolites exhibited a considerable persistence

  8. Local tissue distribution of fissile nuclides

    International Nuclear Information System (INIS)

    Smith, J.M.

    1981-01-01

    Conventional tissue-section autoradiography of alpha-emitting actinide elements may require prohibitively long exposure times. Neutron-induced or fission-track autoradiography can be used for fissile nuclides such as 233 U, 235 U, and 239 Pu to circumvent this difficulty. The detection limit for these nuclides is about 4 x 10 -13 (weight fraction). This paper describes a specific technique for determining their microdistribution with histologically stained tissue sections

  9. Alveolar bone tissue engineering using composite scaffolds for drug delivery

    Directory of Open Access Journals (Sweden)

    Tomonori Matsuno

    2010-08-01

    Full Text Available For many years, bone graft substitutes have been used to reconstruct bone defects in orthopedic and dental fields. However, synthetic bone substitutes such as hydroxyapatite or β-tricalcium phosphate have no osteoinductive or osteogenic abilities. Bone tissue engineering has also been promoted as an alternative approach to regenerating bone tissue. To succeed in bone tissue engineering, osteoconductive scaffolding biomaterials should provide a suitable environment for osteogenic cells and provide local controlled release of osteogenic growth factors. In addition, the scaffold for the bone graft substitute should biodegrade to replace the newly formed bone. Recent advances in bone tissue engineering have allowed the creation of composite scaffolds with tailored functional properties. This review focuses on composite scaffolds that consist of synthetic ceramics and natural polymers as drug delivery carriers for alveolar bone tissue engineering.

  10. Pericyte-targeting drug delivery and tissue engineering

    Directory of Open Access Journals (Sweden)

    Kang E

    2016-05-01

    Full Text Available Eunah Kang,1 Jong Wook Shin2 1School of Chemical Engineering and Material Science, 2Division of Allergic and Pulmonary Medicine, Department of Internal Medicine, College of Medicine, Chung-Ang University, Dongjak-Gu, Seoul, South Korea Abstract: Pericytes are contractile mural cells that wrap around the endothelial cells of capillaries and venules. Depending on the triggers by cellular signals, pericytes have specific functionality in tumor microenvironments, properties of potent stem cells, and plasticity in cellular pathology. These features of pericytes can be activated for the promotion or reduction of angiogenesis. Frontier studies have exploited pericyte-targeting drug delivery, using pericyte-specific peptides, small molecules, and DNA in tumor therapy. Moreover, the communication between pericytes and endothelial cells has been applied to the induction of vessel neoformation in tissue engineering. Pericytes may prove to be a novel target for tumor therapy and tissue engineering. The present paper specifically reviews pericyte-specific drug delivery and tissue engineering, allowing insight into the emerging research targeting pericytes. Keywords: pericytes, pericyte-targeting drug delivery, tissue engineering, platelet-derived growth factor, angiogenesis, vascular remodeling

  11. Determination and Distribution Study of Pogostone in Rat Tissues by ...

    African Journals Online (AJOL)

    BEH C18 column with acetonitrile-water containing 0.1 % formic acid (55:45, v/v) as the mobile phase, ... Keywords: Ultra-fast liquid chromatography, Tissue distribution, Pogostone, Honokiol, Rats .... sample extraction, storage, and intermittent.

  12. Electrospun nanofibrous materials for tissue engineering and drug delivery

    Directory of Open Access Journals (Sweden)

    Wenguo Cui, Yue Zhou and Jiang Chang

    2010-01-01

    Full Text Available The electrospinning technique, which was invented about 100 years ago, has attracted more attention in recent years due to its possible biomedical applications. Electrospun fibers with high surface area to volume ratio and structures mimicking extracellular matrix (ECM have shown great potential in tissue engineering and drug delivery. In order to develop electrospun fibers for these applications, different biocompatible materials have been used to fabricate fibers with different structures and morphologies, such as single fibers with different composition and structures (blending and core-shell composite fibers and fiber assemblies (fiber bundles, membranes and scaffolds. This review summarizes the electrospinning techniques which control the composition and structures of the nanofibrous materials. It also outlines possible applications of these fibrous materials in skin, blood vessels, nervous system and bone tissue engineering, as well as in drug delivery.

  13. Current advances in mathematical modeling of anti-cancer drug penetration into tumor tissues.

    Science.gov (United States)

    Kim, Munju; Gillies, Robert J; Rejniak, Katarzyna A

    2013-11-18

    Delivery of anti-cancer drugs to tumor tissues, including their interstitial transport and cellular uptake, is a complex process involving various biochemical, mechanical, and biophysical factors. Mathematical modeling provides a means through which to understand this complexity better, as well as to examine interactions between contributing components in a systematic way via computational simulations and quantitative analyses. In this review, we present the current state of mathematical modeling approaches that address phenomena related to drug delivery. We describe how various types of models were used to predict spatio-temporal distributions of drugs within the tumor tissue, to simulate different ways to overcome barriers to drug transport, or to optimize treatment schedules. Finally, we discuss how integration of mathematical modeling with experimental or clinical data can provide better tools to understand the drug delivery process, in particular to examine the specific tissue- or compound-related factors that limit drug penetration through tumors. Such tools will be important in designing new chemotherapy targets and optimal treatment strategies, as well as in developing non-invasive diagnosis to monitor treatment response and detect tumor recurrence.

  14. Tissue distribution of histo-blood group antigens

    DEFF Research Database (Denmark)

    Ravn, V; Dabelsteen, Erik

    2000-01-01

    carrier carbohydrate chains. Histo-blood group antigens are found in most epithelial tissues. Meanwhile, several factors influence the type, the amount, and the histological distribution of histoblood group antigens, i.e. the ABO, Lewis, and saliva-secretor type of the individual, and the cell- and tissue......The introduction of immunohistochemical techniques and monoclonal antibodies to specific carbohydrate epitopes has made it possible to study in detail the tissue distribution of histo-blood group antigens and related carbohydrate structures. The present paper summarizes the available data...... concerning the histological distribution of histo-blood group antigens and their precursor structures in normal human tissues. Studies performed have concentrated on carbohydrate antigens related to the ABO, Lewis, and TTn blood group systems, i.e. histo-blood group antigens carried by type 1, 2, and 3 chain...

  15. Fibronectin distribution in epithelial and associated tissues of the rat

    DEFF Research Database (Denmark)

    Couchman, J R; Gibson, W T; Thom, D

    1979-01-01

    Specific antiserum was used to investigate the distribution of the extracellular glycoprotein, fibronectin, in rat skin and tongue tissue by light and electron microscopy with immunofluorescence and immunoperoxidase techniques. We conclude that fibronectin is absent from stable, differentiated...... parts of tissues, such as the sebaceous glands or the matrix, medulla, cortex, and cuticles of the hair and the inner and outer root sheaths, or even in tissues in which there is some cell movement, such as the epidermis. It is, however, characteristic of sites at which cell division is occurring...... in contact with an extracellular scaffolding, such as basement membrane or loose connective tissue. Conspicuous examples were in the glassy membrane and connective tissue sheath associated with the follicular epithelium, the basement membrane underlying vascular endothelial cells, the connective tissues...

  16. MR Histoanatomical Distribution of 290 Soft-tissue Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Moon, Tae Yong; Lee, In Sook; Lee, Gee Won; Kim, Jeung Il; Choi, Kyung Un; Kim, Won Taek [Pusan National University Hospital, Busan (Korea, Republic of)

    2008-12-15

    This study was designed too identify the MR histoanatomical distribution of soft-tissue tumors. A total of 290 soft-tissue tumors of 281 patients were analyzed by the use of MR imaging and were pathologically confirmed after surgical resection or a biopsy. There were 120 malignant soft-tissue tumors including tumors of an intermediate malignancy and 170 benign tumors. The histoanatomical locations were divided into three types: 'type I' with superficial layer tumors that involved the cutaneous and subcutaneous tissue, 'type II' with deep layer tumors that involved the muscle or tendon and 'type III' with soft tissue tumors that involved both the superficial and deep layers. Soft-tissue tumors with more than three cases with a frequency of more than 75% included dermatofibrosarcoma protuberans, glomus tumor, angiolipoma, leiomyosarcoma and lymphoma as 'type I' tumors. 'Type II' tumors with more than three cases with a frequency of more than 75% included liposarcoma, fibromatosis, papillary endothelial hyperplasia and rhabdomyosarcoma. 'Type III' tumors with more than three cases with a frequency of more than 50% included neurofibromatosis. The MR histoanatomical distributions of soft tissue tumors are useful in the differential pathological diagnosis when a soft-tissue tumor has a nonspecific MR appearance.

  17. Overcoming cellular and tissue barriers to improve liposomal drug delivery

    Science.gov (United States)

    Kohli, Aditya G.

    Forty years of liposome research have demonstrated that the anti-tumor efficacy of liposomal therapies is, in part, driven by three parameters: 1) liposome formulation and lipid biophysics, 2) accumulation and distribution in the tumor, and 3) release of the payload at the site of interest. This thesis outlines three studies that improve on each of these delivery steps. In the first study, we engineer a novel class of zwitterlipids with an inverted headgroup architecture that have remarkable biophysical properties and may be useful for drug delivery applications. After intravenous administration, liposomes accumulate in the tumor by the enhanced permeability and retention effect. However, the tumor stroma often limits liposome efficacy by preventing distribution into the tumor. In the second study, we demonstrate that depletion of hyaluronan in the tumor stroma improves the distribution and efficacy of DoxilRTM in murine 4T1 tumors. Once a liposome has distributed to the therapeutic site, it must release its payload over the correct timescale. Few facile methods exist to quantify the release of liposome therapeutics in vivo. In the third study, we outline and validate a simple, robust, and quantitative method for tracking the rate and extent of release of liposome contents in vivo. This tool should facilitate a better understanding of the pharmacodynamics of liposome-encapsulated drugs in animals. This work highlights aspects of liposome behavior that have prevented successful clinical translation and proposes alternative approaches to improve liposome drug delivery.

  18. Cell-size distribution in epithelial tissue formation and homeostasis.

    Science.gov (United States)

    Puliafito, Alberto; Primo, Luca; Celani, Antonio

    2017-03-01

    How cell growth and proliferation are orchestrated in living tissues to achieve a given biological function is a central problem in biology. During development, tissue regeneration and homeostasis, cell proliferation must be coordinated by spatial cues in order for cells to attain the correct size and shape. Biological tissues also feature a notable homogeneity of cell size, which, in specific cases, represents a physiological need. Here, we study the temporal evolution of the cell-size distribution by applying the theory of kinetic fragmentation to tissue development and homeostasis. Our theory predicts self-similar probability density function (PDF) of cell size and explains how division times and redistribution ensure cell size homogeneity across the tissue. Theoretical predictions and numerical simulations of confluent non-homeostatic tissue cultures show that cell size distribution is self-similar. Our experimental data confirm predictions and reveal that, as assumed in the theory, cell division times scale like a power-law of the cell size. We find that in homeostatic conditions there is a stationary distribution with lognormal tails, consistently with our experimental data. Our theoretical predictions and numerical simulations show that the shape of the PDF depends on how the space inherited by apoptotic cells is redistributed and that apoptotic cell rates might also depend on size. © 2017 The Author(s).

  19. Therapeutic Ultrasound Enhancement of Drug Delivery to Soft Tissues

    Science.gov (United States)

    Lewis, George; Wang, Peng; Lewis, George; Olbricht, William

    2009-04-01

    Effects of exposure to 1.58 MHz focused ultrasound on transport of Evans Blue Dye (EBD) in soft tissues are investigated when an external pressure gradient is applied to induce convective flow through the tissue. The magnitude of the external pressure gradient is chosen to simulate conditions in brain parenchyma during convection-enhanced drug delivery (CED) to the brain. EBD uptake and transport are measured in equine brain, avian muscle and agarose brain-mimicking phantoms. Results show that ultrasound enhances EBD uptake and transport, and the greatest enhancement occurs when the external pressure gradient is applied. The results suggest that exposure of the brain parenchyma to ultrasound could enhance penetration of material infused into the brain during CED therapy.

  20. Trends in drug delivery through tissue barriers containing tight junctions.

    Science.gov (United States)

    Tscheik, Christian; Blasig, Ingolf E; Winkler, Lars

    2013-04-01

    A limitation in the uptake of many drugs is the restricted permeation through tissue barriers. There are two general ways to cross barriers formed by cell layers: by transcytosis or by diffusion through the intercellular space. In the latter, tight junctions (TJs) play the decisive role in the regulation of the barrier permeability. Thus, transient modulation of TJs is a potent strategy to improve drug delivery. There have been extensive studies on surfactant-like absorption enhancers. One of the most effective enhancers found is sodium caprate. However, this modulates TJs in an unspecific fashion. A novel approach would be the specific modulation of TJ-associated marvel proteins and claudins, which are the main structural components of the TJs. Recent studies have identified synthetic peptidomimetics and RNA interference techniques to downregulate the expression of targeted TJ proteins. This review summarizes current progress and discusses the impact on TJs' barrier function.

  1. Dose distribution around ion track in tissue equivalent material

    International Nuclear Information System (INIS)

    Zhang Wenzhong; Guo Yong; Luo Yisheng

    2007-01-01

    Objective: To study the energy deposition micro-specialty of ions in body-tissue or tissue equivalent material (TEM). Methods: The water vapor was determined as the tissue equivalent material, based on the analysis to the body-tissue, and Monte Carlo method was used to simulate the behavior of proton in the tissue equivalent material. Some features of the energy deposition micro-specialty of ion in tissue equivalent material were obtained through the analysis to the data from calculation. Results: The ion will give the energy by the way of excitation and ionization in material, then the secondary electrons will be generated in the progress of ionization, these electron will finished ions energy deposition progress. When ions deposited their energy, large amount energy will be in the core of tracks, and secondary electrons will devote its' energy around ion track, the ion dose distribution is then formed in TEM. Conclusions: To know biological effects of radiation , the research to dose distribution of ions is of importance(significance). (authors)

  2. 21 CFR 1310.11 - Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. 1310.11 Section 1310.11 Food and Drugs DRUG ENFORCEMENT... Reinstatement of exemption for drug products distributed under the Food, Drug and Cosmetic Act. (a) The...

  3. 21 CFR 1310.10 - Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. 1310.10 Section 1310.10 Food and Drugs DRUG ENFORCEMENT... Removal of the exemption of drugs distributed under the Food, Drug and Cosmetic Act. (a) The Administrator...

  4. Tissue Distribution of the MERS-Coronavirus Receptor in Bats

    NARCIS (Netherlands)

    W. Widagdo; L. Begeman (Lineke); D. Schipper (Debby); P.R.W.A. van Run (Peter); Cunningham, A.A. (Andrew A); Kley, N. (Nils); C.B.E.M. Reusken (Chantal); B.L. Haagmans (Bart); J.M.A. van den Brand (Judith)

    2017-01-01

    textabstractMiddle East respiratory syndrome coronavirus (MERS-CoV) has been shown to infect both humans and dromedary camels using dipeptidyl peptidase-4 (DPP4) as its receptor.The distribution of DPP4 in the respiratory tract tissues of humans and camels reflects MERS-CoV tropism.Apart from

  5. Tissue Distribution of the MERS-Coronavirus Receptor in Bats

    NARCIS (Netherlands)

    Widagdo, W; Begeman, Lineke; Schipper, Debby; van Run, Peter R; Cunningham, Andrew A; Kley, Nils; Reusken, Chantal B E M; Haagmans, Bart L; van den Brand, Judith M A

    2017-01-01

    Middle East respiratory syndrome coronavirus (MERS-CoV) has been shown to infect both humans and dromedary camels using dipeptidyl peptidase-4 (DPP4) as its receptor. The distribution of DPP4 in the respiratory tract tissues of humans and camels reflects MERS-CoV tropism. Apart from dromedary

  6. Autoradiographic studies of oleilanilide-3H distribution in rat tissues

    International Nuclear Information System (INIS)

    Negro Alvarez, M.J.; Saez Angulo, R.M.

    1987-01-01

    In this work the possibility that oleilanilides are involved in the pathgenesis of ''toxic syndrome'' is studied. Oleilanilide- 3 H labelled in the anilidi aromatic ring has been used to determine the distribution, localization and incorporation of that compound in several tissues of rats. Liquid scintillation counting for quantitative evaluation of the total radioactivity accumulated in the tissues, as well as autoradiographic techniques have been employed as analytical procedures. Results obtained from measurement of total radioactivity have shown accumulation of oleilanilide or its metabolites in all the studied tissues, mainly in the liver. No specific radioactivity localization has been detected by autoradiographic techniques, being the labelled molecules distributed in cytaplasm and cell interstice. (Author)

  7. Tissue distribution of human acetylcholinesterase and butyrylcholinesterase messenger RNA

    Energy Technology Data Exchange (ETDEWEB)

    Jbilo, O.; Barteles, C.F.; Chatonnet, A.; Toutant, J.P.; Lockridge, O.

    1994-12-31

    Tissue distribution of human acetyicholinesterase and butyryicholinesterase messenger RNA. 1 Cholinesterase inhibitors occur naturally in the calabar bean (eserine), green potatoes (solanine), insect-resistant crab apples, the coca plant (cocaine) and snake venom (fasciculin). There are also synthetic cholinesterase inhibitors, for example man-made insecticides. These inhibitors inactivate acetyicholinesterase and butyrylcholinesterase as well as other targets. From a study of the tissue distribution of acetylcholinesterase and butyrylcholinesterase mRNA by Northern blot analysis, we have found the highest levels of butyrylcholinesterase mRNA in the liver and lungs, tissues known as the principal detoxication sites of the human body. These results indicate that butyrylcholinesterase may be a first line of defense against poisons that are eaten or inhaled.

  8. Distribution of Human papilloma virus genotypes in cervical cancer tissues

    Directory of Open Access Journals (Sweden)

    Stamenković M.

    2014-01-01

    Full Text Available Cervical cancer incidence and mortality rates in Serbia are among the highest in Europe and data on Human papilloma virus (HPV type distribution are scarce. The aim of this study was to determine the prevalence of HPV types in archival specimens of cervical cancer tissues of women in the Serbian population. A total of 45 paraffin-embedded tissue samples of cervical carcinoma were used in this study. The procedure included deparaffinization of tissue samples, DNA extraction, PCR, gel electrophoresis and HPV genotyping by direct sequencing. HPV was detected in 32 samples (71%. Genotyping revealed the presence of 6 high-risk HPV types 16, 18, 33, 45, 53 and 58, where HPV type 16 was the most prevalent type (73.7%. The results of this study and further studies will provide more detailed information about HPV genotype distribution and may contribute to the formulation of national guidelines for the prevention of cervical cancer. [175073

  9. Polycaprolactone thin films for retinal tissue engineering and drug delivery

    Science.gov (United States)

    Steedman, Mark Rory

    This dissertation focuses on the development of polycaprolactone thin films for retinal tissue engineering and drug delivery. We combined these thin films with techniques such as micro and nanofabrication to develop treatments for age-related macular degeneration (AMD), a disease that leads to the death of rod and cone photoreceptors. Current treatments are only able to slow or limit the progression of the disease, and photoreceptors cannot be regenerated or replaced by the body once lost. The first experiments presented focus on a potential treatment for AMD after photoreceptor death has occurred. We developed a polymer thin film scaffold technology to deliver retinal progenitor cells (RPCs) to the affected area of the eye. Earlier research showed that RPCs destined to become photoreceptors are capable of incorporating into a degenerated retina. In our experiments, we showed that RPC attachment to a micro-welled polycaprolactone (PCL) thin film surface enhanced the differentiation of these cells toward a photoreceptor fate. We then used our PCL thin films to develop a drug delivery device capable of sustained therapeutic release over a multi-month period that would maintain an effective concentration of the drug in the eye and eliminate the need for repeated intraocular injections. We first investigated the biocompatibility of PCL in the rabbit eye. We injected PCL thin films into the anterior chamber or vitreous cavity of rabbit eyes and monitored the animals for up to 6 months. We found that PCL thin films were well tolerated in the rabbit eye, showing no signs of chronic inflammation due to the implant. We then developed a multilayered thin film device containing a microporous membrane. We loaded these devices with lyophilized proteins and quantified drug elution for 10 weeks, finding that both bovine serum albumin and immunoglobulin G elute from these devices with zero order release kinetics. These experiments demonstrate that PCL is an extremely useful

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

    Science.gov (United States)

    Poulin, Patrick

    2015-07-01

    fraction in plasma derived from a static in vitro environment might be biased to guide drug design (the old paradigm), and, hence, it is recommended to use a PBPK model to reproduce more accurately the in vivo condition in tissue (the new paradigm). This newly developed approach can be used to predict free drug concentration in diverse tissue compartments for small molecules in toxicology and pharmacology studies, which can be leveraged to optimize the pharmacokinetics drivers of tissue distribution based upon physicochemical and physiological input parameters in an attempt to optimize free drug level in tissue. Overall, this present study provides guidance on the application of plasma and tissue concentration information in PBPK/PD research in preclinical and clinical studies, which is in accordance with the recent literature. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  11. Tissue Distribution Of Chloroaluminium Sulfonated Phthalocyanine In Dogs

    Science.gov (United States)

    M. M.; H. C.; Newman

    1989-06-01

    Chloroaluminum sulfonated phthalocyanine (A1PCS) was administered intravenously to clinically normal dogs, and A1PCS levels were determined in tissues using a sensitive assay. A1PCS accumulated to high levels in liver, spleen, bone marrow, kidney, and lung. These tissue levels confirm previous determinations in mice and rats. Only a small amount of dye was retained in skin and very small amounts in muscle and brain. A1PCS was cleared from the blood within 24 h, and excreted primarily by urine. Serum clearance was faster in males than in females. There were also significant tissue distribution differences between the genders, particularly during the first 12 h. The low levels of A1PCS in skin suggest that cutaneous photosensitivity and toxic skin reactions using this photosensitizer in photodynamic therapy of cancer may be eliminated. The difference in tissue distribution between genders is not only intriguing, but indicates that the optimal time window for treatment of various tissue sites may vary by gender.

  12. Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine

    International Nuclear Information System (INIS)

    Gulyas, Balazs; Halldin, Christer; Sandell, Johan; Farde, Lars; Sovago, Judit; Cselenyi, Zsolt; Vas, Adam; Kiss, Bela; Karpati, Egon

    2002-01-01

    Direct information on the distribution of a drug requires measurements in various tissues. Such data have until now been obtained in animals, or have indirectly been calculated from plasma measurements in humans using mathematical models. Here we suggest the use of positron emission tomography (PET) as a method to obtain direct measurements of drug distribution in the human body. The distribution in body and brain of vinpocetine, a neuroprotective drug widely used in the prevention and treatment of cerebrovascular diseases, was followed after oral administration. Vinpocetine was labelled with carbon-11 and radioactivity was measured by PET in stomach, liver, brain and kidney in six healthy volunteers. The radioactivity in blood and urine as well as the fractions of [ 11 C]vinpocetine and labelled metabolites in plasma were also determined. After oral administration, [ 11 C]vinpocetine appeared immediately in the stomach and within minutes in the liver and the blood. In the blood the level of radioactivity continuously increased until the end of the measurement period, whereas the fraction of the unchanged mother compound decreased. Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the administration of the labelled drug. Brain distribution was heterogeneous, similar to the distribution previously reported after intravenous administration. These findings indicate that vinpocetine, administered orally in humans, readily enters the bloodstream from the stomach and gastrointestinal tract and, consequently, passes the blood-brain barrier and enters the brain. Radioactivity from [ 11 C]vinpocetine was also demonstrated in the kidneys and in urine, indicating that at least a part of the radioactive drug and labelled metabolites is eliminated from the body through the kidneys. This study is the first to demonstrate that PET might be a useful, direct and non-invasive tool to study the distribution and pharmacokinetics of orally

  13. Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine.

    Science.gov (United States)

    Gulyás, Balázs; Halldin, Christer; Sóvágó, Judit; Sandell, Johan; Cselényi, Zsolt; Vas, Adám; Kiss, Béla; Kárpáti, Egon; Farde, Lars

    2002-08-01

    Direct information on the distribution of a drug requires measurements in various tissues. Such data have until now been obtained in animals, or have indirectly been calculated from plasma measurements in humans using mathematical models. Here we suggest the use of positron emission tomography (PET) as a method to obtain direct measurements of drug distribution in the human body. The distribution in body and brain of vinpocetine, a neuroprotective drug widely used in the prevention and treatment of cerebrovascular diseases, was followed after oral administration. Vinpocetine was labelled with carbon-11 and radioactivity was measured by PET in stomach, liver, brain and kidney in six healthy volunteers. The radioactivity in blood and urine as well as the fractions of [(11)C]vinpocetine and labelled metabolites in plasma were also determined. After oral administration, [(11)C]vinpocetine appeared immediately in the stomach and within minutes in the liver and the blood. In the blood the level of radioactivity continuously increased until the end of the measurement period, whereas the fraction of the unchanged mother compound decreased. Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the administration of the labelled drug. Brain distribution was heterogeneous, similar to the distribution previously reported after intravenous administration. These findings indicate that vinpocetine, administered orally in humans, readily enters the bloodstream from the stomach and gastrointestinal tract and, consequently, passes the blood-brain barrier and enters the brain. Radioactivity from [(11)C]vinpocetine was also demonstrated in the kidneys and in urine, indicating that at least a part of the radioactive drug and labelled metabolites is eliminated from the body through the kidneys. This study is the first to demonstrate that PET might be a useful, direct and non-invasive tool to study the distribution and pharmacokinetics of orally

  14. Drug distribution in man: a positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine

    Energy Technology Data Exchange (ETDEWEB)

    Gulyas, Balazs [Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, 171 76 Stockholm (Sweden); Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm (Sweden); Halldin, Christer; Sandell, Johan; Farde, Lars [Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, 171 76 Stockholm (Sweden); Sovago, Judit; Cselenyi, Zsolt [Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, 171 76 Stockholm (Sweden); Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen (Hungary); Vas, Adam; Kiss, Bela; Karpati, Egon [Chemical Works of Gedeon Richter Ltd., Budapest (Hungary)

    2002-08-01

    Direct information on the distribution of a drug requires measurements in various tissues. Such data have until now been obtained in animals, or have indirectly been calculated from plasma measurements in humans using mathematical models. Here we suggest the use of positron emission tomography (PET) as a method to obtain direct measurements of drug distribution in the human body. The distribution in body and brain of vinpocetine, a neuroprotective drug widely used in the prevention and treatment of cerebrovascular diseases, was followed after oral administration. Vinpocetine was labelled with carbon-11 and radioactivity was measured by PET in stomach, liver, brain and kidney in six healthy volunteers. The radioactivity in blood and urine as well as the fractions of [{sup 11}C]vinpocetine and labelled metabolites in plasma were also determined. After oral administration, [{sup 11}C]vinpocetine appeared immediately in the stomach and within minutes in the liver and the blood. In the blood the level of radioactivity continuously increased until the end of the measurement period, whereas the fraction of the unchanged mother compound decreased. Radioactivity uptake and distribution in the brain were demonstrable from the tenth minute after the administration of the labelled drug. Brain distribution was heterogeneous, similar to the distribution previously reported after intravenous administration. These findings indicate that vinpocetine, administered orally in humans, readily enters the bloodstream from the stomach and gastrointestinal tract and, consequently, passes the blood-brain barrier and enters the brain. Radioactivity from [{sup 11}C]vinpocetine was also demonstrated in the kidneys and in urine, indicating that at least a part of the radioactive drug and labelled metabolites is eliminated from the body through the kidneys. This study is the first to demonstrate that PET might be a useful, direct and non-invasive tool to study the distribution and

  15. Distribution of red blood cell antigens in drug-resistant and drug ...

    African Journals Online (AJOL)

    sofo

    Frequency distribution of ABO, Rh-Hr, MN, Kell blood group system antigens were studied in 277 TB patients (151-drug-sensitive and 126 drug-resistant) of pulmonary tuberculosis to know whether there was any association between them, and also between drug resistance and sensitiveness. They were compared with 485 ...

  16. Sialic acid tissue distribution and influenza virus tropism

    OpenAIRE

    Kumlin, Urban; Olofsson, Sigvard; Dimock, Ken; Arnberg, Niklas

    2008-01-01

    Abstract? Avian influenza A viruses exhibit a strong preference for using ?2,3?linked sialic acid as a receptor. Until recently, the presumed lack of this receptor in human airways was believed to constitute an efficient barrier to avian influenza A virus infection of humans. Recent zoonotic outbreaks of avian influenza A virus have triggered researchers to analyse tissue distribution of sialic acid in further detail. Here, we review and extend the current knowledge about sialic acid distribu...

  17. Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues.

    Science.gov (United States)

    See, Gerard Lee; Sagesaka, Ayano; Sugasawa, Satoko; Todo, Hiroaki; Sugibayashi, Kenji

    2017-11-25

    The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. MALDI imaging facilitates new topical drug development process by determining quantitative skin distribution profiles.

    Science.gov (United States)

    Bonnel, David; Legouffe, Raphaël; Eriksson, André H; Mortensen, Rasmus W; Pamelard, Fabien; Stauber, Jonathan; Nielsen, Kim T

    2018-04-01

    Generation of skin distribution profiles and reliable determination of drug molecule concentration in the target region are crucial during the development process of topical products for treatment of skin diseases like psoriasis and atopic dermatitis. Imaging techniques like mass spectrometric imaging (MSI) offer sufficient spatial resolution to generate meaningful distribution profiles of a drug molecule across a skin section. In this study, we use matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to generate quantitative skin distribution profiles based on tissue extinction coefficient (TEC) determinations of four different molecules in cross sections of human skin explants after topical administration. The four drug molecules: roflumilast, tofacitinib, ruxolitinib, and LEO 29102 have different physicochemical properties. In addition, tofacitinib was administrated in two different formulations. The study reveals that with MALDI-MSI, we were able to observe differences in penetration profiles for both the four drug molecules and the two formulations and thereby demonstrate its applicability as a screening tool when developing a topical drug product. Furthermore, the study reveals that the sensitivity of the MALDI-MSI techniques appears to be inversely correlated to the drug molecules' ability to bind to the surrounding tissues, which can be estimated by their Log D values. Graphical abstract.

  19. Assessment of radioactive residues arising from radiolabel instability in a multiple dose tissue distribution study in rats

    Energy Technology Data Exchange (ETDEWEB)

    Slatter, J.G. [Pharmacia Corp., Peapack, NJ (United States); Sams, J.P.; Easter, J.A. [Pharmacia Corp., Kalamazoo, MI (United States)] [and others

    2003-05-01

    Our study objectives were to quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study, to quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations, and to conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds. We compared the excretion and tissue distribution in rats of [{sup 14}C]linezolid, radiolabeled in two different locations, after 7 consecutive once daily [{sup 14}C] oral doses. The radiolabels were in the acetamide (two carbon) and oxazolidinone (isolated carbon) functional groups. Terminal phase tissue residue and excretion data were compared to data from rats dosed orally with [{sup 14}C]sodium acetate. Drug-related radioactivity was excreted rapidly over 24 h. After a single dose, the acetamide and oxazolidinone radiolabel sites both gave 3% of dose as exhaled {sup 14}CO{sub 2}. After 7 daily [{sup 14}C] oral doses, terminal phase radioactive tissue residues were higher from the acetamide radiolabel, relative to the oxazolidinone radiolabel, and were primarily not drug-related. In the definitive tissue distribution study, low concentrations of drug-related radioactivity in skin and thyroid were observed. We conclude that although small amounts of radiolabel instability do not significantly affect single dose tissue radioactivity C{sub max} and area under the curve (AUC), artifacts arising from radiolabel instability can prolong the apparent terminal phase half life and complicate study data interpretation. When possible, it is always preferable to use a completely stable radiolabel site. (author)

  20. Assessment of radioactive residues arising from radiolabel instability in a multiple dose tissue distribution study in rats

    International Nuclear Information System (INIS)

    Slatter, J.G.; Sams, J.P.; Easter, J.A.

    2003-01-01

    Our study objectives were to quantitatively determine the effect of radiolabel instability on terminal phase radioactive tissue residues in a multiple dose tissue distribution study, to quantitatively compare tissue residue artifacts (non drug-related radioactivity) from two chemically-distinct radiolabel locations, and to conduct a definitive multiple dose tissue distribution study using the better of the two radiolabeled compounds. We compared the excretion and tissue distribution in rats of [ 14 C]linezolid, radiolabeled in two different locations, after 7 consecutive once daily [ 14 C] oral doses. The radiolabels were in the acetamide (two carbon) and oxazolidinone (isolated carbon) functional groups. Terminal phase tissue residue and excretion data were compared to data from rats dosed orally with [ 14 C]sodium acetate. Drug-related radioactivity was excreted rapidly over 24 h. After a single dose, the acetamide and oxazolidinone radiolabel sites both gave 3% of dose as exhaled 14 CO 2 . After 7 daily [ 14 C] oral doses, terminal phase radioactive tissue residues were higher from the acetamide radiolabel, relative to the oxazolidinone radiolabel, and were primarily not drug-related. In the definitive tissue distribution study, low concentrations of drug-related radioactivity in skin and thyroid were observed. We conclude that although small amounts of radiolabel instability do not significantly affect single dose tissue radioactivity C max and area under the curve (AUC), artifacts arising from radiolabel instability can prolong the apparent terminal phase half life and complicate study data interpretation. When possible, it is always preferable to use a completely stable radiolabel site. (author)

  1. Tissue distribution of tritiated digoxin and quabain in mice

    International Nuclear Information System (INIS)

    Klopper, J.F.; Atkins, H.L.

    1976-01-01

    Tissue concentration of tritiated digoxin in human subjects appears to be selective in that after a single dose of the radioactive tracer a myocardial concentration of digoxin on an average 24 to 30 times higher than the serum concentration is reached. In patients studied 3.5 to 84 hours after administration of tritiated digoxin, the dose in the heart was found to vary between 1.95 to 4.83 percent. Should it be possible to label digoxin or another cardiac glycoside with a suitable gamma-emitting tracer, its use as a cardiac imaging agent should thus be feasible. This study was undertaken to determine the tissue distribution in mice of tritiated digoxin at various time intervals post injection; and to determine if these values showed any correlation to the previously determined human data. A preliminary study in mice using 3 H-digitoxin revealed no selective uptake in the heart with high uptakes in the liver and gut. Since ouabain has a more rapid clinical onset of action than digoxin, its tissue distribution was included in the study and compared to that of digoxin

  2. Determination of drug residues by CLAR-MS/MS in animal tissues

    International Nuclear Information System (INIS)

    Brenes Jimenez, Jose Eduardo

    2009-01-01

    Produced food of animal origin, present the possibility of occurrence of any contact with substances that have negative effects on the health of people who consume them. The use of drugs in veterinary medicine is one of the possible sources of such waste; so, the conditions for the analysis of some classes of antibiotics in animal tissues are based on the study. Costa Rica and the countries that are export destination, have regulation and programs for control before to be distributed in local markets, or post if it is received any complaint of pollution. The high resolution liquid chromatography coupled to mass spectrometers (CLAR-MS/MS) allows the analysis of analytes monitored, according to the specifications required by the legislation. The cases of two laboratories in Costa Rica are presented as the only ones who have the ability to perform the analysis of drug residues CLAR-MS/MS. (author) [es

  3. Melatonin membrane receptors in peripheral tissues: Distribution and functions

    Science.gov (United States)

    Slominski, Radomir M.; Reiter, Russel J.; Schlabritz-Loutsevitch, Natalia; Ostrom, Rennolds S.; Slominski, Andrzej T.

    2012-01-01

    Many of melatonin’s actions are mediated through interaction with the G-protein coupled membrane bound melatonin receptors type 1 and type 2 (MT1 and MT2, respectively) or, indirectly with nuclear orphan receptors from the RORα/RZR family. Melatonin also binds to the quinone reductase II enzyme, previously defined the MT3 receptor. Melatonin receptors are widely distributed in the body; herein we summarize their expression and actions in non-neural tissues. Several controversies still exist regarding, for example, whether melatonin binds the RORα/RZR family. Studies of the peripheral distribution of melatonin receptors are important since they are attractive targets for immunomodulation, regulation of endocrine, reproductive and cardiovascular functions, modulation of skin pigmentation, hair growth, cancerogenesis, and aging. Melatonin receptor agonists and antagonists have an exciting future since they could define multiple mechanisms by which melatonin modulates the complexity of such a wide variety of physiological and pathological processes. PMID:22245784

  4. Effects of Gingko biloba Extract on Tissue Distribution of Fluoxetine and Venlafaxine in Rats

    Directory of Open Access Journals (Sweden)

    Saad Abdulrahman Hussain

    2015-09-01

    Full Text Available Objective: There are many concerns about the interactions of herbal products with conventional drugs, which are mostly used as multiple drug treatment approach. The present study was designed to evaluate the effect of long-term use of Ginkgo biloba extract (GK on the absorption and tissue distribution of fluoxetine and venlafaxine. Materials and Methods: Forty-six Wistar rats are utilized and allocated into eight groups; 2 groups administered the vehicle and saved as control; 4 groups are treated with 100 and 200 mg/kg of GK extract for 30 days; 2 groups are treated with 40mg/kg verapamil for 10 days. The liver, kidney and brain distribution of fluoxetine and venlafaxine were evaluated after single oral doses using HPLC method. Results: 200 mg/kg GK increases fluoxetine concentrations in all studied organs, while GK 100mg/kg increases venlafaxine levels in kidney tissue and not affected in the other two organs. Conclusion: Thirty days treatment with GK (100 mg/kg increases kidney availability of venlafaxine, while 200 mg GK dose increases fluoxetine availability in the liver, kidney and brain tissues after single oral doses. [J Intercult Ethnopharmacol 2015; 4(3.000: 234-238

  5. Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat

    Directory of Open Access Journals (Sweden)

    Wei-Lun Hung

    2018-04-01

    Full Text Available Tangeretin, 4′,5,6,7,8-pentamethoxyflavone, is one of the major polymethoxyflavones (PMFs existing in citrus fruits, particularly in the peels of sweet oranges and mandarins. Tangeretin has been reported to possess several beneficial bioactivities including anti-inflammatory, anti-proliferative and neuroprotective effects. To achieve a thorough understanding of the biological actions of tangeretin in vivo, our current study is designed to investigate the pharmacokinetics, bioavailability, distribution and excretion of tangeretin in rats. After oral administration of 50 mg/kg bw tangeretin to rats, the Cmax, Tmax and t1/2 were 0.87 ± 0.33 μg/mL, 340.00 ± 48.99 min and 342.43 ± 71.27 min, respectively. Based on the area under the curves (AUC of oral and intravenous administration of tangeretin, calculated absolute oral bioavailability was 27.11%. During tissue distribution, maximum concentrations of tangeretin in the vital organs occurred at 4 or 8 h after oral administration. The highest accumulation of tangeretin was found in the kidney, lung and liver, followed by spleen and heart. In the gastrointestinal tract, maximum concentrations of tangeretin in the stomach and small intestine were found at 4 h, while in the cecum, colon and rectum, tangeretin reached the maximum concentrations at 12 h. Tangeretin excreted in the urine and feces was recovered within 48 h after oral administration, concentrations were only 0.0026% and 7.54%, respectively. These results suggest that tangeretin was mainly eliminated as metabolites. In conclusion, our study provides useful information regarding absorption, distribution, as well as excretion of tangeretin, which will provide a good base for studying the mechanism of its biological effects. Keywords: Tangeretin, Oral bioavailability, Pharmacokinetics, Tissue distribution, Excretion

  6. Absorption, tissue distribution, excretion, and metabolism of clothianidin in rats.

    Science.gov (United States)

    Yokota, Tokunori; Mikata, Kazuki; Nagasaki, Hiromi; Ohta, Kazunari

    2003-11-19

    Absorption, distribution, excretion, and metabolism of clothianidin [(E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine] were investigated after a single oral administration of [nitroimino-(14)C]- or [thiazolyl-2-(14)C]clothianidin to male and female rats at a dose of 5 mg/kg of body weight (bw) (low dose) or 250 mg/kg of bw (high dose). The maximum concentration of carbon-14 in blood occurred 2 h after administration of the low oral dose for both labeled clothianidins, and then the concentration of carbon-14 in blood decreased with a half-life of 2.9-4.0 h. The orally administered carbon-14 was rapidly and extensively distributed to all tissues and organs within 2 h after administration, especially to the kidney and liver, but was rapidly and almost completely eliminated from all tissues and organs with no evidence of accumulation. The orally administered carbon-14 was almost completely excreted into urine and feces within 2 days after administration, and approximately 90% of the administered dose was excreted via urine. The major compound in excreta was clothianidin, accounting for >60% of the administered dose. The major metabolic reactions of clothianidin in rats were oxidative demethylation to form N-(2-chlorothiazol-5-ylmethyl)-N'-nitroguanidine and the cleavage of the carbon-nitrogen bond between the thiazolylmethyl moiety and the nitroguanidine moiety. The part of the molecule containing the nitroguanidine moiety was transformed mainly to N-methyl-N'-nitroguanidine, whereas the thiazol moiety was further metabolized to 2-(methylthio)thiazole-5-carboxylic acid. With the exception of the transiently delayed excretion of carbon-14 at the high-dose level, the rates of biokinetics, excretion, distribution, and metabolism of clothianidin were not markedly influenced by dose level and sex.

  7. Predictive typing of drug-induced neurological sufferings from studies of the distribution of labelled drugs

    International Nuclear Information System (INIS)

    Takasu, T.

    1980-01-01

    A drug given to an animal becomes widely distributed throughout the body, acting on the living mechanisms or structures, and is gradually excreted. Some drugs can remain in some parts of the body for a long period. For example, 14 C-chloramphenical was found to remain preferentially in the salivary gland, liver and bone marrow of mice 24 hours after its oral administration. If such a drug is given repeatedly, it could possibly accumulate gradually in these organs. Thus, when its accumulation in a particular part of the body exceeds a certain level, the living mechanism or structure may possibly be injured. The harmful effects of a drug in repeated administration are called its chronic toxicity. The author discusses whether it is possible to predict the toxicity of a drug by studying its distribution in relation to time, and, if possible, the points in time. This problem is studied especially in relation to the nervous system. (Auth.)

  8. [Drug vectorization or how to modulate tissular and cellular distribution of biologically active compounds].

    Science.gov (United States)

    Couvreur, P

    2001-07-01

    Drug vectorization has undergone considerable development over the last few years. This review focuses on the intravenous route of administration. Colloid formulations allow a modulation of drug tissue distribution. Using liposomes and nanoparticles with unmodified surfaces, drugs can be targeted to macrophages of the reticulum endothelium system. When the liposomes or nanoparticles are covered with hydrophilic or flexible polymers, the vascular phase can be favored in order, for example, to facilitate selective extravasation at a tumor site. Therapeutic applications of these systems are presented. The development of "intelligent" vectors capable of modulating intracellular distribution of an active compounds is an equally interesting approach, for example pH-sensitive liposomes or nanoparticles decorated with folic acid capable of targeting intracellular cytoplasm.

  9. Laser speckle imaging of intra organ drug distribution

    DEFF Research Database (Denmark)

    Postnov, Dmitry D.; Holstein-Rathlou, Niels-Henrik; Sosnovtseva, Olga

    2015-01-01

    Laminar flow in arteries causes streaming and uneven distribution of infused agents within the organ. This may lead to misinterpretation of experimental results and affect treatment outcomes. We monitor dynamical changes of superficial cortical blood flow in the rat kidney following different rou...... routes of administration of the vasoconstrictor angiotensin II. Our analysis reveals the appearance of large scale oscillations of the blood flow caused by inhomogeneous intra organ drug distribution....

  10. Controlled delivery of antiangiogenic drug to human eye tissue using a MEMS device

    KAUST Repository

    Pirmoradi, Fatemeh Nazly; Ou, Kevin; Jackson, John K.; Letchford, Kevin; Cui, Jing; Wolf, Ki Tae; Graber, Florian; Zhao, Tom; Matsubara, Joanne A.; Burt, Helen; Chiao, Mu; Lin, Liwei

    2013-01-01

    We demonstrate an implantable MEMS drug delivery device to conduct controlled and on-demand, ex vivo drug transport to human eye tissue. Remotely operated drug delivery to human post-mortem eyes was performed via a MEMS device. The developed curved

  11. An integrated drug prescription and distribution system: challenges and opportunities.

    Science.gov (United States)

    Lanssiers, R; Everaert, E; De Win, M; Van De Velde, R; De Clercq, H

    2002-01-01

    Using the hospital's drug prescription and distribution system as a guide, benefits and drawbacks of a medical activity management system that is tightly integrated with the supply chain management of a hospital will be discussed from the point of view of various participating healthcare actors.

  12. Distribution of adenosine deaminase complexing protein (ADCP) in human tissues.

    Science.gov (United States)

    Dinjens, W N; ten Kate, J; van der Linden, E P; Wijnen, J T; Khan, P M; Bosman, F T

    1989-12-01

    The normal distribution of adenosine deaminase complexing protein (ADCP) in the human body was investigated quantitatively by ADCP-specific radioimmunoassay (RIA) and qualitatively by immunohistochemistry. In these studies we used a specific rabbit anti-human ADCP antiserum. In all 19 investigated tissues, except erythrocytes, ADCP was found by RIA in the soluble and membrane fractions. From all tissues the membrane fractions contained more ADCP (expressed per mg protein) than the soluble fractions. High membrane ADCP concentrations were found in skin, renal cortex, gastrointestinal tract, and prostate. Immunoperoxidase staining confirmed the predominant membrane-associated localization of the protein. In serous sweat glands, convoluted tubules of renal cortex, bile canaliculi, gastrointestinal tract, lung, pancreas, prostate gland, salivary gland, gallbladder, mammary gland, and uterus, ADCP immunoreactivity was found confined to the luminal membranes of the epithelial cells. These data demonstrate that ADCP is present predominantly in exocrine glands and absorptive epithelia. The localization of ADCP at the secretory or absorptive apex of the cells suggests that the function of ADCP is related to the secretory and/or absorptive process.

  13. Tissue distribution of residual antimony in rats treated with multiple doses of meglumine antimoniate

    Directory of Open Access Journals (Sweden)

    Deise Riba Coelho

    2014-07-01

    Full Text Available Meglumine antimoniate (MA and sodium stibogluconate are pentavalent antimony (SbV drugs used since the mid-1940s. Notwithstanding the fact that they are first-choice drugs for the treatment of leishmaniases, there are gaps in our knowledge of their toxicological profile, mode of action and kinetics. Little is known about the distribution of antimony in tissues after SbV administration. In this study, we evaluated the Sb content of tissues from male rats 24 h and three weeks after a 21-day course of treatment with MA (300 mg SbV/kg body wt/d, subcutaneous. Sb concentrations in the blood and organs were determined by inductively coupled plasma-mass spectrometry. In rats, as with in humans, the Sb blood levels after MA dosing can be described by a two-compartment model with a fast (t1/2 = 0.6 h and a slow (t1/2 >> 24 h elimination phase. The spleen was the organ that accumulated the highest amount of Sb, while bone and thyroid ranked second in descending order of tissues according to Sb levels (spleen >> bone, thyroid, kidneys > liver, epididymis, lungs, adrenals > prostate > thymus, pancreas, heart, small intestines > skeletal muscle, testes, stomach > brain. The pathophysiological consequences of Sb accumulation in the thyroid and Sb speciation in the liver, thyroid, spleen and bone warrant further studies.

  14. Comparative tissue distribution of conformationally restricted radioiodinated vesamicol receptor ligands

    Energy Technology Data Exchange (ETDEWEB)

    Efange, S M.N.; Khare, A B; Langason, R B

    1995-05-01

    Three conformationally restricted analogs of vesamicol, 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-spirol[1H-indene-1,4'- piperidine] (5), 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-3,4-dihydrospiro[indene-1,4'- piperidine] (6) and 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl)]-3,4-dihydrospiro[naphthalene- 1(2H),4'-piperidine] (7), were labelled with iodine-125 and evaluated as potential radioligands for mapping vesamicol receptor (VR) density and cholinergic function in vivo. All compounds showed similar kinetics in most tissues. However, differences were observed in the brain. Although comparable levels of each corresponding enantiomeric pair were obtained initially in the brain, the levels of the dextrorotatory enantiomers (+)-5, (+)-6 and (+)-7 were found to decrease by 72-82% over a period of 3 h. In contrast, the brain levels of the corresponding levorotatory isomers were maintained throughout the duration of the experiment. Among the dextrorotatory isomers, (+)-6 showed the highest brain extraction, while (+)-7 showed the lowest. In tissue dissection experiments, the levels of (+)-5, (+)-6 and (+)-7 were highest in the striatum and moderate to low in the cortex and cerebellum. Co-administration of haloperidol with (+)-6 decreased the levels of the latter in the striatum by 27%, while the levels in the cortex and cerebellum were each reduced by 60%. In addition, haloperidol failed to affect the regional distribution of (+)-7 in the brain. However, both haloperidol and spiperone increased the striatal levels of (+)-5 by 67 and 76%, respectively, suggesting that the binding of this radioligand is related to cholinergic function. Furthermore, haloperidol reduced the concentration of (+)-5 in the cortex and cerebellum by 25 and 33%, respectively, thereby implicating the sigma site as a secondary target for this ligand in the cortex.

  15. Comparative tissue distribution of conformationally restricted radioiodinated vesamicol receptor ligands

    International Nuclear Information System (INIS)

    Efange, S.M.N.; Khare, A.B.; Langason, R.B.

    1995-01-01

    Three conformationally restricted analogs of vesamicol, 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-spirol[1H-indene-1,4'- piperidine] (5), 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl]-3,4-dihydrospiro[indene-1,4'- piperidine] (6) and 1'-[1-(3-iodobenzyl)-4-hydroxypiperidin-3-yl)-3,4-dihydrospiro[naphthalene- 1(2H),4'-piperidine] (7), were labelled with iodine-125 and evaluated as potential radioligands for mapping vesamicol receptor (VR) density and cholinergic function in vivo. All compounds showed similar kinetics in most tissues. However, differences were observed in the brain. Although comparable levels of each corresponding enantiomeric pair were obtained initially in the brain, the levels of the dextrorotatory enantiomers (+)-5, (+)-6 and (+)-7 were found to decrease by 72-82% over a period of 3 h. In contrast, the brain levels of the corresponding levorotatory isomers were maintained throughout the duration of the experiment. Among the dextrorotatory isomers, (+)-6 showed the highest brain extraction, while (+)-7 showed the lowest. In tissue dissection experiments, the levels of (+)-5, (+)-6 and (+)-7 were highest in the striatum and moderate to low in the cortex and cerebellum. Co-administration of haloperidol with (+)-6 decreased the levels of the latter in the striatum by 27%, while the levels in the cortex and cerebellum were each reduced by 60%. In addition, haloperidol failed to affect the regional distribution of (+)-7 in the brain. However, both haloperidol and spiperone increased the striatal levels of (+)-5 by 67 and 76%, respectively, suggesting that the binding of this radioligand is related to cholinergic function. Furthermore, haloperidol reduced the concentration of (+)-5 in the cortex and cerebellum by 25 and 33%, respectively, thereby implicating the sigma site as a secondary target for this ligand in the cortex

  16. Plasma disappearance, urine excretion, and tissue distribution of ribavirin in rats and rhesus monkeys

    International Nuclear Information System (INIS)

    Ferrara, E.A.; Oishi, J.S.; Wannemacher, R.W. Jr.; Stephen, E.L.

    1981-01-01

    Ribavirin has been shown to have broad-spectrum antiviral. To study its tissue distribution and disappearance rate, a single dose of 10 mg/kg which contained 10 microCi of [14C]ribavirin was injected intravenously into rhesus monkeys and intramuscularly into monkeys and rats. Except for peak plasma concentrations and the initial phases of the plasma disappearance and urine excretion curves, no significant difference was observed between plasma, tissue, or urine values for intramuscularly or intravenously injected monkeys. Plasma disappearance curves were triphasic; plasma concentrations of ribavirin were similar for both monkeys and rats. Rats excreted ribavirin in the urine more rapidly and to a greater extent (82% excreted in 24 h) than did monkeys (60% excreted in 72 h). In the rat, only 3% of the injected [14C]ribavirin was detected in expired CO2. Therefore, for both species, urine was the major route for the elimination of labeled ribavirin and its metabolites from the body. In monkeys, the amount of parent drug in blood cells increased through 48 h and remained stable for 72 h, whereas in rats, ribavirin decreased at a rate similar to the plasma disappearance curve. Concentrations of ribavirin at 8 h were consistently higher in monkeys than in rats for all tissues except the brain. Thus, these differences in blood cellular components and organ content and in urine excretion suggested that there was greater tissue retention of ribavirin in monkeys than in rats

  17. Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses.

    Science.gov (United States)

    Morris, Aaron H; Mahal, Rajwant S; Udell, Jillian; Wu, Michelle; Kyriakides, Themis R

    2017-10-01

    Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core-shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-κB (NF-κB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-β (TGF-β)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Facilitated monocyte-macrophage uptake and tissue distribution of superparmagnetic iron-oxide nanoparticles.

    Directory of Open Access Journals (Sweden)

    Arnaud Beduneau

    Full Text Available BACKGROUND: We posit that the same mononuclear phagocytes (MP that serve as target cells and vehicles for a host of microbial infections can be used to improve diagnostics and drug delivery. We also theorize that physical and biological processes such as particle shape, size, coating and opsonization that affect MP clearance of debris and microbes can be harnessed to facilitate uptake of nanoparticles (NP and tissue delivery. METHODS: Monocytes and monocyte-derived macrophages (MDM were used as vehicles of superparamagnetic iron oxide (SPIO NP and immunoglobulin (IgG or albumin coated SPIO for studies of uptake and distribution. IgG coated SPIO was synthesized by covalent linkage and uptake into monocytes and MDM investigated related to size, time, temperature, concentration, and coatings. SPIO and IgG SPIO were infused intravenously into naïve mice. T(2 measures using magnetic resonance imaging (MRI were used to monitor tissue distribution in animals. RESULTS: Oxidation of dextran on the SPIO surface generated reactive aldehyde groups and permitted covalent linkage to amino groups of murine and human IgG and F(ab'(2 fragments and for Alexa Fluor(R 488 hydroxylamine to form a Schiff base. This labile intermediate was immediately reduced with sodium cyanoborohydride in order to stabilize the NP conjugate. Optical density measurements of the oxidized IgG, F(ab'(2, and/or Alexa Fluor(R 488 SPIO demonstrated approximately 50% coupling yield. IgG-SPIO was found stable at 4 degrees C for a period of 1 month during which size and polydispersity index varied little from 175 nm and 200 nm, respectively. In vitro, NP accumulated readily within monocyte and MDM cytoplasm after IgG-SPIO exposure; whereas, the uptake of native SPIO in monocytes and MDM was 10-fold less. No changes in cell viability were noted for the SPIO-containing monocytes and MDM. Cell morphology was not changed as observed by transmission electron microscopy. Compared to unconjugated

  19. Effect of insulin on the tissue distribution of thallium-201

    International Nuclear Information System (INIS)

    Razzak, M.A.

    1980-01-01

    Translocation of potassium under the influence of insulin has been repeatedly demonstrated by various investigators during the past 50 years. Accordingly, it is expected that insulin administration would affect the distribution pattern of the potassium analogue thallium-201. To test the validity of this assumption, the present study was performed on 46 rabbits, with an average weight of 3.9 +- 0.8 pounds. To study the effects of the factors involved in the administration of insulin and its dosage, the rabbits were divided into groups; each group being studied on a separate day. The experimental animals were sacrificed exactly 10 minutes after the intravenous injection of radiothallium. The results of the present study showed that thallium-201 uptake per gram tissue varied from one batch to another. However, the radioactivity uptake per gram by the different organs showed a constant pattern. Among the organs studied, the highest level of radioactivity per gram was encountered in the kidneys and heart, followed by the lungs. Then came the liver and lastly the striated muscles. Insulin administration caused an increase in the radioactivity uptake in all the organs studied. The magnitude of this increment was highest in the heart, kidneys and lungs; moderate in the liver, and slight in the striated muscles. In addition, the effect of insulin occurred at an optimum time that varied with the route of administration and was dose related up to a certain level. (author)

  20. Controlled delivery of antiangiogenic drug to human eye tissue using a MEMS device

    KAUST Repository

    Pirmoradi, Fatemeh Nazly

    2013-01-01

    We demonstrate an implantable MEMS drug delivery device to conduct controlled and on-demand, ex vivo drug transport to human eye tissue. Remotely operated drug delivery to human post-mortem eyes was performed via a MEMS device. The developed curved packaging cover conforms to the eyeball thereby preventing the eye tissue from contacting the actuating membrane. By pulsed operation of the device, using an externally applied magnetic field, the drug released from the device accumulates in a cavity adjacent to the tissue. As such, docetaxel (DTX), an antiangiogenic drug, diffuses through the eye tissue, from sclera and choroid to retina. DTX uptake by sclera and choroid were measured to be 1.93±0.66 and 7.24±0.37 μg/g tissue, respectively, after two hours in pulsed operation mode (10s on/off cycles) at 23°C. During this period, a total amount of 192 ng DTX diffused into the exposed tissue. This MEMS device shows great potential for the treatment of ocular posterior segment diseases such as diabetic retinopathy by introducing a novel way of drug administration to the eye. © 2013 IEEE.

  1. Cryopreservation of Precision-cut Tissue Slices for Application in Drug Metabolism Research

    NARCIS (Netherlands)

    Graaf, Inge Anne Maria de

    2002-01-01

    The research described in this thesis had two important aims. The first was to determine whether tissue slices could be used as an in vitro tool to predict the in vivo metabolism of new drugs. The second aim was to find a manner to store tissue slices for longer time periods by cryopreservation.

  2. A study about trace element distribution in cancer tissue and serum of cancer patients

    International Nuclear Information System (INIS)

    Lee, Jong In; Lee, Eun Joo; Jung, Young Joo

    1993-01-01

    Authers analyzed the trace element distribution of cancer tissue and its corresponding normal tissue and serum of preoperative and postoperative stage in gastric, colon, breast cancer patients. Zinc and rubidium were higher in concentration in breast cancer tissue than in normal tissue. As for the distribution of trace element in serum, bromine became about 10 times higher after gastric resection. This result can be applied to experimental carcinogenesis and to relationship with other prognostic factors. (Author)

  3. Microfluidics Enables Small-Scale Tissue-Based Drug Metabolism Studies With Scarce Human Tissue

    NARCIS (Netherlands)

    van Midwoud, Paul M.; Verpoorte, Elisabeth; Groothuis, Geny M. M.; Merema, M.T.

    2011-01-01

    Early information on the metabolism and toxicity properties of new drug candidates is crucial for selecting the right candidates for further development. Preclinical trials rely on cell-based in vitro tests and animal studies to characterize the in vivo behavior of drug candidates, although neither

  4. Obesity alters adipose tissue macrophage iron content and tissue iron distribution.

    Science.gov (United States)

    Orr, Jeb S; Kennedy, Arion; Anderson-Baucum, Emily K; Webb, Corey D; Fordahl, Steve C; Erikson, Keith M; Zhang, Yaofang; Etzerodt, Anders; Moestrup, Søren K; Hasty, Alyssa H

    2014-02-01

    Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFe(hi), and the remaining ATMs are referred to as MFe(lo). In lean mice, ~25% of the ATMs are MFe(hi); this percentage decreases in obesity owing to the recruitment of MFe(lo) macrophages. Similar to MFe(lo) cells, MFe(hi) ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFe(hi) ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFe(hi) iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFe(hi) ATM phenotype and their reduced capacity to handle iron.

  5. Calculation of neutron radiation energy deposition distribution in subcellular parts of tissue using recombination chamber microdosimetry

    International Nuclear Information System (INIS)

    Golnik, N.; Zielczynski, M.

    1999-01-01

    Recombination chamber microdosimetry was used as an instrument for determination of local neutron radiation energy deposition distribution. The method allows to simulate of subcellular regions of tissue of the order of 70 nm in size. The results obtained qualitatively correspond to relationship between biological efficiency and neutron energy, and show regular differences of distributions achieved by the recombination method and distributions measured using tissue equivalent proportional counters (TEPC), which simulates greater tissue regions of 1 μm in size

  6. Stimuli-responsive hydrogels in drug delivery and tissue engineering.

    Science.gov (United States)

    Sood, Nikhil; Bhardwaj, Ankur; Mehta, Shuchi; Mehta, Abhinav

    2016-01-01

    Hydrogels are the three-dimensional network structures obtained from a class of synthetic or natural polymers which can absorb and retain a significant amount of water. Hydrogels are one of the most studied classes of polymer-based controlled drug release. These have attracted considerable attention in biochemical and biomedical fields because of their characteristics, such as swelling in aqueous medium, biocompatibility, pH and temperature sensitivity or sensitivity towards other stimuli, which can be utilized for their controlled zero-order release. The hydrogels are expected to explore new generation of self-regulated delivery system having a wide array of desirable properties. This review highlights the exciting opportunities and challenges in the area of hydrogels. Here, we review different literatures on stimuli-sensitive hydrogels, such as role of temperature, electric potential, pH and ionic strength to control the release of drug from hydrogels.

  7. Evaluation of Tissue Interactions with Mechanical Elements of a Transscleral Drug Delivery Device

    Directory of Open Access Journals (Sweden)

    Jeffrey T. Borenstein

    2012-03-01

    Full Text Available The goal of this work was to evaluate tissue-device interactions due to implantation of a mechanically operated drug delivery system onto the posterior sclera. Two test devices were designed and fabricated to model elements of the drug delivery device—one containing a free-spinning ball bearing and the other encasing two articulating gears. Openings in the base of test devices modeled ports for drug passage from device to sclera. Porous poly(tetrafluoroethylene (PTFE membranes were attached to half of the gear devices to minimize tissue ingrowth through these ports. Test devices were sutured onto rabbit eyes for 10 weeks. Tissue-device interactions were evaluated histologically and mechanically after removal to determine effects on device function and changes in surrounding tissue. Test devices were generally well-tolerated during residence in the animal. All devices encouraged fibrous tissue formation between the sclera and the device, fibrous tissue encapsulation and invasion around the device, and inflammation of the conjunctiva. Gear devices encouraged significantly greater inflammation in all cases and a larger rate of tissue ingrowth. PTFE membranes prevented tissue invasion through the covered drug ports, though tissue migrated in through other smaller openings. The torque required to turn the mechanical elements increased over 1000 times for gear devices, but only on the order of 100 times for membrane-covered gear devices and less than 100 times for ball bearing devices. Maintaining a lower device profile, minimizing microscale motion on the eye surface and covering drug ports with a porous membrane may minimize inflammation, decreasing the risk of damage to surrounding tissues and minimizing disruption of device operation.

  8. Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

    Science.gov (United States)

    Heinrichs, M. Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D.; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A.; Blumberg, Henry M.; Vashakidze, Sergo

    2017-01-01

    ABSTRACT Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary (n = 6 patients), mass-like (n = 3 patients), or consolidative (n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis (R = −0.66, P = 0.04) and acid-fast bacilli (R = −0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. PMID:28373198

  9. Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis.

    Science.gov (United States)

    Kempker, Russell R; Heinrichs, M Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A; Blumberg, Henry M; Vashakidze, Sergo

    2017-06-01

    Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary ( n = 6 patients), mass-like ( n = 3 patients), or consolidative ( n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis ( R = -0.66, P = 0.04) and acid-fast bacilli ( R = -0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. Copyright © 2017 American Society for Microbiology.

  10. [Methodology for Identification of Inverse Drug Distribution, Spain].

    Science.gov (United States)

    López Pérez, M Arantzazu; Muñoz Arias, Mariano; Vázquez Mourelle, Raquel

    2016-04-04

    The phenomenon of reverse drug trafficking in the legal supply chain is an unlawful practice to serious risks to public health. The aims was to identify proactively pharmacies that carry out these illegal activities. An analysis was performed through the crossing billing data to SAS of 52 million packs of medicines for the 496 pharmacies in the province over a period of 29 months with the drug packaging data supplied by the distribution entities of the province with the implementation of specific indicator defined called 'percentage overbought' allows us to detect those pharmacies at high risk of being involved in this illicit trade. It was tested in two pharmacies one rural and other urban a detour of 5.130 medicine containers and an illicit profit obtained from € 9,591.78 for the first and 9.982 packaging and € 26,885.11 for the second; they had gone unnoticed in previous inspections. The methodology implemented to define a profile of infringing pharmacies high risk in these illicit practices, identify new ones that had not been sanctioned, weigh the drugs for illegal trade and to identify new drugs subject to diversion; also added as a challenge, it helps to adjust accurately and effectively calculate the illicit profit obtained.

  11. The role of the extracellular matrix in tissue distribution of macromolecules in normal and pathological tissues: potential therapeutic consequences.

    Science.gov (United States)

    Wiig, Helge; Gyenge, Christina; Iversen, Per Ole; Gullberg, Donald; Tenstad, Olav

    2008-05-01

    The interstitial space is a dynamic microenvironment that consists of interstitial fluid and structural molecules of the extracellular matrix, such as glycosaminoglycans (hyaluronan and proteoglycans) and collagen. Macromolecules can distribute in the interstitium only in those spaces unoccupied by structural components, a phenomenon called interstitial exclusion. The exclusion phenomenon has direct consequences for plasma volume regulation. Early studies have assigned a major role to collagen as an excluding agent that accounts for the sterical (geometrical) exclusion. More recently, it has been shown that the contribution of negatively charged glycosaminoglycans might also be significant, resulting in an additional electrostatical exclusion effect. This charge effect may be of importance for drug uptake and suggests that either the glycosaminoglycans or the net charge of macromolecular substances to be delivered may be targeted to increase the available volume and uptake of macromolecular therapeutic agents in tumor tissue. Here, we provide an overview of the structural components of the interstitium and discuss the importance the sterical and electrostatical components have on the dynamics of transcapillary fluid exchange.

  12. Distribution of primaquine in human blood: Drug-binding to alpha 1-glycoprotein

    International Nuclear Information System (INIS)

    Kennedy, E.; Frischer, H.

    1990-01-01

    To clarify the distribution of the antimalarial primaquine in human blood, we measured the drug separately in the liquid, cellular, and ultrafiltrate phases. Washed red cells resuspended at a hematocrit of 0.4 were exposed to a submaximal therapeutic level of 250 ng/ml of carbon 14-labeled primaquine. The tracer was recovered quantitatively in separated plasma and red cells. Over 75% of the total labeled drug was found in red cells suspended in saline solution, but only 10% to 30% in red cells suspended in plasma. The plasma effect was not mediated by albumin. Studies with alpha 1-acid glycoprotein (AGP), tris(2-butoxyethyl)phosphate, an agent that displaces AGP-bound drugs, and cord blood known to have decreased AGP established that primaquine binds to physiologic amounts of the glycoprotein in plasma. Red cell primaquine concentration increased linearly as AGP level fell and as the free drug fraction rose. We suggest that clinical blood levels of primaquine include the red cell fraction or whole blood level because (1) erythrocytic primaquine is a sizable and highly variable component of the total drug in blood; (2) this component reflects directly the free drug in plasma, and inversely the extent of binding to AGP; (3) the amount of free primaquine may influence drug transport into specific tissues in vivo; and (4) fluctuations of AGP, an acute-phase reactant that increases greatly in patients with malaria and other infections, markedly affect the partition of primaquine in blood. Because AGP binds many basic drugs, unrecognized primaquine-drug interactions may exist

  13. Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.

    Science.gov (United States)

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

    2007-07-01

    Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate-PEG-PAMAM conjugates, with different degrees of substitution were synthesized by a two-step reaction through a carbodiimide-mediated coupling reaction and loaded with indomethacin. Folate-PEG conjugation increased the drug loading efficiency by 10- to 20-fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half-life and mean residence time for the folate-PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate-PEG conjugates, thereby limiting gastric-related side effect. The time-averaged relative drug exposure (r(e)) of the drug in paw for the folate-PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T(e)) was highest for folate-PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate-PEG-PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side-effects and higher targeting efficiency. Copyright 2007 Wiley Periodicals, Inc.

  14. Tissue distribution of crizotinib and gemcitabine combination in a patient-derived orthotopic mouse model of pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Richard J. Honeywell

    2016-12-01

    Full Text Available Pharmacokinetics focuses on the question whether a drug actually reaches its target in therapeutic concentrations or accumulates elsewhere, potentially causing toxicological or unpredictable side effects. We determined tissue distribution of gemcitabine, an antimetabolite, and crizotinib, a tyrosine-kinase inhibitor targeted against the anaplastic lymphoma kinase (ALK and mesenchymal-epithelial transition factor (c-Met receptors, in a validated orthotopic mouse model for pancreatic cancer. Mice with pancreatic cancer were treated with either oral crizotinib at 25 mg/kg, gemcitabine at 100 mg/kg or with their combination. Two hours after the last gemcitabine dose mice were sacrificed and all available blood/organs/tissues were sampled. Tissue was subsequently analyzed for drug concentrations using a validated liquid chromatography-mass spectrometry (LC-MS/MS technique. In whole blood gemcitabine was about 1.0 µM and crizotinib 2.4 µM in the single treatment, whereas in the combination crizotinib increased the levels of gemcitabine. Crizotinib was found in all major tissues, being highest in the intestine. Comparison of crizotinib alone to the gemcitabine-crizotinib combination showed that crizotinib tissue concentrations were 3-6 fold lower in liver, lung, kidney and spleen, 30-fold lower in the skin, heart and pancreas and 200-fold lower in the brain. Tissue gemcitabine was highest in spleen and skin, being about 5-10 fold higher than in the other tissues, including brain, which still had a relatively high accumulation. In conclusion, both gemcitabine and crizotinib accumulate at clinically active but variable levels in tissues, possibly relating to the effects exerted by these drugs.

  15. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    Science.gov (United States)

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  16. Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

    Directory of Open Access Journals (Sweden)

    Lee JA

    2014-12-01

    Full Text Available Jeong-A Lee,1 Mi-Kyung Kim,1 Hee-Jeong Paek,1 Yu-Ri Kim,2 Meyoung-Kon Kim,2 Jong-Kwon Lee,3 Jayoung Jeong,3 Soo-Jin Choi1 1Department of Food Science and Technology, Seoul Women’s University, Seoul, Republic of Korea; 2Department of Biochemistry and Molecular Biology, Korea University Medical School and College, Seoul, Republic of Korea; 3Toxicological Research Division, National Institute of Food and Drug Safety Evaluation, Chungchungbuk–do, Republic of Korea Purpose: The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods: Silica nanoparticles of two different sizes (20 nm and 100 nm were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results: The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion: The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ

  17. Biomacromolecules as carriers in drug delivery and tissue engineering.

    Science.gov (United States)

    Zhang, Yujie; Sun, Tao; Jiang, Chen

    2018-01-01

    Natural biomacromolecules have attracted increased attention as carriers in biomedicine in recent years because of their inherent biochemical and biophysical properties including renewability, nontoxicity, biocompatibility, biodegradability, long blood circulation time and targeting ability. Recent advances in our understanding of the biological functions of natural-origin biomacromolecules and the progress in the study of biological drug carriers indicate that such carriers may have advantages over synthetic material-based carriers in terms of half-life, stability, safety and ease of manufacture. In this review, we give a brief introduction to the biochemical properties of the widely used biomacromolecule-based carriers such as albumin, lipoproteins and polysaccharides. Then examples from the clinic and in recent laboratory development are summarized. Finally the current challenges and future prospects of present biological carriers are discussed.

  18. Drugs Involved in Dyslipidemia and Obesity Treatment: Focus on Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Sofia Dias

    2018-01-01

    Full Text Available Metabolic syndrome can be defined as a state of disturbed metabolic homeostasis characterized by visceral obesity, atherogenic dyslipidemia, arterial hypertension, and insulin resistance. The growing prevalence of metabolic syndrome will certainly contribute to the burden of cardiovascular disease. Obesity and dyslipidemia are main features of metabolic syndrome, and both can present with adipose tissue dysfunction, involved in the pathogenic mechanisms underlying this syndrome. We revised the effects, and underlying mechanisms, of the current approved drugs for dyslipidemia and obesity (fibrates, statins, niacin, resins, ezetimibe, and orlistat; sibutramine; and diethylpropion, phentermine/topiramate, bupropion and naltrexone, and liraglutide on adipose tissue. Specifically, we explored how these drugs can modulate the complex pathways involved in metabolism, inflammation, atherogenesis, insulin sensitivity, and adipogenesis. The clinical outcomes of adipose tissue modulation by these drugs, as well as differences of major importance for clinical practice between drugs of the same class, were identified. Whether solutions to these issues will be found in further adjustments and combinations between drugs already in use or necessarily in new advances in pharmacology is not known. To better understand the effect of drugs used in dyslipidemia and obesity on adipose tissue not only is challenging for physicians but could also be the next step to tackle cardiovascular disease.

  19. THE JUST DRUG DISTRIBUTION IN THE PERSPECTIVE OF WELFARE STATE

    Directory of Open Access Journals (Sweden)

    Aktieva Tri Tjitrawati

    2014-03-01

    Full Text Available States have obligations to improve equitability of welfare and prosperity of the community. Pharmaceutical is one of the important and strategic industries because of its vital role to support the development of health sector. Lack of regulation on pricing-products, and diversion of social aspects in the drugs trade, either by government or industry, are associated with the paradigm that underlies regulation of the distributions. Prospective policy analysis and functional approach of law are used to find a level of balance of various interest related to the subject, and to find concepts as a basis to construct new paradigm on drugs distribution. Negara berkewajiban untuk meningkatkan kesejahteraan dan kemakmuran masyarakat secara berkeadilan. Industri farmasi merupakan salah satu industri penting dan strategis karena perannya yang vital menunjang pembangunan bidang kesehatan.Terdapat kecenderungan kurangnya peran Pemerintah dalam pricing policy obat, serta diabaikannya aspek sosial dalam perdagangan produk farmasi, baik oleh Pemerintah maupun industri farmasi. Carut marut ini berkaitan dengan ketidakjelasan paradigma yang berujung pada ketidakjelasan kebijakan yang melandasi tatanan distribusi obat. Makalah ini menggunakan analisis kebijakan prospektif dan pendekatan fungsional hukum untuk mengkaji kebijakan distribusi obat yang bersifat multi disiplin dan menemukan konsep baru untuk menemukan titik keseimbangan dari berbagai kepentingan terkait.

  20. Alters Intratumoral Drug Distribution and Affects Therapeutic Synergy of Antiangiogenic Organoselenium Compound

    Directory of Open Access Journals (Sweden)

    Youcef M. Rustum

    2010-01-01

    Full Text Available Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium. Marked potentiation of antitumor activity was observed in H69 tumors that exhibited a well-vascularized, poorly differentiated phenotype. In comparison, modulation of chemotherapeutic efficacy by antiangiogenic selenium was generally lower or absent in well-differentiated tumors with multiple avascular hypoxic, differentiated regions. Tumor histomorphologic heterogeneity was found prevalent in the clinical samples studied and represents a primary and critical physiological barrier to chemotherapy.

  1. Distribution and clearance of PEG-single-walled carbon nanotube cancer drug delivery vehicles in mice.

    Science.gov (United States)

    Bhirde, Ashwin A; Patel, Sachin; Sousa, Alioscka A; Patel, Vyomesh; Molinolo, Alfredo A; Ji, Youngmi; Leapman, Richard D; Gutkind, J Silvio; Rusling, James F

    2010-12-01

    To study the distribution and clearance of polyethylene glycol (PEG)-ylated single-walled carbon nanotube (SWCNTs) as drug delivery vehicles for the anticancer drug cisplatin in mice. PEG layers were attached to SWCNTs and dispersed in aqueous media and characterized using dynamic light scattering, scanning transmission electron microscopy and Raman spectroscopy. Cytotoxicity was assessed in vitro using Annexin-V assay, and the distribution and clearance pathways in mice were studied by histological staining and Raman spectroscopy. Efficacy of PEG-SWCNT-cisplatin for tumor growth inhibition was studied in mice. PEG-SWCNTs were efficiently dispersed in aqueous media compared with controls, and did not induce apoptosis in vitro. Hematoxylin and eosin staining, and Raman bands for SWCNTs in tissues from several vital organs from mice injected intravenously with nanotube bioconjugates revealed that control SWCNTs were lodged in lung tissue as large aggregates compared with the PEG-SWCNTs, which showed little or no accumulation. Characteristic SWCNT Raman bands in feces revealed the presence of bilary or renal excretion routes. Attachment of cisplatin on bioconjugates was visualized with Z-contrast scanning transmission electron microscopy. PEG-SWCNT-cisplatin with the attached targeting ligand EGF successfully inhibited growth of head and neck tumor xenografts in mice. PEG-SWCNTs, as opposed to control SWCNTs, form more highly dispersed delivery vehicles that, when loaded with both cisplatin and EGF, inhibit growth of squamous cell tumors.

  2. Distribution of radioactive phosphorus (32 P) in sheep tissue

    International Nuclear Information System (INIS)

    Lobao, A. de O.

    1973-01-01

    Twelve male lambs (Corriedale) were separated in two groups according to their average age (114 days and 208 days). The animals of each group were selected in twos according to weight to provide duplicates. After a 7 days period of adaptation, during which time the lambs received anunrestricted mineral supplement, they were given intravenous injections of 1 ml of Na 2 H 32 PO 4 . The amount of radioactivity administered varied with time; from 500 μci to 225.9 μci for the 6 younger animals, and from 500 μci to 87.5 μci for the 6 older ones. At 8, 16, and 24 hours after the injections, the animals were anesthetized and sacrificed by bleeding. As well as the serum and blood, pieces of tongue, brain, heart, diaphragm spleen, kidney, liver and bone were collected. These tissues were dried, incinerated and the extracts obtained with H 2 SO 4 counted by Cerenkov radiation in a liquid scintillation counter. The level of inorganic phosphorus in the serum was determined with material obtained the day before the experiment. The younger animals had lower levels of serum inorganic phosphorus and retained higher levels of 32 P on their tissues. The isotope was found in a decreasing order in the following tissues: liver, kidney, spleen heart, and tongue. The brain presented the least retention. The order of magnitude by which the tissues retained the isotope was not influenced by the age of the animals, by the experimental period, or by the level of serum inorganic phosphorus. The amount of phosphorus retained by the tissues was affected not only by the age of the animals, but also by the level of phosphorus in the blood and, for some tissues, by the experimental period [pt

  3. The influence of drug distribution and drug-target binding on target occupancy : The rate-limiting step approximation

    NARCIS (Netherlands)

    Witte, de W.E.A.; Vauquelin, G.; Graaf, van der P.H.; Lange, de E.C.M.

    2017-01-01

    The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as "rebinding" or "diffusion-limited binding". This gives rise to a decreased decline of the drug-target complex concentration as a result of a

  4. Bioprinting of Micro-Organ Tissue Analog for Drug Metabolism Study

    Science.gov (United States)

    Sun, Wei

    An evolving application of tissue engineering is to develop in vitro 3D cell/tissue models for drug screening and pharmacological study. In order to test in space, these in vitro models are mostly manufactured through micro-fabrication techniques and incorporate living cells with MEMS or microfluidic devices. These cell-integrated microfluidic devices, or referred as microorgans, are effective in furnishing reliable and inexpensive drug metabolism and toxicity studies [1-3]. This paper will present an on-going research collaborated between Drexel University and NASA JSC Radiation Physics Laboratory for applying a direct cell printing technique to freeform fabrication of 3D liver tissue analog in drug metabolism study. The paper will discuss modeling, design, and solid freeform fabrication of micro-fluidic flow patterns and bioprinting of 3D micro-liver chamber that biomimics liver physiological microenvironment for enhanced drug metabolization. Technical details to address bioprinting of 3D liver tissue analog, integration with a microfluidic device, and basic drug metabolism study for NASA's interests will presented. 1. Holtorf H. Leslie J. Chang R, Nam J, Culbertson C, Sun W, Gonda S, "Development of a Three-Dimensional Tissue-on-a-Chip Micro-Organ Device for Pharmacokinetic Analysis", the 47th Annual Meeting of the American Society for Cell Biology, Washington, DC, December 1-5, 2007. 2. Chang, R., Nam, J., Culbertson C., Holtorf, H., Jeevarajan, A., Gonda, S. and Sun, W., "Bio-printing and Modeling of Flow Patterns for Cell Encapsulated 3D Liver Chambers For Pharmacokinetic Study", TERMIS North America 2007 Conference and Exposition, Westin Harbour Castle, Toronto, Canada, June 13-16, 2007. 3.Starly, B., Chang, R., Sun, W., Culbertson, C., Holtorf, H. and Gonda, S., "Bioprinted Tissue-on-chip Application for Pharmacokinetic Studies", Proceedings of World Congress on Tissue Engineering and Regenerative Medicine, Pittsburgh, PA, USA, April 24-27, 2006.

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

    International Nuclear Information System (INIS)

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

    2014-01-01

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

  6. 12 Trace Metals Distribution in Fish Tissues, Bottom Sediments and ...

    African Journals Online (AJOL)

    `123456789jkl''''#

    Abstract. Water samples, bottom sediments, Tilapia, and Cat Fish from Okumeshi River in Delta state of Nigeria were analysed ... Keywords: Trace metals, Fish Tissues, Water, Bottom sediments, Okumeshi River. Introduction ..... Grey Mangroove Avicemmia marina (Forsk). ... sewage treatment plant oulet pipe extension on.

  7. Study of trace elements distribution in various tissues structures

    International Nuclear Information System (INIS)

    Kwiatek, W.M.; Marczewska, E.

    1994-01-01

    Many papers have been written during the past ten years about TE study in cancer and normal tissues describing the use of different methods for detection of trace elements. Concentration of TE depends strongly on the sample measured. However, according to our knowledge, the role of TE in cancerous tissue is still known. Therefore, we propose to perform an experiment which will hopefully given us more information about the relationship between the concentration of elements in different tissues. The developing industry localised near Cracow becomes a serious danger for health of it's inhabitants. The negative influence of the air pollution to the living organisms is seen not only in the nature but also in humans. Therefore we want to analyse the trace element contents in the air. Such investigation will give the information about the pollution level in the City. The pollution has its obvious negative influence to health and toxic element concentration level in blood. It is interesting to check if placenta plays an effective role in foetus protection against toxic metals. In order to study this problem, the trace element analysis of placenta tissues will be done by means of synchrotron microbeam. (author). 1 ref

  8. Overview on zein protein: a promising pharmaceutical excipient in drug delivery systems and tissue engineering.

    Science.gov (United States)

    Labib, Gihan

    2018-01-01

    Natural pharmaceutical excipients have been applied extensively in the past decades owing to their safety and biocompatibility. Zein, a natural protein of plant origin offers great benefit over other synthetic polymers used in controlled drug and biomedical delivery systems. It was used in a variety of medical fields including pharmaceutical and biomedical drug targeting, vaccine, tissue engineering, and gene delivery. Being biodegradable and biocompatible, the current review focuses on the history and the medical application of zein as an attractive still promising biopolymer. Areas covered: The current review gives a broadscope on zein as a still promising protein excipient in different fields. Zein- based drug and biomedical delivery systems are discussed with special focus on current and potential application in controlled drug delivery systems, and tissue engineering. Expert opinion: Zein as a protein of natural origin can still be considered a promising polymer in the field of drug delivery systems as well as in tissue engineering. Although different researchers spotted light on zein application in different industrial fields extensively, the feasibility of its use in the field of drug delivery replenished by investigators in recent years has not yet been fully approached.

  9. Tissue distribution and elimination of rotenone in rainbow trout

    Science.gov (United States)

    Gingerich, W.H.

    1986-01-01

    The fate of a single i.v. dose (120 μg/kg) of the piscicide [14C]rotenone was evaluated in rainbow trout for periods up to 72 h after dosing. Rotenone was rapidly cleared from the plasma; less than 2% of the dose remained in the plasma compartment after 20 min. The highest concentrations of rotenone residues (% dose/g tissue) were in the hepatobiliary system, bile, intestine, and in heart, lateral line swimming muscle, and posterior kidney; tissues that are highly dependent on oxidative metabolism. Although rotenone activity was present in all cell fractions examined, greater than 40% was associated with the mitochondrial fraction of liver, kidney, and muscle. More than 85% of the activity extracted from these tissues, except the liver, was parent rotenone. Elimination from whole body and major tissue depots conformed to simple first-order kinetics; the estimated half-life from whole body was 68.5 h. Branchial elimination accounted for 5% of the injected dose over a 4-h period, and urinary elimination was less than 2% over a 48-h period. Rotenone was eliminated essentially unchanged across the gills; however, parent rotenone was not found in either urine or bile. More than 80% of the activity in both urine and bile eluted from HPLC chromatographs as a highly polar fraction that was not hydrolyzed by incubation with either β-glucuronidase or sulfatase. The results imply that hepatobiliary excretion is the major route of elimination for rotenone residues in the trout and that metabolism to a more polar form is a prerequisite for elimination in both the bile and the urine

  10. Distribution and chemical form of mercury in commercial fish tissues.

    Science.gov (United States)

    Watanabe, Naoko; Tayama, Misato; Inouye, Minoru; Yasutake, Akira

    2012-01-01

    We analyzed total Hg concentrations in various tissue samples obtained from 7 commercially available fish species. MeHg contents were also estimated for muscle and liver samples by a selective analysis of inorganic Hg. Among the tissues, high Hg accumulations were shown in liver, muscle, heart and spleen throughout all fish species. Carnivorous fish, such as scorpion fish, sea bream and Japanese whiting, tended to show higher Hg accumulations in the muscle, with the highest Hg levels being shown by scorpion fish. Although the liver was expected to show the highest Hg accumulations among tissues throughout all fish species, the highest accumulation in the liver was observed only in scorpion fish. In contrast, the muscle level was significantly higher than the liver in Pacific saury and Japanese whiting. MeHg accumulated in fish is considered to show a sustained increase throughout the life of the fish, due to its long biological half-life. In fact, in the present study, muscle Hg levels in Japanese whiting, Japanese flying fish, and halfbeak showed good correlations with body weights. However, such correlations were not clear in scorpion fish, sea bream, Jack mackerel and Pacific saury. Selective analyses of inorganic Hg levels revealed that most of the Hg (> 95%) in fish muscle existed as MeHg, while the rates of MeHg contents in the liver varied from 56% in scorpion fish to 84% in Jack mackerel. As a result, fish muscle showed the highest MeHg accumulations in all fish species examined. These results suggest that reliable information on total Hg contents in fish muscle might be sufficient to avoid the risk of MeHg exposure caused by eating fish, even when one consumes other tissues such as fish liver.

  11. Predicting volume of distribution with decision tree-based regression methods using predicted tissue:plasma partition coefficients.

    Science.gov (United States)

    Freitas, Alex A; Limbu, Kriti; Ghafourian, Taravat

    2015-01-01

    Volume of distribution is an important pharmacokinetic property that indicates the extent of a drug's distribution in the body tissues. This paper addresses the problem of how to estimate the apparent volume of distribution at steady state (Vss) of chemical compounds in the human body using decision tree-based regression methods from the area of data mining (or machine learning). Hence, the pros and cons of several different types of decision tree-based regression methods have been discussed. The regression methods predict Vss using, as predictive features, both the compounds' molecular descriptors and the compounds' tissue:plasma partition coefficients (Kt:p) - often used in physiologically-based pharmacokinetics. Therefore, this work has assessed whether the data mining-based prediction of Vss can be made more accurate by using as input not only the compounds' molecular descriptors but also (a subset of) their predicted Kt:p values. Comparison of the models that used only molecular descriptors, in particular, the Bagging decision tree (mean fold error of 2.33), with those employing predicted Kt:p values in addition to the molecular descriptors, such as the Bagging decision tree using adipose Kt:p (mean fold error of 2.29), indicated that the use of predicted Kt:p values as descriptors may be beneficial for accurate prediction of Vss using decision trees if prior feature selection is applied. Decision tree based models presented in this work have an accuracy that is reasonable and similar to the accuracy of reported Vss inter-species extrapolations in the literature. The estimation of Vss for new compounds in drug discovery will benefit from methods that are able to integrate large and varied sources of data and flexible non-linear data mining methods such as decision trees, which can produce interpretable models. Graphical AbstractDecision trees for the prediction of tissue partition coefficient and volume of distribution of drugs.

  12. Novel nanocarriers for topical drug delivery: investigating delivery efficiency and distribution in skin using two-photon microscopy

    Science.gov (United States)

    Kirejev, Vladimir; Guldbrand, Stina; Bauer, Brigitte; Smedh, Maria; Ericson, Marica B.

    2011-03-01

    The complex structure of skin represents an effective barrier against external environmental factors, as for example, different chemical and biochemical compounds, yeast, bacterial and viral infections. However, this impermeability prevents efficient transdermal drug delivery which limits the number of drugs that are able to penetrate the skin efficiently. Current trends in drug application through skin focus on the design and use of nanocarriers for transport of active compounds. The transport systems applied so far have several drawbacks, as they often have low payload, high toxicity, a limited variability of inclusion molecules, or long degradation times. The aim of these current studies is to investigate novel topical drug delivery systems, e.g. nanocarriers based on cyclic oligosaccharides - cyclodextrins (CD) or iron (III)-based metal-organic frameworks (MOF). Earlier studies on cell cultures imply that these drug nanocarriers show promising characteristics compared to other drug delivery systems. In our studies, we use two-photon microscopy to investigate the ability of the nanocarriers to deliver compounds through ex-vivo skin samples. Using near infrared light for excitation in the so called optical window of skin allows deep-tissue visualization of drug distribution and localization. In addition, it is possible to employ two-photon based fluorescence correlation spectroscopy for quantitative analysis of drug distribution and concentrations in different cell layers.

  13. Atomic Force Microscopy Images Label-Free, Drug Encapsulated Nanoparticles In Vivo and Detects Difference in Tissue Mechanical Properties of Treated and Untreated: A Tip for Nanotoxicology

    Science.gov (United States)

    Lamprou, Dimitrios A.; Venkatpurwar, Vinod; Kumar, M. N. V. Ravi

    2013-01-01

    Overcoming the intractable challenge of imaging of label-free, drug encapsulated nanoparticles in tissues in vivo would directly address associated regulatory concerns over 'nanotoxicology'. Here we demonstrate the utility of Atomic Force Microscopy (AFM) for visualising label-free, drug encapsulated polyester particles of ∼280 nm distributed within tissues following their intravenous or peroral administration to rodents. A surprising phenomenon, in which the tissues' mechanical stiffness was directly measured (also by AFM) and related to the number of embedded nanoparticles, was utilised to generate quantitative data sets for nanoparticles localisation. By coupling the normal determination of a drug's pharmacokinetics/pharmacodynamics with post-sacrifice measurement of nanoparticle localisation and number, we present for the first time an experimental design in which a single in vivo study relates the PK/PD of a nanomedicine to its toxicokinetics. PMID:23724054

  14. Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications

    OpenAIRE

    Shi, Jinjun; Votruba, Alexander R.; Farokhzad, Omid C.; Langer, Robert

    2010-01-01

    The application of nanotechnology in medicine, referred to as nanomedicine, is offering numerous exciting possibilities in healthcare. Herein, we discuss two important aspects of nanomedicine—drug delivery and tissue engineering—highlighting the advances we have recently experienced, the challenges we are currently facing, and what we are likely to witness in the near future.

  15. Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications

    Science.gov (United States)

    Shi, Jinjun; Votruba, Alexander R.; Farokhzad, Omid C.; Langer, Robert

    2010-01-01

    The application of nanotechnology in medicine, referred to as nanomedicine, is offering numerous exciting possibilities in healthcare. Herein, we discuss two important aspects of nanomedicine—drug delivery and tissue engineering—highlighting the advances we have recently experienced, the challenges we are currently facing, and what we are likely to witness in the near future. PMID:20726522

  16. Nanotechnology in drug delivery and tissue engineering: from discovery to applications.

    Science.gov (United States)

    Shi, Jinjun; Votruba, Alexander R; Farokhzad, Omid C; Langer, Robert

    2010-09-08

    The application of nanotechnology in medicine, referred to as nanomedicine, is offering numerous exciting possibilities in healthcare. Herein, we discuss two important aspects of nanomedicine, drug delivery and tissue engineering, highlighting the advances we have recently experienced, the challenges we are currently facing, and what we are likely to witness in the near future.

  17. Medical applications of membranes: Drug delivery, artificial organs and tissue engineering

    NARCIS (Netherlands)

    Stamatialis, Dimitrios; Papenburg, B.J.; Girones nogue, Miriam; Saiful, S.; Bettahalli Narasimha, M.S.; Schmitmeier, Stephanie; Wessling, Matthias

    2008-01-01

    This paper covers the main medical applications of artificial membranes. Specific attention is given to drug delivery systems, artificial organs and tissue engineering which seem to dominate the interest of the membrane community this period. In all cases, the materials, methods and the current

  18. In vivo drug release behavior and osseointegration of a doxorubicin-loaded tissue-engineered scaffold

    DEFF Research Database (Denmark)

    Sun, Ming; Chen, Muwan; Wang, Miao

    2016-01-01

    Bone tissue-engineered scaffolds with therapeutic effects must meet the basic requirements as to support bone healing at the defect side and to release an effect drug within the therapeutic window. Here, a rapid prototyped PCL scaffold embedded with chitosan/nanoclay/β-tricalcium phosphate...

  19. The comparative distribution of thorium and plutonium in human tissues

    International Nuclear Information System (INIS)

    Singh, Narayani P.; Shawki Amin Ibrahim; Cohen, Norman; Wrenn, McDonald E.

    1978-01-01

    Thorium is the most chemically and biologically similar natural element to the manmade element plutonium. Both are actinides, and for both the most stable valency state is +4, and solubility in natural body fluids is low. They are classified together in ICRP Lung Model. The present paper deals with the question of whether or not the analogy between the two actinides in terms of deposition and retention in human tissues is a good one. Preliminary results on the thorium contents ( 228,230 Th and 232 Th) of three sets of human tissues from a western U.S. town containing a uranium tailings pile are compared with the reported values of plutonium content of human tissues from the general populations who are exposed to environmental plutonium from fallout of nuclear detonations. Samples were taken at autopsy where sudden death had occurred. For the three isotopes of thorium, the ratio of the content of each (pCi/organ, normalized by organ weight to ICRP Reference Man) in lung to lymph nodes varies from 2-25 for individuals with a mean of 8; this is similar to that we infer from the literature for 239 , 240 Pu which suggests a ratio of lung to lymph nodes with a mean of approximately 7. However, the relative thorium contents of lung and liver are dissimilar, lung/liver for thorium being 3.5 and for plutonium 0.2 to 0.1. Similarly, the ratios of thorium and plutonium content of liver and bone vary significantly; the ratio for thorium is 0.1 and for plutonium 0.8 to 0.5. The most significant observation at this stage is that the relative accumulation of thorium in human liver is much less than that of plutonium. Some of the plausible reasons will be discussed. (author)

  20. Stem cells in drug discovery, tissue engineering, and regenerative medicine: emerging opportunities and challenges.

    Science.gov (United States)

    Nirmalanandhan, Victor Sanjit; Sittampalam, G Sitta

    2009-08-01

    Stem cells, irrespective of their origin, have emerged as valuable reagents or tools in human health in the past 2 decades. Initially, a research tool to study fundamental aspects of developmental biology is now the central focus of generating transgenic animals, drug discovery, and regenerative medicine to address degenerative diseases of multiple organ systems. This is because stem cells are pluripotent or multipotent cells that can recapitulate developmental paths to repair damaged tissues. However, it is becoming clear that stem cell therapy alone may not be adequate to reverse tissue and organ damage in degenerative diseases. Existing small-molecule drugs and biologicals may be needed as "molecular adjuvants" or enhancers of stem cells administered in therapy or adult stem cells in the diseased tissues. Hence, a combination of stem cell-based, high-throughput screening and 3D tissue engineering approaches is necessary to advance the next wave of tools in preclinical drug discovery. In this review, the authors have attempted to provide a basic account of various stem cells types, as well as their biology and signaling, in the context of research in regenerative medicine. An attempt is made to link stem cells as reagents, pharmacology, and tissue engineering as converging fields of research for the next decade.

  1. Determination of 6258-70, a new semi-synthetic taxane, in rat plasma and tissues: Application to the pharmacokinetics and tissue distribution study

    Directory of Open Access Journals (Sweden)

    Simin Zhao

    2016-08-01

    Full Text Available Cancer is the leading cause of death all over the world. Among the chemotherapy drugs, taxanes play an important role in cancer treatment. 6258-70 is a new semi-synthetic taxane which has a broad spectrum of antitumor activity. A fast and reliable high performance liquid chromatography-tandem mass spectrometry (HPLC–MS/MS method was developed for quantification of 6258-70 in rat plasma and tissues in this paper. After extraction by liquid-liquid extraction method with methyl tert-butyl ether, the samples were separated on a Kinetex C18 column (50 mm×2.1 mm, 2.6 µm, Phenomenex, USA within 3 min. The method was fully validated with the matrix effect between 87.7% and 99.5% and the recovery ranging from 80.3% to 90.1%. The intra- and inter-day precisions were less than 9.5% and the accuracy ranged from −3.8% to 6.5%. The reliable method was successfully applied to the pharmacokinetics and tissue distribution studies of 6258-70 after intravenous administration in rats. The pharmacokinetic results indicated that the pharmacokinetic behavior of 6258-70 in rats was in accordance with linear features within tested dosage of 1 to 4 mg/kg, and there was no significant difference between the two genders. The tissue distribution study showed that 6258-70 had an effective penetration, spread widely and rapidly and could cross blood-brain barrier. The results of pharmacokinetics and tissue distribution may provide a guide for future study.

  2. [Application of ultrasound-enhanced gene and drug delivery to the ocular tissue].

    Science.gov (United States)

    Sonoda, Shozo; Yamashita, Toshifumi; Suzuki, Ryo; Maruyama, Kazuo; Sakamoto, Taiji

    2013-01-01

    Visual images provide an immensely rich source of information about the external world. Eye has characteristic structure sensory cells are arranged along the eye wall, and is filled inside with vitreous body. In recent years, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent had widely spread, and numerous number of patients who suffered ocular angiogenic disease such as diabetic retinopathy, age-related macular degeneration and retinal vascular occlusion for the disease, were treated and spared the blindness. Vitreous cavity was regarded as reservoir of drug, intravitreal injection is thought a sort of drug delivery. However, with regard to the administration of a selective drug deliver, it has not yet been solved. Our aim is to establish a new method of gene transfer, drug delivery using low-energy ultrasound to the eye, to date, we confirmed drug and gene deliver to the ocular tissue such as cornea, conjunctiva and retina with high efficiency. In addition, tissue damage was minimal. We have also shown that ultrasound irradiation with combination of a microbubbles or bubble liposome could be introduced drug and gene more effectively. Based on these knowledge, we will focus on development of a new device for intraocular ultrasound exposure and potential for therapeutic application of ultrasound to humans retinal disease such as retinal artery obstruction.

  3. The absorption, tissue distribution and excretion of di-n-octyltin dichloride in rats

    NARCIS (Netherlands)

    Penninks, A.H.; Hilgers, L.; Seinen, W.

    In this study the absorption, tissue distribution and excretion of 14C-labeled di-n-octyltin dichloride ([14C]DOTC) in rats were investigated after oral and intravenous (i.v.) administration. Although after i.v. administration with 1.2 mg [14C]DOTC/kg body weight the tissue radioactivity was about

  4. Levels and distribution of polybrominated diphenyl ethers in various tissues of birds of prey

    International Nuclear Information System (INIS)

    Voorspoels, Stefan; Covaci, Adrian; Lepom, Peter; Jaspers, Veerle L.B.; Schepens, Paul

    2006-01-01

    In the present study, concentrations and tissue distribution of polybrominated diphenyl ethers (PBDEs; IUPAC nos. 28, 47, 99, 100, 153, 154, 183, and 209) were examined in brain, adipose tissue, liver, muscle, and serum of birds of prey. Median ΣPBDE levels (BDE 28-183) in the tissues of sparrowhawks ranged from 360 to 1900 ng/g lipid weight (lw), which was in general one order of magnitude higher than in the tissues of common buzzards (26-130 ng/g lw). There were no differences in PBDE congener patterns between the various tissues within individuals of a certain species. Inter-species differences in PBDE patterns and in particular the percentage of BDE 99, 100 and 153 were, however, pronounced between sparrowhawk and common buzzard. BDE 209 was detected in nearly all serum and in some liver samples, but not in any other tissues. This observation suggests that exposure to BDE 209 is low or that this congener is poorly accumulated. Passive (lipid content related) diffusion could not completely describe the PBDE tissue distribution, e.g. the lowest PBDE-load was measured in brain, a fairly lipid rich tissue. - Distribution of polybrominated diphenyl ethers in birds of prey is tissue dependent

  5. 3-D Bioprinting of Neural Tissue for Applications in Cell Therapy and Drug Screening

    Directory of Open Access Journals (Sweden)

    Michaela Thomas

    2017-11-01

    Full Text Available Neurodegenerative diseases affect millions of individuals in North America and cost the health-care industry billions of dollars for treatment. Current treatment options for degenerative diseases focus on physical rehabilitation or drug therapies, which temporarily mask the effects of cell damage, but quickly lose their efficacy. Cell therapies for the central nervous system remain an untapped market due to the complexity involved in growing neural tissues, controlling their differentiation, and protecting them from the hostile environment they meet upon implantation. Designing tissue constructs for the discovery of better drug treatments are also limited due to the resolution needed for an accurate cellular representation of the brain, in addition to being expensive and difficult to translate to biocompatible materials. 3-D printing offers a streamlined solution for engineering brain tissue for drug discovery or, in the future, for implantation. New microfluidic and bioplotting devices offer increased resolution, little impact on cell viability and have been tested with several bioink materials including fibrin, collagen, hyaluronic acid, poly(caprolactone, and poly(ethylene glycol. This review details current efforts at bioprinting neural tissue and highlights promising avenues for future work.

  6. [Carrier-mediated Transport of Cationic Drugs across the Blood-Tissue Barrier].

    Science.gov (United States)

    Kubo, Yoshiyuki

    2015-01-01

    Studies of neurological dysfunction have revealed the neuroprotective effect of several cationic drugs, suggesting their usefulness in the treatment of neurological diseases. In the brain and retina, blood-tissue barriers such as blood-brain barrier (BBB) and blood-retinal barrier (BRB) are formed to restrict nonspecific solute transport between the circulating blood and neural tissues. Therefore study of cationic drug transport at these barriers is essential to achieve systemic delivery of neuroprotective agents into the neural tissues. In the retina, severe diseases such as diabetic retinopathy and macular degeneration can cause neurological dysfunction that dramatically affects patients' QOL. The BRB is formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB). Blood-to-retina transport of cationic drugs was investigated at the inner BRB, which is known to nourish two thirds of the retina. Blood-to-retinal transport of verapamil suggested that the barrier function of the BRB differs from that of the BBB. Moreover, carrier-mediated transport of verapamil and pyrilamine revealed the involvement of novel organic cation transporters at the inner BRB. The identified transport systems for cationic drugs are sensitive to several cationic neuroprotective and anti-angiogenic agents such as clonidine and propranolol, and the involvement of novel transporters was also suggested in their blood-to-retina transport across the inner BRB.

  7. Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

    Science.gov (United States)

    Subramaniam, B; Claudius, J S

    1990-03-08

    Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful

  8. Adipose tissue content and distribution in children and adolescents with bronchial asthma.

    Science.gov (United States)

    Umławska, Wioleta

    2015-02-01

    The excess of adipose tissue and the pattern of adipose tissue distribution in the body seem to play an important role in the complicated dependencies between obesity and risk of developing asthma. The aim of the present study was to determine nutritional status in children and adolescents with bronchial asthma with special emphasis on adipose tissue distribution evaluated on the basis of skin-fold thicknesses, and to determine the relationships between patterns of adipose tissue distribution and the course of the disease. Anthropometric data on height, weight, circumferences and skin-fold thicknesses were extracted from the medical histories of 261 children diagnosed with asthma bronchitis. Values for children with asthma were compared to Polish national growth reference charts. Distribution of subcutaneous adipose tissue was evaluated using principal components analysis (PCA). Multivariate linear regression analyses tested the effect of three factors on subcutaneous adipose tissue distribution: type of asthma, the severity of the disease and the duration of the disease. Mean body height in the children examined in this study was lower than in their healthy peers. Mean BMI and skin-fold thicknesses were significantly higher and lean body mass was lower in the study group. Excess body fat was noted, especially in girls. Adipose tissue was preferentially deposited in the trunk in girls with severe asthma, as well as in those who had been suffering from asthma for a longer time. The type of asthma, atopic or non-atopic, had no observable effect on subcutaneous adipose tissue distribution in children examined. The data suggest that long-treated subjects and those with severe bronchial asthma accumulate more adipose tissue on the trunk. It is important to regularly monitor nutritional status in children with asthma, especially in those receiving high doses of systemic or inhaled glucocorticosteroids, and long-term treatment as well. Copyright © 2014 Elsevier Ltd. All

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    Bone tissue engineering implants with sustained local drug delivery provide an opportunity for better postoperative care for bone tumor patients because these implants offer sustained drug release at the tumor site and reduce systemic side effects. A rapid prototyped macroporous polycaprolactone......, this scaffold can fulfill the requirements for both bone tissue engineering and local sustained release of an anticancer drug in vitro. These results suggest that the scaffold can be used clinically in reconstructive surgery after bone tumor resection. Moreover, by changing the composition and amount...... of individual components, the scaffold can find application in other tissue engineering areas that need local sustained release of drug....

  10. Core-shell designed scaffolds for drug delivery and tissue engineering.

    Science.gov (United States)

    Perez, Roman A; Kim, Hae-Won

    2015-07-01

    Scaffolds that secure and deliver therapeutic ingredients like signaling molecules and stem cells hold great promise for drug delivery and tissue engineering. Employing a core-shell design for scaffolds provides a promising solution. Some unique methods, such as co-concentric nozzle extrusion, microfluidics generation, and chemical confinement reactions, have been successful in producing core-shelled nano/microfibers and nano/microspheres. Signaling molecules and drugs, spatially allocated to the core and/or shell part, can be delivered in a controllable and sequential manner for optimal therapeutic effects. Stem cells can be loaded within the core part on-demand, safely protected from the environments, which ultimately affords ex vivo culture and in vivo tissue engineering. The encapsulated cells experience three-dimensional tissue-mimic microenvironments in which therapeutic molecules are secreted to the surrounding tissues through the semi-permeable shell. Tuning the material properties of the core and shell, changing the geometrical parameters, and shaping them into proper forms significantly influence the release behaviors of biomolecules and the fate of the cells. This topical issue highlights the immense usefulness of core-shell designs for the therapeutic actions of scaffolds in the delivery of signaling molecules and stem cells for tissue regeneration and disease treatment. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  11. Study of distribution of /sup 169/Yb, /sup 67/Ga and /sup 111/In in tumor tissue by macroautoradiography. Comparison between viable tumor tissue and necrotic tumor tissue

    Energy Technology Data Exchange (ETDEWEB)

    Ando, A; Sanada, S; Hiraki, T [Kanazawa Univ. (Japan). School of Paramedicine; Doishita, K; Ando, I

    1977-01-01

    The localization of /sup 169/Yb, /sup 67/Ga and /sup 111/In in tumor tissues was determined macroautoradiographically. /sup 169/Yb-citrate, /sup 67/Ga-citrate and /sup 111/In-citrate were injected intravenously into rats which had received subcutaneously transplantations of Yoshida sarcoma, and were injected intraperitoneally to the mice which had received subcutaneous transplantations of Ehrlich tumor. These animals were sacrificed 3, 24 and 48 hours after injection. The tumor tissues were frozen in n-hexane (-70/sup 0/C) cooled with dry ice-acetone. After this, the frozen tumor tissues were cut into thin serial sections (10 ..mu..m) in a cryostat (-20/sup 0/C). One of these sections was then placed on x-ray film, and this film was developed after exposure of several days. The next slice of each of these sections were stained using the hematoxylin and eosin. From the observations of these autoradiogram and H-E stained slice, the following results were obtained. Concentration of /sup 169/Yb, /sup 67/Ga and /sup 111/In was predominant in viable tumor tissue rather than in necrotic tumor tissue, regardless of time after administration. /sup 67/Ga and /sup 111/In were distributed uniformly in viable tumor tissue, but there was greater deposition of /sup 169/Yb in viable tumor tissue neighboring the necrotic tumor.

  12. Distribution of /sup 125/I-thyroxine in different organs and tissues of dietically obese rats

    Energy Technology Data Exchange (ETDEWEB)

    Hartmann, K.; Voss, C.; Huebner, G. (Ernst-Moritz-Arndt-Universitaet, Greifswald (German Democratic Republic)); Weber, A. (Ernst-Moritz-Arndt-Universitaet, Greifswald (German Democratic Republic). Radiologische Klinik)

    1985-04-01

    The distribution of /sup 125/I-thyroxine (% dose/g tissue; tissue/plasma radioactivity ratio) was investigated in different tissues of 28-week-old obese Wistar rats. Obesity was induced by high-fat diet (HFD) and confirmed by carcass analysis; in heavy obese animals the relative and absolute fat content is increased twofold and threefold, respectively, compared to control rats fed on a low-fat diet (LFD). Heavy HFD rats exhibit diminished /sup 125/I-T/sub 4/ distribution in the 'slow pool' (fat tissue, muscle) and unchanged values in the 'fast pool' (liver, kidneys) in comparison with LFD rats with low body weight. The differences in distribution presented here are not caused by the diet per se, but they are the consequence of the obesity of the animal, because no differences in the /sup 125/I-T/sub 4/ distribution were found in the /sup 125/I-T/sub 4/ between HFD and LFD rats with relatively equal body weight and body composition. The reduced T/sub 4/ distribution in the fat tissue of obese rats is discussed in connection with possibly decreased lipolysis in this tissue and possible causal participation in the beginning of obesity.

  13. Multimodal Theranostic Nanoformulations Permit Magnetic Resonance Bioimaging of Antiretroviral Drug Particle Tissue-Cell Biodistribution

    Science.gov (United States)

    Kevadiya, Bhavesh D.; Woldstad, Christopher; Ottemann, Brendan M.; Dash, Prasanta; Sajja, Balasrinivasa R.; Lamberty, Benjamin; Morsey, Brenda; Kocher, Ted; Dutta, Rinku; Bade, Aditya N.; Liu, Yutong; Callen, Shannon E.; Fox, Howard S.; Byrareddy, Siddappa N.; McMillan, JoEllyn M.; Bronich, Tatiana K.; Edagwa, Benson J.; Boska, Michael D.; Gendelman, Howard E.

    2018-01-01

    RATIONALE: Long-acting slow effective release antiretroviral therapy (LASER ART) was developed to improve patient regimen adherence, prevent new infections, and facilitate drug delivery to human immunodeficiency virus cell and tissue reservoirs. In an effort to facilitate LASER ART development, “multimodal imaging theranostic nanoprobes” were created. These allow combined bioimaging, drug pharmacokinetics and tissue biodistribution tests in animal models. METHODS: Europium (Eu3+)- doped cobalt ferrite (CF) dolutegravir (DTG)- loaded (EuCF-DTG) nanoparticles were synthesized then fully characterized based on their size, shape and stability. These were then used as platforms for nanoformulated drug biodistribution. RESULTS: Folic acid (FA) decoration of EuCF-DTG (FA-EuCF-DTG) nanoparticles facilitated macrophage targeting and sped drug entry across cell barriers. Macrophage uptake was higher for FA-EuCF-DTG than EuCF-DTG nanoparticles with relaxivities of r2 = 546 mM-1s-1 and r2 = 564 mM-1s-1 in saline, and r2 = 850 mM-1s-1 and r2 = 876 mM-1s-1 in cells, respectively. The values were ten or more times higher than what was observed for ultrasmall superparamagnetic iron oxide particles (r2 = 31.15 mM-1s-1 in saline) using identical iron concentrations. Drug particles were detected in macrophage Rab compartments by dual fluorescence labeling. Replicate particles elicited sustained antiretroviral responses. After parenteral injection of FA-EuCF-DTG and EuCF-DTG into rats and rhesus macaques, drug, iron and cobalt levels, measured by LC-MS/MS, magnetic resonance imaging, and ICP-MS were coordinate. CONCLUSION: We posit that these theranostic nanoprobes can assess LASER ART drug delivery and be used as part of a precision nanomedicine therapeutic strategy. PMID:29290806

  14. Measurement of californium-252 gamma photons depth dose distribution in tissue equivalent material. Vol. 4

    Energy Technology Data Exchange (ETDEWEB)

    Fadel, M A; El-Fiki, M A; Eissa, H M; Abdel-Hafez, A; Naguib, S H [National Institute of Standards, Cairo (Egypt)

    1996-03-01

    Phantom of tissue equivalent material with and without bone was used measuring depth dose distribution of gamma-rays from californium-252 source. The source was positioned at center of perspex walled phantom. Depth dose measurements were recorded for X, Y and Z planes at different distances from source. TLD 700 was used for measuring the dose distribution. Results indicate that implantation of bone in tissue equivalent medium cause changes in the gamma depth dose distribution which varies according to variation in bone geometry. 9 figs.

  15. Correlation of cutaneous tension distribution and tissue oxygenation with acute external tissue expansion

    Directory of Open Access Journals (Sweden)

    Marquardt C

    2009-11-01

    Full Text Available Abstract Today, the biomechanical fundamentals of skin expansion are based on viscoelastic models of the skin. Although many studies have been conducted in vitro, analyses performed in vivo are rare. Here, we present in vivo measurements of the expansion at the skin surface as well as measurement of the corresponding intracutaneous oxygen partial pressure. In our study the average skin stretching was 24%, with a standard deviation of 11%, excluding age or gender dependency. The measurement of intracutaneous oxygen partial pressure produced strong inter-individual fluctuations, including initial values at the beginning of the measurement, as well as varying individual patient reactions to expansion of the skin. Taken together, we propose that even large defect wounds can be closed successfully using the mass displacement caused by expansion especially in areas where soft, voluminous tissue layers are present.

  16. Drug injection into fat tissue with a laser based microjet injector

    Science.gov (United States)

    Han, Tae-hee; Hah, Jung-moo; Yoh, Jack J.

    2011-05-01

    We have investigated a new micro drug jet injector using laser pulse energy. An infrared laser beam of high energy (˜3 J/pulse) is focused inside a driving fluid in a small chamber. The pulse then induces various energy releasing processes, and generates fast microjets through a micronozzle. The elastic membrane of this system plays an important role in transferring mechanical pressure and protecting drug from heat release. In this paper, we offer the sequential images of microjet generation taken by a high speed camera as an evidence of the multiple injections via single pulse. Furthermore, we test the proposed system to penetrate soft animal tissues in order to evaluate its feasibility as an advanced transdermal drug delivery method.

  17. Mechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues

    Science.gov (United States)

    Tzur-Balter, Adi; Shatsberg, Zohar; Beckerman, Margarita; Segal, Ester; Artzi, Natalie

    2015-01-01

    Nanostructured porous silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming its in vivo retention, providing tight control over embedded drug release kinetics. In this work, the relationship between the in vitro and in vivo degradation of PSi under (pre)clinically relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degradation in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumour vicinity that oxidize the silicon scaffold and catalyse its degradation. We further show that PSi degradation in vitro and in vivo correlates in healthy and diseased states when ROS-free or ROS-containing media are used, respectively. Our work demonstrates that understanding the governing mechanisms associated with specific tissue microenvironment permits predictive material performance. PMID:25670235

  18. An approach for quantification of platinum distribution in tissues by LA-ICP-MS imaging using isotope dilution analysis.

    Science.gov (United States)

    Moraleja, I; Mena, M L; Lázaro, A; Neumann, B; Tejedor, A; Jakubowski, N; Gómez-Gómez, M M; Esteban-Fernández, D

    2018-02-01

    Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been revealed as a convenient technique for trace elemental imaging in tissue sections, providing elemental 2D distribution at a quantitative level. For quantification purposes, in the last years several approaches have been proposed in the literature such as the use of CRMs or matrix matched standards. The use of Isotope Dilution (ID) for quantification by LA-ICP-MS has been also described, being mainly useful for bulk analysis but not feasible for spatial measurements so far. In this work, a quantification method based on ID analysis was developed by printing isotope-enriched inks onto kidney slices from rats treated with antitumoral Pt-based drugs using a commercial ink-jet device, in order to perform an elemental quantification in different areas from bio-images. For the ID experiments 194 Pt enriched platinum was used. The methodology was validated by deposition of natural Pt standard droplets with a known amount of Pt onto the surface of a control tissue, where could be quantified even 50pg of Pt, with recoveries higher than 90%. The amount of Pt present in the whole kidney slices was quantified for cisplatin, carboplatin and oxaliplatin-treated rats. The results obtained were in accordance with those previously reported. The amount of Pt distributed between the medullar and cortical areas was also quantified, observing different behavior for the three drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Temperature distribution in target tumor tissue and photothermal tissue destruction during laser immunotherapy

    Science.gov (United States)

    Doughty, Austin; Hasanjee, Aamr; Pettitt, Alex; Silk, Kegan; Liu, Hong; Chen, Wei R.; Zhou, Feifan

    2016-03-01

    Laser Immunotherapy is a novel cancer treatment modality that has seen much success in treating many different types of cancer, both in animal studies and in clinical trials. The treatment consists of the synergistic interaction between photothermal laser irradiation and the local injection of an immunoadjuvant. As a result of the therapy, the host immune system launches a systemic antitumor response. The photothermal effect induced by the laser irradiation has multiple effects at different temperature elevations which are all required for optimal response. Therefore, determining the temperature distribution in the target tumor during the laser irradiation in laser immunotherapy is crucial to facilitate the treatment of cancers. To investigate the temperature distribution in the target tumor, female Wistar Furth rats were injected with metastatic mammary tumor cells and, upon sufficient tumor growth, underwent laser irradiation and were monitored using thermocouples connected to locally-inserted needle probes and infrared thermography. From the study, we determined that the maximum central tumor temperature was higher for tumors of less volume. Additionally, we determined that the temperature near the edge of the tumor as measured with a thermocouple had a strong correlation with the maximum temperature value in the infrared camera measurement.

  20. 77 FR 59156 - Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment Period

    Science.gov (United States)

    2012-09-26

    .... FDA-2012-N-0447] Antimicrobial Animal Drug Sales and Distribution Reporting; Extension of Comment... its regulations relating to records and reports for approved antimicrobial new animal drugs. The... obtaining additional data and information about the extent of antimicrobial drug use in food-producing...

  1. Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization.

    Science.gov (United States)

    Mukhopadhya, Indrani; Murray, Graeme I; Berry, Susan; Thomson, John; Frank, Bruce; Gwozdz, Garry; Ekeruche-Makinde, Julia; Shattock, Robin; Kelly, Charles; Iannelli, Francesco; Pozzi, Gianni; El-Omar, Emad M; Hold, Georgina L; Hijazi, Karolin

    2016-02-01

    The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection. Drug transporter mRNA expression was quantified from colorectal biopsies and cell lines by quantitative real-time PCR. Relative mRNA expression was quantified in Caco-2 cells and colorectal explants after induction with ARVs. Data were analysed using Pearson's product moment correlation (r), hierarchical clustering and principal component analysis (PCA). Expression of 58 of the 84 transporters was documented in colorectal biopsies, with genes for CNT2, P-glycoprotein (P-gp) and MRP3 showing the highest expression. No difference was noted between individual subjects when analysed by age, gender or anatomical site (rectum or recto-sigmoid) (r = 0.95-0.99). High expression of P-gp and CNT2 proteins was confirmed by immunohistochemical staining. Similarity between colorectal tissue and cell-line drug transporter gene expression was variable (r = 0.64-0.84). PCA showed distinct clustering of human colorectal biopsy samples, with the Caco-2 cells defined as the best surrogate system. Induction of Caco-2 cell lines with ARV drugs suggests that darunavir-based microbicides incorporating tenofovir may result in drug-drug interactions likely to affect distribution of individual drugs to sub-epithelial target cells. These findings will help optimize complex formulations of rectal microbicides to realize their full potential as an effective approach for pre-exposure prophylaxis against HIV-1 infection. © The Author 2015. Published by Oxford University Press on behalf of the

  2. The waiting time distribution as a graphical approach to epidemiologic measures of drug utilization

    DEFF Research Database (Denmark)

    Hallas, J; Gaist, D; Bjerrum, L

    1997-01-01

    that effectively conveys some essential utilization parameters for a drug. The waiting time distribution for a group of drug users is a charting of their first prescription presentations within a specified time window. For a drug used for chronic treatment, most current users will be captured at the beginning...... of the window. After a few months, the graph will be dominated by new, incident users. As examples, we present waiting time distributions for insulin, ulcer drugs, systemic corticosteroids, antidepressants, and disulfiram. Appropriately analyzed and interpreted, the waiting time distributions can provide...... information about the period prevalence, point prevalence, incidence, duration of use, seasonality, and rate of prescription renewal or relapse for specific drugs. Each of these parameters has a visual correlate. The waiting time distributions may be an informative supplement to conventional drug utilization...

  3. Penetration and pharmacokinetics of non-steroidal anti-inflammatory drugs in rat prostate tissue.

    Science.gov (United States)

    Yellepeddi, Venkata K; Radhakrishnan, Jayashree; Radhakrishnan, Rajan

    2018-02-01

    Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) involves inflammation of the prostate and affects the quality of life of men of all ages. It is well reported in clinical studies that the treatment for CP/CPPS using nonsteroidal anti-inflammatory drugs (NSAIDs) produced favorable outcomes. However, currently, there are no guidelines on choice of the NSAIDs for the treatment of CP/CPPS. Therefore, in the current research study, we evaluated the prostate tissue penetration of four NSAIDs in rats to provide guidance on choice of NSAIDs for the treatment of CP/CPPS. Male Sprague-Dawley rats were administered orally with four NSAIDs viz. celecoxib, diclofenac, ibuprofen, and naproxen at 500 mg/kg dose. The animals were then sacrificed at various time points, and their prostate tissues were harvested. The NSAIDs were then extracted from the prostate tissues using liquid extraction technique, and their concentration in prostate tissue was quantified using high-performance liquid chromatography (HPLC). The prostate tissue penetration and related pharmacokinetic parameters were evaluated by non-compartmental analysis. The HPLC method for quantifying NSAIDs in prostate tissue resulted in single, sharp peaks without any interference and all validation parameters were within limits. Celecoxib showed the highest area under the curve (AUC) [146.50 ± 2.75 μg/mL*h] of all NSAID's. A two-factor analysis of variance (ANOVA) with replication indicated an overall statistically significant difference in the pharmacokinetic parameters for celecoxib, diclofenac, ibuprofen, and naproxen. This study for the first time reported the relative prostate tissue penetration of four NSAIDs. The pharmacokinetic data indicated that celecoxib has the highest penetration and retention in rat prostate tissues. Therefore, celecoxib may be considered as a better choice for the treatment CP/CPPS involving NSAIDs. © 2017 Wiley Periodicals, Inc.

  4. Convective transport of highly plasma protein bound drugs facilitates direct penetration into deep tissues after topical application

    Science.gov (United States)

    Dancik, Yuri; Anissimov, Yuri G; Jepps, Owen G; Roberts, Michael S

    2012-01-01

    AIMS To relate the varying dermal, subcutaneous and muscle microdialysate concentrations found in man after topical application to the nature of the drug applied and to the underlying physiology. METHODS We developed a physiologically based pharmacokinetic model in which transport to deeper tissues was determined by tissue diffusion, blood, lymphatic and intersitial flow transport and drug properties. The model was applied to interpret published human microdialysis data, estimated in vitro dermal diffusion and protein binding affinity of drugs that have been previously applied topically in vivo and measured in deep cutaneous tissues over time. RESULTS Deeper tissue microdialysis concentrations for various drugs in vivo vary widely. Here, we show that carriage by the blood to the deeper tissues below topical application sites facilitates the transport of highly plasma protein bound drugs that penetrate the skin, leading to rapid and significant concentrations in those tissues. Hence, the fractional concentration for the highly plasma protein bound diclofenac in deeper tissues is 0.79 times that in a probe 4.5 mm below a superficial probe whereas the corresponding fractional concentration for the poorly protein bound nicotine is 0.02. Their corresponding estimated in vivo lag times for appearance of the drugs in the deeper probes were 1.1 min for diclofenac and 30 min for nicotine. CONCLUSIONS Poorly plasma protein bound drugs are mainly transported to deeper tissues after topical application by tissue diffusion whereas the transport of highly plasma protein bound drugs is additionally facilitated by convective blood, lymphatic and interstitial transport to deep tissues. PMID:21999217

  5. Distribution of Hydroxychloroquine in Lymphoid Tissue in a Rabbit Model for HIV Infection

    Science.gov (United States)

    González-Hernández, Iliana; Aguirre-Cruz, Lucinda; Sotelo, Julio; López-Arellano, Raquel; Morales-Hipólito, Adriana

    2014-01-01

    Hydroxychloroquine has been proposed for HIV treatment; however, little is known about its disposition in the lymphatic system, where replication takes place. Therefore, its distribution in lymphoid tissues (Peyer's patches and popliteal, submandibular, femoral, splenic, and prescapular lymph nodes) was evaluated and compared with that in blood. Results showed a high affinity of hydroxychloroquine for all of these tissues, with higher affinity for the splenic and submandibular lymph nodes, suggesting its potential use as a coadjuvant in HIV therapy. PMID:24145523

  6. Distribution of Tributyltin in Tissues of Mature Japanese Whiting, Sillago japonica and Their Eggs

    OpenAIRE

    Shimasaki, Yohei; Oshima, Yuji; Inoue, Yoshiyuki; Shibata, Hisashi; Nakayama, Kei; Inoue, Suguru; Imoto, Hisaya; Kang, Ik Joon; Honjo, Tsuneo

    2008-01-01

    Tributyltin (TBT) has continued to pollute the coastal areas therein following global regulation for its use as an anti-fouling agent. The tissue dynamics of TBT in fish have been extensively documented, but few studies on maternal transfer of TBT have been performed. Previously, we reported that TBT was maternally transferred from parent fish to eggs. The present study examined the distribution of TBT in the tissues and spawned eggs of Japanese whiting, Sillago japonica, after dietary exp...

  7. Bioactive Molecule-loaded Drug Delivery Systems to Optimize Bone Tissue Repair.

    Science.gov (United States)

    Oshiro, Joao Augusto; Sato, Mariana Rillo; Scardueli, Cassio Rocha; Lopes de Oliveira, Guilherme Jose Pimentel; Abucafy, Marina Paiva; Chorilli, Marlus

    2017-01-01

    Bioactive molecules such as peptides and proteins can optimize the repair of bone tissue; however, the results are often unpredictable when administered alone, owing to their short biological half-life and instability. Thus, the development of bioactive molecule-loaded drug delivery systems (DDS) to repair bone tissue has been the subject of intense research. DDS can optimize the repair of bone tissue owing to their physicochemical properties, which improve cellular interactions and enable the incorporation and prolonged release of bioactive molecules. These characteristics are fundamental to favor bone tissue homeostasis, since the biological activity of these factors depends on how accessible they are to the cell. Considering the importance of these DDS, this review aims to present relevant information on DDS when loaded with osteogenic growth peptide and bone morphogenetic protein. These are bioactive molecules that are capable of modulating the differentiation and proliferation of mesenchymal cells in bone tissue cells. Moreover, we will present different approaches using these peptide and protein-loaded DDS, such as synthetic membranes and scaffolds for bone regeneration, synthetic grafts, bone cements, liposomes, and micelles, which aim at improving the therapeutic effectiveness, and we will compare their advantages with commercial systems. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. 3D Photo-Fabrication for Tissue Engineering and Drug Delivery

    Directory of Open Access Journals (Sweden)

    Rúben F. Pereira

    2015-03-01

    Full Text Available The most promising strategies in tissue engineering involve the integration of a triad of biomaterials, living cells, and biologically active molecules to engineer synthetic environments that closely mimic the healing milieu present in human tissues, and that stimulate tissue repair and regeneration. To be clinically effective, these environments must replicate, as closely as possible, the main characteristics of the native extracellular matrix (ECM on a cellular and subcellular scale. Photo-fabrication techniques have already been used to generate 3D environments with precise architectures and heterogeneous composition, through a multi-layer procedure involving the selective photocrosslinking reaction of a light-sensitive prepolymer. Cells and therapeutic molecules can be included in the initial hydrogel precursor solution, and processed into 3D constructs. Recently, photo-fabrication has also been explored to dynamically modulate hydrogel features in real time, providing enhanced control of cell fate and delivery of bioactive compounds. This paper focuses on the use of 3D photo-fabrication techniques to produce advanced constructs for tissue regeneration and drug delivery applications. State-of-the-art photo-fabrication techniques are described, with emphasis on the operating principles and biofabrication strategies to create spatially controlled patterns of cells and bioactive factors. Considering its fast processing, spatiotemporal control, high resolution, and accuracy, photo-fabrication is assuming a critical role in the design of sophisticated 3D constructs. This technology is capable of providing appropriate environments for tissue regeneration, and regulating the spatiotemporal delivery of therapeutics.

  9. Studying the distribution of deep Raman spectroscopy signals using liquid tissue phantoms with varying optical properties.

    Science.gov (United States)

    Vardaki, Martha Z; Gardner, Benjamin; Stone, Nicholas; Matousek, Pavel

    2015-08-07

    In this study we employed large volume liquid tissue phantoms, consisting of a scattering agent (Intralipid), an absorption agent (Indian ink) and a synthesized calcification powder (calcium hydroxyapatite (HAP)) similar to that found in cancerous tissues (e.g. breast and prostate), to simulate human tissues. We studied experimentally the magnitude and origin of Raman signals in a transmission Raman geometry as a function of optical properties of the medium and the location of calcifications within the phantom. The goal was to inform the development of future noninvasive cancer screening applications in vivo. The results provide insight into light propagation and Raman scattering distribution in deep Raman measurements, exploring also the effect of the variation of relative absorbance of laser and Raman photons within the phantoms. Most notably when modeling breast and prostate tissues it follows that maximum signals is obtained from the front and back faces of the tissue with the central region contributing less to the measured spectrum.

  10. Distribution of Tocopherols and Tocotrienols in Guinea Pig Tissues Following Parenteral Lipid Emulsion Infusion.

    Science.gov (United States)

    Xu, Zhidong; Harvey, Kevin A; Pavlina, Thomas M; Zaloga, Gary P; Siddiqui, Rafat A

    2016-07-01

    Tocopherols and tocotrienols possess vitamin E activity and function as the major lipid-soluble antioxidants in the human body. Commercial lipid emulsions are composed of different oils and supply different amounts of vitamin E. The objective of this study was to measure all 8 vitamin E homologs within 4 different commercial lipid emulsions and evaluate their distribution in guinea pig tissues. The distribution of vitamin E homologs within plasma and guinea pig tissues was determined using a high-performance liquid chromatography (HPLC) system. Lipid hydroperoxides in lipid emulsions were determined using a commercial kit (Cayman Chemical Company, Ann Arbor, MI), and malondialdehyde tissue levels were determined using an HPLC system. The lipid emulsions contained variable amounts of tocopherols, which were significantly different between emulsions. Tocotrienols were present at very low concentrations (≤0.3%). We found no correlation between the amount of vitamin E present in the lipid emulsions and lipid peroxidation. Hydroperoxides were the lowest with an olive oil-based emulsion and highest with a fish oil emulsion. The predominant vitamin E homolog in guinea pig tissues was α-tocopherol. No tissues had detectable levels of tocotrienols. Vitamin E levels (primarily α-tocopherol and γ-tocopherol) were highly variable among organ tissues. Plasma levels were a poor reflection of most tissue levels. Vitamin E levels within different lipid emulsions and plasma/tissues are highly variable, and no one tissue or plasma sample serves as a good proxy for levels in other tissues. All study emulsions were well tolerated and did not significantly increase systemic lipid peroxidation. © 2014 American Society for Parenteral and Enteral Nutrition.

  11. Experimental studies on interactions of radiation and cancer chemotherapeutic drugs in normal tissues and a solid tumour

    International Nuclear Information System (INIS)

    Maase, H. van der

    1986-01-01

    The interactions of radiation and seven cancer chemotherapeutic drugs have been investigated in four normal tissues and in a solid C 3 H mouse mammary carcinoma in vivo. The investigated drugs were adriamycin (ADM), bleomycin (BLM), cyclophosphamide (CTX), 5-fluorouracil (5-FU), methotrexate (MTX), mitomycin C (MM-C) and cis-diamminedichloroplatinum(II) (cis-DDP). The drugs enhanced the radiation response in most cases. However, signs of radioprotection was observed for CTX in skin and for MTX in haemopoietic tissue. The interval and the sequence of the two treatment modalities were of utmost importance for the normal tissue reactions. In general, the most serious interactions occurred when drugs were administered simultaneously with or a few hours before radiation. The radiation-modifying effect of the drugs deviated from this pattern in the haemopoietic tissue as the radiation response was most enhanced on drug administration 1-3 days after radiation. Enhancement of the radiation response was generally less pronounced in the tumour model than in the normal tissues. The combined drug-radiation effect was apparently less time-dependent in the tumour than in the normal tissues. (Auth.)

  12. Drug-Loadable Calcium Alginate Hydrogel System for Use in Oral Bone Tissue Repair.

    Science.gov (United States)

    Chen, Luyuan; Shen, Renze; Komasa, Satoshi; Xue, Yanxiang; Jin, Bingyu; Hou, Yepo; Okazaki, Joji; Gao, Jie

    2017-05-06

    This study developed a drug-loadable hydrogel system with high plasticity and favorable biological properties to enhance oral bone tissue regeneration. Hydrogels of different calcium alginate concentrations were prepared. Their swelling ratio, degradation time, and bovine serum albumin (BSA) release rate were measured. Human periodontal ligament cells (hPDLCs) and bone marrow stromal cells (BMSCs) were cultured with both calcium alginate hydrogels and polylactic acid (PLA), and then we examined the proliferation of cells. Inflammatory-related factor gene expressions of hPDLCs and osteogenesis-related gene expressions of BMSCs were observed. Materials were implanted into the subcutaneous tissue of rabbits to determine the biosecurity properties of the materials. The materials were also implanted in mandibular bone defects and then scanned using micro-CT. The calcium alginate hydrogels caused less inflammation than the PLA. The number of mineralized nodules and the expression of osteoblast-related genes were significantly higher in the hydrogel group compared with the control group. When the materials were implanted in subcutaneous tissue, materials showed favorable biocompatibility. The calcium alginate hydrogels had superior osteoinductive bone ability to the PLA. The drug-loadable calcium alginate hydrogel system is a potential bone defect reparation material for clinical dental application.

  13. The impact of currently used oral antihyperglycemic drugs on dysfunctional adipose tissue

    Directory of Open Access Journals (Sweden)

    Tomić-Naglić Dragana

    2017-01-01

    Full Text Available Obesity is a disease with pandemic frequency, often accompanied by chronic metabolic and organic complications. Type 2 diabetes mellitus (T2DM is among the most common metabolic complications of obesity. The first step in the treatment of T2DM is medical nutrition therapy combined with moderate physical activity and with advice to patients to reduce their body weight. Pharmacotherapy starts with metformin, and in the case of inadequate therapeutic response, another antihyperglycemic agent should be added. The most clinical experience exists with sulfonylurea agents, but their use is limited due to high incidence of hypoglycemia and increase in body weight. Based on the fact that dysfunction of adipose tissue can lead to the development of chronic degenerative complications, precise use of drugs with a favorable effect on the functionality of adipose tissue represents an imperative of modern T2DM treatment. Antihyperglycemic drugs of choice in obese individuals are those which cause maturation of adipocytes, improvement of secretion of protective adipokines, and redistribution of fat mass from visceral to subcutaneous depots. Oral antihyperglycemic agents that can affect the functionality of adipose tissue are metformin, SGLT-2 inhibitors, DPP-4 inhibitors, and thiazolidinediones.

  14. Biopolymer-Based Nanoparticles for Drug/Gene Delivery and Tissue Engineering

    Science.gov (United States)

    Nitta, Sachiko Kaihara; Numata, Keiji

    2013-01-01

    There has been a great interest in application of nanoparticles as biomaterials for delivery of therapeutic molecules such as drugs and genes, and for tissue engineering. In particular, biopolymers are suitable materials as nanoparticles for clinical application due to their versatile traits, including biocompatibility, biodegradability and low immunogenicity. Biopolymers are polymers that are produced from living organisms, which are classified in three groups: polysaccharides, proteins and nucleic acids. It is important to control particle size, charge, morphology of surface and release rate of loaded molecules to use biopolymer-based nanoparticles as drug/gene delivery carriers. To obtain a nano-carrier for therapeutic purposes, a variety of materials and preparation process has been attempted. This review focuses on fabrication of biocompatible nanoparticles consisting of biopolymers such as protein (silk, collagen, gelatin, β-casein, zein and albumin), protein-mimicked polypeptides and polysaccharides (chitosan, alginate, pullulan, starch and heparin). The effects of the nature of the materials and the fabrication process on the characteristics of the nanoparticles are described. In addition, their application as delivery carriers of therapeutic drugs and genes and biomaterials for tissue engineering are also reviewed. PMID:23344060

  15. Biopolymer-Based Nanoparticles for Drug/Gene Delivery and Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Keiji Numata

    2013-01-01

    Full Text Available There has been a great interest in application of nanoparticles as biomaterials for delivery of therapeutic molecules such as drugs and genes, and for tissue engineering. In particular, biopolymers are suitable materials as nanoparticles for clinical application due to their versatile traits, including biocompatibility, biodegradability and low immunogenicity. Biopolymers are polymers that are produced from living organisms, which are classified in three groups: polysaccharides, proteins and nucleic acids. It is important to control particle size, charge, morphology of surface and release rate of loaded molecules to use biopolymer-based nanoparticles as drug/gene delivery carriers. To obtain a nano-carrier for therapeutic purposes, a variety of materials and preparation process has been attempted. This review focuses on fabrication of biocompatible nanoparticles consisting of biopolymers such as protein (silk, collagen, gelatin, β-casein, zein and albumin, protein-mimicked polypeptides and polysaccharides (chitosan, alginate, pullulan, starch and heparin. The effects of the nature of the materials and the fabrication process on the characteristics of the nanoparticles are described. In addition, their application as delivery carriers of therapeutic drugs and genes and biomaterials for tissue engineering are also reviewed.

  16. Electro fluido dynamic techniques to design instructive biomaterials for tissue engineering and drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Guarino, Vincenzo, E-mail: vguarino@unina.it; Altobelli, Rosaria; Cirillo, Valentina; Ambrosio, Luigi [Institute for Polymers, Composites and Biomaterials, Department of Chemical Sciences & Materials Technology, National Research Council of Italy, V.le Kennedy 54, Naples (Italy)

    2015-12-17

    A large variety of processes and tools is continuously investigated to discover new solutions to design instructive materials with controlled chemical, physical and biological properties for tissue engineering and drug delivery. Among them, electro fluido dynamic techniques (EFDTs) are emerging as an interesting strategy, based on highly flexible and low-cost processes, to revisit old biomaterial’s manufacturing approach by utilizing electrostatic forces as the driving force for the fabrication of 3D architectures with controlled physical and chemical functionalities to guide in vitro and in vivo cell activities. By a rational selection of polymer solution properties and process conditions, EFDTs allow to produce fibres and/or particles at micro and/or nanometric size scale which may be variously assembled by tailored experimental setups, thus giving the chance to generate a plethora of different 3D devices able to incorporate biopolymers (i.e., proteins, polysaccharides) or active molecules (e.g., drugs) for different applications. Here, we focus on the optimization of basic EFDTs - namely electrospinning, electrospraying and electrodynamic atomization - to develop active platforms (i.e., monocomponent, protein and drug loaded scaffolds and µ-scaffolds) made of synthetic (PCL, PLGA) or natural (chitosan, alginate) polymers. In particular, we investigate how to set materials and process parameters to impart specific morphological, biochemical or physical cues to trigger all the fundamental cell–biomaterial and cell– cell cross-talking elicited during regenerative processes, in order to reproduce the complex microenvironment of native or pathological tissues.

  17. Click hydrogels, microgels and nanogels: emerging platforms for drug delivery and tissue engineering.

    Science.gov (United States)

    Jiang, Yanjiao; Chen, Jing; Deng, Chao; Suuronen, Erik J; Zhong, Zhiyuan

    2014-06-01

    Hydrogels, microgels and nanogels have emerged as versatile and viable platforms for sustained protein release, targeted drug delivery, and tissue engineering due to excellent biocompatibility, a microporous structure with tunable porosity and pore size, and dimensions spanning from human organs, cells to viruses. In the past decade, remarkable advances in hydrogels, microgels and nanogels have been achieved with click chemistry. It is a most promising strategy to prepare gels with varying dimensions owing to its high reactivity, superb selectivity, and mild reaction conditions. In particular, the recent development of copper-free click chemistry such as strain-promoted azide-alkyne cycloaddition, radical mediated thiol-ene chemistry, Diels-Alder reaction, tetrazole-alkene photo-click chemistry, and oxime reaction renders it possible to form hydrogels, microgels and nanogels without the use of potentially toxic catalysts or immunogenic enzymes that are commonly required. Notably, unlike other chemical approaches, click chemistry owing to its unique bioorthogonal feature does not interfere with encapsulated bioactives such as living cells, proteins and drugs and furthermore allows versatile preparation of micropatterned biomimetic hydrogels, functional microgels and nanogels. In this review, recent exciting developments in click hydrogels, microgels and nanogels, as well as their biomedical applications such as controlled protein and drug release, tissue engineering, and regenerative medicine are presented and discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Electro fluido dynamic techniques to design instructive biomaterials for tissue engineering and drug delivery

    International Nuclear Information System (INIS)

    Guarino, Vincenzo; Altobelli, Rosaria; Cirillo, Valentina; Ambrosio, Luigi

    2015-01-01

    A large variety of processes and tools is continuously investigated to discover new solutions to design instructive materials with controlled chemical, physical and biological properties for tissue engineering and drug delivery. Among them, electro fluido dynamic techniques (EFDTs) are emerging as an interesting strategy, based on highly flexible and low-cost processes, to revisit old biomaterial’s manufacturing approach by utilizing electrostatic forces as the driving force for the fabrication of 3D architectures with controlled physical and chemical functionalities to guide in vitro and in vivo cell activities. By a rational selection of polymer solution properties and process conditions, EFDTs allow to produce fibres and/or particles at micro and/or nanometric size scale which may be variously assembled by tailored experimental setups, thus giving the chance to generate a plethora of different 3D devices able to incorporate biopolymers (i.e., proteins, polysaccharides) or active molecules (e.g., drugs) for different applications. Here, we focus on the optimization of basic EFDTs - namely electrospinning, electrospraying and electrodynamic atomization - to develop active platforms (i.e., monocomponent, protein and drug loaded scaffolds and µ-scaffolds) made of synthetic (PCL, PLGA) or natural (chitosan, alginate) polymers. In particular, we investigate how to set materials and process parameters to impart specific morphological, biochemical or physical cues to trigger all the fundamental cell–biomaterial and cell– cell cross-talking elicited during regenerative processes, in order to reproduce the complex microenvironment of native or pathological tissues

  19. Electro fluido dynamic techniques to design instructive biomaterials for tissue engineering and drug delivery

    Science.gov (United States)

    Guarino, Vincenzo; Altobelli, Rosaria; Cirillo, Valentina; Ambrosio, Luigi

    2015-12-01

    A large variety of processes and tools is continuously investigated to discover new solutions to design instructive materials with controlled chemical, physical and biological properties for tissue engineering and drug delivery. Among them, electro fluido dynamic techniques (EFDTs) are emerging as an interesting strategy, based on highly flexible and low-cost processes, to revisit old biomaterial's manufacturing approach by utilizing electrostatic forces as the driving force for the fabrication of 3D architectures with controlled physical and chemical functionalities to guide in vitro and in vivo cell activities. By a rational selection of polymer solution properties and process conditions, EFDTs allow to produce fibres and/or particles at micro and/or nanometric size scale which may be variously assembled by tailored experimental setups, thus giving the chance to generate a plethora of different 3D devices able to incorporate biopolymers (i.e., proteins, polysaccharides) or active molecules (e.g., drugs) for different applications. Here, we focus on the optimization of basic EFDTs - namely electrospinning, electrospraying and electrodynamic atomization - to develop active platforms (i.e., monocomponent, protein and drug loaded scaffolds and µ-scaffolds) made of synthetic (PCL, PLGA) or natural (chitosan, alginate) polymers. In particular, we investigate how to set materials and process parameters to impart specific morphological, biochemical or physical cues to trigger all the fundamental cell-biomaterial and cell- cell cross-talking elicited during regenerative processes, in order to reproduce the complex microenvironment of native or pathological tissues.

  20. Pharmacokinetics and Efficacy of Topically Applied Nonsteroidal Anti-Inflammatory Drugs in Retinochoroidal Tissues in Rabbits

    Science.gov (United States)

    Kida, Tetsuo; Kozai, Seiko; Takahashi, Hiroaki; Isaka, Mitsuyoshi; Tokushige, Hideki; Sakamoto, Taiji

    2014-01-01

    Purpose To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs) in the retinochoroidal tissues of rabbits. Methods The cyclooxygenase (COX) inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. Results The half-maximal inhibitory concentration (IC50) of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026) but not the other two NSAIDs. Conclusions Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit than diclofenac and

  1. Pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs in retinochoroidal tissues in rabbits.

    Directory of Open Access Journals (Sweden)

    Tetsuo Kida

    Full Text Available PURPOSE: To evaluate the pharmacokinetics and efficacy of topically applied nonsteroidal anti-inflammatory drugs (NSAIDs in the retinochoroidal tissues of rabbits. METHODS: The cyclooxygenase (COX inhibitory activity of diclofenac, bromfenac, and amfenac, an active metabolite of nepafenac, were determined using human-derived COX-1 and COX-2. Each of the three NSAIDs was applied topically to rabbits, and after 0.5 to 8 hrs, the concentration of each drug in the aqueous humor and the retinochoroidal tissues was measured by liquid chromatography-tandem mass spectrometry. The pharmacokinetics of the drugs in the tissues after repeated doses as is done on patients was calculated by a simulation software. The inhibitory effect of each NSAID on the breakdown of the blood-retinal barrier was assessed by the vitreous protein concentration on concanavalin A-induced retinochoroidal inflammation in rabbits. RESULTS: The half-maximal inhibitory concentration (IC50 of diclofenac, bromfenac, and amfenac was 55.5, 5.56, and 15.3 nM for human COX-1, and 30.7, 7.45, and 20.4 nM for human COX-2, respectively. The three NSAIDs were detected in the aqueous humor and the retinochoroidal tissue at all-time points. Simulated pharmacokinetics showed that the levels of the three NSAIDs were continuously higher than the IC50 of COX-2, as an index of efficacy, in the aqueous humor, whereas only the bromfenac concentration was continuously higher than the IC50 at its trough level in the retinochoroidal tissues. The intravitreous concentration of proteins was significantly reduced in rabbits that received topical bromfenac (P = 0.026 but not the other two NSAIDs. CONCLUSIONS: Topical bromfenac can penetrate into the retinochoroidal tissues in high enough concentrations to inhibit COX-2 and exerts its inhibitory effect on the blood-retinal barrier breakdown in an experimental retinochoroidal inflammation in rabbits. Topical bromfenac may have a better therapeutic benefit

  2. Study on pharmacokinetics and tissue distribution of the isocorydine derivative (AICD) in rats by HPLC-DAD method

    Institute of Scientific and Technical Information of China (English)

    Yali Chen; Qian Yan; Mei Zhong; Quanyi Zhao; Junxi Liu; Duolong Di; Jinxia Liu

    2015-01-01

    A simple and effective high-performance liquid chromatography with diode-array detection method coupled with a liquid-liquid extraction pretreatment has been developed for determining the pharmacokinetics and tissue distribution of a novel structurally modified derivative(8-acetaminoisocorydine) of isocorydine.According to the in vivo experiments data calculations by DAS 2.0 software,a two-compartment metabolic model was suitable for describing the pharmacokinetic of 8-acetaminoisocorydine in rats.8-Acetamino-isocorydine was absorbed well after oral administration,and the absolute bioavailability was 76.5%.The half-life of 8-acetamino-isocorydine after intravenous and oral administration was 2.2 h and 2.0 h,respectively.In vivo,8-acetamino-isocorydine was highly distributed in the lungs,kidney and liver;however,relatively little entered the brain,suggesting that 8-acetaminoisocorydine could not easily pass through the blood brain barrier.Our work describes the first characterization of the pharmacokinetic parameters and tissue distribution of 8-acetamino-isocorydine.The acquired data will provide useful information for the in vivo pharmacology of 8-acetaminoisocorydine,and can be applied to new drug research.

  3. Comparative pharmacokinetic and tissue distribution profiles of four major bioactive components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe.

    Science.gov (United States)

    Yang, Tao; Liu, Shan; Wang, Chang-Hong; Tao, Yan-Yan; Zhou, Hua; Liu, Cheng-Hai

    2015-10-10

    Fuzheng Huayu recipe (FZHY) is a herbal product for the treatment of liver fibrosis approved by the Chinese State Food and Drug Administration (SFDA), but its pharmacokinetics and tissue distribution had not been investigated. In this study, the liver fibrotic model was induced with intraperitoneal injection of dimethylnitrosamine (DMN), and FZHY was given orally to the model and normal rats. The plasma pharmacokinetics and tissue distribution profiles of four major bioactive components from FZHY were analyzed in the normal and fibrotic rat groups using an ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Results revealed that the bioavailabilities of danshensu (DSS), salvianolic acid B (SAB) and rosmarinic acid (ROS) in liver fibrotic rats increased 1.49, 3.31 and 2.37-fold, respectively, compared to normal rats. There was no obvious difference in the pharmacokinetics of amygdalin (AMY) between the normal and fibrotic rats. The tissue distribution of DSS, SAB, and AMY trended to be mostly in the kidney and lung. The distribution of DSS, SAB, and AMY in liver tissue of the model rats was significantly decreased compared to the normal rats. Significant differences in the pharmacokinetics and tissue distribution profiles of DSS, ROS, SAB and AMY were observed in rats with hepatic fibrosis after oral administration of FZHY. These results provide a meaningful basis for developing a clinical dosage regimen in the treatment of hepatic fibrosis by FZHY. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Dissimilarities in the metabolism of antiretroviral drugs used in HIV pre-exposure prophylaxis in colon and vagina tissues.

    Science.gov (United States)

    To, Elaine E; Hendrix, Craig W; Bumpus, Namandjé N

    2013-10-01

    Attempts to prevent HIV infection through pre-exposure prophylaxis (PrEP) include topical application of anti-HIV drugs to the mucosal sites of infection; however, a potential role for local drug metabolizing enzymes in modulating the exposure of the mucosal tissues to these drugs has yet to be explored. Here we present the first report that enzymes belonging to the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) families of drug metabolizing enzymes are expressed and active in vaginal and colorectal tissue using biopsies collected from healthy volunteers. In doing so, we discovered that dapivirine and maraviroc, a non-nucleoside reverse transcriptase inhibitor and an entry inhibitor currently in development as microbicides for HIV PrEP, are differentially metabolized in colorectal tissue and vaginal tissue. Taken together, these data should help to guide the optimization of small molecules being developed for HIV PrEP. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Integration of distributed computing into the drug discovery process.

    Science.gov (United States)

    von Korff, Modest; Rufener, Christian; Stritt, Manuel; Freyss, Joel; Bär, Roman; Sander, Thomas

    2011-02-01

    Grid computing offers an opportunity to gain massive computing power at low costs. We give a short introduction into the drug discovery process and exemplify the use of grid computing for image processing, docking and 3D pharmacophore descriptor calculations. The principle of a grid and its architecture are briefly explained. More emphasis is laid on the issues related to a company-wide grid installation and embedding the grid into the research process. The future of grid computing in drug discovery is discussed in the expert opinion section. Most needed, besides reliable algorithms to predict compound properties, is embedding the grid seamlessly into the discovery process. User friendly access to powerful algorithms without any restrictions, that is, by a limited number of licenses, has to be the goal of grid computing in drug discovery.

  6. An in vivo approach for globally estimating the drug flow between blood and tissue for nafamostat mesilate: the main hydrolysis site determination in human.

    Science.gov (United States)

    Cao, Yan-Guang; Chen, Yuan-Cheng; Hao, Kun; Zhang, Ming; Liu, Xiao-Quan

    2008-11-01

    Nafamostat mesilate, an ester drug with extensive hydrolysis in vivo, exhibits species difference in the relative contribution for its hydrolysis in blood and tissues. For the rat, the main hydrolysis site may be blood and human may be tissue (mainly by liver). The paper gave in vivo evidence that human tissue may give more contribution for its hydrolysis. In the initial phase of drug administration, the drug accumulating level in tissue was low; the efflux fraction from tissue into blood can be ignorable comparing with the drug influx into tissue. Based on urine and plasma metabolite analysis, we concluded that in the initial phase almost all the drug hydrolysis in blood was excreted into urine. Then according to the initial urine metabolite analysis, we can estimate the drug hydrolysis rate in blood. The rate of drug diffusion from blood into tissues can be deduced based on the mass balance analysis of the initial blood drug. With the estimated rate constants, the drug efflux from tissues into blood was calculated according to equation: OFT-B (efflux from tissues) = OFB-U (blood hydrolysis fraction)+OFB-T (influx into tissues)-DB (hydrolysis in blood). The net flow (influent flux minus effluent flux) represented the drug hydrolysis fraction in tissue. As the result indicated, in human about 20% drug administrated was hydrolyzed in blood and nearly 80% in tissues. The relative hydrolysis fraction indicated that the main hydrolysis site in human body may locate in tissue, which was different to rats.

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

    Science.gov (United States)

    Berezhkovskiy, Leonid M

    2013-02-01

    The steady state, V(ss), terminal volume of distribution, V(β), and the terminal half-life, t(1/2), are commonly obtained from the drug plasma concentration-time profile, C(p)(t), following intravenous dosing. Unlike V(ss) that can be calculated based on the physicochemical properties of drugs considering the equilibrium partitioning between plasma and organ tissues, t(1/2) and V(β) cannot be calculated that way because they depend on the rates of drug transfer between blood and tissues. Considering the physiological pharmacokinetic model pertinent to the terminal phase of drug elimination, a novel equation that calculates t(1/2) (and consequently V(β)) was derived. It turns out that V(ss), the total body clearance, Cl, equilibrium blood-plasma concentration ratio, r; and the physiological parameters of the body such as cardiac output, and blood and tissue volumes are sufficient for determination of terminal kinetics. Calculation of t(1/2) by the obtained equation appears to be in good agreement with the experimentally observed vales of this parameter in pharmacokinetic studies in rat, monkey, dog, and human. The equation for the determination of the pre-exponent of the terminal phase of C(p)(t) is also found. The obtained equation allows to predict t(1/2) in human assuming that V(ss) and Cl were either obtained by allometric scaling or, respectively, calculated in silico or based on in vitro drug stability measurements. For compounds that have high clearance, the derived equation may be applied to calculate r just using the routine data on Cl, V(ss), and t(1/2), rather than doing the in vitro assay to measure this parameter. Copyright © 2012 Wiley Periodicals, Inc.

  8. Hepatoblastoma: A Need for Cell Lines and Tissue Banks to Develop Targeted Drug Therapies

    Directory of Open Access Journals (Sweden)

    Rishi Raj Rikhi

    2016-03-01

    Full Text Available Limited research exists regarding the most aggressive forms of hepatoblastoma. Cell lines of the rare subtypes of hepatoblastoma with poor prognosis are not only difficult to attain, but are challenging to characterize histologically. A community approach to educating parents and families of the need for donated tissue is necessary for scientists to have access to resources for murine models and drug discovery. Herein we describe the currently available resources, the today’s existing gaps in research, and the path to move forward for uniform cure of hepatoblastoma.

  9. A Method for Medical Diagnosis Based on Optical Fluence Rate Distribution at Tissue Surface.

    Science.gov (United States)

    Hamdy, Omnia; El-Azab, Jala; Al-Saeed, Tarek A; Hassan, Mahmoud F; Solouma, Nahed H

    2017-09-20

    Optical differentiation is a promising tool in biomedical diagnosis mainly because of its safety. The optical parameters' values of biological tissues differ according to the histopathology of the tissue and hence could be used for differentiation. The optical fluence rate distribution on tissue boundaries depends on the optical parameters. So, providing image displays of such distributions can provide a visual means of biomedical diagnosis. In this work, an experimental setup was implemented to measure the spatially-resolved steady state diffuse reflectance and transmittance of native and coagulated chicken liver and native and boiled breast chicken skin at 635 and 808 nm wavelengths laser irradiation. With the measured values, the optical parameters of the samples were calculated in vitro using a combination of modified Kubelka-Munk model and Bouguer-Beer-Lambert law. The estimated optical parameters values were substituted in the diffusion equation to simulate the fluence rate at the tissue surface using the finite element method. Results were verified with Monte-Carlo simulation. The results obtained showed that the diffuse reflectance curves and fluence rate distribution images can provide discrimination tools between different tissue types and hence can be used for biomedical diagnosis.

  10. A Method for Medical Diagnosis Based on Optical Fluence Rate Distribution at Tissue Surface

    Directory of Open Access Journals (Sweden)

    Omnia Hamdy

    2017-09-01

    Full Text Available Optical differentiation is a promising tool in biomedical diagnosis mainly because of its safety. The optical parameters’ values of biological tissues differ according to the histopathology of the tissue and hence could be used for differentiation. The optical fluence rate distribution on tissue boundaries depends on the optical parameters. So, providing image displays of such distributions can provide a visual means of biomedical diagnosis. In this work, an experimental setup was implemented to measure the spatially-resolved steady state diffuse reflectance and transmittance of native and coagulated chicken liver and native and boiled breast chicken skin at 635 and 808 nm wavelengths laser irradiation. With the measured values, the optical parameters of the samples were calculated in vitro using a combination of modified Kubelka-Munk model and Bouguer-Beer-Lambert law. The estimated optical parameters values were substituted in the diffusion equation to simulate the fluence rate at the tissue surface using the finite element method. Results were verified with Monte-Carlo simulation. The results obtained showed that the diffuse reflectance curves and fluence rate distribution images can provide discrimination tools between different tissue types and hence can be used for biomedical diagnosis.

  11. Human engineered heart tissue as a model system for drug testing.

    Science.gov (United States)

    Eder, Alexandra; Vollert, Ingra; Hansen, Arne; Eschenhagen, Thomas

    2016-01-15

    Drug development is time- and cost-intensive and, despite extensive efforts, still hampered by the limited value of current preclinical test systems to predict side effects, including proarrhythmic and cardiotoxic effects in clinical practice. Part of the problem may be related to species-dependent differences in cardiomyocyte biology. Therefore, the event of readily available human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) has raised hopes that this human test bed could improve preclinical safety pharmacology as well as drug discovery approaches. However, hiPSC-CM are immature and exhibit peculiarities in terms of ion channel function, gene expression, structural organization and functional responses to drugs that limit their present usefulness. Current efforts are thus directed towards improving hiPSC-CM maturity and high-content readouts. Culturing hiPSC-CM as 3-dimensional engineered heart tissue (EHT) improves CM maturity and anisotropy and, in a 24-well format using silicone racks, enables automated, multiplexed high content readout of contractile function. This review summarizes the principal technology and focuses on advantages and disadvantages of this technology and its potential for preclinical drug screening. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Tissue Distribution of a Therapeutic Monoclonal Antibody Determined by Large Pore Microdialysis.

    Science.gov (United States)

    Jadhav, Satyawan B; Khaowroongrueng, Vipada; Fueth, Matthias; Otteneder, Michael B; Richter, Wolfgang; Derendorf, Hartmut

    2017-09-01

    Therapeutic monoclonal antibodies (mAbs) exhibit limited distribution to the target tissues. Determination of target tissue interstitial concentration of mAbs is an important aspect in the assessment of their pharmacokinetic/pharmacodynamics relationship especially for mAbs targeting membrane bound receptors. The pharmacokinetics of R7072, a full length mAb (IgG) targeting human insulin-like growth factor-1 receptor was evaluated following a single intravenous dose at 1, 6.25, and 25 mg/kg in healthy female SCID-beige mice. R7072 showed linear pharmacokinetics over the dose range tested and was characterized by low systemic clearance and long terminal half-life. Furthermore, interstitial distribution of R7072 was evaluated in liver, skin, kidney, and muscle tissues using large pore microdialysis (MD) after intravenous administration of 10 mg/kg dose in mice. The relative recoveries of R7072 were consistent and similar between in vitro and in vivo MD experiments. The tissue and interstitial concentrations were significantly lower compared to serum concentrations and found to be highest in liver and lowest in muscle. The interstitial concentrations of R7072 were approximately 2-fold to 4-fold lower than corresponding total tissue concentrations. Large pore MD appears to be an attractive approach for direct measurement of pharmacologically relevant concentrations of therapeutic mAbs in tissue interstitial fluid. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  13. Spatial dose and microdose distribution in tissues. Ionization, nuclear reactions, multiple scattering simulation of beam transport

    International Nuclear Information System (INIS)

    Jacquot, C.

    1976-01-01

    Computer simulation and nuclear emulsion and gelatin techniques enabled to give the total elastic and inelastic cross sections and to forecast the spatial microdose distributions in cells, nuclei and molecules. For this purpose, the transport of a beam into tissues having a given composition is calculated, the nuclear reactions are generated and the energy depositions in standard planes perpendicular to the beam are recorded

  14. Screening in larval zebrafish reveals tissue-specific distribution of fifteen fluorescent compounds

    Directory of Open Access Journals (Sweden)

    Yuxiao Yao

    2017-09-01

    Full Text Available The zebrafish is a prominent vertebrate model for low-cost in vivo whole organism screening. In our recent screening of the distribution patterns of fluorescent compounds in live zebrafish larvae, fifteen compounds with tissue-specific distributions were identified. Several compounds were observed to accumulate in tissues where they were reported to induce side-effects, and compounds with similar structures tended to be enriched in the same tissues, with minor differences. In particular, we found three novel red fluorescent bone-staining dyes: purpurin, lucidin and 3-hydroxy-morindone; purpurin can effectively label bones in both larval and adult zebrafish, as well as in postnatal mice, without significantly affecting bone mass and density. Moreover, two structurally similar chemotherapeutic compounds, doxorubicin and epirubicin, were observed to have distinct distribution preferences in zebrafish. Epirubicin maintained a relatively higher concentration in the liver, and performed better in inhibiting hepatic hyperplasia caused by the over-expression of krasG12V. In total, our study suggests that the transparent zebrafish larvae serve as valuable tools for identifying tissue-specific distributions of fluorescent compounds.

  15. Intratrabecular distribution of tissue stiffness and mineralization in developing trabecular bone

    NARCIS (Netherlands)

    Mulder, L.; Koolstra, J.H.; Toonder, den J.M.J.; Eijden, van T.M.G.J.

    2007-01-01

    The purpose of this study was to investigate the relation between bone tissue stiffness and degree of mineralization distribution and to examine possible changes during prenatal development. Understanding this may provide insight into adaptation processes and into deformation mechanisms of the bone

  16. Abcb1 in Pigs: Molecular cloning, tissues distribution, functional analysis, and its effect on pharmacokinetics of enrofloxacin

    Science.gov (United States)

    Guo, Tingting; Huang, Jinhu; Zhang, Hongyu; Dong, Lingling; Guo, Dawei; Guo, Li; He, Fang; Bhutto, Zohaib Ahmed; Wang, Liping

    2016-01-01

    P-glycoprotein (P-gp) is one of the best-known ATP-dependent efflux transporters, contributing to differences in pharmacokinetics and drug-drug interactions. Until now, studies on pig P-gp have been scarce. In our studies, the full-length porcine P-gp cDNA was cloned and expressed in a Madin-Darby Canine Kidney (MDCK) cell line. P-gp expression was then determined in tissues and its role in the pharmacokinetics of oral enrofloxacin in pigs was studied. The coding region of pig Abcb1 gene was 3,861 bp, encoding 1,286 amino acid residues (Mw = 141,966). Phylogenetic analysis indicated a close evolutionary relationship between porcine P-gp and those of cow and sheep. Pig P-gp was successfully stably overexpressed in MDCK cells and had efflux activity for rhodamine 123, a substrate of P-gp. Tissue distribution analysis indicated that P-gp was highly expressed in brain capillaries, small intestine, and liver. In MDCK-pAbcb1 cells, enrofloxacin was transported by P-gp with net efflux ratio of 2.48 and the efflux function was blocked by P-gp inhibitor verapamil. High expression of P-gp in the small intestine could modify the pharmacokinetics of orally administrated enrofloxacin by increasing the Cmax, AUC and Ka, which was demonstrated using verapamil, an inhibitor of P-gp. PMID:27572343

  17. Investigating the effects of ABC transporter-based acquired drug resistance mechanisms at the cellular and tissue scale.

    Science.gov (United States)

    Liu, Cong; Krishnan, J; Xu, Xiao Yun

    2013-03-01

    In this paper we systematically investigate the effects of acquired drug resistance at the cellular and tissue scale, with a specific focus on ATP-binding cassette (ABC) transporter-based mechanisms and contrast this with other representative intracellular resistance mechanisms. This is done by developing in silico models wherein the drug resistance mechanism is overlaid on a coarse-grained description of apoptosis; these cellular models are coupled with interstitial drug transport, allowing for a transparent examination of the effect of acquired drug resistances at the tissue level. While ABC transporter-mediated resistance mechanisms counteract drug effect at the cellular level, its tissue-level effect is more complicated, revealing unexpected trends in tissue response as drug stimuli are systematically varied. Qualitatively different behaviour is observed in other drug resistance mechanisms. Overall the paper (i) provides insight into the tissue level functioning of a particular resistance mechanism, (ii) shows that this is very different from other resistance mechanisms of an apparently similar type, and (iii) demonstrates a concrete instance of how the functioning of a negative feedback based cellular adaptive mechanism can have unexpected higher scale effects.

  18. Influence of lead injection on calcium-45 distribution in hard tissues of rats

    International Nuclear Information System (INIS)

    Sato, Makoto

    1978-01-01

    This study determines the relationship between calcium distribution in hard tissues and age. The distribution of calcium was examined by using calcium-45 as tracer. Further, influences of such environmental toxic heavy metals as lead, cadmium and mercury upon calcium metabolism were determined. According to checks performed on 3-week-old rats, calcium-45 distributions in hard tissues from 6 hours to 6 days after injection were greater in the following tissues in the order listed: femurs, incisors, molars. In 2-week-old rats, the calcium distributions throughout the body were about the same. In 3-week-old rats, however, they were graded in descending order from femur to incisors, and then to molars. In rats of 18 weeks or more, the distribution of calcium-45 in the femur decreased. A slow increase was noted in calcium-45 deposits in the incisors of rats of four or more weeks; this increase remained constant at a very low level in rats of more than eight weeks. Calcium-45 distribution in rats of 61 weeks of age was graded in this descending order: incisors, femurs, and molars. In the group injected with calcium-45 and lead acetate, calcium-45 distribution was significantly less in 3-week-old than in 3-month-old rats. The following are percentages of calcium-45 distribution in rats to which 100 mg/kg of lead (equivalent of 1/3 of LD 50 were injected, when 100-percent distribution is assumed for controls; 3-week-old rats: femur 48 percent, incisors 49 percent, and molars 40 percent, 3-month-old rats: femurs 73 percent, incisors 67 percent, and molars 71 percent. No difference was observed in calcium-45 uptake between rats to whom injections of cadmium and mercury equivalent to 1/3 of a dose of LD 50 had been administered and rats who received only a single injection of calcium-45. (auth.)

  19. Pharmacokinetics of warfarin in rats: role of serum protein binding and tissue distribution

    International Nuclear Information System (INIS)

    Cheung, W.K.

    1985-01-01

    The purpose of this study was to explore the role of serum protein binding and tissue distribution in the non-linear pharmacokinetics of warfarin in rats. The first phase of the research was an attempt to elucidate the causes of intersubject differences in serum protein binding of warfarin in rats. It was found that the distribution of S-warfarin between blood and liver, kidneys, muscle, or fatty tissue was non-linear. Based on the tissue distribution data obtained, a physiologically-based pharmacokinetic model was developed to describe the time course of S-warfarin concentrations in the serum and tissues of rats. The proposed model was able to display the dose-dependent pharmacokinetics of warfarin in rats. Namely a lower clearance and a smaller apparent volume of distribution with increasing dose, which appear to be due to the presence of capacity-limited, high-affinity binding sites for warfarin in various tissues. To determine if the binding of warfarin to the high-affinity binding sites in the liver of rats is reversible, concentrations of S-warfarin in the liver and serum of rats were monitored for a very long time after an intravenous injection of a 1 mg/kg dose. In another study in rats, non-radioactive warfarin was found to be able to displace tissue-bound C 14 -warfarin which was administered about 200 hours before the i.v. injection of the non-radioactive warfarin, showing that the binding of warfarin to the high-affinity binding sites in the body is persistent and reversible

  20. Examining the spatial distribution of law enforcement encounters among people who inject drugs after implementation of Mexico's drug policy reform.

    Science.gov (United States)

    Gaines, Tommi L; Beletsky, Leo; Arredondo, Jaime; Werb, Daniel; Rangel, Gudelia; Vera, Alicia; Brouwer, Kimberly

    2015-04-01

    In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n = 461) recruited through targeted sampling, we identified hotspots of extra-judicial encounters (e.g., physical/sexual abuse, syringe confiscation, and money extortion by law enforcement) and routine authorized encounters (e.g., being arrested or stopped but not arrested) using point density maps and the Getis-Ord Gi* statistic calculated at the neighborhood-level. Approximately half of the participants encountered law enforcement more than once in a calendar year and nearly one third of these encounters did not result in arrest but involved harassment or abuse by law enforcement. Statistically significant hotspots of law enforcement encounters were identified in a limited number of neighborhoods located in areas with known drug markets. At the local-level, law enforcement activities continue to target drug users despite a national drug policy that emphasizes drug treatment diversion rather than punitive enforcement. There is a need for law enforcement training and improved monitoring of policing tactics to better align policing with public health goals.

  1. Distribution of α-aminoisobutyric acid in tissues of lean and genetically obese mice

    International Nuclear Information System (INIS)

    Tews, J.K.; Harper, A.E.

    1989-01-01

    Distribution of tracer amounts of the nonmetabolizable neutral amino acid α-[1- 14 C]aminoisobutyric acid (AIB) between blood and several tissues was measured in lean and ob/ob mice over an 8-hr period. As AIB was injected on the basis of body weight and as ob/ob mice have a relatively low blood volume, absolute concentrations of AIB in blood and tissues were almost always higher in the obese than the lean mice. However, the ratio of AIB concentration in the tissues to that in the blood was clearly higher in skeletal muscle, diaphragm, and brain, and possibly higher in liver of the lean than of the obese animals. Ratios in heart were similar. The results suggest that lean and genetically obese mice differ in their capacity to transport amino acids between blood and various tissues

  2. Drug membrane interaction and the importance for drug transport, distribution, accumulation, efficacy and resistance.

    Science.gov (United States)

    Seydel, J K; Coats, E A; Cordes, H P; Wiese, M

    1994-10-01

    Some aspects of drug membrane interaction and its influence on drug transport, accumulation, efficacy and resistance have been discussed. The interactions manifest themselves macroscopically in changes in the physical and thermodynamic properties of "pure membranes" or bilayers. As various amounts of foreign molecules enter the membrane, in particular the main gel to liquid crystalline phase transition can be dramatically changed. This may change permeability, cell-fusion, cell resistance and may also lead to changes in conformation of the embedded receptor proteins. Furthermore, specific interactions with lipids may lead to drug accumulation in membranes and thus to much larger concentrations at the active site than present in the surrounding water phase. The lipid environment may also lead to changes in the preferred conformation of drug molecules. These events are directly related to drug efficacy. The determination of essential molecular criteria for the interaction could be used to design new and more selective therapeutics. This excursion in some aspects of drug membrane interaction underlines the importance of lipids and their interaction with drug molecules for our understanding of drug action, but this is not really a new thought but has been formulated in 1884 by THUDICUM: "Phospholipids are the centre, life and chemical soul of all bioplasm whatsoever, that of plants as well as of animals".

  3. Secreted phospholipase A(2) as a new enzymatic trigger mechanism for localised liposomal drug release and absorption in diseased tissue

    DEFF Research Database (Denmark)

    Davidsen, Jesper; Jørgensen, K.; Andresen, Thomas Lars

    2003-01-01

    Polymer-coated liposomes can act as versatile drug-delivery systems due to long vascular circulation time and passive targeting by leaky blood vessels in diseased tissue. We present an experimental model system illustrating a new principle for improved and programmable drug-delivery, which takes ...

  4. Finite element model to study temperature distribution in skin and deep tissues of human limbs.

    Science.gov (United States)

    Agrawal, Mamta; Pardasani, K R

    2016-12-01

    The temperature of body tissues is viewed as an indicator of tissue response in clinical applications since ancient times. The tissue temperature depends on various physical and physiological parameters like blood flow, metabolic heat generation, thermal conductivity of tissues, shape and size of organs etc. In this paper a finite element model has been proposed to study temperature distribution in skin and deep tissues of human limbs. The geometry of human limb is taken as elliptical tapered shape. It is assumed that outer surface of the limb is exposed to the environment. The appropriate boundary conditions have been framed based on physical conditions of the problem. The model has been developed for a three dimensional steady state case. Hexahedral circular sectoral elements are used to discretize the region. The results have been computed to obtain temperature profiles and study the relation of tissue temperature with the parameters like atmospheric temperature, rate of evaporation, thickness of tissues layers and shape of the limb. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Visualizing metabolite distribution and enzymatic conversion in plant tissues by desorption electrospray ionization mass spectrometry imaging

    DEFF Research Database (Denmark)

    Li, Bin; Baden, Camilla Knudsen; Hansen, Natascha Kristine Krahl

    2013-01-01

    In comparison to the technology platforms developed to localize transcripts and proteins, imaging tools for visualization of metabolite distributions in plant tissues are less well developed and lack versatility. This hampers our understanding of plant metabolism and dynamics. In this study we...... demonstrate that Desorption Electrospray Ionization Mass Spectrometry Imaging (DESI-MSI) of tissue imprints on porous Teflon can be used to accurately image the distribution of even labile plant metabolites such as hydroxynitrile glucosides, which normally undergo enzymatic hydrolysis by specific ß......-glucosidases upon cell disruption. This fast and simple sample preparation resulted in no substantial differences in the distribution and ratios of all hydroxynitrile glucosides between leaves from wildtype Lotus japonicus and a ß-glucosidase mutant plant lacking the ability to hydrolyze certain hydroxynitrile...

  6. Platform for Rapid Delivery of Biologics and Drugs to Ocular Cells and Tissues Following Combat Associated Trauma

    Science.gov (United States)

    2013-09-01

    death pathways such as apoptosis subsequent to acute trauma as soon as possible, ideally by self- administration of a drug or a biologic that can be... Drugs to Ocular Tissues Including Retina and Cornea . Mol Ther, 2007;16(1):107- 14. 3. Read SP, Cashman SM, and Kumar-Singh R: POD...1 AD_________________ Award Number: W81XWH-12-1-0374 TITLE: Platform for Rapid Delivery of Biologics and Drugs to Ocular Cells

  7. Classification of fibroglandular tissue distribution in the breast based on radiotherapy planning CT

    International Nuclear Information System (INIS)

    Juneja, Prabhjot; Evans, Philip; Windridge, David; Harris, Emma

    2016-01-01

    Accurate segmentation of breast tissues is required for a number of applications such as model based deformable registration in breast radiotherapy. The accuracy of breast tissue segmentation is affected by the spatial distribution (or pattern) of fibroglandular tissue (FT). The goal of this study was to develop and evaluate texture features, determined from planning computed tomography (CT) data, to classify the spatial distribution of FT in the breast. Planning CT data of 23 patients were evaluated in this study. Texture features were derived from the radial glandular fraction (RGF), which described the distribution of FT within three breast regions (posterior, middle, and anterior). Using visual assessment, experts grouped patients according to FT spatial distribution: sparse or non-sparse. Differences in the features between the two groups were investigated using the Wilcoxon rank test. Classification performance of the features was evaluated for a range of support vector machine (SVM) classifiers. Experts found eight patients and 15 patients had sparse and non-sparse spatial distribution of FT, respectively. A large proportion of features (>9 of 13) from the individual breast regions had significant differences (p <0.05) between the sparse and non-sparse group. The features from middle region had most significant differences and gave the highest classification accuracy for all the SVM kernels investigated. Overall, the features from middle breast region achieved highest accuracy (91 %) with the linear SVM kernel. This study found that features based on radial glandular fraction provide a means for discriminating between fibroglandular tissue distributions and could achieve a classification accuracy of 91 %

  8. Noncontact 3-D Speckle Contrast Diffuse Correlation Tomography of Tissue Blood Flow Distribution.

    Science.gov (United States)

    Huang, Chong; Irwin, Daniel; Zhao, Mingjun; Shang, Yu; Agochukwu, Nneamaka; Wong, Lesley; Yu, Guoqiang

    2017-10-01

    Recent advancements in near-infrared diffuse correlation techniques and instrumentation have opened the path for versatile deep tissue microvasculature blood flow imaging systems. Despite this progress there remains a need for a completely noncontact, noninvasive device with high translatability from small/testing (animal) to large/target (human) subjects with trivial application on both. Accordingly, we discuss our newly developed setup which meets this demand, termed noncontact speckle contrast diffuse correlation tomography (nc_scDCT). The nc_scDCT provides fast, continuous, portable, noninvasive, and inexpensive acquisition of 3-D tomographic deep (up to 10 mm) tissue blood flow distributions with straightforward design and customization. The features presented include a finite-element-method implementation for incorporating complex tissue boundaries, fully noncontact hardware for avoiding tissue compression and interactions, rapid data collection with a diffuse speckle contrast method, reflectance-based design promoting experimental translation, extensibility to related techniques, and robust adjustable source and detector patterns and density for high resolution measurement with flexible regions of interest enabling unique application-specific setups. Validation is shown in the detection and characterization of both high and low contrasts in flow relative to the background using tissue phantoms with a pump-connected tube (high) and phantom spheres (low). Furthermore, in vivo validation of extracting spatiotemporal 3-D blood flow distributions and hyperemic response during forearm cuff occlusion is demonstrated. Finally, the success of instrument feasibility in clinical use is examined through the intraoperative imaging of mastectomy skin flap.

  9. Tissue distribution of enrofloxacin after intramammary or simulated systemic administration in isolated perfused sheep udders.

    Science.gov (United States)

    López Cadenas, Cristina; Fernández Martínez, Nélida; Sierra Vega, Matilde; Diez Liébana, Maria J; Gonzalo Orden, Jose M; Sahagún Prieto, Ana M; García Vieitez, Juan J

    2012-11-01

    To determine the tissue distribution of enrofloxacin after intramammary or simulated systemic administration in isolated perfused sheep udders by measuring its concentration at various sample collection sites. 26 udders (obtained following euthanasia) from 26 healthy lactating sheep. For each isolated udder, 1 mammary gland was perfused with warmed, gassed Tyrode solution. Enrofloxacin (1 g of enrofloxacin/5 g of ointment) was administered into the perfused gland via the intramammary route or systemically via the perfusion fluid (equivalent to a dose of 5 mg/kg). Samples of the perfusate were obtained every 30 minutes for 180 minutes; glandular tissue samples were obtained at 2, 4, 6, and 8 cm from the teat base after 180 minutes. The enrofloxacin content of the perfusate and tissue samples was analyzed via high-performance liquid chromatography with UV detection. After intramammary administration, maximun perfusate enrofloxacin concentration was detected at 180 minutes and, at this time, mean tissue enrofloxacin concentration was detected and mean tissue enrofloxacin concentration was 123.80, 54.48, 36.72, and 26.42 μg/g of tissue at 2, 4, 6, and 8 cm from the teat base, respectively. Following systemic administration, perfusate enrofloxacin concentration decreased with time and, at 180 minutes, tissue enrofloxacin concentrations ranged from 40.38 to 35.58 μg/g of tissue. By 180 minutes after administration via the intramammary or systemic route in isolated perfused sheep mammary glands, mean tissue concentration of enrofloxacin was greater than the minimum inhibitory concentration required to inhibit growth of 90% of many common mastitis pathogens in sheep. Use of either route of administration (or in combination) appears suitable for the treatment of acute mastitis in sheep.

  10. 21 CFR 212.90 - What actions must I take to control the distribution of PET drug products?

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 4 2010-04-01 2010-04-01 false What actions must I take to control the... POSITRON EMISSION TOMOGRAPHY DRUGS (Eff. 12-12-2011) Distribution § 212.90 What actions must I take to control the distribution of PET drug products? (a) Written distribution procedures. You must establish...

  11. Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery.

    Science.gov (United States)

    Kizawa, Hideki; Nagao, Eri; Shimamura, Mitsuru; Zhang, Guangyuan; Torii, Hitoshi

    2017-07-01

    The liver plays a central role in metabolism. Although many studies have described in vitro liver models for drug discovery, to date, no model has been described that can stably maintain liver function. Here, we used a unique, scaffold-free 3D bio-printing technology to construct a small portion of liver tissue that could stably maintain drug, glucose, and lipid metabolism, in addition to bile acid secretion. This bio-printed normal human liver tissue maintained expression of several kinds of hepatic drug transporters and metabolic enzymes that functioned for several weeks. The bio-printed liver tissue displayed glucose production via cAMP/protein kinase A signaling, which could be suppressed with insulin. Bile acid secretion was also observed from the printed liver tissue, and it accumulated in the culture medium over time. We observed both bile duct and sinusoid-like structures in the bio-printed liver tissue, which suggested that bile acid secretion occurred via a sinusoid-hepatocyte-bile duct route. These results demonstrated that our bio-printed liver tissue was unique, because it exerted diverse liver metabolic functions for several weeks. In future, we expect our bio-printed liver tissue to be applied to developing new models that can be used to improve preclinical predictions of long-term toxicity in humans, generate novel targets for metabolic liver disease, and evaluate biliary excretion in drug development.

  12. Altered distributions of bone tissue mineral and collagen properties in women with fragility fractures.

    Science.gov (United States)

    Wang, Zhen Xiang; Lloyd, Ashley A; Burket, Jayme C; Gourion-Arsiquaud, Samuel; Donnelly, Eve

    2016-03-01

    Heterogeneity of bone tissue properties is emerging as a potential indicator of altered bone quality in pathologic tissue. The objective of this study was to compare the distributions of tissue properties in women with and without histories of fragility fractures using Fourier transform infrared (FTIR) imaging. We extended a prior study that examined the relationship of the mean FTIR properties to fracture risk by analyzing in detail the widths and the tails of the distributions of FTIR properties in biopsies from fracture and non-fracture cohorts. The mineral and matrix properties of cortical and trabecular iliac crest tissue were compared in biopsies from women with a history of fragility fracture (+Fx; n=21, age: mean 54±SD 15y) and with no history of fragility fracture (-Fx; n=12, age: 57±5y). A subset of the patients included in the -Fx group were taking estrogen-plus-progestin hormone replacement therapy (HRT) (-Fx+HRT n=8, age: 58±5y) and were analyzed separately from patients with no history of HRT (-Fx-HRT n=4, age: 56±7y). When the FTIR parameter mean values were examined by treatment group, the trabecular tissue of -Fx-HRT patients had a lower mineral:matrix ratio (M:M) and collagen maturity (XLR) than that of -Fx+HRT patients (-22% M:M, -18% XLR) and +Fx patients (-17% M:M, -18% XLR). Across multiple FTIR parameters, tissue from the -Fx-HRT group had smaller low-tail (5th percentile) values than that from the -Fx+HRT or +Fx groups. In trabecular collagen maturity and crystallinity (XST), the -Fx-HRT group had smaller low-tail values than those in the -Fx+HRT group (-16% XLR, -5% XST) and the +Fx group (-17% XLR, -7% XST). The relatively low values of trabecular mineral:matrix ratio and collagen maturity and smaller low-tail values of collagen maturity and crystallinity observed in the -Fx-HRT group are characteristic of younger tissue. Taken together, our data suggest that the presence of newly formed tissue that includes small/imperfect crystals

  13. Novel scalable silicone elastomer and poly(2-hydroxyethyl methacrylate) (PHEMA) composite materials for tissue engineering and drug delivery applications

    DEFF Research Database (Denmark)

    Mohanty, Soumyaranjan; Hemmingsen, Mette; Wojcik, Magdalena

    2013-01-01

    material with increased hydrophilicity in regard to virgin silicone elastomer, making it suitable as a scaffold for tissue engineering and with the concomitant possibility for delivering drug from the scaffold to the tissue. Interpenetrating polymer networks (IPNs) of silicone elastomer and PHEMA......In recent years hydrogels have received increasing attention as potential materials for applications in regenerative medicine. They can be used for scaffold materials providing structural integrity to tissue constructs, for controlled delivery of drugs and proteins to cell and tissues......, and for support materials in tissue growth. However, the real challenge is to obtain sufficiently good mechanical properties of the hydrogel. The present study shows the combination of two normally non-compatible materials, silicone elastomer and poly(2-hydroxyethyl methacrylate) (PHEMA), into a novel composite...

  14. Photon beam dose distributions for patients with implanted temporary tissue expanders

    Science.gov (United States)

    Asena, A.; Kairn, T.; Crowe, S. B.; Trapp, J. V.

    2015-01-01

    This study examines the effects of temporary tissue expanders (TTEs) on the dose distributions of photon beams in breast cancer radiotherapy treatments. EBT2 radiochromic film and ion chamber measurements were taken to quantify the attenuation and backscatter effects of the inhomogeneity. Results illustrate that the internal magnetic port present in a tissue expander causes a dose reduction of approximately 25% in photon tangent fields immediately downstream of the implant. It was also shown that the silicone elastomer shell of the tissue expander reduced the dose to the target volume by as much as 8%. This work demonstrates the importance for an accurately modelled high-density implant in the treatment planning system for post-mastectomy breast cancer patients.

  15. Distribution of latex particles in lung and lymph node tissues of rats and dogs

    International Nuclear Information System (INIS)

    Mueller, H.L; Muggenburg, B.A.; Gillett, N.A.; Guilmette, R.A.

    1988-01-01

    The distribution of fluorescent poly sytrene microspheres in different lung compartments, with differing particle numbers within individual lung and lymph node cells was examined In methacrylate-embedded tissue slices. Rat tissues were analyzed at 1, 7 and 13 days after particle instillation, dog tissues at 7 and 13 days. A much higher fraction of particles was seen in the lung interstitium and in lung-associated lymph nodes in dogs than in rats. Particle concentrations in TBLN cells were generally very low in both species, but were high in free alveolar cells after high particle numbers were instilled, and increased from 1 to 13 days, suggesting that alveolar cells with few particles were cleared faster than those wth high ingested particle numbers. (author)

  16. Kinetics of tissue distribution and elimination of 4,4'-methylene bis(2-chloroaniline) in rats

    International Nuclear Information System (INIS)

    Tobes, M.C.; Brown, L.E.; Chin, B.; Marsh, D.D.

    1983-01-01

    The tissue distribution kinetics and elimination of 4,4'-methylene bis(2-chloroaniline) (MBOCA) in rats was studied after a single dose of [ 14 C]MBOCA (0.49 mg/kg body weight, i.v.). The highest concentrations of radioactivity were in the small intestine, liver, adipose, lung, kidney, skin, and adrenals. For most tissues, a rapid decrease in radioactivity was followed by a slower decrease except for the small intestine, adipose and skin which demonstrated transient increases. Subcellular distribution in liver at 1 h showed radioactivity in all cell fractions. Although very lipophilic, [ 14 C]MBOCA was completely eliminated within 48 h with the major route via the feces (73.4%). (Auth.)

  17. Tissue-specific distribution of secondary metabolites in rapeseed (Brassica napus L..

    Directory of Open Access Journals (Sweden)

    Jingjing Fang

    Full Text Available Four different parts, hypocotyl and radicle (HR, inner cotyledon (IC, outer cotyledon (OC, seed coat and endosperm (SE, were sampled from mature rapeseed (Brassica napus L. by laser microdissection. Subsequently, major secondary metabolites, glucosinolates and sinapine, as well as three minor ones, a cyclic spermidine conjugate and two flavonoids, representing different compound categories, were qualified and quantified in dissected samples by high-performance liquid chromatography with diode array detection and mass spectrometry. No qualitative and quantitative difference of glucosinolates and sinapine was detected in embryo tissues (HR, IC and OC. On the other hand, the three minor compounds were observed to be distributed unevenly in different rapeseed tissues. The hypothetic biological functions of the distribution patterns of different secondary metabolites in rapeseed are discussed.

  18. Tissue distribution of 1,2-14C-vinyl chloride in rats

    International Nuclear Information System (INIS)

    Buchter, A.; Bolt, H.M.; Kappus, H.; Bolt, W.

    1977-01-01

    Rats have been pretreatet with 6-nitro-1.2.3-benzothiadiazole which completely blocks the metabolism of vinyl chloride. If the animals are exposed to atmospheric vinyl chloride, the formation of an equilibrium between the compound in the gas phase and in the animal's organism is observed. Unmetabolized vinyl chloride is accumulated in the adipose tissue. The distribution pattern of vinyl in different organs of the rat is constant over the concentration range of 25-10,000 ppm of vinyl chloride in the exposure atmosphere. The distribution of metabolites of vinyl chloride contrasts to that of the original compound; metabolites primarily are concentrated in liver and in kidneys. (orig.) [de

  19. The distribution of controlled drugs on banknotes via counting machines.

    Science.gov (United States)

    Carter, James F; Sleeman, Richard; Parry, Joanna

    2003-03-27

    Bundles of paper, similar to sterling banknotes, were counted in banks in England and Wales. Subsequent analysis showed that the counting process, both by machine and by hand, transferred nanogram amounts of cocaine to the paper. Crystalline material, similar to cocaine hydrochloride, could be observed on the surface of the paper following counting. The geographical distribution of contamination broadly followed Government statistics for cocaine usage within the UK. Diacetylmorphine, Delta(9)-tetrahydrocannabinol (THC) and 3,4-methylenedioxymethylamphetamine (MDMA) were not detected during this study.

  20. Comparative autoradiographic investigations on the tissue distribution of benfotiamine versus thiamine in mice.

    Science.gov (United States)

    Hilbig, R; Rahmann, H

    1998-05-01

    The tissue distribution of two therapeutically applied preparations of B-vitamins were investigated in blood and selected organs (liver, brain, muscle, kidney) of laboratory mice using autoradiographic techniques. Incorporation of lipid-soluble 3H-benfotiamine (CAS 22457-89-2) and water-soluble 3H-thiaminehydrochloride (CAS 67-03-8) (200 microCi, equivalent to 105 mg vitamin/kg body weight) was monitored between 0.75 and 168 h after an oral or subcutaneous administration. The labelled tissue slices were autoradiographically analysed after a differential histochemical extraction procedure to evaluate the respective total radioactivity, the uptake into lipid-soluble, water-soluble and residual macromolecular compounds. Evaluation of these autoradiographic data (given as mumol vitamin preparation/mg tissue equivalent) proved that benfotiamine is incorporated much better than thiaminehydrochloride independent of the administration mode. In muscle and brain tissue a 5 to 25 fold higher amount of tracer incorporation was registered following benfotiamine as compared with the thiamine application, whereas in all other organs the difference in the label was mostly between 10 and 40%. Concerning the organ specific distribution, liver and kidney were the structures labelled highest by both substances and administration procedures. In the liver, concerning all incorporation times, a higher proportion of residual macromolecular compounds was found, whereas in the kidney the proportions of lipid- as well as of water-soluble materials prevailed. These data should be clinically relevant.

  1. Distribution of abdominal adipose tissue as a predictor of hepatic steatosis assessed by MRI

    Energy Technology Data Exchange (ETDEWEB)

    Ducluzeau, P.-H. [Department of endocrinology-Diabetology-Nutrition, Universitary Hospital of Angers, Faculty of Medicine of Angers (France); Manchec-Poilblanc, P., E-mail: Manchecp@yahoo.f [Department of Radiology, Universitary Hospital of Angers, Faculty of Medicine of Angers (France); Roullier, V. [Department of Radiology, Universitary Hospital of Angers, Faculty of Medicine of Angers (France); LISA, Laboratoire d' Ingenierie des Systemes Automatises, Universitary Hospital of Angers, Faculty of Medicine of Angers (France); Cesbron, E. [Department of digestive and liver disease, Universitary hospital of Angers, Faculty of Medicine of Angers (France); Lebigot, J. [Department of Radiology, Universitary Hospital of Angers, Faculty of Medicine of Angers (France); Bertrais, S. [HIFIH Laboratory, UPRES EA 3859, IFR 132, Universitary Hospital of Angers, Faculty of Medicine of Angers (France); Aube, C. [Department of Radiology, Universitary Hospital of Angers, Faculty of Medicine of Angers (France); HIFIH Laboratory, UPRES EA 3859, IFR 132, Universitary Hospital of Angers, Faculty of Medicine of Angers (France)

    2010-09-15

    Aim: To evaluate the relationship between the distribution of visceral and subcutaneous adipose tissue and hepatic steatosis assessed using magnetic resonance imaging (MRI). Materials and methods: One T1-weighted, in-/out-of-phase, single-section sequence at the L3/L4 level and one multi-echo gradient MRI (MGRE) sequence were performed on 65 patients [19 females and 46 males; age 57 {+-} 9.5 years; body mass index (BMI) 31 {+-} 5.1 kg/m{sup 2}]. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) surfaces, and hepatic steatosis were automatically calculated using in-house software. Weight, height, BMI, waist circumference, hip circumference, and waist:hip ratio were recorded. The probability of having a steatosis greater than 10% on MRI was evaluated by receiver operating characteristic (ROC) curves. Results: The anthropometric parameter best correlated to hepatic steatosis was the waist-to-hip ratio (r = 0.301). VAT and proportion of VAT were correlated to liver fat content (r = 0.307 and r = 0.249, respectively). No significant correlations were found for BMI, hip circumference, and SAT. The area under the receiver operating characteristics (AUROCs) for the relationship between liver steatosis and BMI, waist circumference, waist:hip ratio, VAT surface, and proportion of VAT, were respectively 0.52, 0.63, 0.71, 0.73 and 0.75. Conclusion: Adipose tissue distribution is more relevant than total fat mass when assessing the possibility of liver steatosis in overweight patients.

  2. Tissue distribution and developmental expression of type XVI collagen in the mouse.

    Science.gov (United States)

    Lai, C H; Chu, M L

    1996-04-01

    The expression of a recently identified collagen, alpha 1 (XVI), in adult mouse tissue and developing mouse embryo was examined by immunohistochemistry and in situ hybridization. A polyclonal antiserum was raised against a recombinant fusion protein, which contained a segment of 161 amino acids in the N-terminal noncollagenous domain of the human alpha 1 (XVI) collagen. Immunoprecipitation of metabolically labelled human or mouse fibroblast cell lysates with this antibody revealed a major, bacterial collagenase sensitive polypeptide of approximately 210 kDa. The size agrees with the prediction from the full-length cDNA. Immunofluorescence examination of adult mouse tissues using the affinity purified antibody revealed a rather broad distribution of the protein. The heart, kidney, intestine, ovary, testis, eye, arterial walls and smooth muscles all exhibited significant levels of expression, while the skeletal muscle, lung and brain showed very restricted and low signals. During development, no significant expression of the mRNA or protein was observed in embryo of day 8 of gestation, but strong signals was detected in placental trophoblasts. Expression in embryos was detectable first after day 11 of gestation with weak positive signals appearing in the heart. In later stages of development, stronger RNA hybridizations were observed in a variety of tissues, particularly in atrial and ventricular walls of the developing heart, spinal root neural fibers and skin. These data demonstrate that type XVI collagen represents another collagenous component widely distributed in the extracellular matrix and may contribute to the structural integrity of various tissues.

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

    Directory of Open Access Journals (Sweden)

    Deborah G Nguyen

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

  4. Effect of food intake on the tissue distribution of gallium-67: concise communication

    International Nuclear Information System (INIS)

    Hayes, R.L.; Szymendera, J.J.; Byrd, B.L.

    1979-01-01

    Fasting affects the body retention and tissue distribution of Ga-67 in experimental animals. In Ga-67 experiments, therefore, a difference in food intake between treated and control animals might result in confusing side effects. We have observed this in irradiation studies. It is suggested that a fasting regimen should be imposed in any Ga-67 animal study where an alteration in food intake might be experienced in the treated group

  5. Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

    Science.gov (United States)

    Lee, Jeong-A; Kim, Mi-Kyung; Paek, Hee-Jeong; Kim, Yu-Ri; Kim, Meyoung-Kon; Lee, Jong-Kwon; Jeong, Jayoung; Choi, Soo-Jin

    2014-01-01

    Purpose The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods Silica nanoparticles of two different sizes (20 nm and 100 nm) were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ distribution was not affected by particle size or animal sex. In vivo, silica nanoparticles were found to retain their particulate form, although more decomposition was observed in kidneys, especially for 20 nm particles. Urinary and fecal excretion pathways were determined to play roles in the elimination of silica nanoparticles, but 20 nm particles were secreted more rapidly, presumably because they are more easily decomposed. These findings will be of interest to those seeking to predict

  6. Establishing the impact of temporary tissue expanders on electron and photon beam dose distributions.

    Science.gov (United States)

    Asena, A; Kairn, T; Crowe, S B; Trapp, J V

    2015-05-01

    This study investigates the effects of temporary tissue expanders (TTEs) on the dose distributions in breast cancer radiotherapy treatments under a variety of conditions. Using EBT2 radiochromic film, both electron and photon beam dose distribution measurements were made for different phantoms, and beam geometries. This was done to establish a more comprehensive understanding of the implant's perturbation effects under a wider variety of conditions. The magnetic disk present in a tissue expander causes a dose reduction of approximately 20% in a photon tangent treatment and 56% in electron boost fields immediately downstream of the implant. The effects of the silicon elastomer are also much more apparent in an electron beam than a photon beam. Evidently, each component of the TTE attenuates the radiation beam to different degrees. This study has demonstrated that the accuracy of photon and electron treatments of post-mastectomy patients is influenced by the presence of a tissue expander for various beam orientations. The impact of TTEs on dose distributions establishes the importance of an accurately modelled high-density implant in the treatment planning system for post-mastectomy patients. Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

  7. Temperature distribution analysis of tissue water vaporization during microwave ablation: experiments and simulations.

    Science.gov (United States)

    Ai, Haiming; Wu, Shuicai; Gao, Hongjian; Zhao, Lei; Yang, Chunlan; Zeng, Yi

    2012-01-01

    The temperature distribution in the region near a microwave antenna is a critical factor that affects the entire temperature field during microwave ablation of tissue. It is challenging to predict this distribution precisely, because the temperature in the near-antenna region varies greatly. The effects of water vaporisation and subsequent tissue carbonisation in an ex vivo porcine liver were therefore studied experimentally and in simulations. The enthalpy and high-temperature specific absorption rate (SAR) of liver tissues were calculated and incorporated into the simulation process. The accuracy of predictions for near-field temperatures in our simulations has reached the level where the average maximum error is less than 5°C. In addition, a modified thermal model that accounts for water vaporisation and the change in the SAR distribution pattern is proposed and validated with experiment. The results from this study may be useful in the clinical practice of microwave ablation and can be applied to predict the temperature field in surgical planning.

  8. Regenerative Medicine, Disease Modelling, and Drug Discovery in Human Pluripotent Stem Cell-Derived Kidney Tissue

    Directory of Open Access Journals (Sweden)

    Navin Gupta

    2017-08-01

    Full Text Available The multitude of research clarifying critical factors in embryonic organ development has been instrumental in human stem cell research. Mammalian organogenesis serves as the archetype for directed differentiation protocols, subdividing the process into a series of distinct intermediate stages that can be chemically induced and monitored for the expression of stage-specific markers. Significant advances over the past few years include established directed differentiation protocols of human embryonic stem cells and human induced pluripotent stem cells (hiPSC into human kidney organoids in vitro. Human kidney tissue in vitro simulates the in vivo response when subjected to nephrotoxins, providing a novel screening platform during drug discovery to facilitate identification of lead candidates, reduce developmental expenditures, and reduce future rates of drug-induced acute kidney injury. Patient-derived hiPSC, which bear naturally occurring DNA mutations, may allow for modelling of human genetic diseases to enable determination of pathological mechanisms and screening for novel therapeutics. In addition, recent advances in genome editing with clustered regularly interspaced short palindromic repeats (CRISPR/Cas9 enable the generation of specific mutations to study genetic disease, with non-mutated lines serving as an ideal isogenic control. The growing population of patients with end-stage kidney disease is a worldwide healthcare problem, with high morbidity and mortality rates, that warrants the discovery of novel forms of renal replacement therapy. Coupling the outlined advances in hiPSC research with innovative bioengineering techniques, such as decellularised kidney and three-dimensional printed scaffolds, may contribute to the development of bioengineered transplantable human kidney tissue as a means of renal replacement therapy.

  9. Distribution of Basement Membrane Molecules, Laminin and Collagen Type IV, in Normal and Degenerated Cartilage Tissues.

    Science.gov (United States)

    Foldager, Casper Bindzus; Toh, Wei Seong; Gomoll, Andreas H; Olsen, Bjørn Reino; Spector, Myron

    2014-04-01

    The objective of the present study was to investigate the presence and distribution of 2 basement membrane (BM) molecules, laminin and collagen type IV, in healthy and degenerative cartilage tissues. Normal and degenerated tissues were obtained from goats and humans, including articular knee cartilage, the intervertebral disc, and meniscus. Normal tissue was also obtained from patella-tibial enthesis in goats. Immunohistochemical analysis was performed using anti-laminin and anti-collagen type IV antibodies. Human and goat skin were used as positive controls. The percentage of cells displaying the pericellular presence of the protein was graded semiquantitatively. When present, laminin and collagen type IV were exclusively found in the pericellular matrix, and in a discrete layer on the articulating surface of normal articular cartilage. In normal articular (hyaline) cartilage in the human and goat, the proteins were found co-localized pericellularly. In contrast, in human osteoarthritic articular cartilage, collagen type IV but not laminin was found in the pericellular region. Nonpathological fibrocartilaginous tissues from the goat, including the menisci and the enthesis, were also positive for both laminin and collagen type IV pericellularly. In degenerated fibrocartilage, including intervertebral disc, as in degenerated hyaline cartilage only collagen type IV was found pericellularly around chondrocytes but with less intense staining than in non-degenerated tissue. In calcified cartilage, some cells were positive for laminin but not type IV collagen. We report differences in expression of the BM molecules, laminin and collagen type IV, in normal and degenerative cartilaginous tissues from adult humans and goats. In degenerative tissues laminin is depleted from the pericellular matrix before collagen type IV. The findings may inform future studies of the processes underlying cartilage degeneration and the functional roles of these 2 extracellular matrix proteins

  10. Distribution of Basement Membrane Molecules, Laminin and Collagen Type IV, in Normal and Degenerated Cartilage Tissues

    Science.gov (United States)

    Toh, Wei Seong; Gomoll, Andreas H.; Olsen, Bjørn Reino; Spector, Myron

    2014-01-01

    Objective: The objective of the present study was to investigate the presence and distribution of 2 basement membrane (BM) molecules, laminin and collagen type IV, in healthy and degenerative cartilage tissues. Design: Normal and degenerated tissues were obtained from goats and humans, including articular knee cartilage, the intervertebral disc, and meniscus. Normal tissue was also obtained from patella-tibial enthesis in goats. Immunohistochemical analysis was performed using anti-laminin and anti–collagen type IV antibodies. Human and goat skin were used as positive controls. The percentage of cells displaying the pericellular presence of the protein was graded semiquantitatively. Results: When present, laminin and collagen type IV were exclusively found in the pericellular matrix, and in a discrete layer on the articulating surface of normal articular cartilage. In normal articular (hyaline) cartilage in the human and goat, the proteins were found co-localized pericellularly. In contrast, in human osteoarthritic articular cartilage, collagen type IV but not laminin was found in the pericellular region. Nonpathological fibrocartilaginous tissues from the goat, including the menisci and the enthesis, were also positive for both laminin and collagen type IV pericellularly. In degenerated fibrocartilage, including intervertebral disc, as in degenerated hyaline cartilage only collagen type IV was found pericellularly around chondrocytes but with less intense staining than in non-degenerated tissue. In calcified cartilage, some cells were positive for laminin but not type IV collagen. Conclusions: We report differences in expression of the BM molecules, laminin and collagen type IV, in normal and degenerative cartilaginous tissues from adult humans and goats. In degenerative tissues laminin is depleted from the pericellular matrix before collagen type IV. The findings may inform future studies of the processes underlying cartilage degeneration and the functional

  11. The distribution of presumptive thoracic paraganglionic tissue in the common marmoset (Callithrix jacchus

    Directory of Open Access Journals (Sweden)

    Clarke J.A.

    2002-01-01

    Full Text Available The aortic-pulmonary regions (APR of seven adult marmosets (Callithrix jacchus and the region of the right subclavian artery of a further three marmosets were diffusion-fixed with 10% buffered formol-saline solution. In both regions serial 5-µm sections were cut and stained by the Martius yellow, brilliant crystal scarlet and soluble blue method. Presumptive thoracic paraganglionic (PTP tissue was only observed in the APR. PTP tissue was composed of small groups of cells that varied in size and number. The distribution of the groups of cells was extremely variable, so much so that it would be misleading to attempt to classify their position; they were not circumscribed by a connective tissue capsule, but were always related to the thoracic branches of the left vagus nerve. The cells lay in loose areolar tissue characteristic of this part of the mediastinum and received their blood supply from small adjacent connective tissue arterioles. Unlike the paraganglionic tissue found in the carotid body the cells in the thorax did not appear to have a profuse capillary blood supply. There was, however, a close cellular-neural relationship. The cells, 10-15 µm in diameter, were oval or rounded in appearance and possessed a central nucleus and clear cytoplasm. No evidence was found that these cells possessed a 'companion' cell reminiscent of the arrangement of type 1 and type 2 cells in the carotid body. In conclusion, we found evidence of presumed paraganglionic tissue in the APR of the marmoset which, however, did not show the characteristic histological features of the aortic body chemoreceptors that have been described in some non-primate mammals. A survey of the mediastina of other non-human primates is required to establish whether this finding is atypical for these animals.

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

    Science.gov (United States)

    Chen, Muwan; Le, Dang QS; Hein, San; Li, Pengcheng; Nygaard, Jens V; Kassem, Moustapha; Kjems, Jørgen; Besenbacher, Flemming; Bünger, Cody

    2012-01-01

    Bone tissue engineering implants with sustained local drug delivery provide an opportunity for better postoperative care for bone tumor patients because these implants offer sustained drug release at the tumor site and reduce systemic side effects. A rapid prototyped macroporous polycaprolactone scaffold was embedded with a porous matrix composed of chitosan, nanoclay, and β-tricalcium phosphate by freeze-drying. This composite scaffold was evaluated on its ability to deliver an anthracycline antibiotic and to promote formation of mineralized matrix in vitro. Scanning electronic microscopy, confocal imaging, and DNA quantification confirmed that immortalized human bone marrow-derived mesenchymal stem cells (hMSC-TERT) cultured in the scaffold showed high cell viability and growth, and good cell infiltration to the pores of the scaffold. Alkaline phosphatase activity and osteocalcin staining showed that the scaffold was osteoinductive. The drug-release kinetics was investigated by loading doxorubicin into the scaffold. The scaffolds comprising nanoclay released up to 45% of the drug for up to 2 months, while the scaffold without nanoclay released 95% of the drug within 4 days. Therefore, this scaffold can fulfill the requirements for both bone tissue engineering and local sustained release of an anticancer drug in vitro. These results suggest that the scaffold can be used clinically in reconstructive surgery after bone tumor resection. Moreover, by changing the composition and amount of individual components, the scaffold can find application in other tissue engineering areas that need local sustained release of drug. PMID:22904634

  13. Introduction for the special issue on recent advances in drug delivery across tissue barriers.

    Science.gov (United States)

    Mrsny, Randall J; Brayden, David J

    2016-01-01

    This special issue of Tissue Barriers contains a series of reviews with the common theme of how biological barriers established at epithelial tissues limit the uptake of macromolecular therapeutics. By improving our functional understanding of these barriers, the majority of the authors have highlighted potential strategies that might be applied to the non-invasive delivery of biopharmaceuticals that would otherwise require an injection format for administration. Half of the articles focus on the potential of particular technologies to assist oral delivery of peptides, proteins and other macromolecules. These include use of prodrug chemistry to improve molecule stability and permeability, and the related potential for oral delivery of poorly permeable agents by cell-penetrating peptides and dendrimers. Safety aspects of intestinal permeation enhancers are discussed, along with the more recent foray into drug-device combinations as represented by intestinal microneedles and externally-applied ultrasound. Other articles highlight the crossover between food research and oral delivery based on nanoparticle technology, while the final one provides a fascinating interpretation of the physiological problems associated with subcutaneous insulin delivery and how inefficient it is at targeting the liver.

  14. Excipient-drug pharmacokinetic interactions: Effect of disintegrants on efflux across excised pig intestinal tissues

    Directory of Open Access Journals (Sweden)

    Werner Gerber

    2018-04-01

    Full Text Available Pharmaceutical excipients were designed originally to be pharmacologically inert. However, certain excipients were found to have altering effects on drug pharmacodynamics and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst others. In this study, five disintegrants from different chemical classes were evaluated for P-glycoprotein (P-gp related inhibition and tight junction modulation effects. Bi-directional transport studies of the model compound, Rhodamine 123 (R123 were conducted in the absence (control group and presence (experimental groups of four concentrations of each selected disintegrant across excised pig jejunum tissue. The results showed that some of the selected disintegrants (e.g. Ac-di-sol® and Kollidon® CL-M increased R123 absorptive transport due to inhibition of P-gp related efflux, while another disintegrant (e.g. sodium alginate changed R123 transport due to inhibition of P-gp in conjunction with a transient opening of the tight junctions in a concentration dependent way. It may be concluded that the co-application of some disintegrants to the intestinal epithelium may lead to pharmacokinetic interactions with drugs that are susceptible to P-gp related efflux. However, the clinical significance of these in vitro permeation findings should be confirmed by means of in vivo studies. Keywords: Disintegrants, Excipient, Ex vivo, P-glycoprotein, Pharmacokinetic interactions, Rhodamine 123

  15. Effect of heterogeneous microvasculature distribution on drug delivery to solid tumour

    International Nuclear Information System (INIS)

    Zhan, Wenbo; Xu, Xiao Yun; Gedroyc, Wladyslaw

    2014-01-01

    Most of the computational models of drug transport in vascular tumours assume a uniform distribution of blood vessels through which anti-cancer drugs are delivered. However, it is well known that solid tumours are characterized by dilated microvasculature with non-uniform diameters and irregular branching patterns. In this study, the effect of heterogeneous vasculature on drug transport and uptake is investigated by means of mathematical modelling of the key physical and biochemical processes in drug delivery. An anatomically realistic tumour model accounting for heterogeneous distribution of blood vessels is reconstructed based on magnetic resonance images of a liver tumour. Numerical simulations are performed for different drug delivery modes, including direct continuous infusion and thermosensitive liposome-mediated delivery, and the anti-cancer effectiveness is evaluated through changes in tumour cell density based on predicted intracellular concentrations. Comparisons are made between regions of different vascular density, and between the two drug delivery modes. Our numerical results show that both extra- and intra-cellular concentrations in the liver tumour are non-uniform owing to the heterogeneous distribution of tumour vasculature. Drugs accumulate faster in well-vascularized regions, where they are also cleared out more quickly, resulting in less effective tumour cell killing in these regions. Compared with direct continuous infusion, the influence of heterogeneous vasculature on anti-cancer effectiveness is more pronounced for thermosensitive liposome-mediated delivery. (paper)

  16. Tissue distribution and elimination after oral and intravenous administration of different titanium dioxide nanoparticles in rats

    Science.gov (United States)

    2014-01-01

    Objective The aim of this study was to obtain kinetic data that can be used in human risk assessment of titanium dioxide nanomaterials. Methods Tissue distribution and blood kinetics of various titanium dioxide nanoparticles (NM-100, NM-101, NM-102, NM-103, and NM-104), which differ with respect to primary particle size, crystalline form and hydrophobicity, were investigated in rats up to 90 days post-exposure after oral and intravenous administration of a single or five repeated doses. Results For the oral study, liver, spleen and mesenteric lymph nodes were selected as target tissues for titanium (Ti) analysis. Ti-levels in liver and spleen were above the detection limit only in some rats. Titanium could be detected at low levels in mesenteric lymph nodes. These results indicate that some minor absorption occurs in the gastrointestinal tract, but to a very limited extent. Both after single and repeated intravenous (IV) exposure, titanium rapidly distributed from the systemic circulation to all tissues evaluated (i.e. liver, spleen, kidney, lung, heart, brain, thymus, reproductive organs). Liver was identified as the main target tissue, followed by spleen and lung. Total recovery (expressed as % of nominal dose) for all four tested nanomaterials measured 24 h after single or repeated exposure ranged from 64-95% or 59-108% for male or female animals, respectively. During the 90 days post-exposure period, some decrease in Ti-levels was observed (mainly for NM-100 and NM-102) with a maximum relative decrease of 26%. This was also confirmed by the results of the kinetic analysis which revealed that for each of the investigated tissues the half-lifes were considerable (range 28–650 days, depending on the TiO2-particle and tissue investigated). Minor differences in kinetic profile were observed between the various particles, though these could not be clearly related to differences in primary particle size or hydrophobicity. Some indications were observed for an

  17. Distribution of polybrominated diphenyl ethers in Japanese autopsy tissue and body fluid samples.

    Science.gov (United States)

    Hirai, Tetsuya; Fujimine, Yoshinori; Watanabe, Shaw; Nakano, Takeshi

    2012-09-01

    Brominated flame retardants are components of many plastics and are used in products such as cars, textiles, televisions, and personal computers. Human exposure to polybrominated diphenyl ether (PBDE) flame retardants has increased exponentially during the last three decades. Our objective was to measure the body burden and distribution of PBDEs and to determine the concentrations of the predominant PBDE congeners in samples of liver, bile, adipose tissue, and blood obtained from Japanese autopsy cases. Tissues and body fluids obtained from 20 autopsy cases were analyzed. The levels of 25 PBDE congeners, ranging from tri- to hexa-BDEs, were assessed. The geometric means of the sum of the concentrations of PBDE congeners having detection frequencies >50 % (ΣPBDE) in the blood, liver, bile, and adipose tissue were 2.4, 2.6, 1.4, and 4.3 ng/g lipid, respectively. The most abundant congeners were BDE-47 and BDE-153, followed by BDE-100, BDE-99, and BDE-28+33. These concentrations of PBDE congeners were similar to other reports of human exposure in Japan but were notably lower than concentrations than those reported in the USA. Significant positive correlations were observed between the concentrations of predominant congeners and ΣPBDE among the samples analyzed. The ΣPBDE concentration was highest in the adipose tissue, but PBDEs were distributed widely among the tissues and body fluids analyzed. The PBDE levels observed in the present study are similar to those reported in previous studies in Japan and significantly lower than those reported in the USA.

  18. Layer-by-layer assembled multilayers and polymeric nanoparticles for drug delivery in tissue engineering applications

    Science.gov (United States)

    Mehrotra, Sumit

    Tissues and organs in vivo are structured in three dimensional (3-D) ordered assemblies to maintain their metabolic functions. In the case of an injury, certain tissues lack the regenerative abilities without an external supportive environment. In order to regenerate the natural in vivo environment post-injury, there is a need to design three-dimensional (3-D) tissue engineered constructs of appropriate dimensions along with strategies that can deliver growth factors or drugs at a controlled rate from such constructs. This thesis focuses on the applications of hydrogen bonded (H-bonded) nanoscale layer-by-layer (LbL) assembled multilayers for time controlled drug delivery, fabrication of polymeric nanoparticles as drug delivery carriers, and engineering 3-D cellular constructs. Axonal regeneration in the central nervous system after spinal cord injury is often disorganized and random. To support linear axonal growth into spinal cord lesion sites, certain growth factors, such as brain-derived neurotrophic factor (BDNF), needs to be delivered at a controlled rate from an array of uniaxial channels patterned in a scaffold. In this study, we demonstrate for the first time that H-bonded LbL assembled degradable thin films prepared over agarose hydrogel, whereby the protein was loaded separately from the agarose fabrication, provided sustained release of protein under physiological conditions for more than four weeks. Further, patterned agarose scaffolds implanted at the site of a spinal cord injury forms a reactive cell layer of leptomeningeal fibroblasts in and around the scaffold. This limits the ability of axons to reinnervate the spinal cord. To address this challenge, we demonstrate the time controlled release of an anti-mitotic agent from agarose hydrdgel to control the growth of the reactive cell layer of fibroblasts. Challenges in tissue engineering can also be addressed using gene therapy approaches. Certain growth factors in the body are known to inhibit

  19. Investigation of the Relationship of Some Antihypertensive Drugs with Oxidant/Antioxidant Parameters and DNA Damage on Rat Uterus Tissue

    OpenAIRE

    Mustafa Talip Sener; Hamit Hakan Alp; Beyzagul Polat; Bunyamin Borekci; Yakup Kumtepe; Nesrin Gursan; Serkan Kumbasar; Suleyman Salman; Halis Suleyman

    2011-01-01

    Background In this study, we investigated the effects of treatment with chronic antihypertensive drugs (clonidine, methyldopa, amlodipine, ramipril and rilmenidine) on oxidant-antioxidant parameters and toxic effects on DNA in rat uterus tissue. In addition, uterus tissues were examined histopathologically. Materials and Methods A total of 36 albino Wistar rats were divided into the following six groups: 0.075 mg/kg clonidine group; 100 mg/kg methyldopa group; 2 mg/kg amlodipine group; 2.5 mg...

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

    Directory of Open Access Journals (Sweden)

    Chen M

    2012-08-01

    Full Text Available Muwan Chen,1,2 Dang QS Le,1,2 San Hein,2 Pengcheng Li,1 Jens V Nygaard,2 Moustapha Kassem,3 Jørgen Kjems,2 Flemming Besenbacher,2 Cody Bünger11Orthopaedic Research Lab, Aarhus University Hospital, Aarhus C, Denmark; 2Interdisciplinary Nanoscience Center (iNANO, Aarhus University, Aarhus C, Denmark; 3Department of Endocrinology and Metabolism, Odense University Hospital, Odense C, DenmarkAbstract: Bone tissue engineering implants with sustained local drug delivery provide an opportunity for better postoperative care for bone tumor patients because these implants offer sustained drug release at the tumor site and reduce systemic side effects. A rapid prototyped macroporous polycaprolactone scaffold was embedded with a porous matrix composed of chitosan, nanoclay, and β-tricalcium phosphate by freeze-drying. This composite scaffold was evaluated on its ability to deliver an anthracycline antibiotic and to promote formation of mineralized matrix in vitro. Scanning electronic microscopy, confocal imaging, and DNA quantification confirmed that immortalized human bone marrow-derived mesenchymal stem cells (hMSC-TERT cultured in the scaffold showed high cell viability and growth, and good cell infiltration to the pores of the scaffold. Alkaline phosphatase activity and osteocalcin staining showed that the scaffold was osteoinductive. The drug-release kinetics was investigated by loading doxorubicin into the scaffold. The scaffolds comprising nanoclay released up to 45% of the drug for up to 2 months, while the scaffold without nanoclay released 95% of the drug within 4 days. Therefore, this scaffold can fulfill the requirements for both bone tissue engineering and local sustained release of an anticancer drug in vitro. These results suggest that the scaffold can be used clinically in reconstructive surgery after bone tumor resection. Moreover, by changing the composition and amount of individual components, the scaffold can find application in other

  1. Tissue distribution of berberine and its metabolites after oral administration in rats.

    Directory of Open Access Journals (Sweden)

    Xiang-Shan Tan

    Full Text Available Berberine (BBR has been confirmed to have multiple bioactivities in clinic, such as cholesterol-lowering, anti-diabetes, cardiovascular protection and anti- inflammation. However, BBR's plasma level is very low; it cannot explain its pharmacological effects in patients. We consider that the in vivo distribution of BBR as well as of its bioactive metabolites might provide part of the explanation for this question. In this study, liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC/MS(n-IT-TOF as well as liquid chromatography that coupled with tandem mass spectrometry (LC-MS/MS was used for the study of tissue distribution and pharmacokinetics of BBR in rats after oral administration (200 mg/kg. The results indicated that BBR was quickly distributed in the liver, kidneys, muscle, lungs, brain, heart, pancreas and fat in a descending order of its amount. The pharmacokinetic profile indicated that BBR's level in most of studied tissues was higher (or much higher than that in plasma 4 h after administration. BBR remained relatively stable in the tissues like liver, heart, brain, muscle, pancreas etc. Organ distribution of BBR's metabolites was also investigated paralleled with that of BBR. Thalifendine (M1, berberrubine (M2 and jatrorrhizine (M4, which the metabolites with moderate bioactivity, were easily detected in organs like the liver and kidney. For instance, M1, M2 and M4 were the major metabolites in the liver, among which the percentage of M2 was up to 65.1%; the level of AUC (0-t (area under the concentration-time curve for BBR or the metabolites in the liver was 10-fold or 30-fold higher than that in plasma, respectively. In summary, the organ concentration of BBR (as well as its bioactive metabolites was higher than its concentration in the blood after oral administration. It might explain BBR's pharmacological effects on human diseases in clinic.

  2. Distribution of /sup 51/Cr labelled endotoxin on tissue and intracellular organella in mice

    Energy Technology Data Exchange (ETDEWEB)

    Saito, K; Suzuki, M; Okuaki, A; Saito, M [Fukushima Medical Coll. (Japan)

    1976-10-01

    The distribution of /sup 51/Cr labelled endotoxin was investigated in mice. The degree of toxicity between non-labelled endotoxin and /sup 51/Cr labelled endotoxin did not change. /sup 51/Cr-endotoxin was distributed in the highest levels in the liver, and to a lesser degree in the intestine, lungs, spleen and kidneys. The affinity of the tissue to /sup 51/Cr-endotoxin was strongest in the liver followed by the spleen, lungs, kidneys and intestine. /sup 51/Cr-endotoxin was distributed mainly in the mitochondrial fraction and the nuclear fraction in the intracellular species. /sup 51/Cr-endotoxin was distributed only in the liver and the intestine when a small dose was administered. It was also distributed in the lungs, spleen and kidneys when a large dose was given, but the uptake in the liver was somewhat limited. /sup 51/Cr-endotoxin was distributed mainly in the liver and the spleen in the mice that survived one week.

  3. Insulin resistance, hepatic lipid and adipose tissue distribution in HIV infected men

    Science.gov (United States)

    He, Qing; Engelson, Ellen S.; Ionescu, Gabriel; Glesby, Marshall J.; Albu, Jeanine B.; Kotler, Donald P.

    2010-01-01

    Background A large proportion of HIV-infected subjects on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. Design and methods We performed a cross-sectional analysis of baseline data from twenty-three HIV-infected participants in 3 prospective clinical studies. Magnetic resonance spectroscopy was applied to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole body adipose tissue compartments, i.e., subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes as well as inter-muscular adipose tissue (IMAT) subcompartment, and omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. Homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Results Hepatic lipid content correlated significantly with total VAT (r=0.62, p=0.0014) but not with SAT (r=0.053, p=0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r=0.67, p=0.0004) and RPAT (r=0.53, p=0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r=0.61, p=0.057 and 0.68, p=0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. Conclusion Hepatic lipid content is associated with VAT volume, especially the omental-mesenteric subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men. PMID:18572755

  4. Insulin resistance, hepatic lipid and adipose tissue distribution in HIV-infected men.

    Science.gov (United States)

    He, Qing; Engelson, Ellen S; Ionescu, Gabriel; Glesby, Marshall J; Albu, Jeanine B; Kotler, Donald P

    2008-01-01

    A large proportion of HIV-infected patients on antiretroviral medication develop insulin resistance, especially in the context of fat redistribution. This study investigates the interrelationships among fat distribution, hepatic lipid content, and insulin resistance in HIV-infected men. We performed a cross-sectional analysis of baseline data from 23 HIV-infected participants in three prospective clinical studies. Magnetic resonance spectroscopy was used to quantify hepatic lipid concentrations. Magnetic resonance imaging was used to quantify whole-body adipose tissue compartments: that is, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes, as well as the intermuscular adipose tissue (IMAT) subcompartment and the omental-mesenteric adipose tissue (OMAT) and retroperitoneal adipose tissue (RPAT) subcompartments of VAT. The homeostasis model for assessment of insulin resistance (HOMA-IR) was calculated from fasting glucose and insulin concentrations. Hepatic lipid content correlated significantly with total VAT (r = 0.62, P = 0.0014), but not with SAT (r = 0.053, P = 0.81). In univariate analysis, hepatic lipid content was associated with the OMAT (r = 0.67, P = 0.0004) and RPAT (r = 0.53, P = 0.009) subcompartments; HOMA-IR correlated with both VAT and hepatic lipid contents (r = 0.61, P = 0.057 and r = 0.68, P = 0.0012, respectively). In stepwise linear regression models, hepatic lipid had the strongest associations with OMAT and with HOMA-IR. Hepatic lipid content is associated with VAT volume, especially the OMAT subcompartment, in HIV-infected men. Hepatic lipid content is associated with insulin resistance in HIV-infected men. Hepatic lipid content might mediate the relationship between VAT and insulin resistance among treated, HIV-infected men.

  5. Accumulation and in vivo tissue distribution of pollutant elements in Erica andevalensis

    International Nuclear Information System (INIS)

    Rossini Oliva, S.; Valdes, B.; Leidi, E.O.

    2009-01-01

    Erica andevalensis is an endemic shrub from an area in the southwest of Spain (Andalucia) characterized by acidic and contaminated soils. Scanning electron microscopy (SEM) of samples after conventional or cryo-fixation preparation protocols was used for morphological and anatomical studies. SEM coupled with EDX-analysis was employed to localise and quantify different elements within plant parts (leaves, stems and roots) in samples collected in the field. Morphological studies revealed that the species has typical adaptive structures to drought-stress such as rolled needle-like leaves, sunken stomata and a thick waxy cuticle on the upper epidermis. Roots were associated with fungi which formed intra and extra-cellular mycelia. The SEM studies showed that Cu was not sequestrated into the root tissues and was uniformly distributed in leaf tissues. Meanwhile, Pb was only localised within epidermal root tissues which indicates that its sequestration in an external matrix might represent a tolerance mechanism in this species. Iron was uniformly distributed throughout the leaves, while in roots it was predominantly retained on the epidermal cell walls. The exclusion and tolerance mechanisms adopted by this species to survive in mining areas indicate that it can be used successfully in the re-vegetation of contaminated areas

  6. The zinc distribution in prostate tissues using X-ray microfluorescence with synchrotron radiation

    International Nuclear Information System (INIS)

    Leitao, Roberta G.; Anjos, Marcelino J.; Canellas, Catarine G.L.; Pereira, Marcelo O.; Pereira, Gabriela R.; Lopes, Ricardo T.

    2009-01-01

    Many elements play an essential role in a number of biological processes as activators or inhibitors of cellular and enzymatic activity. The topographic and quantitative elemental analysis of pathologically changed tissues may shed some new light on processes leading to the degeneration of cells in case of selected diseases. Zinc concentration in a prostate gland is much higher than that in other human tissues. The high concentration of zinc in the prostate suggests that zinc may play a role in prostate health. The aim of this work was to study the elemental distribution for Zinc in prostate tissues from patterns of relative fluorescence intensities. The measurements were performed in standard geometry of 45 deg incidence, exciting with a white beam and using a conventional system collimation orthogonal slits) in the XRF beam line at the Synchrotron Light National Laboratory (Campinas, Brazil). The prostate glands were cut into pieces (slice) with thickness of 0.5 mm. The results showed the zinc distribution was not uniform for different zones of the prostate analyzed. (author)

  7. Accumulation and in vivo tissue distribution of pollutant elements in Erica andevalensis

    Energy Technology Data Exchange (ETDEWEB)

    Rossini Oliva, S. [Department of Plant Biology and Ecology, University of Seville, Avda. Reina Mercedes s/n, Apartado de Correo 1095, 41080 Sevilla (Spain)], E-mail: sabina@us.es; Valdes, B. [Department of Plant Biology and Ecology, University of Seville, Avda. Reina Mercedes s/n, Apartado de Correo 1095, 41080 Sevilla (Spain); Leidi, E.O. [Department of Plant Biotechnology, IRNAS-CSIC, Avda. Reina Mercedes 10, 41012 Sevilla (Spain)

    2009-03-01

    Erica andevalensis is an endemic shrub from an area in the southwest of Spain (Andalucia) characterized by acidic and contaminated soils. Scanning electron microscopy (SEM) of samples after conventional or cryo-fixation preparation protocols was used for morphological and anatomical studies. SEM coupled with EDX-analysis was employed to localise and quantify different elements within plant parts (leaves, stems and roots) in samples collected in the field. Morphological studies revealed that the species has typical adaptive structures to drought-stress such as rolled needle-like leaves, sunken stomata and a thick waxy cuticle on the upper epidermis. Roots were associated with fungi which formed intra and extra-cellular mycelia. The SEM studies showed that Cu was not sequestrated into the root tissues and was uniformly distributed in leaf tissues. Meanwhile, Pb was only localised within epidermal root tissues which indicates that its sequestration in an external matrix might represent a tolerance mechanism in this species. Iron was uniformly distributed throughout the leaves, while in roots it was predominantly retained on the epidermal cell walls. The exclusion and tolerance mechanisms adopted by this species to survive in mining areas indicate that it can be used successfully in the re-vegetation of contaminated areas.

  8. Tissue distributions of fluoride and its toxicity in the gills of a freshwater teleost, Cyprinus carpio.

    Science.gov (United States)

    Cao, Jinling; Chen, Jianjie; Wang, Jundong; Wu, Xiangtian; Li, Yundong; Xie, Lingtian

    2013-04-15

    Fish take up fluoride directly from water and are susceptible to fluoride contamination of their environment. In this study, we examined the tissue distributions of fluoride and its toxicity in the gills of the common carp (Cyprinus carpio) chronically exposed to fluoride. Carp were exposed to a range of aqueous fluoride (35-124 mg/L) and sampled at 30, 60 and 90 days. The accumulation of fluoride in the tissues increased with the level and duration of exposure. Steady state was not achieved under the experimental conditions. The gills accumulated the highest levels of fluoride followed by the liver>brain>kidney>muscle>intestine. A dose-dependent inhibition was observed for the enzyme activities of Na(+)-K(+)-ATPase and Ca(2+)-ATPase in the gills after the fish were exposed for 90 days. Also, accumulation of fluoride was associated with the inhibition of superoxide dismutase (SOD) activities and a dose-dependent stimulation of malondialdehyde (MDA) levels in the gill tissues, suggesting that fluoride promoted oxidative stress in the fish. Microscopic examinations revealed injuries to gill tissues and chloride cells, with the severity of injury increasing with exposure concentration. These results suggest that chronic exposure to elevated concentrations of fluoride may induce toxicity in the common carp. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Oral absorption and tissue distribution of a new squalenoyl anticancer nanomedicine

    Energy Technology Data Exchange (ETDEWEB)

    Harivardhan Reddy, L.; Ferreira, Humberto; Dubernet, Catherine [Univ. Paris-Sud XI, Faculte de Pharmacie, UMR CNRS 8612, IFR 141 (France); Mouelhi, Sinda Lepetre; Desmaele, Didier [Universite Paris XI, Faculte de Pharmacie, UMR CNRS 8076 Biocis (France); Rousseau, Bernard [CEA, Bio Organic Chemistry and Labeled Compounds Division (France); Couvreur, Patrick [Univ. Paris-Sud XI, Faculte de Pharmacie, UMR CNRS 8612, IFR 141 (France)], E-mail: patrick.couvreur@u-psud.fr

    2008-05-15

    Recently, we had discovered that the linkage of nucleoside analogues to squalene, a precursor in the sterol biosynthesis, led to amphiphilic molecules, which self-organized in water as nanoassemblies of 100-300 nm in diameter, irrespective of the nucleoside analogue used. Thus, it was observed that the 4-(N)-trisnorsqualenoylgemcitabine (SQdFdC), the squalenoyl prodrug of the anticancer nucleoside analogue gemcitabine, was impressively more active than its parent compound gemcitabine, both in vitro and in vivo on experimental leukaemia. Since squalene, which is a natural constituent of shark liver and olive oil, is known to be absorbed orally, we investigated in this short note the absorption and tissue distribution of {sup 3}H-radiolabelled SQdFdC nanoassemblies comparatively to {sup 3}H-gemcitabine after oral administration to mice. Whereas gemcitabine was found to be rapidly absorbed (t{sub max} = 1 h), this compound underwent a rapid clearance from the plasma. Conversely, the SQdFdC nanoassemblies displayed slower absorption followed by the progressive tissue accumulation, and they exhibited a lower clearance rate. The accumulation of the SQdFdC nanoassemblies in tissues such as pancreas, thymus, lung, liver and spleen (except at 1 h post-administration) was similar to that of the gemcitabine, yet exhibited significantly greater penetration and retention into the stomach and intestinal tissues comparatively to gemcitabine. Thus, the SQdFdC nanoassemblies could be of potential interest in the treatment of gastrointestinal tumours by oral route.

  10. Atmospheric inorganic contaminants and their distribution inside stem tissues of Fraxinus excelsior L

    Energy Technology Data Exchange (ETDEWEB)

    Catinon, M.; Asta, J.; Tissut, M.; Ravanel, P. [Univ Grenoble 1, LECA, Equipe Perturbat Environm and Xenobiot, UMR 5553, Grenoble (France); Ayrault, S. [CEA Saclay, DSM, Lab Sci Climat and Environm, CEA-CNRS-UVSQ, F-91191 Gif Sur Yvette (France); Daudin, L. [CEA Saclay, DSM, Lab Pierre Sue, CEA-CNRS, F-91191 Gif Sur Yvette (France); Sevin, L. [CNRS, Ctr Rech Petrog and Geochim, SARM, F-54501 Vandoeuvre Les Nancy (France)

    2008-07-01

    The elements present on and in 4-year-old stem of Fraxinus excelsior L. were analysed and estimated quantitatively. The superficial deposit on the bark is a complex mixture mainly composed of organic matter, mineral nutrients, clay and anthropogenic elements coming from the atmosphere. The elements present inside the stem tissues represent a total amount which is generally much higher than the superficial deposit. The distribution of elements such as Ca, K, Fe, Mn, Zn, Cu and Pb was shown by PIXE analysis in stem transversal cuttings, showing the presence of solid multi mineral particles only inside the suber. A new strategy of mechanical tissues isolation on fresh stems was carried out in order to obtain high amounts of each tissue allowing an accurate ICP-MS analysis and estimation of {>=} 20 elements in each tissue. A concentration decreasing gradient was measured for each element from suber to wood and pith in good agreement with the PIXE results. In the dividing cells of the vascular cambium, elements concentrations were very high since the cell wall weight was minimal. When expressing the amounts of each element per bark area unit, the whole bark content was only twice the wood + pith content for the studied elements. All these results suggest that, in Fraxinus stems, the root uptake and xylem transport of elements are generally not intense enough to hide the atmospheric flux of mineral contaminants. (authors)

  11. A study of the distribution of schistosomicidal drug H-3-7505 in mice

    International Nuclear Information System (INIS)

    Hao, T.

    1985-01-01

    The authors have studied the distribution of H-3 labelled schistosomicidal drug in mice by autoradiography. The H-3-labelled substances were found in liver and kidney and in successfully decreasing amounts in brain, lung, heart, fat, testis, pancreas and spleen. In various cells the silver granules were present mainly in the cytoplasms but a few in the nucleus. After administration of this labelled schistosomicidal drug, the mice were killed and studied in groups successively at 4, 8, 24 hrs. No difference in the distribution of silver granules were observed. This fact indicated that, this drug was rapidly absorbed and highly concentrated with a long duration of reservation in liver. All of these favours the schistosomicidal effect of the drug. As this drug was highly concentrated in the cytoplasm of liver cells, that might provide a pathophysiologic basis for the explanation of jaundice in the clinical practice. Moreover, the appearance of toxic reaction in nervous system may be related to the relatively high concentration of the drug distributed in the brain

  12. 21 CFR 809.40 - Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs...

    Science.gov (United States)

    2010-04-01

    ... OTC test sample collection systems for drugs of abuse testing. 809.40 Section 809.40 Food and Drugs... Restrictions on the sale, distribution, and use of OTC test sample collection systems for drugs of abuse testing. (a) Over-the-counter (OTC) test sample collection systems for drugs of abuse testing (§ 864.3260...

  13. Drug quality in South Africa: perceptions of key players involved in medicines distribution.

    Science.gov (United States)

    Patel, Aarti; Norris, Pauline; Gauld, Robin; Rades, Thomas

    2009-01-01

    Substandard medicines contribute to poor public health and affect development, especially in the developing world. However knowledge of how manufacturers, distributors and providers understand the concept of drug quality and what strategies they adopt to ensure drug quality is limited, particularly in the developing world. The purpose of this paper is to explore pharmaceutical manufacturers', distributors' and providers' perceptions of drug quality in South Africa and how they ensure the quality of drugs during the distribution process. The approach taken was qualitative data collection through key informant interviews using a semi-structured interview guide. Transcripts were analysed thematically in Johannesburg, Pretoria and Durban, South Africa. Participants were recruited purposefully from a South African pharmaceutical manufacturer, SA subsidiaries of international manufacturers, national distribution companies, national wholesaler, public and private sector pharmacists, and a dispensing doctor. In total, ten interviews were conducted. Participants described drug quality in terms of the product and the processes involved in manufacturing and handling the product. Participants identified purchasing registered medicines from licensed suppliers, use of standard operating procedures, and audits between manufacturer and distributor and/or provider as key strategies employed to protect medicine quality. Effective communication amongst all stakeholders, especially in terms of providing feedback regarding complaints about medicine quality, appears as a potential area of concern, which would benefit from further research. The paper hightlights that ensuring medicine quality should be a shared responsibility amongst all involved in the distribution process to prevent medicines moving from one distribution system (public) into another (private).

  14. Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients

    Directory of Open Access Journals (Sweden)

    Hanae Takatsuki, PhD

    2016-10-01

    Full Text Available Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creutzfeldt-Jakob disease patients at autopsy. Although infectivity of the sporadic form is thought to be restricted within the central nervous system, results showed that prion-seeding activities reach 106/g from a 50% seeding dose in non-neuronal tissues, suggesting that prion-seeding activity exists in non-neural organs, and we suggested that non-neural tissues of 106/g SD50 did not exist the infectivity.

  15. Prion-Seeding Activity Is widely Distributed in Tissues of Sporadic Creutzfeldt-Jakob Disease Patients.

    Science.gov (United States)

    Takatsuki, Hanae; Fuse, Takayuki; Nakagaki, Takehiro; Mori, Tsuyoshi; Mihara, Ban; Takao, Masaki; Iwasaki, Yasushi; Yoshida, Mari; Murayama, Shigeo; Atarashi, Ryuichiro; Nishida, Noriyuki; Satoh, Katsuya

    2016-10-01

    Human prion diseases are neurodegenerative disorders caused by abnormally folded prion proteins in the central nervous system. These proteins can be detected using the quaking-induced conversion assay. Compared with other bioassays, this assay is extremely sensitive and was used in the present study to determine prion distribution in sporadic Creutzfeldt-Jakob disease patients at autopsy. Although infectivity of the sporadic form is thought to be restricted within the central nervous system, results showed that prion-seeding activities reach 10 6 /g from a 50% seeding dose in non-neuronal tissues, suggesting that prion-seeding activity exists in non-neural organs, and we suggested that non-neural tissues of 10 6 /g SD50 did not exist the infectivity. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  16. Tissue distribution of 3H-corticosterone in response to stress

    International Nuclear Information System (INIS)

    Kolta, M.G.; Soliman, K.F.A.

    1981-01-01

    The level and distribution of 3 H-corticosterone ( 3 H-B) was investigated in adult male Sprague-Dawley rats in response to diethyl ether stress, epinephrine (EP) and/or dexamethasone administration. Diethyl ether stress caused a significant increase in the 3 H-B counts by some of the body tissues and brain regions studied. Plasma 3 H-B counts in the stressed rats were found to be twice as much as in the control animals. When EP (1.0 mg/kg) was injected, the tissue-plasma ratios of 3 H-B were significantly lower (P 3 H-B count in the plasma in response to diethyl ether stress or EP may indicate a decline in rate of corticosterone metabolism. (author)

  17. Distribution of lymphocyte subsets in the small intestine lymphoid tissue of 1-month-old lambs.

    Science.gov (United States)

    Corpa, J M; Juste, R A; García Marín, J F; Reyes, L E; González, J; Pérez, V

    2001-04-01

    Distribution of lymphocyte subpopulations along the small intestine lymphoid tissue has been examined in 1-month-old lambs using flow cytometric and immunohistochemical techniques. Monoclonal antibodies against CD4, CD8, gamma delta, CD45R and B receptors have been employed in samples from continuous ileal Peyer's patch (IPP), discrete jejunal Peyer's patches (JPP), ileocaecal valve lymphoid tissue (ICVPP), mesenteric lymph node (MLN) and intra-epithelial (IEL) and lamina propria (LPL) lymphocytes. Histological studies were also done. Differences in the lymphocyte distribution have been observed between some of the regions examined, especially between IPP and JPP for most of the markers. A remarkable feature was the existence of morphological and lymphocyte distribution differences between ICVPP and IPP, locations that had been traditionally considered as similar. The antibody against CD45R receptor used in this study, that was supposed to mark B cells and some T cells, detected cell populations located in the dome of the follicles in all the samples, whereas the centre was negative. Lymphocytes positive to the B marker employed were located mainly in the centre, suggesting that both antibodies would mark B cells in different maturation status.

  18. Distribution of cyclosporine A in ocular tissues after topical administration of cyclosporine A cationic emulsions to pigmented rabbits.

    Science.gov (United States)

    Daull, Philippe; Lallemand, Frédéric; Philips, Betty; Lambert, Grégory; Buggage, Ronald; Garrigue, Jean-Sébastien

    2013-03-01

    The aim of this study was to compare the ocular and systemic distribution of cyclosporine A (CsA) in rabbits after the instillation of preservative-free CsA cationic and anionic emulsions. For the single-dose pharmacokinetic (PK) study, rabbits were instilled with 50 μL of the test material. For the multiple-dose PK study, rabbits were instilled twice daily with Restasis or once daily with NOVA22007 for 10 days. At each time point, the cornea, conjunctiva, and whole blood were harvested for CsA quantification. Ocular and systemic distribution were determined after 4 times daily instillations with 50 μL of 3H-CsA cationic and anionic emulsions for 7 days. Restasis was used as a reference in all studies. Single-dose PK data demonstrated that NOVA22007 0.1% and 0.05% delivered higher CsA concentrations to the cornea than Restasis [concentration maximum (C max): 2692, 1372, and 748 ng/g, respectively] and have a better exposition (area under the curve). Conjunctival Cmax values were 1914, 696, and 849 ng/g and area under the curve values were 3984, 2796, and 2515 ng/g · h, for either dose of the cationic emulsions and Restasis, respectively. The multiple-dose PK and the 3H-CsA distribution data demonstrated that the systemic distribution after repeated instillations was low and comparable for all emulsions. These data demonstrate that the CsA cationic emulsions were more effective than Restasis at delivering CsA to target tissues, thus confirming the potential advantage of cationic emulsions over anionic emulsions as vehicle for ocular drug delivery for the treatment of ocular surface diseases.

  19. Automated local bright feature image analysis of nuclear protein distribution identifies changes in tissue phenotype

    International Nuclear Information System (INIS)

    Knowles, David; Sudar, Damir; Bator, Carol; Bissell, Mina

    2006-01-01

    The organization of nuclear proteins is linked to cell and tissue phenotypes. When cells arrest proliferation, undergo apoptosis, or differentiate, the distribution of nuclear proteins changes. Conversely, forced alteration of the distribution of nuclear proteins modifies cell phenotype. Immunostaining and fluorescence microscopy have been critical for such findings. However, there is an increasing need for quantitative analysis of nuclear protein distribution to decipher epigenetic relationships between nuclear structure and cell phenotype, and to unravel the mechanisms linking nuclear structure and function. We have developed imaging methods to quantify the distribution of fluorescently-stained nuclear protein NuMA in different mammary phenotypes obtained using three-dimensional cell culture. Automated image segmentation of DAPI-stained nuclei was generated to isolate thousands of nuclei from three-dimensional confocal images. Prominent features of fluorescently-stained NuMA were detected using a novel local bright feature analysis technique, and their normalized spatial density calculated as a function of the distance from the nuclear perimeter to its center. The results revealed marked changes in the distribution of the density of NuMA bright features as non-neoplastic cells underwent phenotypically normal acinar morphogenesis. In contrast, we did not detect any reorganization of NuMA during the formation of tumor nodules by malignant cells. Importantly, the analysis also discriminated proliferating non-neoplastic cells from proliferating malignant cells, suggesting that these imaging methods are capable of identifying alterations linked not only to the proliferation status but also to the malignant character of cells. We believe that this quantitative analysis will have additional applications for classifying normal and pathological tissues

  20. Distribution of abdominal adipose tissue as a predictor of hepatic steatosis assessed by MRI

    International Nuclear Information System (INIS)

    Ducluzeau, P.-H.; Manchec-Poilblanc, P.; Roullier, V.; Cesbron, E.; Lebigot, J.; Bertrais, S.; Aube, C.

    2010-01-01

    Aim: To evaluate the relationship between the distribution of visceral and subcutaneous adipose tissue and hepatic steatosis assessed using magnetic resonance imaging (MRI). Materials and methods: One T1-weighted, in-/out-of-phase, single-section sequence at the L3/L4 level and one multi-echo gradient MRI (MGRE) sequence were performed on 65 patients [19 females and 46 males; age 57 ± 9.5 years; body mass index (BMI) 31 ± 5.1 kg/m 2 ]. Visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) surfaces, and hepatic steatosis were automatically calculated using in-house software. Weight, height, BMI, waist circumference, hip circumference, and waist:hip ratio were recorded. The probability of having a steatosis greater than 10% on MRI was evaluated by receiver operating characteristic (ROC) curves. Results: The anthropometric parameter best correlated to hepatic steatosis was the waist-to-hip ratio (r = 0.301). VAT and proportion of VAT were correlated to liver fat content (r = 0.307 and r = 0.249, respectively). No significant correlations were found for BMI, hip circumference, and SAT. The area under the receiver operating characteristics (AUROCs) for the relationship between liver steatosis and BMI, waist circumference, waist:hip ratio, VAT surface, and proportion of VAT, were respectively 0.52, 0.63, 0.71, 0.73 and 0.75. Conclusion: Adipose tissue distribution is more relevant than total fat mass when assessing the possibility of liver steatosis in overweight patients.

  1. Continuous tissue glucose monitoring correlates with measurement of intermittent capillary glucose in patients with distributive shock.

    Science.gov (United States)

    Ballesteros, D; Martínez, Ó; Blancas Gómez-Casero, R; Martín Parra, C; López Matamala, B; Estébanez, B; Chana, M

    2015-10-01

    Intermittent glycemic measurements in patients admitted to the intensive care unit (ICU) can result in episodes of severe hypoglycemia or in a poor control of glycemia range. We designed a study to assess accuracy and reliability of continuous monitoring of tissue glucose for patients with distributive shock. Consecutive patients admitted to the ICU with a diagnosis of distributive shock and the need of insulin infusion for glycemic control were included in the study. These patients were implanted a Continuous Glucose Control Monitoring System (CGMS) with the sensor inserted subcutaneously into the abdominal wall. CGMS values were recorded every 5min. Capillary glucose (CG) was monitored for adjusting insulin perfusion according to the ICU protocol. Correlation between both methods was assessed. A total of 11,673 CGMS and 348 CG values were recorded. In five patients, CGMS failed to detect tissue glucose. A glucose value <3.33mmol/l (<60mg/dl) was observed in 3.6% of CGMS and in 0.29% CG values. 295 pairs of measurements were included in the statistical analysis for correlation assessment. The intraclass correlation coefficient was 0.706. The Pearson correlation coefficient was 0.71 (p<0.0001, 95% CI 0.65-0.76). The mean of differences between both measurement methods was 0.22mmol/l (3.98mg/dl) (95% CI 0.66-7.31). When the Continuous Glucose Control Monitoring System (CGMS) is able to obtain data (75% of the patients), there is correlation between the values obtained by this method and capillary blood glucose in patients with distributive shock. CGMS can detect more episodes of glycemic excursions outside the normal range than intermittent capillary glucose monitoring. Variables that may impair glucose metabolism and peripheral soft tissues perfusion could impair CGMS measurements. Copyright © 2014 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

  2. Mechanisms of Vascular Damage by Hemorrhagic Snake Venom Metalloproteinases: Tissue Distribution and In Situ Hydrolysis

    Science.gov (United States)

    Baldo, Cristiani; Jamora, Colin; Yamanouye, Norma; Zorn, Telma M.; Moura-da-Silva, Ana M.

    2010-01-01

    Background Envenoming by viper snakes constitutes an important public health problem in Brazil and other developing countries. Local hemorrhage is an important symptom of these accidents and is correlated with the action of snake venom metalloproteinases (SVMPs). The degradation of vascular basement membrane has been proposed as a key event for the capillary vessel disruption. However, SVMPs that present similar catalytic activity towards extracellular matrix proteins differ in their hemorrhagic activity, suggesting that other mechanisms might be contributing to the accumulation of SVMPs at the snakebite area allowing capillary disruption. Methodology/Principal Findings In this work, we compared the tissue distribution and degradation of extracellular matrix proteins induced by jararhagin (highly hemorrhagic SVMP) and BnP1 (weakly hemorrhagic SVMP) using the mouse skin as experimental model. Jararhagin induced strong hemorrhage accompanied by hydrolysis of collagen fibers in the hypodermis and a marked degradation of type IV collagen at the vascular basement membrane. In contrast, BnP1 induced only a mild hemorrhage and did not disrupt collagen fibers or type IV collagen. Injection of Alexa488-labeled jararhagin revealed fluorescent staining around capillary vessels and co-localization with basement membrane type IV collagen. The same distribution pattern was detected with jararhagin-C (disintegrin-like/cysteine-rich domains of jararhagin). In opposition, BnP1 did not accumulate in the tissues. Conclusions/Significance These results show a particular tissue distribution of hemorrhagic toxins accumulating at the basement membrane. This probably occurs through binding to collagens, which are drastically hydrolyzed at the sites of hemorrhagic lesions. Toxin accumulation near blood vessels explains enhanced catalysis of basement membrane components, resulting in the strong hemorrhagic activity of SVMPs. This is a novel mechanism that underlies the difference between

  3. Distribution of lymphatic tissues and autonomic nerves in supporting ligaments around the cervix uteri.

    Science.gov (United States)

    Zhang, Jianping; Feng, Lanlan; Lu, Yi; Guo, Dongxia; Xi, Tengteng; Wang, Xiaochun

    2013-05-01

    To investigate the distribution of lymphatic tissues and nerves in the supporting ligaments around the cervix uteri for their tomographical relationship, 9 adult female cadavers were used in this study. Following the incision of all supporting ligaments around the cervix, hematoxylin and esosin (H&E) and immunohistochemical staining of various sections of these ligaments was performed to enable the distribution of lymph tissues and autonomic nerves to be observed. Four lymph nodes were identified in three cadaver specimens. Three lymph nodes were present at a distance of 2.0 cm from the cervix in the cranial side of the cardinal ligaments (CLs), and one lymph node was located at a distance of 4.0 cm from the cervix in the cranial side of the uterosacral ligament (USL). The lymphatic vessels were dispersed in the CLs, scattered in the cervical side of the USLs, and occasionally distributed in the vesicouterine ligaments (VULs). In the CLs, parasympathetic nerves were located at the pelvic lateral wall and went downwards and medially into the cervix, while sympathetic fibers were located in the middle and lower parts of the ligaments. In the USLs, the autonomic nerves, which consisted primarily of sympathetic fibers, went downwards and laterally from the pelvic wall to the cervix. In the VULs, parasympathetic and sympathetic nerves were located in the inner sides of the vesical veins in the deep layers of the ligaments. It is concluded that there are few lymphatic tissues in the supporting ligaments around the cervix uteri, and that nerve‑sparing radical hysterectomy (NSRH) may be a safe method for the treatment of early‑stage cervical cancer.

  4. Tissue

    Directory of Open Access Journals (Sweden)

    David Morrissey

    2012-01-01

    Full Text Available Purpose. In vivo gene therapy directed at tissues of mesenchymal origin could potentially augment healing. We aimed to assess the duration and magnitude of transene expression in vivo in mice and ex vivo in human tissues. Methods. Using bioluminescence imaging, plasmid and adenoviral vector-based transgene expression in murine quadriceps in vivo was examined. Temporal control was assessed using a doxycycline-inducible system. An ex vivo model was developed and optimised using murine tissue, and applied in ex vivo human tissue. Results. In vivo plasmid-based transgene expression did not silence in murine muscle, unlike in liver. Although maximum luciferase expression was higher in muscle with adenoviral delivery compared with plasmid, expression reduced over time. The inducible promoter cassette successfully regulated gene expression with maximum levels a factor of 11 greater than baseline. Expression was re-induced to a similar level on a temporal basis. Luciferase expression was readily detected ex vivo in human muscle and tendon. Conclusions. Plasmid constructs resulted in long-term in vivo gene expression in skeletal muscle, in a controllable fashion utilising an inducible promoter in combination with oral agents. Successful plasmid gene transfection in human ex vivo mesenchymal tissue was demonstrated for the first time.

  5. Influence of the chemical composition of human tissues on dose distributions in hadron-therapy

    International Nuclear Information System (INIS)

    Batin, E.

    2008-06-01

    To compute the dose distribution, treatment planning systems require the exact anatomical location of tissues provided by computed tomography (CT) and the exact range of hadron beams in tissues based on the water equivalent ratio (WER). Since CT numbers are determined with x-rays and with an energy different from that used in hadron-therapy, a relation between CT numbers and the WER must to be established. We propose a determination of the WER with a Monte-Carlo simulation (GEANT4). We have determined the WER for 76 human tissues for a 135 MeV proton beam and for a 290 MeV/A carbon beam. The difference between the stoichiometric calibration and the simulated WER is lower than 1%. An additional 2% uncertainty that arises from the uncertainty in the CT numbers measurement should also be considered. The calculated WER were used to convert the deposited energy curve into the human tissue deposited energy curve for a 135 MeV proton beam and for a 290 MeV/A carbon beam. For both beams, the difference between the rescaled Bragg peak location and the one from the simulated curve is lower than 0.5 mm over the whole range of CT numbers. The differences between the maximum deposited energy can reach 3% for the proton beam in bones and vary between 1.5% and 3.5% for all tissues for the carbon beam. The scaling in two dimensions can be improved by using an additional factor that takes the scattering into account. (author)

  6. DISTRIBUTION Of AFLATOXIN B1 FROM POULTRY FEED TO DIFFERENT BODY TISSUES OF BROILERS

    Directory of Open Access Journals (Sweden)

    Farida Begum, A. Rehman1, G. Maliha and J. Nuzhat

    2001-07-01

    Full Text Available This study was carried out to know the distribution of aflatoxin B1 In various edible tissues of broilers from poultry feed at the stage of marketing. For this purpose liver, kidney, dressed meat and poultry feed of the representative flocks were collected and oven dried. The aflatoxin B1 contents of the samples were .e; determined through thin layer chromatography, The data thus collected were statistically analyzed and the results showed that the aflatoxin B1 level was higher (P<0.01 in liver as compared to kidneys and meat.

  7. Examining the Spatial Distribution of Law Enforcement Encounters among People Who Inject Drugs after Implementation of Mexico’s Drug Policy Reform

    OpenAIRE

    Gaines, Tommi L.; Beletsky, Leo; Arredondo, Jaime; Werb, Daniel; Rangel, Gudelia; Vera, Alicia; Brouwer, Kimberly

    2014-01-01

    In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n = 461) ...

  8. Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution.

    Science.gov (United States)

    Clewe, Oskar; Karlsson, Mats O; Simonsson, Ulrika S H

    2015-12-01

    Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid ≥ LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.

  9. Are predictions of cancer response to targeted drugs, based on effects in unrelated tissues, the 'Black Swan' events?

    Science.gov (United States)

    Kurbel, Beatrica; Golem, Ante Zvonimir; Kurbel, Sven

    2015-01-01

    Adverse effects of targeted drugs on normal tissues can predict the cancer response. Rash correlates with efficacy of erlotinib, cetuximab and gefitinib and onset of arterial hypertension with response to bevacizumab, sunitinib, axitinib and sorafenib, possible examples of 'Black Swan' events, unexpected scientific observations, as described by Karl Popper in 1935. The proposition is that our patients have individual intrinsic variants of cell growth control, important for tumor response and adverse effects on tumor-unrelated tissue. This means that the lack of predictive side effects in healthy tissue is linked with poor results of tumor therapy when tumor resistance is caused by mechanisms that protect all cells of that patient from the targeted drug effects.

  10. 3D Printing of Calcium Phosphate Ceramics for Bone Tissue Engineering and Drug Delivery.

    Science.gov (United States)

    Trombetta, Ryan; Inzana, Jason A; Schwarz, Edward M; Kates, Stephen L; Awad, Hani A

    2017-01-01

    Additive manufacturing, also known as 3D printing, has emerged over the past 3 decades as a disruptive technology for rapid prototyping and manufacturing. Vat polymerization, powder bed fusion, material extrusion, and binder jetting are distinct technologies of additive manufacturing, which have been used in a wide variety of fields, including biomedical research and tissue engineering. The ability to print biocompatible, patient-specific geometries with controlled macro- and micro-pores, and to incorporate cells, drugs and proteins has made 3D-printing ideal for orthopaedic applications, such as bone grafting. Herein, we performed a systematic review examining the fabrication of calcium phosphate (CaP) ceramics by 3D printing, their biocompatibility in vitro, and their bone regenerative potential in vivo, as well as their use in localized delivery of bioactive molecules or cells. Understanding the advantages and limitations of the different 3D printing approaches, CaP materials, and bioactive additives through critical evaluation of in vitro and in vivo evidence of efficacy is essential for developing new classes of bone graft substitutes that can perform as well as autografts and allografts or even surpass the performance of these clinical standards.

  11. Human iPSC-derived cardiomyocytes and tissue engineering strategies for disease modeling and drug screening.

    Science.gov (United States)

    Smith, Alec S T; Macadangdang, Jesse; Leung, Winnie; Laflamme, Michael A; Kim, Deok-Ho

    Improved methodologies for modeling cardiac disease phenotypes and accurately screening the efficacy and toxicity of potential therapeutic compounds are actively being sought to advance drug development and improve disease modeling capabilities. To that end, much recent effort has been devoted to the development of novel engineered biomimetic cardiac tissue platforms that accurately recapitulate the structure and function of the human myocardium. Within the field of cardiac engineering, induced pluripotent stem cells (iPSCs) are an exciting tool that offer the potential to advance the current state of the art, as they are derived from somatic cells, enabling the development of personalized medical strategies and patient specific disease models. Here we review different aspects of iPSC-based cardiac engineering technologies. We highlight methods for producing iPSC-derived cardiomyocytes (iPSC-CMs) and discuss their application to compound efficacy/toxicity screening and in vitro modeling of prevalent cardiac diseases. Special attention is paid to the application of micro- and nano-engineering techniques for the development of novel iPSC-CM based platforms and their potential to advance current preclinical screening modalities. Published by Elsevier Inc.

  12. 3D Printing of Calcium Phosphate Ceramics for Bone Tissue Engineering and Drug Delivery

    Science.gov (United States)

    Trombetta, Ryan; Inzana, Jason A.; Schwarz, Edward M.; Kates, Stephen L.; Awad, Hani A.

    2016-01-01

    Additive manufacturing, also known as 3D printing, has emerged over the past 3 decades as a disruptive technology for rapid prototyping and manufacturing. Vat polymerization, powder bed fusion, material extrusion, and binder jetting are distinct technologies of additive manufacturing, which have been used in a wide variety of fields, including biomedical research and tissue engineering. The ability to print biocompatible, patient-specific geometries with controlled macro- and micropores, and to incorporate cells, drugs and proteins has made 3D-printing ideal for orthopaedic applications, such as bone grafting. Herein, we performed a systematic review examining the fabrication of calcium phosphate (CaP) ceramics by 3D printing, their biocompatibility in vitro, and their bone regenerative potential in vivo, as well as their use in localized delivery of bioactive molecules or cells. Understanding the advantages and limitations of the different 3D printing approaches, CaP materials, and bioactive additives through critical evaluation of in vitro and in vivo evidence of efficacy is essential for developing new classes of bone graft substitutes that can perform as well as autografts and allografts or even surpass the performance of these clinical standards. PMID:27324800

  13. Tissue distribution and tumour localization of 99m-technetium-labelled liposomes in cancer patients

    Energy Technology Data Exchange (ETDEWEB)

    Richardson, V J; Ryman, B E; Jewkes, R F; Jeyasingh, K; Tattersall, M N.H.; Newlands, E S; Kaye, S B

    1979-07-01

    The possible use of liposomes (Phospholipid vesicles) to direct cytotoxic drugs to tumours led to the investigation of the tissue localization of i.v. injected sup(99m) Tc-labelled liposomes in cancer patients. 20 mg or 300 mg doses of liposomal lipid (7:2:1 molar ratio of phosphatidylcholine: cholesterol: phosphatidic acid) were used in a study of 13 patients with advanced cancer and one with polycythaemia rubra vera (PRV). In all cases except the patient with PRV the major site of uptake of the label was the liver and spleen. In the patient with PRV the liver uptake was greatly reduced and the major site of uptake was found in regions corresponding to marrow. With the exception of one patient with a primary hepatoma, there was no significant tumour uptake of the label.

  14. Label Distribution in Tissues of Wheat Seedlings Cultivated with Tritium-Labeled Leonardite Humic Acid

    Science.gov (United States)

    Kulikova, Natalia A.; Abroskin, Dmitry P.; Badun, Gennady A.; Chernysheva, Maria G.; Korobkov, Viktor I.; Beer, Anton S.; Tsvetkova, Eugenia A.; Senik, Svetlana V.; Klein, Olga I.; Perminova, Irina V.

    2016-06-01

    Humic substances (HS) play important roles in the biotic-abiotic interactions of the root plant and soil contributing to plant adaptation to external environments. However, their mode of action on plants remains largely unknown. In this study the HS distribution in tissues of wheat seedlings was examined using tritium-labeled humic acid (HA) derived from leonardite (a variety of lignites) and microautoradiography (MAR). Preferential accumulation of labeled products from tritiated HA was found in the roots as compared to the shoots, and endodermis was shown to be the major control point for radial transport of label into vascular system of plant. Tritium was also found in the stele and xylem tissues indicating that labeled products from tritiated HA could be transported to shoot tissues via the transpiration stream. Treatment with HA lead to an increase in the content of polar lipids of photosynthetic membranes. The observed accumulation of labeled HA products in root endodermis and positive impact on lipid synthesis are consistent with prior reported observations on physiological effects of HS on plants such as enhanced growth and development of lateral roots and improvement/repairs of the photosynthetic status of plants under stress conditions.

  15. Radiation effect on 67Ga retention and distribution in mouse tissues

    International Nuclear Information System (INIS)

    Mainwaring, H.R.; Swartzendruber, D.C.; Lushbaugh, C.C.; Idoyaga-Vargas, N.L.; Watson, E.E.

    1976-01-01

    We have studied the effect of external x irradiation on the whole-body retention and tissue distribution of gallium-67 ( 67 Ga) in mice over a period of 20 days. Adult male C57BL/6 Cum mice were injected intraperitoneally with 5 μCi 67 Ga 24 hr before, immediately before, immediately after, or 24 hr after whole-body x-ray exposure to 450 R. Control mice received 67 Ga injections and sham irradiation. Increased excretion and reduced soft-tissue concentrations of 67 Ga occurred in irradiated mice. The greatest effect was observed when the radionuclide was injected 24 hr after irradiation and assayed 24 hr later. An analysis of variance of the retention data showed that the differences between the groups were significant at the 99 percent confidence level. Exponential least-squares analysis of whole-body counting results revealed three compartments in the biological retention data. The long-lived compartment possibly corresponds to 67 Ga bound relatively tightly in certain body tissues and lost slowly. The two remaining compartments have been tentatively identified as circulating unbound 67 Ga that is lost rapidly and circulating bound 67 Ga that is lost less rapidly

  16. The pea SAD short-chain dehydrogenase/reductase: quinone reduction, tissue distribution, and heterologous expression.

    Science.gov (United States)

    Scherbak, Nikolai; Ala-Häivälä, Anneli; Brosché, Mikael; Böwer, Nathalie; Strid, Hilja; Gittins, John R; Grahn, Elin; Eriksson, Leif A; Strid, Åke

    2011-04-01

    The pea (Pisum sativum) tetrameric short-chain alcohol dehydrogenase-like protein (SAD) family consists of at least three highly similar members (SAD-A, -B, and -C). According to mRNA data, environmental stimuli induce SAD expression. The aim of this study was to characterize the SAD proteins by examining their catalytic function, distribution in pea, and induction in different tissues. In enzyme activity assays using a range of potential substrates, the SAD-C enzyme was shown to reduce one- or two-ring-membered quinones lacking long hydrophobic hydrocarbon tails. Immunological assays using a specific antiserum against the protein demonstrated that different tissues and cell types contain small amounts of SAD protein that was predominantly located within epidermal or subepidermal cells and around vascular tissue. Particularly high local concentrations were observed in the protoderm of the seed cotyledonary axis. Two bow-shaped rows of cells in the ovary and the placental surface facing the ovule also exhibited considerable SAD staining. Ultraviolet-B irradiation led to increased staining in epidermal and subepidermal cells of leaves and stems. The different localization patterns of SAD suggest functions both in development and in responses to environmental stimuli. Finally, the pea SAD-C promoter was shown to confer heterologous wound-induced expression in Arabidopsis (Arabidopsis thaliana), which confirmed that the inducibility of its expression is regulated at the transcriptional level.

  17. Tissue Distribution and Elimination of Ciguatoxins in Tridacna maxima (Tridacnidae, Bivalvia Fed Gambierdiscus polynesiensis

    Directory of Open Access Journals (Sweden)

    Mélanie Roué

    2018-05-01

    Full Text Available Ciguatera is a foodborne disease caused by the consumption of seafood contaminated with ciguatoxins (CTXs. Ciguatera-like poisoning events involving giant clams (Tridacna maxima are reported occasionally from Pacific islands communities. The present study aimed at providing insights into CTXs tissue distribution and detoxification rate in giant clams exposed to toxic cells of Gambierdiscus polynesiensis, in the framework of seafood safety assessment. In a first experiment, three groups of tissue (viscera, flesh and mantle were dissected from exposed individuals, and analyzed for their toxicity using the neuroblastoma cell-based assay (CBA-N2a and liquid chromatography-tandem mass spectrometry (LC-MS/MS analyses. The viscera, flesh, and mantle were shown to retain 65%, 25%, and 10% of the total toxin burden, respectively. All tissues reached levels above the safety limit recommended for human consumption, suggesting that evisceration alone, a practice widely used among local populations, is not enough to ensure seafood safety. In a second experiment, the toxin content in contaminated giant clams was followed at different time points (0, 2, 4, and 6 days post-exposure. Observations suggest that no toxin elimination is visible in T. maxima throughout 6 days of detoxification.

  18. Tissue Distribution and Elimination of Ciguatoxins in Tridacna maxima (Tridacnidae, Bivalvia) Fed Gambierdiscus polynesiensis.

    Science.gov (United States)

    Roué, Mélanie; Darius, Hélène Taiana; Ung, André; Viallon, Jérôme; Sibat, Manoella; Hess, Philipp; Amzil, Zouher; Chinain, Mireille

    2018-05-10

    Ciguatera is a foodborne disease caused by the consumption of seafood contaminated with ciguatoxins (CTXs). Ciguatera-like poisoning events involving giant clams ( Tridacna maxima ) are reported occasionally from Pacific islands communities. The present study aimed at providing insights into CTXs tissue distribution and detoxification rate in giant clams exposed to toxic cells of Gambierdiscus polynesiensis , in the framework of seafood safety assessment. In a first experiment, three groups of tissue (viscera, flesh and mantle) were dissected from exposed individuals, and analyzed for their toxicity using the neuroblastoma cell-based assay (CBA-N2a) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses. The viscera, flesh, and mantle were shown to retain 65%, 25%, and 10% of the total toxin burden, respectively. All tissues reached levels above the safety limit recommended for human consumption, suggesting that evisceration alone, a practice widely used among local populations, is not enough to ensure seafood safety. In a second experiment, the toxin content in contaminated giant clams was followed at different time points (0, 2, 4, and 6 days post-exposure). Observations suggest that no toxin elimination is visible in T. maxima throughout 6 days of detoxification.

  19. Evaluation of the Ca2+ distribution in aortic tissue of spontaneously hypertensive and normotensive rats

    International Nuclear Information System (INIS)

    Spieker, C.; Zidek, W.; von Bassewitz, D.B.; Heck, D.; Rahn, K.H.

    1991-01-01

    In the present study, particle-induced X-ray emission (PIXE) was used to get information on the spatial distribution of Ca 2+ in aortas of spontaneously hypertensive rats (SHR) and normotensive controls aged 1 week, 4 weeks, and 12 weeks. To differentiate changes in Ca 2+ metabolism in hypertensive arteries from secondary phenomena due to the arteriosclerosis, the animals were examined in the earliest stage of hypertension. It was found that the Ca 2+ content was not elevated in the aortic smooth muscle of SHR aged 1 week (n = 11), as compared to normotensive controls (n = 10) (186.8 +/- 89.9 micrograms Ca 2+ /g tissue v 254.0 +/- 173.3 micrograms Ca 2+ /g). The Ca 2+ content was raised (P less than .05) in the aortic smooth muscle of SHR aged 4 weeks (n = 13), as compared to 12 WKY rats (4 weeks) (726.0 +/- 130.4 micrograms Ca 2+ /g tissue v 440.3 +/- 214.4 micrograms Ca 2+ /g) and in 17 SHR (3 months), as compared to 13 WKY rats, respectively (3390.1 +/- 729.9 micrograms Ca 2+ /g tissue v 1632.1 +/- 569.5 micrograms Ca 2+ /g). The results confirm the age-related increase in the arterial Ca 2+ content in normotensive rats and demonstrate additionally that this age-related rise in arterial Ca 2+ content is accelerated in SHR

  20. Label Distribution in Tissues of Wheat Seedlings Cultivated with Tritium-Labeled Leonardite Humic Acid

    Science.gov (United States)

    Kulikova, Natalia A.; Abroskin, Dmitry P.; Badun, Gennady A.; Chernysheva, Maria G.; Korobkov, Viktor I.; Beer, Anton S.; Tsvetkova, Eugenia A.; Senik, Svetlana V.; Klein, Olga I.; Perminova, Irina V.

    2016-01-01

    Humic substances (HS) play important roles in the biotic-abiotic interactions of the root plant and soil contributing to plant adaptation to external environments. However, their mode of action on plants remains largely unknown. In this study the HS distribution in tissues of wheat seedlings was examined using tritium-labeled humic acid (HA) derived from leonardite (a variety of lignites) and microautoradiography (MAR). Preferential accumulation of labeled products from tritiated HA was found in the roots as compared to the shoots, and endodermis was shown to be the major control point for radial transport of label into vascular system of plant. Tritium was also found in the stele and xylem tissues indicating that labeled products from tritiated HA could be transported to shoot tissues via the transpiration stream. Treatment with HA lead to an increase in the content of polar lipids of photosynthetic membranes. The observed accumulation of labeled HA products in root endodermis and positive impact on lipid synthesis are consistent with prior reported observations on physiological effects of HS on plants such as enhanced growth and development of lateral roots and improvement/repairs of the photosynthetic status of plants under stress conditions. PMID:27350412

  1. Residues of veterinary drugs in eggs and their distribution between yolk and white

    NARCIS (Netherlands)

    Kan, C.A.; Petz, M.

    2000-01-01

    Veterinary drugs and feed additives (especially some coccidiostats) can be absorbed by the digestive tract of laying hens and transferred to the egg. Physicochemical characteristics of these compounds determine their pharmacokinetic behavior and distribution to and within the egg. Traditionally the

  2. Design of shared unit-dose drug distribution network using multi-level particle swarm optimization.

    Science.gov (United States)

    Chen, Linjie; Monteiro, Thibaud; Wang, Tao; Marcon, Eric

    2018-03-01

    Unit-dose drug distribution systems provide optimal choices in terms of medication security and efficiency for organizing the drug-use process in large hospitals. As small hospitals have to share such automatic systems for economic reasons, the structure of their logistic organization becomes a very sensitive issue. In the research reported here, we develop a generalized multi-level optimization method - multi-level particle swarm optimization (MLPSO) - to design a shared unit-dose drug distribution network. Structurally, the problem studied can be considered as a type of capacitated location-routing problem (CLRP) with new constraints related to specific production planning. This kind of problem implies that a multi-level optimization should be performed in order to minimize logistic operating costs. Our results show that with the proposed algorithm, a more suitable modeling framework, as well as computational time savings and better optimization performance are obtained than that reported in the literature on this subject.

  3. Distribution of Interleukin-22-secreting Immune Cells in Conjunctival Associated Lymphoid Tissue.

    Science.gov (United States)

    Yoon, Chang Ho; Lee, Daeseung; Jeong, Hyun Jeong; Ryu, Jin Suk; Kim, Mee Kum

    2018-04-01

    Interleukin (IL)-22 is a cytokine involved in epithelial cell regeneration. Currently, no research studies have analyzed the distribution of the three distinct IL-22-secreting cell populations in human or mouse conjunctiva. This study investigated the distribution of the three main populations of IL-22-secreting immune cells, αβ Th cells, γδ T cells, or innate cells (innate lymphoid cells [ILCs] or natural killer cells), in conjunctival associated lymphoid tissues (CALTs) in human and mouse models. We collected discarded cadaveric bulbar conjunctival tissue specimens after preservation of the corneo-limbal tissue for keratoplasty from four enucleated eyes of the domestic donor. The bulbar conjunctiva tissue, including the cornea from normal (n = 27) or abraded (n = 4) B6 mice, were excised and pooled in RPMI 1640 media. After the lymphoid cells were gated in forward and side scattering, the αβ Th cells, γδ T cells, or innate lymphoid cells were positively or negatively gated using anti-CD3, anti-γδ TCR, and anti-IL-22 antibodies, with a FACSCanto flow cytometer. In normal human conjunctiva, the percentage and number of cells were highest in αβ Th cells, followed by γδ T cells and CD3- γδ TCR- IL-22+ innate cells (presumed ILCs, pILCs) (Kruskal-Wallis test, p = 0.012). In normal mice keratoconjunctiva, the percentage and total number were highest in γδ T cells, followed by αβ Th cells and pILCs (Kruskal-Wallis test, p = 0.0004); in corneal abraded mice, the population of αβ Th cells and pILCs tended to increase. This study suggests that three distinctive populations of IL-22-secreting immune cells are present in CALTs of both humans and mice, and the proportions of IL-22+αβ Th cells, γδ T cells, and pILCs in CALTs in humans might be differently distributed from those in normal mice. © 2018 The Korean Ophthalmological Society.

  4. Effect of tissue inhomogeneity on dose distribution of point sources of low-energy electrons

    International Nuclear Information System (INIS)

    Kwok, C.S.; Bialobzyski, P.J.; Yu, S.K.; Prestwich, W.V.

    1990-01-01

    Perturbation in dose distributions of point sources of low-energy electrons at planar interfaces of cortical bone (CB) and red marrow (RM) was investigated experimentally and by Monte Carlo codes EGS and the TIGER series. Ultrathin LiF thermoluminescent dosimeters were used to measure the dose distributions of point sources of 204 Tl and 147 Pm in RM. When the point sources were at 12 mg/cm 2 from a planar interface of CB and RM equivalent plastics, dose enhancement ratios in RM averaged over the region 0--12 mg/cm 2 from the interface were measured to be 1.08±0.03 (SE) and 1.03±0.03 (SE) for 204 Tl and 147 Pm, respectively. The Monte Carlo codes predicted 1.05±0.02 and 1.01±0.02 for the two nuclides, respectively. However, EGS gave consistently 3% higher dose in the dose scoring region than the TIGER series when point sources of monoenergetic electrons up to 0.75 MeV energy were considered in the homogeneous RM situation or in the CB and RM heterogeneous situation. By means of the TIGER series, it was demonstrated that aluminum, which is normally assumed to be equivalent to CB in radiation dosimetry, leads to an overestimation of backscattering of low-energy electrons in soft tissue at a CB--soft-tissue interface by as much as a factor of 2

  5. Distribution of biotransformation of methyl mercuric chloride in different tissues of mice

    International Nuclear Information System (INIS)

    Mehra, M.; Choi, B.H.

    1981-01-01

    The distribution of 203 Hg radioactivity has been studied in various organs of adult male and female mice from one hour to 21 days after treating with 203 Hg-labeled methyl mercuric chloride (MMC). The amount of methyl mercury (MeHg) and inorganic mercury (Hg) has also beam determined by injecting single doses of non-radioactive MMC, and subsequently measuring total, organic and inorganic Hg content by atomic absorption technique. In addition, photoemulsion histochemical method (PEHM) was used to demonstrate localization of Hg grains in various cellular compartments of organs and tissues. The highest levels of radioactivity were attained at 7 hours post-treatment on all organs except for brain and testis. The testis showed the highest radioactivity at one day and the brain at two days post-treatment. MeHg persisted in brain over a longer period though the level was not as high. The content of MeHg and inorganic Hg was maximum in kidneys as compared to other organs. The brain and the reproductive organs contained the least amoun of inorganic Hg. By PEHM, Hg grains were most prominently observed in the sinusoids, Kupfer cells, hepatic cells and bile duct epithelium of liver; in the lumen of blood vessels, convoluted and collecting tubules of kidneys; and in the gastrointestinal epithelium. The pattern of uptake and distribution of MeHg correlated well with the morphological demonstration of Hg grains in tissue sections. (author)

  6. Preparation and evaluation of enrofloxacin microspheres and tissue distribution in rats.

    Science.gov (United States)

    Yang, Fan; Kang, Jijun; Yang, Fang; Zhao, Zhensheng; Kong, Tao; Zeng, Zhenling

    2015-01-01

    New enrofloxacin microspheres were formulated, and their physical properties, lung-targeting ability, and tissue distribution in rats were examined. The microspheres had a regular and round shape. The mean diameter was 10.06 µm, and the diameter of 89.93% of all microspheres ranged from 7.0 µm to 30.0 µm. Tissue distribution of the microspheres was evaluated along with a conventional enrofloxacin preparation after a single intravenous injection (7.5 mg of enrofloxacin/kg bw). The results showed that the elimination half-life (t1/2β) of enrofloxacin from lung was prolonged from 7.94 h for the conventional enrofloxacin to 13.28 h for the microspheres. Area under the lung concentration versus time curve from 0 h to ∞ (AUC00∞) was increased from 11.66 h·µg/g to 508.00 h·µg/g. The peak concentration (Cmax) in lung was increased from 5.95 µg/g to 93.36 µg/g. Three lung-targeting parameters were further assessed and showed that the microspheres had remarkable lung-targeting capabilities.

  7. Tissue distribution patterns of solubilized metals from internalized tungsten alloy in the F344 rat

    Directory of Open Access Journals (Sweden)

    Vernieda B. Vergara

    2016-06-01

    Full Text Available Because of its unique physical and chemical properties, tungsten has been increasingly utilized in a variety of civilian and military applications. This expanded use also raises the risk of human exposure through internalization by various routes. In most cases the toxicological and carcinogenic properties of these tungsten-based compounds are not known nor are the dissolution biokinetics and ultimate fate of the associated metals. Using a laboratory rodent model system designed to assess the health effects of embedded metals, and a tungsten alloy comprised of tungsten (91.1%, nickel (6.0%, and cobalt (2.9%, we investigated the tissue distribution patterns of the metals over a six month period. Despite its perceived insolubility, tungsten rapidly solubilized from the implanted metal fragments, as did nickel and cobalt. All three metals distributed systemically over time with extremely elevated levels of all three metals found in kidney, liver, and spleen. Unexpectedly, tungsten was found to cross the blood-brain and blood-testis barriers and localize in those tissues. These results, along with recent reports suggesting that tungsten is a tumor promoter, raises serious concerns as to the long-term health effects of exposure to tungsten and tungsten-based compounds.

  8. Tissue distribution and functional analysis of vitellogenin-6 of Toxocara canis.

    Science.gov (United States)

    Zhu, Hong-Hong; Ma, Guang-Xu; Luo, Yong-Fang; Luo, Yong-Li; Yin, Sha-Sha; Xiong, Yi; Zhou, Rong-Qiong

    2017-06-01

    Toxocara canis is an common intestinal nematode of canids and the principal causative agent of human toxocariasis. Vitellogenin (Vg), a source of amino acids and lipids in the eggs, are considered to play an important role in embryo development of a wide range of organisms. In the present study, the transcriptional levels of Tc-vit-6 gene in male and female adult T. canis were determined by quantitative real-time PCR, which indicated high transcription of Tc-vit-6 in the intestine, reproductive tract and body wall of male and female adult T. canis. The fragment of Tc-vit-6 encoding a vWD domain, was cloned and expressed to produce a rabbit anti-TcvWD polyclonal antibody. Tissue distribution of TcVg6 was detected by immunohistochemical assays, which showed predominant distribution of TcVg6 in the tissues of intestine, as well as reproductive tract (including some of the germ cells) and musculature of male and female adult worms. Collectively, these results indicated multiple biological roles of TcVg6 apart from that in the reproduction of T. canis. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Tissue distribution and elimination of BDE 47 in mice following a single oral dose

    Energy Technology Data Exchange (ETDEWEB)

    Staskal, D. [Curriculum in Toxicology, Chapel Hill, NC (United States); Diliberto, J.; DeVito, M.; Birnbaum, L. [US EPA, ORD, NHEERL, ETD, RTP (United States)

    2004-09-15

    2,2',4,4'-Tetrabromodiphenyl ether (BDE 47) is a polybrominated diphenyl ether (PBDE) congener which is part of a class of brominated flame retardants (BFRs) commonly used in a variety of highly flammable consumer goods. Concern for the effects of PBDEs has increased significantly in recent years as their presence has been detected in environmental samples and in human tissues at steadily increasing concentrations. Despite its small contribution to the PBDE global production and usage, BDE 47 is the major congener found in environmental samples and human tissue. Limited toxicology studies suggest that BDE 47 is a developmental neurotoxicant and an endocrine disruptor however, several data gaps exist and must be investigated in order to evaluate the human health risk of BDE 47. This study investigated basic toxicokinetic properties of BDE 47 in female C57BL/6J mice. Here we report the effect of time on the absorption, distribution, and excretion following a single, oral dose of 14C-labeled BDE 47. Animals were administered 1.0mg BDE 47/kg bw, a dose chosen based on previous studies. Distribution and elimination were monitored at several time points ranging from 1 hour to 21 days following exposure. Data from these basic toxicokinetic studies will be applied to studies investigating the toxicokinetics of BDE 47 in a developmental model as well as in the development of a physiologically-based pharmacokinetic (PBPK) model.

  10. Determination of optical properties, drug concentration, and tissue oxygenation in human pleural tissue before and after Photofrin-mediated photodynamic therapy

    Science.gov (United States)

    Ong, Yi Hong; Padawer-Curry, Jonah; Finlay, Jarod C.; Kim, Michele M.; Dimofte, Andreea; Cengel, Keith; Zhu, Timothy C.

    2018-02-01

    PDT efficacy depends on the concentration of photosensitizer, oxygen, and light delivery in patient tissues. In this study, we measure the in-vivo distribution of important dosimetric parameters, namely the tissue optical properties (absorption μa (λ) and scattering μs ' (λ) coefficients), photofrin concentration (cphotofrin), blood oxygen saturation (%StO2), and total hemoglobin concentration (THC), before and after PDT. We characterize the inter- and intra-patient heterogeneity of these quantities and explore how these properties change as a result of PDT treatment. The result suggests the need for real-time dosimetry during PDT to optimize the treatment condition depending on the optical and physiological properties.

  11. Mitoxantrone Loaded Superparamagnetic Nanoparticles for Drug Targeting: A Versatile and Sensitive Method for Quantification of Drug Enrichment in Rabbit Tissues Using HPLC-UV

    Directory of Open Access Journals (Sweden)

    Rainer Tietze

    2010-01-01

    Full Text Available In medicine, superparamagnetic nanoparticles bound to chemotherapeutics are currently investigated for their feasibility in local tumor therapy. After intraarterial application, these particles can be accumulated in the targeted area by an external magnetic field to increase the drug concentration in the region of interest (Magnetic-Drug-Targeting. We here present an analytical method (HPLC-UV, to detect pure or ferrofluid-bound mitoxantrone in a complex matrix even in trace amounts in order to perform biodistribution studies. Mitoxantrone could be extracted in high yields from different tissues. Recovery of mitoxantrone in liver tissue (5000 ng/g was 76±2%. The limit of quantification of mitoxantrone standard was 10 ng/mL ±12%. Validation criteria such as linearity, precision, and stability were evaluated in ranges achieving the FDA requirements. As shown for pilot samples, biodistribution studies can easily be performed after application of pure or ferrofluid-bound mitoxantrone.

  12. Distribution and accumulation of rotenone in tissues of warm water fishes

    International Nuclear Information System (INIS)

    Rach, J.J.; Gingerich, W.H.

    1986-01-01

    The tissue distribution of rotenoid residues was determined in tissues of common carp Cyprinus carpio (88.2 g), bluegills Lepomis macrochirus (47.9 g), and yellow perch Perca flavescens (67.7 g) after the fish were exposed to 50μg/L of rotenone-6a 14 C(15.9 x 10 4 Bq/μM). Exposures were terminated 1 h after the fish were moribund and failed to respond to gentle prodding. The fish were dissected, and various tissues were oxidized to determine 14 C-rotenone accumulation and distribution. Major rotenone metabolites were identified by gradient-elution high performance liquid chromatography. The exposure time required for fish to reach total incapacitation was 3 h for bluegills and yellow perch, and 11.25 h for common carp. The mean rotenoid concentrations (μg/100g fish) in the whole body were 22.4 in yellow perch, 39.7 in bluegills, and 107.8 in common carp. The percentage of rotenone-derived 14 C activity was higher in the carcass components than in the head or viscera; the skin and bone contained about 60% of the carcass activity. The highest relative rotenoid concentrations were found in the liver, bile, gills, brain, and heart. Percentages of total rotenoid material as parent rotenone were highest in yellow perch (70.0 in the viscera and 84.4 in the fillet), followed by those for bluegills (22.7 and 27.8) and common carp (9.7 and 48.5)

  13. Tissue distribution and effects of fasting and obesity on the ghrelin axis in mice.

    Science.gov (United States)

    Morash, Michael G; Gagnon, Jeffrey; Nelson, Stephanie; Anini, Younes

    2010-08-09

    Ghrelin is a 28 amino acid peptide hormone derived from the 117 amino acid proghrelin, following cleavage by proprotein convertase 1 (PC1). In this study, we comprehensively assessed the tissue distribution and the effect of fasting and obesity on preproghrelin, Exon-4D, PC1 and GOAT expression and proghrelin-derived peptide (PGDP) secretion. The stomach was the major source of preproghrelin expression and PDGPs, followed by the small intestine. The remaining peripheral tissues (including the brain and pancreas) contained negligible expression levels. We detected obestatin in all stomach proghrelin cells, however, 22% of proghrelin cells in the small intestine did not express obestatin. There were strain differences in ghrelin secretion in response to fasting between CD1 and C57BL/6 mice. After a 24 hour-fast, CD1 mice had increased plasma levels of total ghrelin and obestatin with no change in preproghrelin mRNA or PGDP tissues levels. C57BL/6 mice showed a different response to a 24 hour-fast having increased proghrelin mRNA expression, stomach acylated ghrelin peptide and no change in plasma obestatin in C57BL/6 mice. In obese mice (ob/ob and diet-induced obesity (DIO)) there was a significant increase in preproghrelin mRNA levels while tissue and plasma PGDP levels were significantly reduced. Fasting did not affect PGDP in obese mice. Obese models displayed differences in GOAT expression, which was elevated in DIO mice, but reduced in ob/ob mice. We did not find co-localization of the leptin receptor in ghrelin expressing stomach cells, ruling out a direct effect of leptin on stomach ghrelin synthesis and secretion. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  14. Distribution of trace elements in tissues of shrimp species Litopenaeus vannamei (Boone, 1931 from Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    E. Silva

    Full Text Available Abstract In this study, concentrations of trace elements in tissues of shrimp species (Litopenaeus vannamei from farming and zone natural coastal located in the northeastern Brazil were investigated. The elements determination was performed by optical emission spectrometry with inductively coupled plasma (ICP OES. The following ranges of concentrations in the tissues were obtained in µg g–1 dry weight: Al: 13.4-886.5, Cd: 0.93-1.80; Cu: 24.8-152; Fe: 3.2-410.9; Mn: 0.36-24.4; Se: 0.094-9.81 and Zn: 20.3-109.4. The shrimp muscle can be a good iron source (about 88.9 mg–1g dry weight. The distribution of Se concentration in tissues showed much variation between locations, and the concentration levels found in shrimp muscles of wild samples were high, where its levels in 67% of muscle and 50% of others tissues samples exceeded the ANVISA limit, indicating evidence of selenium bioaccumulation. Significant correlation was observed between the following pairs of elements: Fe-Zn (r= –0.70, Mn-Cu (r= –0.74, Se-Cu (r= –0.68, Se-Mn (r= 0.82 in the muscles; Fe-Al (r= 0.99, Mn-Al (r= 0.62, Mn-Fe (r= 0.62, Se-Al (r = 0.88, Se-Fe (r= 0.87, Se-Mn (r= 0.58 in the exoskeleton and Cu-Zn (r = 0.68, Al-Cu (r= 0.88, Fe-Cu (r= 0.95 and Fe-Al (r= 0.97 in the viscera.

  15. Bioavailability and nervous tissue distribution of pyrethroid insecticide cyfluthrin in rats.

    Science.gov (United States)

    Rodríguez, José-Luis; Ares, Irma; Martínez, Marta; Martínez-Larrañaga, María-Rosa; Anadón, Arturo; Martínez, María-Aránzazu

    2018-05-08

    Toxicokinetics of cyfluthrin after single oral [20 mg/kg body weight (bw)] and intravenous (IV) (3 mg/kg bw) doses were studied in rats. Serial blood samples were obtained after oral and IV administration. Brain tissue samples were also collected after oral administration. Cyfluthrin concentrations in plasma and brain tissues (hypothalamus, striatum, hippocampus and frontal cortex) were quantified using liquid chromatography tandem mass spectrometry (LC/MS). Cyfluthrin disposition was best described by the use of a two-compartment open model. When given orally, plasma kinetics showed an extensive oral absorption of cyfluthrin and a slow elimination. The area under the concentration-time curve [AUC (0-24h) ] and maximal plasma concentration (Cmax) were 6.11 ± 1.06 mg h/L and 0.385 ± 0.051 μg/mL, respectively; β phase elimination half-life (T 1/2 β) was (17.15 ± 1.67 h). Oral bioavailability was found to be 71.60 ± 12.36%. After oral administration, cyfluthrin was widely distributed to brain tissues. AUC (0-24h) was significant higher in all tested brain tissues than in plasma. The largest discrepancy was found for hypothalamus. AUC (0-24h) , Cmax and T 1/2 β in hypothalamus were 19.36 ± 2.56 mg h/L, 1.21 ± 0.11 μg/g and 22.73 ± 1.60 h, respectively. Assuming the identified toxicokinetics parameters, this study serves to better understand mammalian toxicity of pyrethroid cyfluthrin and to design further studies to characterize its neurotoxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Financial Effect of a Drug Distribution Model Change on a Health System.

    Science.gov (United States)

    Turingan, Erin M; Mekoba, Bijan C; Eberwein, Samuel M; Roberts, Patricia A; Pappas, Ashley L; Cruz, Jennifer L; Amerine, Lindsey B

    2017-06-01

    Background: Drug manufacturers change distribution models based on patient safety and product integrity needs. These model changes can limit health-system access to medications, and the financial impact on health systems can be significant. Objective: The primary aim of this study was to determine the health-system financial impact of a manufacturer's change from open to limited distribution for bevacizumab (Avastin), rituximab (Rituxan), and trastuzumab (Herceptin). The secondary aim was to identify opportunities to shift administration to outpatient settings to support formulary change. Methods: To assess the financial impact on the health system, the cost minus discount was applied to total drug expenditure during a 1-year period after the distribution model change. The opportunity analysis was conducted for three institutions within the health system through chart review of each inpatient administration. Opportunity cost was the sum of the inpatient administration cost and outpatient administration margin. Results: The total drug expenditure for the study period was $26 427 263. By applying the cost minus discount, the financial effect of the distribution model change was $1 393 606. A total of 387 administrations were determined to be opportunities to be shifted to the outpatient setting. During the study period, the total opportunity cost was $1 766 049. Conclusion: Drug expenditure increased for the health system due to the drug distribution model change and loss of cost minus discount. The opportunity cost of shifting inpatient administrations could offset the increase in expenditure. It is recommended to restrict bevacizumab, rituximab, and trastuzumab through Pharmacy & Therapeutics Committees to outpatient use where clinically appropriate.

  17. Microfocus study of metal distribution and speciation in tissue extracted from revised metal on metal hip implants

    International Nuclear Information System (INIS)

    Hart, Alister J; Sandison, Ann; Quinn, Paul; Mosselmans, J Frederick W; Sampson, Barry; Atkinson, Kirk D; Skinner, John A; Goode, Angela; Powell, Jonathan J

    2009-01-01

    Unexplained tissue inflammation in metal-on-metal hip replacements is suspected to be caused by implant-derived nanoparticles. The aim of this study was to investigate the nature of the metal particles in tissue surrounding metal-on-metal (MOM) hips that has been extracted during revision. Mapping of tissue surrounding the failed MOM hips was performed using microfocus X-ray Fluorescence (XRF). This revealed mainly Cr which was localized to the cellular regions. There was co-localisation of Co, were present, to areas of high Cr abundance. XANES of the tissue and appropriate standards revealed that the most common species were Cr(III) and Co(II). EXAFS analysis of the tissue and various metal standards revealed that the most abundant implant-related species was Cr(III) phosphate. Different tissue preparation methods, including frozen sectioning, were examined but were found not to affect the distribution or speciation of the metals in the tissue.

  18. Microfocus study of metal distribution and speciation in tissue extracted from revised metal on metal hip implants

    Energy Technology Data Exchange (ETDEWEB)

    Hart, Alister J [Department of Orthopaedic Surgery, Imperial College and Imperial College Healthcare NHS Trust, Charing Cross Hospital Campus, Fulham Palace Rd, London W6 8RF (United Kingdom); Sandison, Ann [Department of Histopathology, Imperial College and Imperial College Healthcare NHS Trust, Charing Cross Hospital Campus, Fulham Palace Rd, London W6 8RF (United Kingdom); Quinn, Paul; Mosselmans, J Frederick W [Science Division, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxon, OX11 0DE (United Kingdom); Sampson, Barry [Department of Clinical Biochemistry, Imperial College and Imperial College Healthcare NHS Trust, Charing Cross Hospital Campus, Fulham Palace Rd, London W6 8RF (United Kingdom); Atkinson, Kirk D [8 Nuclear Department Defence Academy College of Management and Technology HMS Sultan Military Road Gosport PO12 3BY (United Kingdom); Skinner, John A [Department of Orthopaedics, Royal National Orthopaedic Hospital, HA7 4LP (United Kingdom); Goode, Angela [Dept of Materials, Imperial College London, SW7 2AZ (United Kingdom); Powell, Jonathan J, E-mail: Paul.Quinn@diamond.ac.u [Medical Research Council Human Nutrition Research Centre, Cambridge CB1 9NL (United Kingdom)

    2009-11-15

    Unexplained tissue inflammation in metal-on-metal hip replacements is suspected to be caused by implant-derived nanoparticles. The aim of this study was to investigate the nature of the metal particles in tissue surrounding metal-on-metal (MOM) hips that has been extracted during revision. Mapping of tissue surrounding the failed MOM hips was performed using microfocus X-ray Fluorescence (XRF). This revealed mainly Cr which was localized to the cellular regions. There was co-localisation of Co, were present, to areas of high Cr abundance. XANES of the tissue and appropriate standards revealed that the most common species were Cr(III) and Co(II). EXAFS analysis of the tissue and various metal standards revealed that the most abundant implant-related species was Cr(III) phosphate. Different tissue preparation methods, including frozen sectioning, were examined but were found not to affect the distribution or speciation of the metals in the tissue.

  19. Distribution of Spiked Drugs between Milk Fat, Skim Milk, Whey, Curd, and Milk Protein Fractions: Expansion of Partitioning Models.

    Science.gov (United States)

    Lupton, Sara J; Shappell, Nancy W; Shelver, Weilin L; Hakk, Heldur

    2018-01-10

    The distributions of eight drugs (acetaminophen, acetylsalicylic acid/salicylic acid, ciprofloxacin, clarithromycin, flunixin, phenylbutazone, praziquantel, and thiamphenicol) were determined in milk products (skim milk, milk fat, curd, whey, and whey protein) and used to expand a previous model (from 7 drugs to 15 drugs) for predicting drug distribution. Phenylbutazone and praziquantel were found to distribute with the lipid and curd phases (≥50%). Flunixin distribution was lower but similar in direction (12% in milk fat, 39% in curd). Acetaminophen, ciprofloxacin, and praziquantel preferentially associated with casein proteins, whereas thiamphenicol and clarithromycin associated preferentially to whey proteins. Regression analyses for log [milk fat]/[skim milk] and log [curd]/[whey] had r 2 values of 0.63 and 0.67, respectively, with p of <0.001 for 15 drugs (7 previously tested and 8 currently tested). The robustness of the distribution model was enhanced by doubling the number of drugs originally tested.

  20. The effect of reticuloendothelial blockade on the blood clearance and tissue distribution of liposomes

    International Nuclear Information System (INIS)

    Souhami, R.L.; Patel, H.M.; Ryman, B.E.

    1981-01-01

    The blood clearance and tissue distribution of liposomes have been studied in mice subjected to reticuloendothelial blockade with dextran sulphate or carbon. The liposomes have been labelled in the lipid membranes with [ 3 H]-cholesterol, [ 14 C]phosphatidylcholine and/or 99 sup(m)Tc and the content with [ 14 C]inulin. Reticuloendothelial blockade has been shown to slow the rate of clearance of neutral, positively and negatively charged liposomes and of both small unilamellar vesicles and large multilamellar vesicles. In normal animals, the liver uptake accounted for only 20-55% of the total injected radioactivity, the amount varying with the charge and size of the liposomes. Following blockade, the liver uptake of charged and neutral multilamellar liposomes was depressed. This was also true for negatively charged small unilamellar vesicles. The degree of depression of hepatic uptake was between 25-50%, which contrasts with the 80-90% reduction in uptake of a wholly phagocytosed particle (sheep red cells). This difference suggets that mechanisms other than Kupffer cell phagocytosis are also responsible for the normal uptake of liposomes into the liver. In the case of neutral and positively charged small unilamellar vesicles, delayed clearance due to blockade was not associated with depressed hepatic uptake. The site of action of blockading agents for these preparations is not clear. With all preparations of liposomes, blockade produced a slight and variable increase in uptake in the lung and spleen. The alteration of distribution of liposomes by reticuloendothelial blockade is therefore not great and the value of the technique in modifying the tissue distribution of substances within liposomes may be limited. (orig.)

  1. Minor rheumatology: Nonsystemic rheumatic disease of juxta-articular soft tissues of the upper extremity. Part 2. Drug and non-drug treatments

    Directory of Open Access Journals (Sweden)

    Andrei Evgenyevich Karateev

    2015-01-01

    Full Text Available The treatment of rheumatic diseases of juxta-articular soft tissues (RDJAST of the upper extremity (rotator cuff tendinitis, epicondylitis, de Quervain’s syndrome, trigger finger, carpal tunnel syndrome entails a combination of drug and nondrug therapies. The basic agents that have been proven to be efficacious in this pathology are nonsteroidal anti-inflammatory drugs (NSAIDs and glucocorticosteroids (GCs. The paper considers the largest and known studies that are an evidence base for the expediency of using agents, such NSAIDs, local administration of GCs, hyaluronic acid, and plateletrich plasma, as well as different non-drug treatments, in RDJAST. The latter (physiotherapy, exercises, and rehabilitation programs should be regarded as a necessary component of the therapeutic process in patients with RDJAST-associated chronic pain. Preservation of obvious pain and impaired function despite medical therapy should be regarded as an indication for surgical treatment.

  2. Neighborhood safety and adipose tissue distribution in African Americans: the Jackson Heart Study.

    Directory of Open Access Journals (Sweden)

    Do Quyen Pham

    Full Text Available Patterns of fat distribution are heavily influenced by psychological stress, sex, and among women, by menopause status. Emerging evidence suggests the lack of perceived neighborhood safety due to crime may contribute to psychological stress and obesity among exposed residents. Our objective is to determine if perceived neighborhood safety is associated with abdominal adiposity among African-American men and women, and among pre- and postmenopausal women in the Jackson Heart Study.We examined associations between perceived neighborhood safety, fat distribution, and other individual-level covariates among Jackson Heart Study participants (N = 2,881. Abdominal adiposity was measured via computed tomography scans measuring the volumes of visceral, subcutaneous and total adipose tissue. We also measured body mass index (BMI, and waist circumference. Multivariable regression models estimated associations between perceived neighborhood safety, adiposity, and covariates by sex and menopause status.Adjusting for all covariates, women who strongly disagreed their neighborhood was safe from crime had a higher BMI compared to women who felt safe [Std B 0.083 95% CI (0.010, 0.156]. Premenopausal women who felt most unsafe had higher BMI, waist circumference, and volumes of visceral and total adipose tissue than those who felt safe [Std B 0.160 (0.021, 0.299, Std B 0.142 (0.003, 0.280, Std B 0.150 (0.014, 0.285, Std B 0.154 (0.019, 0.290, respectively]. We did not identify associations between neighborhood safety and adiposity among men and postmenopausal women.Our data suggest that abdominal adipose tissue distribution patterns are associated with perceived neighborhood safety in some groups, and that patterns may differ by sex and menopause status, with most associations observed among pre-menopausal women. Further research is needed to elucidate whether there are causal mechanisms underlying sex and menopause-status differences that may mediate

  3. Distribution of polycyclic aromatic hydrocarbons in subcellular root tissues of ryegrass (Lolium multiflorum Lam.)

    Science.gov (United States)

    2010-01-01

    Background Because of the increasing quantity and high toxicity to humans of polycyclic aromatic hydrocarbons (PAHs) in the environment, several bioremediation mechanisms and protocols have been investigated to restore PAH-contaminated sites. The transport of organic contaminants among plant cells via tissues and their partition in roots, stalks, and leaves resulting from transpiration and lipid content have been extensively investigated. However, information about PAH distributions in intracellular tissues is lacking, thus limiting the further development of a mechanism-based phytoremediation strategy to improve treatment efficiency. Results Pyrene exhibited higher uptake and was more recalcitrant to metabolism in ryegrass roots than was phenanthrene. The kinetic processes of uptake from ryegrass culture medium revealed that these two PAHs were first adsorbed onto root cell walls, and they then penetrated cell membranes and were distributed in intracellular organelle fractions. At the beginning of uptake (< 50 h), adsorption to cell walls dominated the subcellular partitioning of the PAHs. After 96 h of uptake, the subcellular partition of PAHs approached a stable state in the plant water system, with the proportion of PAH distributed in subcellular fractions being controlled by the lipid contents of each component. Phenanthrene and pyrene primarily accumulated in plant root cell walls and organelles, with about 45% of PAHs in each of these two fractions, and the remainder was retained in the dissolved fraction of the cells. Because of its higher lipophilicity, pyrene displayed greater accumulation factors in subcellular walls and organelle fractions than did phenanthrene. Conclusions Transpiration and the lipid content of root cell fractions are the main drivers of the subcellular partition of PAHs in roots. Initially, PAHs adsorb to plant cell walls, and they then gradually diffuse into subcellular fractions of tissues. The lipid content of intracellular

  4. Monocyte-mediated delivery of polymeric backpacks to inflamed tissues: a generalized strategy to deliver drugs to treat inflammation.

    Science.gov (United States)

    Anselmo, Aaron C; Gilbert, Jonathan B; Kumar, Sunny; Gupta, Vivek; Cohen, Robert E; Rubner, Michael F; Mitragotri, Samir

    2015-02-10

    Targeted delivery of drugs and imaging agents to inflamed tissues, as in the cases of cancer, Alzheimer's disease, Parkinson's disease, and arthritis, represents one of the major challenges in drug delivery. Monocytes possess a unique ability to target and penetrate into sites of inflammation. Here, we describe a broad approach to take advantage of the natural ability of monocytes to target and deliver flat polymeric particles ("Cellular Backpacks") to inflamed tissues. Cellular backpacks attach strongly to the surface of monocytes but do not undergo phagocytosis due to backpack's size, disk-like shape and flexibility. Following attachment of backpacks, monocytes retain important cellular functions including transmigration through an endothelial monolayer and differentiation into macrophages. In two separate in vivo inflammation models, backpack-laden monocytes exhibit increased targeting to inflamed tissues. Cellular backpacks, and their abilities to attach to monocytes without impairing monocyte functions and 'hitchhike' to a variety of inflamed tissues, offer a new platform for both cell-mediated therapies and broad targeting of inflamed tissues. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Glucosinolate profile and distribution among plant tissues and phenological stages of field-grown horseradish.

    Science.gov (United States)

    Agneta, Rosa; Lelario, Filomena; De Maria, Susanna; Möllers, Christian; Bufo, Sabino Aurelio; Rivelli, Anna Rita

    2014-10-01

    Profile and distribution of glucosinolates (GLS) were detected in plant tissues of horseradish at different developmental stages: beginning of vegetative re-growth, flowering and silique formation. The GLS profile varied widely in the different tissues: we identified 17 GLS in roots and sprouts, one of which was not previously characterized in horseradish, i.e. the 2(S)-hydroxy-2-phenylethyl-GLS (glucobarbarin) and/or 2(R)-hydroxy-2-phenylethyl-GLS (epiglucobarbarin), 11 already found in the roots, including the putative 2-methylsulfonyl-oxo-ethyl-GLS, and 5 previously recognized only in the sprouts. Fifteen of those GLS were also identified in young and cauline leaves, 12 in the mature leaves and 13 in the inflorescences. No difference in GLS profile was observed in plant among the phenological stages. Differences in concentrations of GLS, quantified as desulfated, were found in plant. At the beginning of vegetative re-growth, sprouts while showing the same profile of the roots were much richer in GLS having the highest total GLS concentrations (117.5 and 7.7μmolg(-1) dry weight in sprouts and roots, respectively). During flowering and silique forming stages, the roots still maintained lower amount of total GLS (7.4μmolg(-1) of dry weight, on average) with respect to the epigeous tissues, in which mature and young leaves showed the highest total concentrations (70.5 and 73.8μmolg(-1) of dry weight on average, respectively). Regardless of the phenological stages, the aliphatic GLS were always predominant in all tissues (95%) followed by indolic (2.6%) and benzenic (2.4%) GLS. Sinigrin contributed more than 90% of the total GLS concentration. Aliphatic GLS concentrations were much higher in the epigeous tissues, particularly in the mature and young leaves, while benzenic and indolic GLS concentrations were higher in the roots. Through the phenological stages, GLS concentration increased in young and mature leaves and decreased in cauline leaves and inflorescences

  6. Modified n-HA/PA66 scaffolds with chitosan coating for bone tissue engineering: cell stimulation and drug release.

    Science.gov (United States)

    Zou, Qin; Li, Junfeng; Niu, Lulu; Zuo, Yi; Li, Jidong; Li, Yubao

    2017-09-01

    The dipping-drying procedure and cross-linking method were used to make drug-loaded chitosan (CS) coating on nano-hydroxyapatite/polyamide66 (nHA/PA66) composite porous scaffold, endowing the scaffold controlled drug release functionality. The prefabricated scaffold was immersed into an aqueous drug/CS solution in a vacuum condition and then crosslinked by vanillin. The structure, porosity, composition, compressive strength, swelling ratio, drug release and cytocompatibility of the pristine and coating scaffolds were investigated. After coating, the scaffold porosity and pore interconnection were slightly decreased. Cytocompatibility performance was observed through an in vitro experiment based on cell attachment and the MTT assay by MG63 cells which revealed positive cell viability and increasing proliferation over the 11-day period in vitro. The drug could effectively release from the coated scaffold in a controlled fashion and the release rate was sustained for a long period and highly dependent on coating swelling, suggesting the possibility of a controlled drug release. Our results demonstrate that the scaffold with drug-loaded crosslinked CS coating can be used as a simple technique to render the surfaces of synthetic scaffolds active, thus enabling them to be a promising high performance biomaterial in bone tissue engineering.

  7. The cellular distribution of histone H5 in embryonic and adult tissues of Xenopus laevis and chicken

    NARCIS (Netherlands)

    Moorman, A. F.; de Boer, P. A.; Lamers, W. H.; Charles, R.

    1986-01-01

    The cellular distribution of histone H5 in embryonic and adult tissues of Xenopus laevis and chicken has been established with monoclonal antibodies to histone H5. Both in Xenopus and in chicken, the protein has presumably a more widespread cellular distribution than hitherto expected but is absent

  8. Distribution of soya-saponin in brain and peripheral tissue after peritoneal injection

    International Nuclear Information System (INIS)

    Zhu Shigong; Wang Jianchun; Zhang Peiyin

    1997-01-01

    125 I-soya-saponin was prepared to study the distribution of soya-saponin in body of rat, as well as in different areas of brain when peritoneal injection. The results showed that the peak value of radioactive soya-saponin in all tissue appeared at 30 min after peritoneal injection. There were higher radioactivities in brain and suprarene comparing with other organs. The highest radioactivity was seen in hypothalamus among the every brain areas. It is a first report that soyasaponin can pass through the blood brain barrier when peripheral injection. The result also supported the opinion that soyasaponin might act on the hypothalamus and central regulation of cardiovascular system. Another finding was that soyasaponin also showed a higher affinity with adrenal gland, which indicated that the soyasaponin might possess of peripheral effect for regulation of cardiovascular system as well

  9. Tissue distribution of epimucosally applied 3H DNFB: an autoradiographic study

    International Nuclear Information System (INIS)

    Warfvinge, G.; Larsson, Aa.

    1988-01-01

    The distribution of 3 H-labeled 2,4-dinitrofluorobenzene (DNFB) has been autoradiographically investigated in buccal mucosa after topical application to sensitized or nonsensitized rats. The rats were killed between 3 min and 24 h after challenge. No significant labeling pattern differences were found between plastic embedded and frozen sections. Surface epithelium was heavily labeled and labeled cells were observed in the lamina propria shortly (3-6 min) after application. These cells were clearly dendritic. Specific accumulation of hapten in epithelial Langerhans cells (LC) could not be clearly demonstrated. The connective tissue labeling gradually diminished and at 24 h post-elicitation, remaining label could be detected only in the epithelial surface layers. (author)

  10. Tissue astaxanthin and canthaxanthin distribution in rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar).

    Science.gov (United States)

    Page, G I; Davies, S J

    2006-01-01

    A comparative investigation of tissue carotenoid distribution between rainbow trout, Oncorhynchus mykiss, and Atlantic salmon, Salmo salar, was undertaken to identify the relative efficiency of utilization of astaxanthin and canthaxanthin. Higher apparent digestibility coefficients (ADCs) (96% in trout vs. 28-31% in salmon; Ptrout vs. 5.5% in salmon; Ptrout. Astaxanthin deposition was higher than canthaxanthin in rainbow trout, while the reverse was true for Atlantic salmon, suggesting species-specificity in carotenoid utilization. The white muscle (95% in trout vs. 93% in salmon) and kidneys (0.5% in trout vs. 0.2% in salmon) represented higher proportions of the total body carotenoid pool in rainbow trout than in Atlantic salmon (Ptrout; Ptrout. Liver catabolism is suspected to be a critical determinant in carotenoid clearance, with higher catabolism expected in Atlantic salmon than in rainbow trout.

  11. Distribution of phenolic compounds and antioxidant capacity in apples tissues during ripening.

    Science.gov (United States)

    Alberti, Aline; Zielinski, Acácio Antonio Ferreira; Couto, Marcelo; Judacewski, Priscila; Mafra, Luciana Igarashi; Nogueira, Alessandro

    2017-05-01

    The effect of variety and ripening stage on the distribution of phenolic compounds and in vitro antioxidant capacity of Gala, Fuji Suprema and Eva apples were evaluated. Hydroxycinnamic acids, flavonoids, flavanols, flavonols, dihydrochalcones and antioxidant activity (FRAP and DPPH) were assessed in the epicarp, mesocarp and endocarp of three varieties at three ripening stages (unripe, ripe and senescent). The Fuji Suprema variety distinguished by its content of flavonols at senescent stage, while Eva variety distinguished by its content of dihydrochalcones (unripe stage) and anthocyanins (ripe stage). In general, phenolic acids and flavonoids decreased with ripening in the epicarp and endocarp. However, in the mesocarp, the effect of ripening was related with the apple variety. Hierarchical cluster analysis confirmed the influence of ripening in the apple tissue. The evolution of these compounds during ripening occurred irregularly and it was influenced by the variety.

  12. Distribution in rat tissues of modulator-binding protein of particulate nature

    International Nuclear Information System (INIS)

    Sobue, K.; Muramoto, Y.; Kakiuchi, S.; Yamazaki, R.

    1979-01-01

    Studies on Ca 2+ -activatable cyclic nucleotide phosphodiesterase led to the discovery of a protein modulator that is required for the activation of this enzyme by Ca 2+ . Later, this protein has been shown to cause the Ca 2+ -dependent activation of several enzymes that include phosphodiesterase, adenylate cyclase, a protein kinase from muscles, phosphorylase b kinase, actomyosin ATPase, membranous ATPase from erythrocytes and nerve synapses. Thus, modulator protein appears to be an intracellular mediator of actions of Ca 2+ . The present work shows the distribution of this particulate modulator-binding component in rat tissues. This paper also describes the labeling of modulator protein with tritium without deteriorating its biological activities and application of this 3 H-modulator protein to the determination of the Ca ++ dependent binding of modulator protein with membranous protein. This technique proves to be useful in studying enzymes or proteins whose functions are regulated by Ca ++ /modulator protein system. (Auth.)

  13. Nanoparticle enabled transdermal drug delivery systems for enhanced dose control and tissue targeting

    Science.gov (United States)

    Palmer, Brian C.; DeLouise, Lisa A.

    2017-01-01

    Transdermal drug delivery systems have been around for decades, and current technologies (e.g. patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases. PMID:27983701

  14. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting.

    Science.gov (United States)

    Palmer, Brian C; DeLouise, Lisa A

    2016-12-15

    Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

  15. Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting

    Directory of Open Access Journals (Sweden)

    Brian C. Palmer

    2016-12-01

    Full Text Available Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

  16. Tissue distribution of aryl hydrocarbon receptor in the intestine: Implication of putative roles in tumor suppression

    International Nuclear Information System (INIS)

    Ikuta, Togo; Kurosumi, Masafumi; Yatsuoka, Toshimasa; Nishimura, Yoji

    2016-01-01

    Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc"M"i"n"/"+mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression. - Highlights: • In the normal intestine, AhR was mainly localized in stroma containing immune cells. • In the tumor tissue, AhR expression was found in both stromal and tumor cells. • AhR knockdown promoted cell growth in colon cancer cell lines.

  17. Uptake, distribution, and incorporation of 59Fe in tissue and blood of rainbow trout (Salmo gairdneri)

    International Nuclear Information System (INIS)

    Walker, R.L.

    1975-01-01

    A study was designed to evaluate the storage iron facilities in various tissues and to trace the distribution of radioiron in tissues and blood following an intraperitoneal (i.p.) injection of 59 Fe. Iron deficiency anemia was induced in an experimental group of rainbow trout in order to measure its effect on red blood cell production and mobilization of storage iron. Most of the 59 Fe was absorbed from the peritoneal cavity within 24 hrs. after the i.p. injection. Equilibrium between the plasma 59 Fe pool and that of the tissue was established by day 8. Experimental fish RBC 59 Fe content increased to 70 to 80 percent of the initial injected dose by day 16 compared to 50 percent in the controls. This was attributed to the difference in reticulocyte count which was 10 to 12 percent for the bled and 2 to 3 percent for control fish. The rate that iron is incorporated into hemoglobin by immature red cells is much slower (about half) than the rate of RBC 59 Fe uptake, thus, iron is temporarily stored in the cytoplasm. The iron for hemoglobin formation was obtained from liver iron stores which dropped from 12 percent to less than 1 percent of the initial injected dose by day 16. Total iron concentration in liver decreased from 200 to less than 100 μg Fe/g. The decrease in liver iron may have stimulated iron absorption by the intestine and pyloric caeca. There is evidence for a feedback mechanism mediated by transferrin

  18. Arsenic-induced biochemical and genotoxic effects and distribution in tissues of Sprague-Dawley rats

    Science.gov (United States)

    Patlolla, Anita K.; Todorov, Todor I.; Tchounwou, Paul B.; van der Voet, Gijsbert; Centeno, Jose A.

    2012-01-01

    Arsenic (As) is a well documented human carcinogen. However, its mechanisms of toxic action and carcinogenic potential in animals have not been conclusive. In this research, we investigated the biochemical and genotoxic effects of As and studied its distribution in selected tissues of Sprague–Dawley rats. Four groups of six male rats, each weighing approximately 60 ± 2 g, were injected intraperitoneally, once a day for 5 days with doses of 5, 10, 15, 20 mg/kg BW of arsenic trioxide. A control group was also made of 6 animals injected with distilled water. Following anaesthetization, blood was collected and enzyme analysis was performed by spectrophotometry following standard protocols. At the end of experimentation, the animals were sacrificed, and the lung, liver, brain and kidney were collected 24 h after the fifth day treatment. Chromosome and micronuclei preparation was obtained from bone marrow cells. Arsenic exposure significantly increased (p < 0.05) the activities of plasma alanine aminotransferase–glutamate pyruvate transaminase (ALT/GPT), and aspartate aminotransferase–glutamate oxaloacetate transaminase (AST/GOT), as well as the number of structural chromosomal aberrations (SCA) and frequency of micronuclei (MN) in the bone marrow cells. In contrast, the mitotic index in these cells was significantly reduced (p < 0.05). These findings indicate that aminotransferases are candidate biomarkers for arsenic-induced hepatotoxicity. Our results also demonstrate that As has a strong genotoxic potential, as measured by the bone marrow SCA and MN tests in Sprague–Dawley rats. Total arsenic concentrations in tissues were measured by inductively coupled plasma mass spectrometry (ICP-MS). A dynamic reaction cell (DRC) with hydrogen gas was used to eliminate the ArCl interference at mass 75, in the measurement of total As. Total As doses in tissues tended to correlate with specific exposure levels.

  19. Tissue distribution of aryl hydrocarbon receptor in the intestine: Implication of putative roles in tumor suppression

    Energy Technology Data Exchange (ETDEWEB)

    Ikuta, Togo, E-mail: togo@cancer-c.pref.saitama.jp [Department of Cancer Prevention, Research Institute for Clinical Oncology, Saitama Cancer Center, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Kurosumi, Masafumi, E-mail: mkurosumi@cancer-c.pref.saitama.jp [Division of Pathology, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Yatsuoka, Toshimasa, E-mail: yatsuoka-gi@umin.ac.jp [Division of Gastroenterological Surgery, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan); Nishimura, Yoji, E-mail: yojinish@cancr-c.pref.saitama.jp [Division of Gastroenterological Surgery, Saitama Cancer Center, 780 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806 (Japan)

    2016-05-01

    Intestinal homeostasis is maintained by complex interactions between intestinal microorganisms and the gut immune system. Dysregulation of gut immunity may lead to inflammatory disorders and tumorigenesis. We previously have shown the tumor suppressive effects of aryl hydrocarbon receptor (AhR) in intestinal carcinogenesis. In the present study, we investigated AhR distribution in the mouse and human intestine by histochemical analysis. In the normal intestine, AhR was mainly localized in the stroma containing immune cells in the lamina propria and lymphoid follicles. On the other hand, in the tumor tissue from human colon cancer and that developed in Apc{sup Min/+}mice, AhR expression was elevated. AhR immunostaining was found in both stromal and tumor cells. Although AhR was localized in the cytoplasm of tumor cells in most cases, nuclear AhR was also observed in some. AhR knockdown using siRNA resulted in significant promotion of cell growth in colon cancer cell lines. Furthermore, AhR activation by AhR ligands supplemented in culture medium suppressed cell growth. Our study results suggest that tumor suppressive roles of AhR are estimated in two distinct ways: in normal tissue, AhR is associated with tumor prevention by regulating gut immunity, whereas in tumor cells, it is involved in growth suppression. - Highlights: • In the normal intestine, AhR was mainly localized in stroma containing immune cells. • In the tumor tissue, AhR expression was found in both stromal and tumor cells. • AhR knockdown promoted cell growth in colon cancer cell lines.

  20. The absorption, tissue distribution and excretion of Di-n-Octylten dichloride in rats

    International Nuclear Information System (INIS)

    Penninks, A.H.; Hilgers, Luuk; Seinen, Willem

    1987-01-01

    In this study the absorption, tissue distribution and excretion of 14 C-labeled di-n-octyltin dichloride ([ 14 C] DOTC) in rats were investigated after oral and intravenous (i.v.) administration with 6.3 mg [ 14 C] DOTC/Kg body weight, the relative tissue accumulation was found to be the same after oral and i.v. dosage. The highest amount of radioactivity was found in liver and kidney, and to a lesser degree in adrenal, pituitary and thyroid glands. The lowest activity was recovered from blood and brain. No selective accumulation was observed in thymus, although it has been reported that thymus atrophy is the most sensitive parameter of DOTC toxicity in rats. For all tissues a time dependent decrease in radioactivity was found, except for kidney. The excretion of radioactivity in feces and urine was determined after a single i.v. or oral dose of l.2 and 2 mg [ 14 C] DOTC, respectively. After i.v. administration most of the radioactivity was excreted in the feces which was characterized by a biphasic excretion pattern. In orally treated rats more than 80% of the radioactivity was already excreted in the feces during the first day after administration. This indicated that only a small part of the DOTC was absorbed, which was calculated to be approximately 20% of the dose. Similar half-life values of 8.3 and 8.9 days were obtained from the fecal excretion of radioactivity after the i.v. and oral administration, respectively. The urinary excretion of radioactivity appeared to be independent of the body burden, since the daily amount of radioactivity excreted in urine was nearly the same independent of the route of administration as well as the time after administration. 26 refs. (author)

  1. Comparison of the distribution of fluorine-18 fluoromisonidazole, deoxyglucose and methionine in tumour tissue

    International Nuclear Information System (INIS)

    Kubota, Kazuo; Tada, Masao; Yamada, Susumu; Hori, Katsuyoshi; Saito, Sachiko; Sato, Kazunori; Fukuda, Hiroshi; Iwata, Ren; Ido, Tatsuo

    1999-01-01

    To evaluate the tumour imaging potential of fluorine-18 fluoromisonidazole (FMISO), we studied FMISO uptake in an experimental tumour model and examined the correlation between intratumoral distributions of FMISO, 14 C-2-deoxyglucose (2DG) and 14 C-methionine (Met). The study was performed using control rats with the AH109A tumour and rats with the same tumour under local hypoxia. Tumour uptake of FMISO was constant between 30 min and 2 h after injection, and the tumour to muscle ratio was 2 from 2 to 4 h. A tumour study with FMISO was scheduled at 2 h. Double-tracer autoradiography of the tumour demonstrated that in the areas of high FMISO uptake, there was low uptake of Met, while areas of low FMISO uptake showed high Met uptake. FMISO showed high grain density in the rim of the tumour surrounding the necrotic area. 2DG showed a more uniform distribution over the entire section of viable cells. The mean uptake of FMISO by hypoxic, radioresistant tumours was significantly higher than that by the control tumours (P<0.05), while both 2DG and Met uptake by the control tumours was higher than uptake by hypoxic tumours. When individual tumours were examined, the uptake of FMISO was inversely correlated with that of Met (r = -0.507, P<0.02), while 2DG showed almost uniform uptake with no significant correlation to FMISO. In conclusion, hypoxic and radioresistant tumours could be identified by increased FMISO uptake in our model, consistent with findings reported by others. We found a large overlap in the distribution of FMISO and 2DG within the tumour, but only a small overlap in the distribution of FMISO and Met. A combination of FMISO and other tracers in positron emission tomography or single-photon emission tomography studies might be more helpful than single-tracer studies in predicting the response of tumour tissues to radiotherapy. (orig.)

  2. Tissue distribution and toxicity effects of myclobutanil enantiomers in lizards (Eremias argus).

    Science.gov (United States)

    Chen, Li; Li, Ruiting; Diao, Jinling; Tian, Zhongnan; Di, Shanshan; Zhang, Wenjun; Cheng, Cheng; Zhou, Zhiqiang

    2017-11-01

    In recent years, serious environmental pollution has caused a decrease in the abundance of many species worldwide. Reptiles are the most diverse group of terrestrial vertebrates. There are large amounts of toxicological data available regarding myclobutanil, but the adverse effects of myclobutanil on lizards has not been widely reported. In this study, treatment groups were orally administered a single-dose of myclobutanil (20mg/kg body weight (bw)). Subsequently, it was found that there were differences in myclobutanil levels between the different tissues and concentrations also changed with degradation time. The tissue concentrations of myclobutanil decreased in the order of: stomach > liver > lung > blood > testis > kidney > heart > brain. Based on our results, the liver and testis were considered to be the main target organs in lizards, indicating that the myclobutanil could induce potential hepatic and reproductive toxicity on lizards. Meanwhile, it was also demonstrated that the toxic effects of myclobutanil was different in different species, and the distribution of different pesticides in lizards were different. Copyright © 2017. Published by Elsevier Inc.

  3. PCBs and PCDD/Fs distribution in tissues and organs of marine animals in Russian Arctic

    Energy Technology Data Exchange (ETDEWEB)

    Amirova, Z.; Kruglov, E.; Loshkina, E.; Khalilov, R. [Environmental Research and Protection Centre, Ufa (Russian Federation); Melnikov, S.; Vlasov, S. [Regional Centre Monitoring of the Arctic, St. Petersburg (Russian Federation)

    2004-09-15

    Studies of persistent organic pollutants (POPs) in the Russian Arctic were conducted recently by a Arctic Monitoring and Assessment Program (AMAP) project. This project developed new data on the POPs pollution levels in the environment and biosphere, including PCBs and PCDD/Fs, in arctic regions of Russia. Transboundary transport and biomagnification within food chains in arctic regions result in POPs accumulation in tissues of fish and marine animals. The aim of this study was to determine the concentration of indicator PCBs, co-planar PCBs and PCDD/Fs in different tissues and organs of seals, walruses and whales caught near the seashore of Chukotski Peninsula (settlement of Lavrenty), Russia, to determine the background level of arctic biota pollution and to study distribution of toxicants in organisms of marine animals. Sampling was made in the course of the 1{sup st} and the 2{sup nd} stages of the 4{sup th} phase of Raipon/AMAP/GEF project ''Persistent Toxic Substances (PTS), Food Security and Indigenous Peoples of the Russian North'' in 2002 by researchers of the Regional Center for Monitoring of the Arctic (RCMA), St. Petersburg, Russia.

  4. Analysis of elemental concentration censored distributions in breast malignant and breast benign neoplasm tissues

    International Nuclear Information System (INIS)

    Kubala-Kukus, A.; Banas, D.; Braziewicz, J.; Gozdz, S.; Majewska, U.; Pajek, M.

    2007-01-01

    The total reflection X-ray fluorescence method was applied to study the trace element concentrations in human breast malignant and breast benign neoplasm tissues taken from the women who were patients of Holycross Cancer Centre in Kielce (Poland). These investigations were mainly focused on the development of new possibilities of cancer diagnosis and therapy monitoring. This systematic comparative study was based on relatively large (∼ 100) population studied, namely 26 samples of breast malignant and 68 samples of breast benign neoplasm tissues. The concentrations, being in the range from a few ppb to 0.1%, were determined for thirteen elements (from P to Pb). The results were carefully analysed to investigate the concentration distribution of trace elements in the studied samples. The measurements of concentration of trace elements by total reflection X-ray fluorescence were limited, however, by the detection limit of the method. It was observed that for more than 50% of elements determined, the concentrations were not measured in all samples. These incomplete measurements were treated within the statistical concept called left-random censoring and for the estimation of the mean value and median of censored concentration distributions, the Kaplan-Meier estimator was used. For comparison of concentrations in two populations, the log-rank test was applied, which allows to compare the censored total reflection X-ray fluorescence data. Found statistically significant differences are discussed in more details. It is noted that described data analysis procedures should be the standard tool to analyze the censored concentrations of trace elements analysed by X-ray fluorescence methods

  5. Multielemental accumulation and its intracellular distribution in tissues of some aquatic birds

    International Nuclear Information System (INIS)

    Nam, Dong-Ha; Anan, Yasumi; Ikemoto, Tokutaka; Tanabe, Shinsuke

    2005-01-01

    This study was aimed at determining multielemental concentration and its intracellular distribution in selected tissues of cormorant and waterfowl species. Non-essential elements such as Hg, Tl, Cd, Pb and V in tissues were generally consistent with those in ingested items, indicating the significance of food sources of non-essential metal accumulation in great cormorants and mallards. Great cormorants and four waterfowl species examined reflected natural background levels of toxic metals such as Cd, Hg and Pb as well as some essential elements, indicating no specific metal exposure from local sources. Most of Cu, Zn, Se, Rb, Ag, Cd, Cs, and Hg contents were present in the hepatocytosolic fraction, whereas a large percentage of V and Mo were present in insoluble fraction in great cormorant, mallard, and spot-billed duck. The major role of these subcelluar fractions in elemental regulation accounts for the high percentage contribution of each cellular fraction to the total metal contents. Cadmium and Cu are chiefly sequestered through binding to metallothioneins (MTs) of hepatocytosolic fraction in these three avian species. Both MTs and high-molecular-weight substance (HMWS) for Zn and low-molecular-weight substance (LMWS) for Rb were also involved in their sequestration in cytosolic fractions. Relatively different species-specific cytosolic substances were responsible for varying degrees of Ag, Mn, and Co accumulation. It is worth noting that these intracellular metal levels in birds are closely regulated by metal-associated cellular constituents. Therefore, risk assessment studies of metal accumulation in such wild birds should take intracellular metal distribution and specific cellular constituents into account

  6. Tissue and stage-specific distribution of Wolbachia in Brugia malayi.

    Directory of Open Access Journals (Sweden)

    Kerstin Fischer

    2011-05-01

    Full Text Available BACKGROUND: Most filarial parasite species contain Wolbachia, obligatory bacterial endosymbionts that are crucial for filarial development and reproduction. They are targets for alternative chemotherapy, but their role in the biology of filarial nematodes is not well understood. Light microscopy provides important information on morphology, localization and potential function of these bacteria. Surprisingly, immunohistology and in situ hybridization techniques have not been widely used to monitor Wolbachia distribution during the filarial life cycle. METHODS/PRINCIPAL FINDINGS: A monoclonal antibody directed against Wolbachia surface protein and in situ hybridization targeting Wolbachia 16S rRNA were used to monitor Wolbachia during the life cycle of B. malayi. In microfilariae and vector stage larvae only a few cells contain Wolbachia. In contrast, large numbers of Wolbachia were detected in the lateral chords of L4 larvae, but no endobacteria were detected in the genital primordium. In young adult worms (5 weeks p.i., a massive expansion of Wolbachia was observed in the lateral chords adjacent to ovaries or testis, but no endobacteria were detected in the growth zone of the ovaries, uterus, the growth zone of the testis or the vas deferens. Confocal laser scanning and transmission electron microscopy showed that numerous Wolbachia are aligned towards the developing ovaries and single endobacteria were detected in the germline. In inseminated females (8 weeks p.i. Wolbachia were observed in the ovaries, embryos and in decreasing numbers in the lateral chords. In young males Wolbachia were found in distinct zones of the testis and in large numbers in the lateral chords in the vicinity of testicular tissue but never in mature spermatids or spermatozoa. CONCLUSIONS: Immunohistology and in situ hybridization show distinct tissue and stage specific distribution patterns for Wolbachia in B. malayi. Extensive multiplication of Wolbachia occurs in the

  7. Uptake, retention and organ/tissue distribution of 137Cs by Japanese catfish (Silurus asotus Linnaeus)

    International Nuclear Information System (INIS)

    Malek, M.A.; Nakahara, M.; Nakamura, R.

    2004-01-01

    The work describes the uptake, retention/biological elimination and organ/tissue distribution of 137 Cs by freshwater Japanese catfish (Silurus asotus Linnaeus) under laboratory conditions. The fish were divided into three groups based on their size and age and reared in 137 Cs-spiked water. The concentration of 137 Cs in the whole body of the live fish was measured at regular intervals up to 60 days. A significant accumulation of 137 Cs was found, but a steady state condition was not achieved by the end of the experiment. The bioaccumulation factors at steady state and the required time to reach steady state were estimated to be 1.55 and 255 days, 1.76 and 180 days and 1.99 and 160 days for large, medium and small size fish, respectively. To determine the effective half-life of 137 Cs, the fish were transferred and reared in the non-contaminated host water. The concentration of the remaining 137 Cs in the whole body of the live fish was measured up to 66 days. The average effective half-life of 137 Cs in the fish species was found to be ∼142 days for fish of all sizes. The distribution of 137 Cs in different organs/tissues of the fish was determined. Accumulation of 137 Cs in muscle/flesh of the fish was found to be ∼75% of whole body accumulation. The uptake rate and the retention capability of juvenile fish were found to be higher and therefore, these were more susceptible to 137 Cs than adult and old fish, and could be an important source of 137 Cs in the human food chain

  8. Biomagnification and tissue distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss).

    Science.gov (United States)

    Goeritz, Ina; Falk, Sandy; Stahl, Thorsten; Schäfers, Christoph; Schlechtriem, Christian

    2013-09-01

    The present study investigated the biomagnification potential as well as the substance and tissue-specific distribution of perfluoroalkyl substances (PFASs) in market-size rainbow trout (Oncorhynchus mykiss). Rainbow trout with an average body weight of 314 ± 21 g were exposed to perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) in the diet for 28 d. The accumulation phase was followed by a 28-d depuration phase, in which the test animals were fed with nonspiked trout feed. On days 0, 7, 14, 28, 31, 35, 42, and 56 of the present study, fish were sampled from the test basin for PFAS analysis. Biomagnification factors (BMFs) for all test compounds were determined based on a kinetic approach. Distribution factors were calculated for each test compound to illustrate the disposition of PFASs in rainbow trout after 28 d of exposure. Dietary exposure of market-size rainbow trout to PFASs did not result in biomagnification; BMF values were calculated as 0.42 for PFOS, >0.23 for PFNA, >0.18 for PFHxS, >0.04 for PFOA, and >0.02 for PFBS, which are below the biomagnification threshold of 1. Liver, blood, kidney, and skin were identified as the main target tissues for PFASs in market-size rainbow trout. Evidence was shown that despite relative low PFAS contamination, the edible parts of the fish (the fillet and skin) can significantly contribute to the whole-body burden. Copyright © 2013 SETAC.

  9. Intracellular co-delivery of Sr ion and phenamil drug through mesoporous bioglass nanocarriers synergizes BMP signaling and tissue mineralization.

    Science.gov (United States)

    Lee, Jung-Hwan; Mandakhbayar, Nandin; El-Fiqi, Ahmed; Kim, Hae-Won

    2017-09-15

    Inducing differentiation and maturation of resident multipotent stem cells (MSCs) is an important strategy to regenerate hard tissues in mal-calcification conditions. Here we explore a co-delivery approach of therapeutic molecules comprised of ion and drug through a mesoporous bioglass nanoparticle (MBN) for this purpose. Recently, MBN has offered unique potential as a nanocarrier for hard tissues, in terms of high mesoporosity, bone bioactivity (and possibly degradability), tunable delivery of biomolecules, and ionic modification. Herein Sr ion is structurally doped to MBN while drug Phenamil is externally loaded as a small molecule activator of BMP signaling, for the stimulation of osteo/odontogenesis and mineralization of human MSCs derived from dental pulp. The Sr-doped MBN (85Si:10Ca:5Sr) sol-gel processed presents a high mesoporosity with a pore size of ∼6nm. In particular, Sr ion is released slowly at a daily rate of ∼3ppm per mg nanoparticles for up to 7days, a level therapeutically effective for cellular stimulation. The Sr-MBN is internalized to most MSCs via an ATP dependent macropinocytosis within hours, increasing the intracellular levels of Sr, Ca and Si ions. Phenamil is loaded maximally ∼30% into Sr-MBN and then released slowly for up to 7days. The co-delivered molecules (Sr ion and Phenamil drug) have profound effects on the differentiation and maturation of cells, i.e., significantly enhancing expression of osteo/odontogenic genes, alkaline phosphatase activity, and mineralization of cells. Of note, the stimulation is a result of a synergism of Sr and Phenamil, through a Trb3-dependent BMP signaling pathway. This biological synergism is further evidenced in vivo in a mal-calcification condition involving an extracted tooth implantation in dorsal subcutaneous tissues of rats. Six weeks post operation evidences the osseous-dentinal hard tissue formation, which is significantly stimulated by the Sr/Phenamil delivery, based on histomorphometric

  10. Influence of tissue- and cell-scale extracellular matrix distribution on the mechanical properties of tissue-engineered cartilage

    NARCIS (Netherlands)

    Khoshgoftar, M.; Wilson, W.; Ito, K.; Donkelaar, C.C. van

    2013-01-01

    The insufficient load-bearing capacity of today's tissue- engineered (TE) cartilage limits its clinical application. Generally, cartilage TE studies aim to increase the extracellular matrix (ECM) content, as this is thought to determine the load-bearing properties of the cartilage. However, there

  11. Influence of tissue- and cell-scale extracellular matrix distribution on the mechanical properties of tissue engineered cartilage

    NARCIS (Netherlands)

    Khoshgoftar, M.; Wilson, W.; Ito, K.; Donkelaar, van C.C.

    2013-01-01

    The insufficient load-bearing capacity of today’s tissue- engineered (TE) cartilage limits its clinical application. Generally, cartilage TE studies aim to increase the extracellular matrix (ECM) content, as this is thought to determine the load-bearing properties of the cartilage. However, there

  12. Topical nonsteroidal anti-inflammatory drugs for the treatment of pain due to soft tissue injury: diclofenac epolamine topical patch

    OpenAIRE

    Lionberger, David

    2010-01-01

    David R Lionberger1, Michael J Brennan21Southwest Orthopedic Group, Houston, TX, USA; 2Department of Medicine, Bridgeport Hospital, Bridgeport, CT, USAAbstract: The objective of this article is to review published clinical data on diclofenac epolamine topical patch 1.3% (DETP) in the treatment of acute soft tissue injuries, such as strains, sprains, and contusions. Review of published literature on topical nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac, and DETP in patients with ac...

  13. Drug intercalation in layered double hydroxide clay: Application in the development of a nanocomposite film for guided tissue regeneration

    DEFF Research Database (Denmark)

    Chakraborti, M.; Jackson, J.K.; Plackett, David

    2011-01-01

    It has been proposed that localized and controlled delivery of alendronate and tetracycline to periodontal pocket fluids via guided tissue regeneration (GTR) membranes may be a valuable adjunctive treatment for advanced periodontitis. The objectives of this work were to develop a co...... evidence of intercalation in the LDH clay particles. The dual drug loaded nanocomposite films were biocompatible with osteoblasts and after 5 week incubations, significant increase in alkaline phosphatase activity and bone nodule formation were observed....

  14. Tissue uptake, distribution and elimination of {sup 14}C-PFOA in zebrafish (Danio rerio)

    Energy Technology Data Exchange (ETDEWEB)

    Ulhaq, Mazhar [Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-750 07 Uppsala (Sweden); Sundström, Maria [Environmental Chemistry Unit, Department of Materials and Environmental Chemistry, Stockholm University, SE-106 91 Stockholm (Sweden); Larsson, Pia; Gabrielsson, Johan [Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-750 07 Uppsala (Sweden); Bergman, Åke [Environmental Chemistry Unit, Department of Materials and Environmental Chemistry, Stockholm University, SE-106 91 Stockholm (Sweden); Norrgren, Leif [Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-750 07 Uppsala (Sweden); Örn, Stefan, E-mail: Stefan.Orn@slu.se [Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, SE-750 07 Uppsala (Sweden)

    2015-06-15

    Highlights: • Bioconcentration of PFOA at steady-state was approximately 20–30 times. • High concentrations were observed in bile and intestines implying enterohepatic circulation. • PFOA accumulated in oocytes indicating maternal transfer. - Abstract: Perfluorooctanoic acid (PFOA) is a long-chain perfluorinated chemical that has been shown to be non-degradable and persistent in the environment. Laboratory studies on bioconcentration and compound-specific tissue distribution in fish can be valuable for prediction of the persistence and environmental effects of the chemicals. In the present study male and female zebrafish (Danio rerio) were continuously exposed to 10 μg/L of radiolabeled perfluorooctanoic acid ({sup 14}C-PFOA) for 40 days, after which the exposed fish were transferred to fresh clean water for another 80 days wash-out period. At defined periodic intervals during the uptake and wash-out, fish were sampled for liquid scintillation counting and whole body autoradiography to profile the bioconcentration and tissue distribution of PFOA. The steady-state concentration of {sup 14}C-PFOA in the zebrafish was reached within 20–30 days of exposure. The concentration-time course of {sup 14}C-PFOA displayed a bi-exponential decline during washout, with a terminal half-life of approximately 13–14 days. At steady-state the bioconcentration of {sup 14}C-PFOA into whole-body fish was approximately 20–30 times greater than that of the exposure concentration, with no differences between females and males. The bioconcentration factors for liver and intestine were approximately 100-fold of the exposure medium, while in brain, ovary and gall bladder the accumulation factors were in the range 15–20. Whole-body autoradiograms confirmed the highest labeling of PFOA in bile and intestines, which implies enterohepatic circulation of PFOA. The {sup 14}C-PFOA was also observed in maturing vitellogenic oocytes, suggesting chemical accumulation via yolk proteins

  15. Sequestration, tissue distribution and developmental transmission of cyanogenic glucosides in a specialist insect herbivore.

    Science.gov (United States)

    Zagrobelny, Mika; Olsen, Carl Erik; Pentzold, Stefan; Fürstenberg-Hägg, Joel; Jørgensen, Kirsten; Bak, Søren; Møller, Birger Lindberg; Motawia, Mohammed Saddik

    2014-01-01

    Considering the staggering diversity of bioactive natural products present in plants, insects are only able to sequester a small number of phytochemicals from their food plants. The mechanisms of how only some phytochemicals are sequestered and how the sequestration process takes place remains largely unknown. In this study the model system of Zygaena filipendulae (Lepidoptera) and their food plant Lotus corniculatus is used to advance the knowledge of insect sequestration. Z. filipendulae larvae are dependent on sequestration of the cyanogenic glucosides linamarin and lotaustralin from their food plant, and have a much lower fitness if reared on plants without these compounds. This study investigates the fate of the cyanogenic glucosides during ingestion, sequestration in the larvae, and in the course of insect ontogeny. To this purpose, double-labeled linamarin and lotaustralin were chemically synthesized carrying two stable isotopes, a (2)H labeled aglucone and a (13)C labeled glucose moiety. In addition, a small amount of (14)C was incorporated into the glucose residue. The isotope-labeled compounds were applied onto cyanogenic L. corniculatus leaves that were subsequently presented to the Z. filipendulae larvae. Following ingestion by the larvae, the destiny of the isotope labeled cyanogenic glucosides was monitored in different tissues of larvae and adults at selected time points, using radio-TLC and LC-MS analyses. It was shown that sequestered compounds are taken up intact, contrary to earlier hypotheses where it was suggested that the compounds would have to be hydrolyzed before transport across the gut. The uptake from the larval gut was highly stereo selective as the β-glucosides were retained while the α-glucosides were excreted and recovered in the frass. Sequestered compounds were rapidly distributed into all analyzed tissues of the larval body, partly retained throughout metamorphosis and transferred into the adult insect where they were

  16. Biocompatible nanocomposite scaffolds based on copolymer-grafted chitosan for bone tissue engineering with drug delivery capability

    International Nuclear Information System (INIS)

    Saber-Samandari, Samaneh; Saber-Samandari, Saeed

    2017-01-01

    Significant efforts have been made to develop a suitable biocompatible scaffold for bone tissue engineering. In this work, a chitosan-graft-poly(acrylic acid-co-acrylamide)/hydroxyapatite nanocomposite scaffold was synthesized through a novel multi-step route. The prepared scaffolds were characterized for crystallinity, morphology, elemental analysis, chemical bonds, and pores size in their structure. The mechanical properties (i.e. compressive strength and elastic modulus) of the scaffolds were examined. Further, the biocompatibility of scaffolds was determined by MTT assays on HUGU cells. The result of cell culture experiments demonstrated that the prepared scaffolds have good cytocompatibility without any cytotoxicity, and with the incorporation of hydroxyapatite in their structure improves cell viability and proliferation. Finally, celecoxib as a model drug was efficiently loaded into the prepared scaffolds because of the large specific surface area. The in vitro release of the drug displayed a biphasic pattern with a low initial burst and a sustained release of up to 14 days. Furthermore, different release kinetic models were employed for the description of the release process. The results suggested that the prepared cytocompatible and non-toxic nanocomposite scaffolds might be efficient implants and drug carriers in bone-tissue engineering. - Highlights: • A series of biocompatible scaffolds were synthesized through a novel multi-step route. • The mechanical properties of the scaffolds were found close to those of trabecular bone. • The prepared scaffolds were able to load celecoxib efficiently as a model drug. • The celecoxib release was mainly controlled by a Fickian diffusion process. • The scaffold can be efficient as an implant for tissue engineering and drug delivery.

  17. Biocompatible nanocomposite scaffolds based on copolymer-grafted chitosan for bone tissue engineering with drug delivery capability

    Energy Technology Data Exchange (ETDEWEB)

    Saber-Samandari, Samaneh, E-mail: samaneh.saber@gmail.com [Department of Chemistry, Eastern Mediterranean University, Gazimagusa, TRNC via Mersin 10 (Turkey); Saber-Samandari, Saeed, E-mail: saeedss@aut.ac.ir [New Technologies Research Center, Amirkabir University of Technology, Tehran (Iran, Islamic Republic of)

    2017-06-01

    Significant efforts have been made to develop a suitable biocompatible scaffold for bone tissue engineering. In this work, a chitosan-graft-poly(acrylic acid-co-acrylamide)/hydroxyapatite nanocomposite scaffold was synthesized through a novel multi-step route. The prepared scaffolds were characterized for crystallinity, morphology, elemental analysis, chemical bonds, and pores size in their structure. The mechanical properties (i.e. compressive strength and elastic modulus) of the scaffolds were examined. Further, the biocompatibility of scaffolds was determined by MTT assays on HUGU cells. The result of cell culture experiments demonstrated that the prepared scaffolds have good cytocompatibility without any cytotoxicity, and with the incorporation of hydroxyapatite in their structure improves cell viability and proliferation. Finally, celecoxib as a model drug was efficiently loaded into the prepared scaffolds because of the large specific surface area. The in vitro release of the drug displayed a biphasic pattern with a low initial burst and a sustained release of up to 14 days. Furthermore, different release kinetic models were employed for the description of the release process. The results suggested that the prepared cytocompatible and non-toxic nanocomposite scaffolds might be efficient implants and drug carriers in bone-tissue engineering. - Highlights: • A series of biocompatible scaffolds were synthesized through a novel multi-step route. • The mechanical properties of the scaffolds were found close to those of trabecular bone. • The prepared scaffolds were able to load celecoxib efficiently as a model drug. • The celecoxib release was mainly controlled by a Fickian diffusion process. • The scaffold can be efficient as an implant for tissue engineering and drug delivery.

  18. Pathology, clinical signs, and tissue distribution of Toxoplasma gondii in experimentally infected reindeer (Rangifer tarandus

    Directory of Open Access Journals (Sweden)

    Émilie Bouchard

    2017-12-01

    Full Text Available Toxoplasma gondii is a zoonotic parasite found in vertebrates worldwide for which felids serve as definitive hosts. Despite low densities of felids in northern Canada, Inuit people in some regions show unexpectedly high levels of exposure, possibly through handling and consumption of Arctic wildlife. Free-ranging caribou (Rangifer tarandus are widely harvested for food across the Canadian North, show evidence of seroexposure to T. gondii, and are currently declining in numbers throughout the Arctic. We experimentally infected three captive reindeer (conspecific with caribou with 1000, 5000 or 10,000 oocysts of T. gondii via stomach intubation to assess clinical signs of infection, pathology, and tissue distribution. An unexposed reindeer served as a negative control. Signs of stress, aggression, and depression were noted for the first two weeks following infection. By 4 weeks post infection, all infected reindeer were positive on a modified agglutination test at the highest titer tested (1:200 for antibodies to T. gondii. At 20 weeks post infection, no gross abnormalities were observed on necropsy. Following histopathology and immunohistochemistry, tissue cysts were visualized in the reindeer given the highest and lowest dose of oocysts. Focal pleuritis and alveolitis were associated with respiratory problems in reindeer given the middle dose. DNA of T. gondii was detected following traditional DNA extraction and conventional PCR on 25 mg samples from 17/33 muscles and organs, and by magnetic capture DNA extraction from 100 g samples from all 26 tissues examined. This research demonstrated that reindeer/caribou can serve as intermediate hosts for T. gondii, and that the parasite may be associated with health effects in wildlife. The presence of T. gondii in all tissues tested, many of which are commonly consumed raw, smoked, or dried in northern communities, suggests that caribou may serve as a source of human exposure to T

  19. Sexual dimorphism in circulating leptin concentrations is not accounted for by differences in adipose tissue distribution.

    Science.gov (United States)

    Rosenbaum, M; Pietrobelli, A; Vasselli, J R; Heymsfield, S B; Leibel, R L

    2001-09-01

    Circulating concentrations of leptin normalized to total adipose tissue mass are significantly greater in females than in males. Rates of leptin expression (per gram of adipose tissue) are significantly greater in subcutaneous (SAT) than visceral (VAT) adipose tissue and the relative amount of fat stored as SAT vs VAT is significantly greater in pre-menopausal females than in males. Gender-related differences in the relative amounts of SAT and VAT may account for the greater circulating leptin concentration relative to fat-mass in females than males. We examined body composition and anatomic fat distribution by dual energy X-ray-absorptiometry (DEXA) and magnetic resonance imaging (MRI), and post-absorptive circulating concentrations of leptin and insulin in 58 subjects (26 females, 32 males). Stepwise multiple linear regression analyses, treating gender as a dichotomous variable, were performed to determine inter-relationships among leptin concentrations and insulin concentrations, VAT and SAT. Body composition by DEXA and MRI were highly correlated (r(2)=0.97, P<0.0001). There were significant gender effects on leptin/total fat mass (males, 0.17+/-0.01 ng/ml/kg; females, 0.49+/-0.05 ng/ml/kg; P<0.0001) and relative amounts of fat in SAT and VAT depots (ratio of SAT/VAT; males, 12.3+/-1.5; females, 32.9+/-3.2; P<0.0001). Circulating leptin concentration was significantly correlated with insulin concentration (P=0.001), SAT (P<0.0001) and gender (P=0.033). Circulating concentrations of insulin were significantly correlated with VAT, but not SAT, in males and with SAT, but not VAT, in females. The sexual dimorphism in the relationship between leptin and adipose tissue mass cannot be explained by differences in the relative amounts of VAT and SAT. Thus, the sexual dimorphism in plasma leptin concentration appears to reflect, at least in part, effects of circulating concentrations of gonadal steroids (especially androgens) and/or primary genetic differences that are

  20. Recent progress in the synthesis of poly(organo)phosphazenes and their applications in tissue engineering and drug delivery

    Science.gov (United States)

    Khan, R. U.; Wang, L.; Yu, H.; Zain-ul-Abdin; Akram, M.; Wu, J.; Haroon, M.; Ullah, R. S.; Deng, Zh; Xia, X.

    2018-02-01

    It is a highly desirable goal of researchers to develop effective biomaterials with minimum recovery time and affordable treatment expense for tissue engineering and drug delivery. In this scenario, numerous synthetic and natural polymers have been used. Among those synthetic polymers, polyorganophosphazenes (POPs) have got much attention as highly promising candidates for applications in tissue engineering and drug delivery. Polyorganophosphazenes are hybrid polymers containing inorganic backbone consisting of alternating nitrogen and phosphorus atoms with two organic side groups. POPs possess a wide range of unique properties, i.e., synthetic flexibility, biocompatibility, osteocompatibility, osteoinductivity, sustainability and degradability into harmless end products with predictable degradation rate and adjustable mechanical strength. Moreover, their tunable hydrophilic/hydrophobic and stimuli responsive properties add extra points to their use in biomedical applications. In addition, their various polymeric forms, i.e., microspheres, nano/microfibres, micelles, membranes, polymersomes, hydrogels and nano-conjugate linear polymers provide different carriers to efficiently deliver various hydrophilic/hydrophobic therapeutic agents both in vitro and in vivo. This review focuses on the most recent progress that has been made in the synthesis and applications of POPs in tissue engineering and their different polymeric forms used for drug delivery. Moreover, we have also summarized the effect of different side groups on the overall efficiency of POPs. The bibliography includes 239 references.

  1. Uptake, tissue distribution and metabolism of the insecticide endosulfan in Jenynsia multidentata (Anablepidae, Cyprinodontiformes)

    International Nuclear Information System (INIS)

    Ballesteros, M.L.; Gonzalez, M.; Wunderlin, D.A.; Bistoni, M.A.; Miglioranza, K.S.B.

    2011-01-01

    The study reports the accumulation, distribution and metabolism of technical endosulfan in Jenynsia multidentata. Adult females were exposed to acute sublethal concentrations (0.072, 0.288 and 1.4 μg L -1 ). After 24 h, fish were sacrificed and gills, liver, brain, intestine and muscle were removed. Results show that both isomers of technical-grade endosulfan (α- and β-) are accumulated in fish tissues and biotransformation to endosulfan sulfate occurs at all concentrations tested. Significantly differences in endosulfan accumulation were only found at 1.4 μg L -1 but not between the lowest concentrations. However a similar distribution pattern was observed at all exposure levels where liver, intestine and brain had the highest levels of α-, β-endosulfan and endosulfan sulfate. Moreover, liver and brain showed the highest endosulfan sulfate:α-endosulfan ratios due to high biotransfomation capacity. J. multidentata demonstrated to be a sensitive species under exposure to technical endosulfan and, therefore, could be used to assess aquatic pollution. - Highlights: → Acute exposure of Jenynsia multidentata to technical-grade endosulfan. → Endosulfan bioaccumulation in different organs of Jenynsia multidentata. → Technical-grade endosulfan biotransformation to endosulfan sulfate. - Endosulfan is accumulated in organs of J. multidentata as well as biotransformed to endosulfan sulfate, which relative abundance points out the time from exposure.

  2. Uptake, tissue distribution and metabolism of the insecticide endosulfan in Jenynsia multidentata (Anablepidae, Cyprinodontiformes)

    Energy Technology Data Exchange (ETDEWEB)

    Ballesteros, M.L., E-mail: mlballesteros@efn.uncor.edu [Universidad Nacional de Cordoba, Facultad de Ciencias Exactas Fisicas y Naturales, Catedra Diversidad Animal II, Av. Velez Sarsfield 299, 5000 Cordoba (Argentina); Universidad Nacional de Mar del Plata, Facultad de Ciencias Exactas y Naturales, Laboratorio de Ecotoxicologia, Funes 3350, 7600 Mar del Plata (Argentina); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) (Argentina); Gonzalez, M. [Universidad Nacional de Mar del Plata, Facultad de Ciencias Exactas y Naturales, Laboratorio de Ecotoxicologia, Funes 3350, 7600 Mar del Plata (Argentina); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) (Argentina); Wunderlin, D.A. [Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) (Argentina); Universidad Nacional de Cordoba-CONICET, Facultad de Ciencias Quimicas, Dto. Quimica Organica-CIBICI, Haya de la Torre y Medina Allende, Ciudad Universitaria, 5000 Cordoba (Argentina); Bistoni, M.A. [Universidad Nacional de Cordoba, Facultad de Ciencias Exactas Fisicas y Naturales, Catedra Diversidad Animal II, Av. Velez Sarsfield 299, 5000 Cordoba (Argentina); Miglioranza, K.S.B. [Universidad Nacional de Mar del Plata, Facultad de Ciencias Exactas y Naturales, Laboratorio de Ecotoxicologia, Funes 3350, 7600 Mar del Plata (Argentina); Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET) (Argentina)

    2011-06-15

    The study reports the accumulation, distribution and metabolism of technical endosulfan in Jenynsia multidentata. Adult females were exposed to acute sublethal concentrations (0.072, 0.288 and 1.4 {mu}g L{sup -1}). After 24 h, fish were sacrificed and gills, liver, brain, intestine and muscle were removed. Results show that both isomers of technical-grade endosulfan ({alpha}- and {beta}-) are accumulated in fish tissues and biotransformation to endosulfan sulfate occurs at all concentrations tested. Significantly differences in endosulfan accumulation were only found at 1.4 {mu}g L{sup -1} but not between the lowest concentrations. However a similar distribution pattern was observed at all exposure levels where liver, intestine and brain had the highest levels of {alpha}-, {beta}-endosulfan and endosulfan sulfate. Moreover, liver and brain showed the highest endosulfan sulfate:{alpha}-endosulfan ratios due to high biotransfomation capacity. J. multidentata demonstrated to be a sensitive species under exposure to technical endosulfan and, therefore, could be used to assess aquatic pollution. - Highlights: > Acute exposure of Jenynsia multidentata to technical-grade endosulfan. > Endosulfan bioaccumulation in different organs of Jenynsia multidentata. > Technical-grade endosulfan biotransformation to endosulfan sulfate. - Endosulfan is accumulated in organs of J. multidentata as well as biotransformed to endosulfan sulfate, which relative abundance points out the time from exposure.

  3. A short review on human exposure to and tissue distribution of per- and polyfluoroalkyl substances (PFASs).

    Science.gov (United States)

    Jian, Jun-Meng; Chen, Da; Han, Fu-Juan; Guo, Ying; Zeng, Lixi; Lu, Xingwen; Wang, Fei

    2018-09-15

    PFASs are widely distributed in natural and living environment and can enter human bodies via different routes. Many studies have reported that PFASs may be associated with human diseases, such as urine acid and thyroid diseases. In this study, we reviewed PFAS levels in human bodies reported in past seven years, including blood, urine, milk, and tissues (hair and nails). Most studies focused on human blood. Blood type, spatiality, human age, and gender were found to have a strong relationship with PFAS levels in blood samples. The PFAS distribution in urine samples was reported to be associated with the chain length of PFASs and human gender. Urinary excretion was found to be an important pathway of PFAS elimination. PFAS levels in human milk might be affected by various factors, such as mothers' age, dietary habit, parity of mothers and the interval of interpregnancy. Data in hair and nails remain very limited, but these matrices offer a non-invasive approach to evaluate human exposure to PFASs. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Nd : YAG surgical laser effects in canine prostate tissue: temperature and damage distribution

    NARCIS (Netherlands)

    van Nimwegen, S. A.; L'Eplattenier, H. F.; Rem, A. I.; van der Lugt, J. J.; Kirpensteijn, J.

    2009-01-01

    An in vitro model was used to predict short-term, laser-induced, thermal damage in canine prostate tissue. Canine prostate tissue samples were equipped with thermocouple probes to measure tissue temperature at 3, 6, 9 and 12 mm depths. The tissue surface was irradiated with a Nd:YAG laser in contact

  5. Machine Learning of Human Pluripotent Stem Cell-Derived Engineered Cardiac Tissue Contractility for Automated Drug Classification

    Directory of Open Access Journals (Sweden)

    Eugene K. Lee

    2017-11-01

    Full Text Available Accurately predicting cardioactive effects of new molecular entities for therapeutics remains a daunting challenge. Immense research effort has been focused toward creating new screening platforms that utilize human pluripotent stem cell (hPSC-derived cardiomyocytes and three-dimensional engineered cardiac tissue constructs to better recapitulate human heart function and drug responses. As these new platforms become increasingly sophisticated and high throughput, the drug screens result in larger multidimensional datasets. Improved automated analysis methods must therefore be developed in parallel to fully comprehend the cellular response across a multidimensional parameter space. Here, we describe the use of machine learning to comprehensively analyze 17 functional parameters derived from force readouts of hPSC-derived ventricular cardiac tissue strips (hvCTS electrically paced at a range of frequencies and exposed to a library of compounds. A generated metric is effective for then determining the cardioactivity of a given drug. Furthermore, we demonstrate a classification model that can automatically predict the mechanistic action of an unknown cardioactive drug.

  6. Investigation of the Relationship of Some Antihypertensive Drugs with Oxidant/Antioxidant Parameters and DNA Damage on Rat Uterus Tissue

    Directory of Open Access Journals (Sweden)

    Mustafa Talip Sener

    2011-01-01

    Full Text Available Background: In this study, we investigated the effects of treatment with chronic antihypertensivedrugs (clonidine, methyldopa, amlodipine, ramipril and rilmenidine on oxidant-antioxidantparameters and toxic effects on DNA in rat uterus tissue. In addition, uterus tissues were examinedhistopathologically.Materials and Methods: A total of 36 albino Wistar rats were divided into the following six groups:0.075 mg/kg clonidine group; 100 mg/kg methyldopa group; 2 mg/kg amlodipine group; 2.5 mg/kgramipril group; 0.5 mg/kg rilmenidine group; and the healthy group. Rats underwent chronic drugadministration for 30 days and at the end, biochemical and histopathological examinations wereperformed. All data were subjected to one-way ANOVA test.Results: We divided these drugs into the following three groups according to their effects on ratuteri: (I mild negative effects (clonidine, (II moderate negative effects (rilmenidine, methyldopaand (III drugs which had severe negative effects (amlodipine, ramipril.Conclusion: These data may help with selection of antihypertensive drugs, in order to determinewhich drugs have the lowest toxicity in pregnant and non-pregnant (pre-pregnancy women.

  7. Intrabronchial Microdialysis: Effects of Probe Localization on Tissue Trauma and Drug Penetration into the Pulmonary Epithelial Lining Fluid

    DEFF Research Database (Denmark)

    Rottbøll, Lisa Amanda Holm; Skovgaard, Kerstin; Barington, Kristiane

    2015-01-01

    (PELF). The objective of this study was to investigate the effect of intrabronchial microdialysis on the integrity of the bronchial epithelium. Microdialysis sampling in PELF in proximal (n=4) and distal bronchi (n=4) was performed after intravenous inulin and florfenicol administration in anaesthetized...... pigs. Inulin was used as a marker molecule of permeability of the epithelium, and florfenicol was used as test drug. Bronchial tissue was examined by histopathology (distal and proximal bronchi) and gene expression analysis (RT-qPCR, proximal bronchi) at the termination of the experiment (6.5hr....... Likewise, florfenicol penetration into PELF was unaffected by bronchial histopathology. However, this independency of pathology on drug penetration may not be valid for other antibiotics. We conclude that short-term microdialysis drug quantification can be performed in proximal bronchi without disruption...

  8. Pharmacokinetics and tissue distribution of enrofloxacin after single intramuscular injection in Pacific white shrimp.

    Science.gov (United States)

    Fang, X; Zhou, J; Liu, X

    2018-02-01

    The pharmacokinetic properties and tissue distribution of enrofloxacin (EF) were investigated after single intramuscular (i.m.) dose of 10 mg/kg body weight (b.w.) in Pacific white shrimp at 22 to 25°C. EF and its metabolite ciprofloxacin (CF) were determined by high-performance liquid chromatography. After i.m. administration, EF was absorbed quickly, and the peak of EF concentration (C max ) reached at first time point in hemolymph. The volume of distribution V d(area) of EF was 3.84 L/kg, indicating that the distribution of EF was good. The area under the concentration-time curve (AUC) of EF was 90.1 and 274.2 μg hr/ml in muscle and hepatopancreas, respectively, which was higher than 75.8 μg hr/ml in hemolymph. The EF elimination was slow in muscle and hepatopancreas with the half-life (T 1/2β ) of 52.3 and 75.8 hr, respectively. CF, the mainly metabolite of EF, was detected in hemolymph, muscle and hepatopancreas. The C max was 0.030, 0.013 and 0.218 μg/ml, respectively. Based on a minimum inhibitory concentration (MIC) of 0.006-0.032 μg/ml for susceptible strains, EF i.m. injected at a dose 10 mg/kg could be efficacious against common pathogenic bacteria of Pacific white shrimp. © 2017 John Wiley & Sons Ltd.

  9. Gauss-Kronrod-Trapezoidal Integration Scheme for Modeling Biological Tissues with Continuous Fiber Distributions

    Science.gov (United States)

    Hou, Chieh; Ateshian, Gerard A.

    2015-01-01

    Fibrous biological tissues may be modeled using a continuous fiber distribution (CFD) to capture tension-compression nonlinearity, anisotropic fiber distributions, and load-induced anisotropy. The CFD framework requires spherical integration of weighted individual fiber responses, with fibers contributing to the stress response only when they are in tension. The common method for performing this integration employs the discretization of the unit sphere into a polyhedron with nearly uniform triangular faces (finite element integration or FEI scheme). Although FEI has proven to be more accurate and efficient than integration using spherical coordinates, it presents three major drawbacks: First, the number of elements on the unit sphere needed to achieve satisfactory accuracy becomes a significant computational cost in a finite element analysis. Second, fibers may not be in tension in some regions on the unit sphere, where the integration becomes a waste. Third, if tensed fiber bundles span a small region compared to the area of the elements on the sphere, a significant discretization error arises. This study presents an integration scheme specialized to the CFD framework, which significantly mitigates the first drawback of the FEI scheme, while eliminating the second and third completely. Here, integration is performed only over the regions of the unit sphere where fibers are in tension. Gauss-Kronrod quadrature is used across latitudes and the trapezoidal scheme across longitudes. Over a wide range of strain states, fiber material properties, and fiber angular distributions, results demonstrate that this new scheme always outperforms FEI, sometimes by orders of magnitude in the number of computational steps and relative accuracy of the stress calculation. PMID:26291492

  10. A Gauss-Kronrod-Trapezoidal integration scheme for modeling biological tissues with continuous fiber distributions.

    Science.gov (United States)

    Hou, Chieh; Ateshian, Gerard A

    2016-01-01

    Fibrous biological tissues may be modeled using a continuous fiber distribution (CFD) to capture tension-compression nonlinearity, anisotropic fiber distributions, and load-induced anisotropy. The CFD framework requires spherical integration of weighted individual fiber responses, with fibers contributing to the stress response only when they are in tension. The common method for performing this integration employs the discretization of the unit sphere into a polyhedron with nearly uniform triangular faces (finite element integration or FEI scheme). Although FEI has proven to be more accurate and efficient than integration using spherical coordinates, it presents three major drawbacks: First, the number of elements on the unit sphere needed to achieve satisfactory accuracy becomes a significant computational cost in a finite element (FE) analysis. Second, fibers may not be in tension in some regions on the unit sphere, where the integration becomes a waste. Third, if tensed fiber bundles span a small region compared to the area of the elements on the sphere, a significant discretization error arises. This study presents an integration scheme specialized to the CFD framework, which significantly mitigates the first drawback of the FEI scheme, while eliminating the second and third completely. Here, integration is performed only over the regions of the unit sphere where fibers are in tension. Gauss-Kronrod quadrature is used across latitudes and the trapezoidal scheme across longitudes. Over a wide range of strain states, fiber material properties, and fiber angular distributions, results demonstrate that this new scheme always outperforms FEI, sometimes by orders of magnitude in the number of computational steps and relative accuracy of the stress calculation.

  11. Ex vivo preparations of human tissue for drug metabolism, toxicity and transport

    NARCIS (Netherlands)

    Groothuis, Genoveva

    2012-01-01

    Before new drugs are allowed on the market, their safety and metabolite profile should be extensively tested, as often reactive metabolites are the ultimate toxicant. The exposure of the target cell to the drug and its metabolites is determined by the expression levels of the transporters and the

  12. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Science.gov (United States)

    2010-04-01

    ... DRUG ADMINISTRATION HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS Current Good Tissue Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF...

  13. Distribution of Animal Drugs among Curd, Whey, and Milk Protein Fractions in Spiked Skim Milk and Whey.

    Science.gov (United States)

    Shappell, Nancy W; Shelver, Weilin L; Lupton, Sara J; Fanaselle, Wendy; Van Doren, Jane M; Hakk, Heldur

    2017-02-01

    It is important to understand the partitioning of drugs in processed milk and milk products, when drugs are present in raw milk, in order to estimate the potential consumer exposure. Radioisotopically labeled erythromycin, ivermectin, ketoprofen, oxytetracycline, penicillin G, sulfadimethoxine, and thiabendazole were used to evaluate the distribution of animal drugs among rennet curd, whey, and protein fractions from skim cow milk. Our previous work reported the distribution of these same drugs between skim and fat fractions of milk. Drug distribution between curd and whey was significantly correlated (R 2 = 0.70) to the drug's lipophilicity (log P), with improved correlation using log D (R 2 = 0.95). Distribution of drugs was concentration independent over the range tested (20-2000 nM). With the exception of thiabendazole and ivermectin, more drug was associated with whey protein than casein on a nmol/g protein basis (oxytetracycline experiment not performed). These results provide insights into the distribution of animal drug residues, if present in cow milk, among milk fractions, with possible extrapolation to milk products.

  14. Effects of Long-term Use of Polyphenols on the Absorption and Tissue Distribution of Orally Administered Metformin and Atenolol in Rats

    Directory of Open Access Journals (Sweden)

    Saad Abdulrahman Hussain

    2013-06-01

    Full Text Available Aim: To evaluate the effect of long-term use of silibinin, epigallocatechin (ECGC, quercetin and rutin on the absorption and tissue distribution of metformin and atenolol. Materials and Methods: Thirty male rats were used, allocated into 5 groups and treated as follow: 1st group treated with olive oil and served as control; the other 4 groups were treated with either silibinin, EPGC, quercetin or rutin, administered orally as oily solutions for 30 days. At day 30, a 300mg/kg metformin and 50mg/kg atenolol were administered orally; 3.0 hrs later, the animals were sacrificed and blood samples, tissues of brain, kidney and liver were obtained for evaluation of the drugs level. Results: The polyphenols increased both serum and tissue levels of metformin compared with controls. This effect was relatively varied according to the structural differences among flavonoids. Conclusion: Long-term use of supraphysiological doses of flavonoids increase absorption of Zn, Cu and Fe and their tissue availability in brain, kidney and liver; this effect seems to be different with variations in structural features. [J Intercult Ethnopharmacol 2013; 2(3.000: 147-154

  15. Calculation of dose distribution in compressible breast tissues using finite element modeling, Monte Carlo simulation and thermoluminescence dosimeters

    Science.gov (United States)

    Mohammadyari, Parvin; Faghihi, Reza; Mosleh-Shirazi, Mohammad Amin; Lotfi, Mehrzad; Rahim Hematiyan, Mohammad; Koontz, Craig; Meigooni, Ali S.

    2015-12-01

    Compression is a technique to immobilize the target or improve the dose distribution within the treatment volume during different irradiation techniques such as AccuBoost® brachytherapy. However, there is no systematic method for determination of dose distribution for uncompressed tissue after irradiation under compression. In this study, the mechanical behavior of breast tissue between compressed and uncompressed states was investigated. With that, a novel method was developed to determine the dose distribution in uncompressed tissue after irradiation of compressed breast tissue. Dosimetry was performed using two different methods, namely, Monte Carlo simulations using the MCNP5 code and measurements using thermoluminescent dosimeters (TLD). The displacement of the breast elements was simulated using a finite element model and calculated using ABAQUS software. From these results, the 3D dose distribution in uncompressed tissue was determined. The geometry of the model was constructed from magnetic resonance images of six different women volunteers. The mechanical properties were modeled by using the Mooney-Rivlin hyperelastic material model. Experimental dosimetry was performed by placing the TLD chips into the polyvinyl alcohol breast equivalent phantom. The results determined that the nodal displacements, due to the gravitational force and the 60 Newton compression forces (with 43% contraction in the loading direction and 37% expansion in the orthogonal direction) were determined. Finally, a comparison of the experimental data and the simulated data showed agreement within 11.5%  ±  5.9%.

  16. Calculation of dose distribution in compressible breast tissues using finite element modeling, Monte Carlo simulation and thermoluminescence dosimeters

    International Nuclear Information System (INIS)

    Mohammadyari, Parvin; Faghihi, Reza; Mosleh-Shirazi, Mohammad Amin; Lotfi, Mehrzad; Hematiyan, Mohammad Rahim; Koontz, Craig; Meigooni, Ali S

    2015-01-01

    Compression is a technique to immobilize the target or improve the dose distribution within the treatment volume during different irradiation techniques such as AccuBoost ® brachytherapy. However, there is no systematic method for determination of dose distribution for uncompressed tissue after irradiation under compression. In this study, the mechanical behavior of breast tissue between compressed and uncompressed states was investigated. With that, a novel method was developed to determine the dose distribution in uncompressed tissue after irradiation of compressed breast tissue. Dosimetry was performed using two different methods, namely, Monte Carlo simulations using the MCNP5 code and measurements using thermoluminescent dosimeters (TLD). The displacement of the breast elements was simulated using a finite element model and calculated using ABAQUS software. From these results, the 3D dose distribution in uncompressed tissue was determined. The geometry of the model was constructed from magnetic resonance images of six different women volunteers. The mechanical properties were modeled by using the Mooney–Rivlin hyperelastic material model. Experimental dosimetry was performed by placing the TLD chips into the polyvinyl alcohol breast equivalent phantom. The results determined that the nodal displacements, due to the gravitational force and the 60 Newton compression forces (with 43% contraction in the loading direction and 37% expansion in the orthogonal direction) were determined. Finally, a comparison of the experimental data and the simulated data showed agreement within 11.5%  ±  5.9%. (paper)

  17. Combination of MALDI-MSI and cassette dosing for evaluation of drug distribution in human skin explant

    DEFF Research Database (Denmark)

    Sørensen, Isabella S; Janfelt, Christian; Nielsen, Mette Marie B

    2017-01-01

    Study of skin penetration and distribution of the drug compounds in the skin is a major challenge in the development of topical drug products for treatment of skin diseases. It is crucial to have fast and efficacious screening methods which can provide information concerning the skin penetration ...... that combination of MALDI-MSI and cassette dosing can be used as a medium throughput screening tool at an early stage in the drug discovery/development process. Graphical abstract Investigation of drug distribution in human skin explant by MALDI-MSI after cassette dosing....

  18. Topical nonsteroidal anti-inflammatory drugs for the treatment of pain due to soft tissue injury: diclofenac epolamine topical patch

    Directory of Open Access Journals (Sweden)

    David R Lionberger

    2010-11-01

    Full Text Available David R Lionberger1, Michael J Brennan21Southwest Orthopedic Group, Houston, TX, USA; 2Department of Medicine, Bridgeport Hospital, Bridgeport, CT, USAAbstract: The objective of this article is to review published clinical data on diclofenac epolamine topical patch 1.3% (DETP in the treatment of acute soft tissue injuries, such as strains, sprains, and contusions. Review of published literature on topical nonsteroidal anti-inflammatory drugs (NSAIDs, diclofenac, and DETP in patients with acute soft tissue injuries was included. Relevant literature was identified on MEDLINE using the search terms topical NSAIDs, diclofenac, diclofenac epolamine, acute pain, sports injury, soft tissue injury, strain, sprain, and contusion, and from citations in retrieved articles covering the years 1978–2008. Review of published, randomized clinical trials and meta-analyses shows that topical NSAIDs are significantly more effective than placebo in relieving acute pain; the pooled average relative benefit was 1.7 (95% confidence interval, 1.5–1.9. In a limited number of comparisons, topical and oral NSAIDs provided comparable pain relief, but the use of topical agents produced lower plasma drug concentrations and fewer systemic adverse events (AEs. The physical–chemical properties of diclofenac epolamine make it well suited for topical use. In patients with acute soft tissue injuries treated with DETP, clinical data report an analgesic benefit within hours of the first application, and significant pain relief relative to placebo within 3 days. Moreover, DETP displayed tolerability comparable with placebo; the most common AEs were pruritus and other application site reactions. Review of published literature suggests that DETP is generally safe and well tolerated, clinically efficacious, and a rational treatment option for patients experiencing acute pain associated with strains, sprains, and contusions, and other localized painful conditions

  19. Pharmacokinetics and tissue distribution of recombinant human tumor necrosis factor-alpha in mice

    International Nuclear Information System (INIS)

    Ferraiolo, B.L.; Moore, J.A.; Crase, D.; Gribling, P.; Wilking, H.; Baughman, R.A.

    1988-01-01

    The serum pharmacokinetics and the major organs of accumulation of recombinant human tumor necrosis factor-alpha (rHuTNF) were determined in BDF1 mice after intravenous and intramuscular administration. Serum concentrations of immunoreactive protein were determined by enzyme-linked immunosorbent assay, and radioactivity was quantitated by beta and gamma scintigraphy. The serum pharmacokinetics of labeled and unlabeled rHuTNF were identical when administered by the intravenous route. After intravenous doses of 165 to 320 micrograms/kg, the clearance was 2.9-3.6 ml/hr, the initial volume of distribution was 1.4-1.6 ml (70-80 ml/kg), and the half-life was 18.5-19.2 min. Intramuscular administration of 320 micrograms/kg resulted in a peak serum concentration of 112 ng/ml. The time of the peak concentration was 1 hr, and the bioavailability of the intramuscular dose was 12%. The data suggest that the disposition of this protein may be biexponential. If this is the case, the terminal phase would appear to account for less than 1% of the total AUC. Since serum concentrations in the terminal phase are at the sensitivity limit of the assay, a single half-life is reported. 125I-Labeled and metabolically labeled 3H-rHuTNF were used to examine tissue distribution. After intravenous 125I-rHuTNF administration, the rank order of accumulation of the 125I-radiolabel in the major organs (per cent dose per organ over 1440 min) was: liver greater than kidney greater than lung greater than heart greater than spleen. This rank order of accumulation was confirmed by intravenous 3H-rHuTNF administration

  20. Tissue distribution and excretion of copper-67 intraperitoneally administered to rats fed fructose or starch

    International Nuclear Information System (INIS)

    Holbrook, J.; Fields, M.; Smith, J.C. Jr.; Reiser, S.

    1986-01-01

    It has been suggested that impaired gut absorption of copper is the cause of the exacerbated copper deficiency signs in rats fed fructose when compared to rats fed starch. The present study was designed to examine how rats fed fructose or starch diets, either copper-deficient or supplemented, distributed and excreted 67 Cu when the isotope was administered i.p. Intraperitoneal administration was chosen in an effort to circumvent primary gut absorption as a factor in the metabolism of 67 Cu. After 7 wk of dietary treatment, rats received an i.p. injection of 67 Cu and were placed in metabolic cages for 4 d. Regardless of dietary carbohydrate, copper-deficient rats retained similar levels of radioactivity in various tissues and excreted similar amounts of 67 Cu in feces and urine. This similarity in copper metabolism in copper-deficient rats fed either fructose or starch when the gut was circumvented for isotope administration suggests that the gut could be responsible, at least in part, for the exacerbated signs associated with the copper deficiency in rats fed fructose. The possibility is discussed that alterations in metabolism may increase the requirement for copper when fructose is the main dietary carbohydrate

  1. Effect of laser beam on temperature distribution on artificial cylindrical shaped hard tissue bones

    Science.gov (United States)

    Al-Akhras, M.-Ali H.; Qaseer, Mohammad-Khair; Albiss, B. A.; Gezawa, Umar S.

    2018-02-01

    Samples from fresh lamb chest bones were made in cylindrical shapes to study the time variation of temperature T as functions of the cylindrical radius and depth when its front surface exposed to a laser beam of 110Mw power and 642nm wavelength. The laser beam was directed at the center of the front surface of the horizontal cylinder. The measurements were done in vacuum and at atmospheric pressure. Our data reveal the linear variation of T with time, followed by a gradual increase before it reaches a plateau value at higher time. This sort of behavior independent of the radius or the depth where the temperature was measured. Moreover, the maximum variation occurs on the front surface where the laser beam was hitting and diminishes gradually with depth deep inside the cylinder. Data at atmospheric pressure showed less changes in temperature. The temperature distribution in bone due to laser irradiation is very important for a rational use of laser therapy as well as in the surgery to minimizes the thermal tissue damage.

  2. Spatial distribution of the trace elements zinc, strontium and lead in human bone tissue.

    Science.gov (United States)

    Pemmer, B; Roschger, A; Wastl, A; Hofstaetter, J G; Wobrauschek, P; Simon, R; Thaler, H W; Roschger, P; Klaushofer, K; Streli, C

    2013-11-01

    Trace elements are chemical elements in minute quantities, which are known to accumulate in the bone. Cortical and trabecular bones consist of bone structural units (BSUs) such as osteons and bone packets of different mineral content and are separated by cement lines. Previous studies investigating trace elements in bone lacked resolution and therefore very little is known about the local concentration of zinc (Zn), strontium (Sr) and lead (Pb) in BSUs of human bone. We used synchrotron radiation induced micro X-ray fluorescence analysis (SR μ-XRF) in combination with quantitative backscattered electron imaging (qBEI) to determine the distribution and accumulation of Zn, Sr, and Pb in human bone tissue. Fourteen human bone samples (10 femoral necks and 4 femoral heads) from individuals with osteoporotic femoral neck fractures as well as from healthy individuals were analyzed. Fluorescence intensity maps were matched with BE images and correlated with calcium (Ca) content. We found that Zn and Pb had significantly increased levels in the cement lines of all samples compared to the surrounding mineralized bone matrix. Pb and Sr levels were found to be correlated with the degree of mineralization. Interestingly, Zn intensities had no correlation with Ca levels. We have shown for the first time that there is a differential accumulation of the trace elements Zn, Pb and Sr in BSUs of human bone indicating different mechanisms of accumulation. © 2013. Published by Elsevier Inc. All rights reserved.

  3. Trace Elements Distribution in Human Gallstones, Bile and Gallbladder Tissues Using Instrumental Neutron Activation Analysis

    International Nuclear Information System (INIS)

    Abugassa, I. O.; Khrbish, Y. S.; Bshir, A. T.; Doubali, K.; Abugassa, S. O.

    2007-01-01

    This study focuses on the elemental distribution in different types of gallstones; bile and gallbladder tissues using neutron activation analysis technique based on k0-INAA method in Tajura center. Samples were collected from patients who undergone open surgery of gallbladder (cholecystectomy) at El-khadra University Hospital in Tripoli, aged between 23-80 yr. The samples obtained from patients who don't suffer from any chronic diseases, therefore, they were not taking any medications that might elevate the concentration of certain elements in the body. Samples were prepared and lyophilized by different process in a clean room. All samples were irradiated in the reactor and measured in the neutron activation laboratory. In order to obtain accurate results, Au and Zr flux monitors were irradiated with the samples for flux ratio (f) and α determinations and to account for any flux variations within the container. The irradiations of the samples were carried out in the reactor channels VCR11 and VCR12 for 8 hours under f (32 and 14) and α parameters (0.0183, 0.1678) respectively. More than 20 elements were determined in the above mentioned samples. Several SRM were irradiated with the samples to insure the reliability of the results.

  4. Mathematical modeling of degradation for bulk-erosive polymers: applications in tissue engineering scaffolds and drug delivery systems.

    Science.gov (United States)

    Chen, Yuhang; Zhou, Shiwei; Li, Qing

    2011-03-01

    The degradation of polymeric biomaterials, which are widely exploited in tissue engineering and drug delivery systems, has drawn significant attention in recent years. This paper aims to develop a mathematical model that combines stochastic hydrolysis and mass transport to simulate the polymeric degradation and erosion process. The hydrolysis reaction is modeled in a discrete fashion by a fundamental stochastic process and an additional autocatalytic effect induced by the local carboxylic acid concentration in terms of the continuous diffusion equation. Illustrative examples of microparticles and tissue scaffolds demonstrate the applicability of the model. It is found that diffusive transport plays a critical role in determining the degradation pathway, whilst autocatalysis makes the degradation size dependent. The modeling results show good agreement with experimental data in the literature, in which the hydrolysis rate, polymer architecture and matrix size actually work together to determine the characteristics of the degradation and erosion processes of bulk-erosive polymer devices. The proposed degradation model exhibits great potential for the design optimization of drug carriers and tissue scaffolds. Copyright © 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  5. Accumulation of plutonium in mammalian wildlife tissues: comparison of recent data with the ICRP distribution models

    Energy Technology Data Exchange (ETDEWEB)

    Johansen, M.; Child, D.; Davis, E.; Hotchkis, M.; Payne, T. [Australian Nuclear Science and Technology Org. (Australia); Ikeda-Ohno, A. [University of New South Wales (Australia); Twining, J. [Austral Radioecology (Australia)

    2014-07-01

    We examined the distribution of plutonium (Pu) in the tissues of mammalian wildlife to address the paucity of such data under environmental exposure conditions. Pu activity concentrations were measured in Macropus rufus (red kangaroo), Oryctolagus cuniculus (European rabbit), and Pseudomys hermannsburgensis (sandy inland mouse)inhabiting the relatively undisturbed, semi-arid conditions at the former Taranaki weapons test site at Maralinga, Australia. Of the absorbed Pu (distributed via circulatory and lymph systems) accumulation was foremost in bone (83% ±10% SD), followed by muscle (9% ±10%), liver (7% ±7%), kidneys (0.5% ±0.3%), and heart (0.4% ±0.4%). The bone values are higher than those reported in ICRP 19 and 48 (45-50% bone), while the liver values are lower than ICRP values (30-45% liver). The ICRP values were based on data dominated by relatively soluble forms of Pu, including prepared solutions and single-atom ions produced by decay following the volatilisation of uranium during nuclear detonation (fallout Pu, ICRP 1986). In contrast, the Maralinga data relates to low-soluble forms of Pu used in tests designed to simulate accidental release and dispersal. We measured Pu in lung, GI-tract and the skin and fur as distinct from the absorbed Pu in bone, liver, muscle, and kidneys. Compared with the mean absorbed activity concentrations, the results for lung tissues were higher by up to one order of magnitude, and those in the GI tract contents and the washed skin/fur were higher by more than two orders of magnitude. These elevated levels are consistent with the presence of low-soluble Pu, including particulate forms, which pass through, or adhere upon, certain organs, but are not readily absorbed into the bloodstream. This more transitory Pu can provide dose to the lung and GI tract organs, as well as provide potential transfer of contamination when consumed in predator-prey food chains, or during human foodstuff consumption. For example, activity

  6. Short-peptide-based molecular hydrogels: novel gelation strategies and applications for tissue engineering and drug delivery

    Science.gov (United States)

    Wang, Huaimin; Yang, Zhimou

    2012-08-01

    Molecular hydrogels hold big potential for tissue engineering and controlled drug delivery. Our lab focuses on short-peptide-based molecular hydrogels formed by biocompatible methods and their applications in tissue engineering (especially, 3D cell culture) and controlled drug delivery. This feature article firstly describes our recent progresses of the development of novel methods to form hydrogels, including the strategy of disulfide bond reduction and assistance with specific protein-peptide interactions. We then introduce the applications of our hydrogels in fields of controlled stem cell differentiation, cell culture, surface modifications of polyester materials by molecular self-assembly, and anti-degradation of recombinant complex proteins. A novel molecular hydrogel system of hydrophobic compounds that are only formed by hydrolysis processes was also included in this article. The hydrogels of hydrophobic compounds, especially those of hydrophobic therapeutic agents, may be developed into a carrier-free delivery system for long term delivery of therapeutic agents. With the efforts in this field, we believe that molecular hydrogels formed by short peptides and hydrophobic therapeutic agents can be practically applied for 3D cell culture and long term drug delivery in near future, respectively.

  7. Localized increase of tissue oxygen tension by magnetic targeted drug delivery

    Science.gov (United States)

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

    2014-07-01

    Hypoxia is the major hindrance to successful radiation therapy of tumors. Attempts to increase the oxygen (O2) tension (PO2) of tissue by delivering more O2 have been clinically disappointing, largely due to the way O2 is transported and released by the hemoglobin (Hb) within the red blood cells (RBCs). Systemic manipulation of O2 transport increases vascular resistance due to metabolic autoregulation of blood flow to prevent over oxygenation. This study investigates a new technology to increase O2 delivery to a target tissue by decreasing the Hb-O2 affinity of the blood circulating within the targeted tissue. As the Hb-O2 affinity decreases, the tissue PO2 to satisfy tissue O2 metabolic needs increases without increasing O2 delivery or extraction. Paramagnetic nanoparticles (PMNPs), synthetized using gadolinium oxide, were coated with the cell permeable Hb allosteric effector L35 (3,5-trichlorophenylureido-phenoxy-methylpropionic acid). L35 decreases Hb affinity for O2 and favors the release of O2. The L35-coated PMNPs (L35-PMNPs) were intravenously infused (10 mg kg-1) to hamsters instrumented with the dorsal window chamber model. A magnetic field of 3 mT was applied to localize the effects of the L35-PMNPs to the window chamber. Systemic O2 transport characteristics and microvascular tissue oxygenation were measured after administration of L35-PMNPs with and without magnetic field. The tissue PO2 in untreated control animals was 25.2 mmHg. L35-PMNPs without magnetic field decreased tissue PO2 to 23.4 mmHg, increased blood pressure, and reduced blood flow, largely due to systemic modification of Hb-O2 affinity. L35-PMNPs with magnetic field increased tissue PO2 to 27.9 mmHg, without systemic or microhemodynamic changes. These results indicate that localized modification of Hb-O2 affinity can increase PO2 of target tissue without affecting systemic O2 delivery or triggering O2 autoregulation mechanisms. This technology can be used to treat local hypoxia and to

  8. Effect of certain variables on the tumor and tissue distribution of tracers. Salicylates and vasoactive drugs

    International Nuclear Information System (INIS)

    Halpern, S.E.; Hagan, P.; Stern, P.; Gordon, R.; Dabbs, J.

    1981-01-01

    Attempts were made to increase the viable tumor concentration of 54Mn and 67Ga in a rat hepatoma model by administering rat angiotensin, tolazoline, and salicylates. Salicylates increased the tumor concentrations of 54Mn and improved 65Mn viable tumor/background ratios. 67Ga was not affected by the salicylates. The salicylate effect appeared to be mediated by intracellular mechanisms rather than alterations in plasma protein binding. Rat angiotensin slightly increased the concentrations of 67Ga in the tumors but not enough to suggest that it would be useful clinically. Tolazoline did not increase tumor uptake of the tracers

  9. Vertical distribution of total carbon, nitrogen and phosphorus in sediments of Drug Spring Lake, Wudalianchi

    Science.gov (United States)

    Zeng, Ying; Yang, Chen

    2018-02-01

    The content of total organic carbon, total nitrogen and total phosphorus in sediments of Drug Spring Lake was detected and their vertical distribution characteristic was analysed. Results showed that there were significant changes to the content of total organic carbon, total nitrogen and total phosphorus in different depth of the columnar sediments. Their highest content both appeared in the interval of 10cm to 25cm corresponding to the period of 1980s to 1990s, when the tourism of Wudalianchi scenic area began to develop. It reflected the impact of human activities on the Drug Spring Lake. That means the regulation was still not enough, although a series of pollution control measures adopted by the government in recent years had initial success.

  10. Determination of drug, excipients and coating distribution in pharmaceutical tablets using NIR-CI

    Directory of Open Access Journals (Sweden)

    Anna Palou

    2012-04-01

    Full Text Available The growing interest of the pharmaceutical industry in Near Infrared-Chemical Imaging (NIR-CI is a result of its high usefulness for quality control analyses of drugs throughout their production process (particularly of its non-destructive nature and expeditious data acquisition. In this work, the concentration and distribution of the major and minor components of pharmaceutical tablets are determined and the spatial distribution from the internal and external sides has been obtained. In addition, the same NIR-CI allowed the coating thickness and its surface distribution to be quantified. Images were processed to extract the target data and calibration models constructed using the Partial Least Squares (PLS algorithms. The concentrations of Active Pharmaceutical Ingredient (API and excipients obtained for uncoated cores were essentially identical to the nominal values of the pharmaceutical formulation. But the predictive ability of the calibration models applied to the coated tablets decreased as the coating thickness increased. Keywords: Near infrared Chemical Imaging (NIR-CI, Hyperspectral imaging, Component distribution, Tablet coating distribution, Partial Least Squares (PLS regression

  11. Engineering dextran-based scaffolds for drug delivery and tissue repair

    Science.gov (United States)

    Sun, Guoming; Mao, Jeremy J

    2015-01-01

    Owing to its chemically reactive hydroxyl groups, dextran can be modified with different functional groups to form spherical, tubular and 3D network structures. The development of novel functional scaffolds for efficient controlled release and tissue regeneration has been a major research interest, and offers promising therapeutics for many diseases. Dextran-based scaffolds are naturally biodegradable and can serve as bioactive carriers for many protein biomolecules. The reconstruction of the in vitro microenvironment with proper signaling cues for large-scale tissue regenerative scaffolds has yet to be fully developed, and remains a significant challenge in regenerative medicine. This paper will describe recent advances in dextran-based polymers and scaffolds for controlled release and tissue engineering. Special attention is given to the development of dextran-based hydrogels that are precisely manipulated with desired structural properties and encapsulated with defined angiogenic growth factors for therapeutic neovascularization, as well as their potential for wound repair. PMID:23210716

  12. Zinc accumulation and distribution over tissues in Noccaea сaerulescens in nature and in hydroponics : a comparison

    NARCIS (Netherlands)

    Kozhevnikova, Anna D.; Seregin, I. V.; Gosti, F.; Schat, H.

    2017-01-01

    Aims: Zinc distribution at the tissue level is studied almost exclusively in lab-grown plants. It is essential to establish to what extent the patterns observed in lab-grown plants are corresponding with those in nature. To this end, we compared Zn localization in Noccaea caerulescens growing in its

  13. TISSUE DISTRIBUTION OF INORGANIC ARSENIC (AS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV)

    Science.gov (United States)

    TISSUE DISTRIBUTION OF INORGANIC ARSENIC (iAs) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (AsV). E M Kenyon1, L M Del Razo2, and M F Hughes1. 1NHEERL, ORD, US EPA, RTP, NC, USA; 2CINVESTAV-IPN, Mexico City, Mexico.The relationship o...

  14. 3D Printing of Tissue Engineered Constructs for in vitro Modeling of Disease Progression and Drug Screening

    Science.gov (United States)

    Vanderburgh, Joseph; Sterling, Julie A.

    2016-01-01

    2D cell culture and preclinical animal models have traditionally been implemented for investigating the underlying cellular mechanisms of human disease progression. However, the increasing significance of 3D versus 2D cell culture has initiated a new era in cell culture research in which 3D in vitro models are emerging as a bridge between traditional 2D cell culture and in vivo animal models. Additive manufacturing (AM, also known as 3D printing), defined as the layer-by-layer fabrication of parts directed by digital information from a 3D computer-aided design (CAD) file, offers the advantages of simultaneous rapid prototyping and biofunctionalization as well as the precise placement of cells and extracellular matrix with high resolution. In this review, we highlight recent advances in 3D printing of tissue engineered constructs (TECs) that recapitulate the physical and cellular properties of the tissue microenvironment for investigating mechanisms of disease progression and for screening drugs. PMID:27169894

  15. Intravenous Exposure of Pregnant Mice to Silver Nanoparticles: Silver Tissue Distribution and Effects in Maternal and Extra-Embryonic Tissues and Embryos

    Science.gov (United States)

    Austin, Carlye Anne

    This research explores the tissue distribution of silver, as well as adverse effects in pregnant mice and embryos, following prenatal silver nanoparticle (AgNP) exposure. Chapter one of this dissertation is a survey of the published literature on the reproductive and/or developmental toxicity of AgNPs. The available data indicate that AgNPs adversely affect sperm count, viability, and/or motility both in vivo and in vitro, and cause apoptosis and necrosis in spermatogonial stem cells and testicular cells. Additionally, AgNP exposure results in mortality and morphological deformities in fish embryos, but produces no adverse effects in chicken embryos. The current published research on in vivo AgNP exposure to mammals during gestation consists of only three studies, one of which is described in chapter two of this dissertation. These studies report results that may suggest a potential for adverse effects on fetal development (e.g. , decreased viability and fetal and placental weights, increased incidence of developmentally young embryos), but additional research is needed. Chapter two of this dissertation investigates the distribution of silver in tissues of pregnant mice and gestation day (GD) 10 embryos following intravenous maternal exposure to 50 nm AgNPs during early organogenesis (GDs 7-9). Examinations of embryo morphology and histology were also performed. Results demonstrated the presence of silver in all organs and tissues examined. Silver concentrations were highest in liver, spleen, and visceral yolk sac, and lowest in embryos. Groups of mice were also treated with soluble silver nitrate, and the pattern of silver tissue distribution following silver nitrate exposure was similar to that which followed AgNP treatment. Transmission electron microscopy-energy dispersive x-ray spectroscopy (TEM-EDS) confirmed the presence of vesicle-bound nanoparticulate silver in visceral yolk sac endoderm, but not mesoderm. This finding, along with the high silver

  16. Effect of Pressurized Metered Dose Inhaler Spray Characteristics and Particle Size Distribution on Drug Delivery Efficiency.

    Science.gov (United States)

    Yousefi, Morteza; Inthavong, Kiao; Tu, Jiyuan

    2017-10-01

    A key issue in pulmonary drug delivery is improvement of the delivery device for effective and targeted treatment. Pressurized metered dose inhalers (pMDIs) are the most popular aerosol therapy device for treating lung diseases. This article studies the effect of spray characteristics: injection velocity, spray cone angle, particle size distribution (PSD), and its mass median aerodynamic diameter (MMAD) on drug delivery. An idealized oral airway geometry, extending from mouth to the main bronchus, was connected to a pMDI device. Inhalation flow rates of 15, 30, and 60 L/min were used and drug particle tracking was a one-way coupled Lagrangian model. The results showed that most particles deposited in the pharynx, where the airway has a reduced cross-sectional area. Particle deposition generally decreased with initial spray velocity and with increased spray cone angle for 30 and 60 L/min flow rates. However, for 15 L/min flow rate, the deposition increased slightly with an increase in the spray velocity and cone angle. The effect of spray cone angle was more significant than the initial spray velocity on particle deposition. When the MMAD of a PSD was reduced, the deposition efficiency also reduces, suggesting greater rates of particle entry into the lung. The deposition rate showed negligible change when the MMAD was more than 8 μm. Spray injection angle and velocity change the drug delivery efficacy; however, the efficiency shows more sensitivity to the injection angle. The 30 L/min airflow rate delivers spray particles to the lung more efficiently than 15 and 60 L/min airflow rate, and reducing MMAD can help increase drug delivery to the lung.

  17. Influence trend of temperature distribution in skin tissue generated by different exposure dose pulse laser

    Science.gov (United States)

    Shan, Ning; Wang, Zhijing; Liu, Xia

    2014-11-01

    Laser is widely applied in military and medicine fields because of its excellent capability. In order to effectively defend excess damage by laser, the thermal processing theory of skin tissue generated by laser should be carried out. The heating rate and thermal damage area should be studied. The mathematics model of bio-tissue heat transfer that is irradiated by laser is analyzed. And boundary conditions of bio-tissue are discussed. Three layer FEM grid model of bio-tissue is established. The temperature rising inducing by pulse laser in the tissue is modeled numerically by adopting ANSYS software. The changing trend of temperature in the tissue is imitated and studied under the conditions of different exposure dose pulse laser. The results show that temperature rising in the tissue depends on the parameters of pulse laser largely. In the same conditions, the pulse width of laser is smaller and its instant power is higher. And temperature rising effect in the tissue is very clear. On the contrary, temperature rising effect in the tissue is lower. The cooling time inducing by temperature rising effect in the tissue is longer along with pulse separation of laser is bigger. And the temperature difference is bigger in the pulse period.

  18. The distribution of radiolabelled drug in animals infected with cutaneous leishmaniasis: comparison of free and liposome-bound sodium stibogluconate

    International Nuclear Information System (INIS)

    New, R.R.C.; Chance, M.L.; Critchley, M.

    1982-01-01

    Sodium stibogluconate, labelled with antimony 125, was used to study the altered distribution of drugs, entrapped by positively and negatively charged liposomes, used to treat cutaneous leishmaniasis. (U.K.)

  19. Topical nonsteroidal anti-inflammatory drugs for the treatment of pain due to soft tissue injury: diclofenac epolamine topical patch.

    Science.gov (United States)

    Lionberger, David R; Brennan, Michael J

    2010-11-10

    The objective of this article is to review published clinical data on diclofenac epolamine topical patch 1.3% (DETP) in the treatment of acute soft tissue injuries, such as strains, sprains, and contusions. Review of published literature on topical nonsteroidal anti-inflammatory drugs (NSAIDs), diclofenac, and DETP in patients with acute soft tissue injuries was included. Relevant literature was identified on MEDLINE using the search terms topical NSAIDs, diclofenac, diclofenac epolamine, acute pain, sports injury, soft tissue injury, strain, sprain, and contusion, and from citations in retrieved articles covering the years 1978-2008. Review of published, randomized clinical trials and meta-analyses shows that topical NSAIDs are significantly more effective than placebo in relieving acute pain; the pooled average relative benefit was 1.7 (95% confidence interval, 1.5-1.9). In a limited number of comparisons, topical and oral NSAIDs provided comparable pain relief, but the use of topical agents produced lower plasma drug concentrations and fewer systemic adverse events (AEs). The physical-chemical properties of diclofenac epolamine make it well suited for topical use. In patients with acute soft tissue injuries treated with DETP, clinical data report an analgesic benefit within hours of the first application, and significant pain relief relative to placebo within 3 days. Moreover, DETP displayed tolerability comparable with placebo; the most common AEs were pruritus and other application site reactions. Review of published literature suggests that DETP is generally safe and well tolerated, clinically efficacious, and a rational treatment option for patients experiencing acute pain associated with strains, sprains, and contusions, and other localized painful conditions.

  20. The tissue distribution and excretion study of paeoniflorin-6'-O-benzene sulfonate (CP-25) in rats.

    Science.gov (United States)

    Zhao, Mingyi; Zhou, Peng; Yu, Jun; James, Asenso; Xiao, Feng; Wang, Chun; Wei, Wei

    2018-03-09

    Paeoniflorin-6'-O-benzene sulfonate (code: CP-25) is a novel ester derivative of paeoniflorin (Pae). Compared to Pae, CP-25 has higher lipid solubility, bioavailability and better bioactivity. However, the tissue distribution and excretion of CP-25 still remain unknown. The LC-MS method was applied to investigate the tissue distribution and excretion of CP-25 in rats. As such, 50 mg/kg of CP-25 and Pae were administered to rats in multiple doses via an oral route. CP-25 and Pae were distributed widely and rapidly in all the tested tissues. Compared with Pae, the concentrations of CP-25 were almost increased evidently in most tissues. The highest CP-25 level was found in the liver (1476.33 ± 535.20 ng/g, male; 1970.38 ± 177.21 ng/g, female) at 3 h, and a high concentration of CP-25 was detected in male and female intestine, synovium, muscle, lung, and brain. Following a single oral dose of 50 mg/kg of CP-25 in rats, the total excretion of CP-25 was merely 21.8% (18.40, 3.19 and 0.22% for feces, bile and urine, respectively) in males; and was approximately 21.3% (14.04, 7.16 and 0.14% for feces, bile and urine, respectively) in females. The results indicated that the CP-25 concentration was higher in major tissues than Pae; CP-25 was primarily excreted through the feces; and there were gender-related differences in the tissue distribution and excretion.

  1. Tissue distribution of enrofloxacin in African clawed frogs (Xenopus laevis) after intramuscular and subcutaneous administration.

    Science.gov (United States)

    Felt, Stephen; Papich, Mark G; Howard, Antwain; Long, Tyler; McKeon, Gabriel; Torreilles, Stéphanie; Green, Sherril

    2013-03-01

    As part of an enrofloxacin pharmacokinetic study, concentrations of enrofloxacin and ciprofloxacin (metabolite) were measured in various tissues (brain, heart, kidney, liver, lung, and spleen) collected from treated (subcutaneous delivery, n = 3; intramuscular delivery, n = 3; untreated controls, n = 2) adult female Xenopus laevis by using HPLC. Enrofloxacin was rapidly absorbed after administration by either route and readily diffused into all sampled tissues. Enrofloxacin and ciprofloxacin were present in the tissue samples collected at 8 h. The highest average tissue concentrations for enrofloxacin were found in kidney, with the lowest concentrations in liver. Ciprofloxacin tissue concentrations paralleled but were always lower than those of enrofloxacin for all time points and tissues except brain and kidney. These results, together with previously published pharmacokinetic data and known minimal inhibitory concentrations of common pathogenic bacteria, provide a strong evidence-based rationale for choosing enrofloxacin to treat infectious diseases in X. laevis.

  2. Genetic diversity of Plasmodium falciparum and distribution of drug resistance haplotypes in Yemen.

    Science.gov (United States)

    Al-Hamidhi, Salama; Mahdy, Mohammed A K; Al-Hashami, Zainab; Al-Farsi, Hissa; Al-mekhlafi, Abdulsalam M; Idris, Mohamed A; Beja-Pereira, Albano; Babiker, Hamza A

    2013-07-15

    Despite evident success of malaria control in many sites in the Arabian Peninsula, malaria remains endemic in a few spots, in Yemen and south-west of Saudi Arabia. In addition to local transmission, imported malaria sustains an extra source of parasites that can challenge the strengths of local control strategies. This study examined the genetic diversity of Plasmodium falciparum in Yemen and mutations of drug resistant genes, to elucidate parasite structure and distribution of drug resistance genotypes in the region. Five polymorphic loci (MSP-2, Pfg377 and three microsatellites on chromosome 8) not involved in anti-malarial drug resistance, and four drug resistant genes (pfcrt, pfmdr1, dhfr and dhps) were genotyped in 108 P. falciparum isolates collected in three sites in Yemen: Dhamar, Hodeidah and Taiz. High diversity was seen in non-drug genes, pfg377 (He = 0.66), msp-2 (He = 0.80) and three microsatellites on chr 8, 7.7 kb (He = 0.88), 4.3 kb (He = 0.77) and 0.8 kb (He = 0.71). There was a high level of mixed-genotype infections (57%), with an average 1.8 genotypes per patient. No linkage disequilibrium was seen between drug resistant genes and the non-drug markers (p Yemen is indicative of a large parasite reservoir, which represents a challenge to control efforts. The presence of two distinct pfcrt genotype, CVIET and SVMNT, suggests that chloroquine resistance can possibly be related to a migratory path from Africa and Asia. The absence of the triple mutant dhfr genotype (IRN) and dhps mutations supports the use of artesunate + sulphadoxine-pyrimethamine as first-line therapy. However, the prevalent pfmdr1 genotype NFSND [21%] has previously been associated with tolerance/resistance response to artemisinin combination therapy (ACT). Regular surveys are, therefore, important to monitor spread of pfmdr1 and dhfr mutations and response to ACT.

  3. Illicit drug detection with laser 1: investigation of optimal parameters in stomach tissue

    Science.gov (United States)

    Özer, Ayşen Gürkan; Tabakoğlu, Haşim Özgür; Cengiz, Salih

    2014-05-01

    The main purpose of this study is to establish radiation-safe scanning of passersby at high security areas, such as airports and customs. The stomach was selected as the organ to be analyzed. In order to determine whether a substance found inside a human body as wrapped in a plastic bag is filled narcotics or not, many substances in white powder form including morphine-HCL were inspected. Inspection was carried out with on-ionizing radiation by irradiating stomach tissue with laser light. Optical transmittance of lamb stomach tissue was analyzed at different wavelengths. We showed that detection by 650-nm diode laser irradiation would be suitable for such a radiation-safe scan. Different materials were also investigated for absorptive properties, and closed system Raman studies were performed. The spectrum of a molecule found inside white powder placed behind the lamb stomach tissue was detected as a fingerprint. This allowed the detection of target substances without any physical contact or damage to the biological tissue.

  4. Physiologically Distributed Loading Patterns Drive the Formation of Zonally Organized Collagen Structures in Tissue-Engineered Meniscus.

    Science.gov (United States)

    Puetzer, Jennifer L; Bonassar, Lawrence J

    2016-07-01

    The meniscus is a dense fibrocartilage tissue that withstands the complex loads of the knee via a unique organization of collagen fibers. Attempts to condition engineered menisci with compression or tensile loading alone have failed to reproduce complex structure on the microscale or anatomic scale. Here we show that axial loading of anatomically shaped tissue-engineered meniscus constructs produced spatial distributions of local strain similar to those seen in the meniscus when the knee is loaded at full extension. Such loading drove formation of tissue with large organized collagen fibers, levels of mechanical anisotropy, and compressive moduli that match native tissue. Loading accelerated the development of native-sized and aligned circumferential and radial collagen fibers. These loading patterns contained both tensile and compressive components that enhanced the major biochemical and functional properties of the meniscus, with loading significantly improved glycosaminoglycan (GAG) accumulation 200-250%, collagen accumulation 40-55%, equilibrium modulus 1000-1800%, and tensile moduli 500-1200% (radial and circumferential). Furthermore, this study demonstrates local changes in mechanical environment drive heterogeneous tissue development and organization within individual constructs, highlighting the importance of recapitulating native loading environments. Loaded menisci developed cartilage-like tissue with rounded cells, a dense collagen matrix, and increased GAG accumulation in the more compressively loaded horns, and fibrous collagen-rich tissue in the more tensile loaded outer 2/3, similar to native menisci. Loaded constructs reached a level of organization not seen in any previous engineered menisci and demonstrate great promise as meniscal replacements.

  5. Exercise and type 2 diabetes mellitus: changes in tissue-specific fat distribution and cardiac function.

    Science.gov (United States)

    Jonker, Jacqueline T; de Mol, Pieter; de Vries, Suzanna T; Widya, Ralph L; Hammer, Sebastiaan; van Schinkel, Linda D; van der Meer, Rutger W; Gans, Rijk O B; Webb, Andrew G; Kan, Hermien E; de Koning, Eelco J P; Bilo, Henk J G; Lamb, Hildo J

    2013-11-01

    To prospectively assess the effects of an exercise intervention on organ-specific fat accumulation and cardiac function in type 2 diabetes mellitus. Written informed consent was obtained from all participants, and the study protocol was approved by the medical ethics committee. The study followed 12 patients with type 2 diabetes mellitus (seven men; mean age, 46 years ± 2 [standard error]) before and after 6 months of moderate-intensity exercise, followed by a high-altitude trekking expedition with exercise of long duration. Abdominal, epicardial, and paracardial fat volume were measured by using magnetic resonance (MR) imaging. Cardiac function was quantified with cardiac MR, and images were analyzed by a researcher who was supervised by a senior researcher (4 and 21 years of respective experience in cardiac MR). Hepatic, myocardial, and intramyocellular triglyceride (TG) content relative to water were measured with proton MR spectroscopy at 1.5 and 7 T. Two-tailed paired t tests were used for statistical analysis. Exercise reduced visceral abdominal fat volume from 348 mL ± 57 to 219 mL ± 33 (P Exercise decreased hepatic TG content from 6.8% ± 2.3 to 4.6% ± 1.6 (P Exercise did not change epicardial fat volume (P = .9), myocardial TG content (P = .9), intramyocellular lipid content (P = .3), or cardiac function (P = .5). A 6-month exercise intervention in type 2 diabetes mellitus decreased hepatic TG content and visceral abdominal and paracardial fat volume, which are associated with increased cardiovascular risk, but cardiac function was unaffected. Tissue-specific exercise-induced changes in body fat distribution in type 2 diabetes mellitus were demonstrated in this study. RSNA, 2013

  6. Pathogen infection distribution and drug resistance analysis of patients with severe liver disease

    Directory of Open Access Journals (Sweden)

    Xi CHEN

    2018-04-01

    Full Text Available Objective To explore the infection distribution and drug resistance of pathogens in patients with severe liver disease, and provide reference for clinical medication. Methods Retrospective analysis of the microbiological specimens from patients with severe liver disease in Department of Infection of our hospital from August 2014 to November 2016 and the drug susceptibility testing were carried out by means of K-B disc diffusion method after bacterial culturing, and the distribution and drug resistance of pathogens were analyzed. Results Totally 17 of 73 patients with severe liver disease developed hospital infection (23.3%. 104 strains of bacteria were isolated and 78 strains out of them were multidrug-resistant bacteria (75.0%. Among them, 28(26.9% strains were gram-positive coccus, mainly consisting of Staphylococcus aureus and Staphylococcus epidermidis, and 58(55.8% were gram-negative coccus, mainly composed of Escherichia coli, Klebsiella pneumonia and Acinetobacter baumannii, and 18(17.3% strains fungi. S.aureus and enterococci were resistant to penicillin, erythromycin and levofloxacin, the resistance rates were above 80.0%, but had low resistance rates to vancomycin, teicoplanin and tigecycline. The resistance rates of E.coli and K.pneumoniae to piperacillin, cefazolin and cefuroxime sodium were above 85.0%, but they had lower resistance rates to tigecycline and amikacin. Acinetobacter baumannii was 100% resistant to piperacillin and tazobactam, ceftazidime, imipenem and amikacin, but had low resistance to tigecycline and minocycline. Conclusions Multi-drug resistant bacteria are the main bacterial pathogens in patients with severe liver disease and have a high resistance rate to commonly used antibiotics, empirical treatment in the population at high risk of multidrug-resistant bacteria infections requires the use of broad-spectrum or high-grade antibiotics (e.g. carbapenems or tigecycline and drugs against specific pathogenic

  7. Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues.

    Science.gov (United States)

    Wang, Chunyi; Mao, Jinghe; Redfield, Samantha; Mo, Yinyuan; Lage, Janice M; Zhou, Xinchun

    2014-10-01

    Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data in benign and malignant tissues from the same organ/tissue were then compared using the Student's t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (in either the nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft

  8. Micro-distribution of uranium in bone after contamination: new insight into its mechanism of accumulation into bone tissue

    Energy Technology Data Exchange (ETDEWEB)

    Bourgeois, Damien [ICSM, LHYS, Bagnols-sur-Ceze (France); Burt-Pichat, Brigitte [INSERM, UMR 1033 Lyon (France); Lyon Univ. (France); Le Goff, Xavier [ICSM, L2ME, Bagnols-sur-Ceze (France)

    2015-09-15

    After internal contamination, uranium rapidly distributes in the body; up to 20 % of the initial dose is retained in the skeleton, where it remains for years. Several studies suggest that uranium has a deleterious effect on the bone cell system, but little is known regarding the mechanisms leading to accumulation of uranium in bone tissue. We have performed synchrotron radiation-based micro-X-ray fluorescence (SR μ-XRF) studies to assess the initial distribution of uranium within cortical and trabecular bones in contaminated rats' femurs at the micrometer scale. This sensitive technique with high spatial resolution is the only method available that can be successfully applied, given the small amount of uranium in bone tissue. Uranium was found preferentially located in calcifying zones in exposed rats and rapidly accumulates in the endosteal and periosteal area of femoral metaphyses, in calcifying cartilage and in recently formed bone tissue along trabecular bone. Furthermore, specific localized areas with high accumulation of uranium were observed in regions identified as micro-vessels and on bone trabeculae. These observations are of high importance in the study of the accumulation of uranium in bone tissue, as the generally proposed passive chemical sorption on the surface of the inorganic part (apatite) of bone tissue cannot account for these results. Our study opens original perspectives in the field of exogenous metal bio-mineralization.

  9. Distribution of Rotundone and Possible Translocation of Related Compounds Amongst Grapevine Tissues in Vitis vinifera L. cv. Shiraz

    Science.gov (United States)

    Zhang, Pangzhen; Fuentes, Sigfredo; Wang, Yueying; Deng, Rui; Krstic, Mark; Herderich, Markus; Barlow, Edward W. R.; Howell, Kate

    2016-01-01

    Rotundone is an attractive wine aroma compound, especially important for cool climate Shiraz. Its presence in wine is mainly from the grape skin, but can also be found in non-grape tissues, such as leaves and stems. Whether rotundone is produced independently within different grapevine tissues or transported amongst non-grape tissues and grape berries remains unclear. The current study investigated the distribution of this compound in different vine tissues during development and studied the most likely mode of rotundone translocation—via phloem—using stable isotope feeding. In addition, local production of rotundone induced by herbivore feeding was assessed. Results showed that rotundone was firstly detected in the petioles and peduncles/rachises within the development of Vitis vinifera L. cv. Shiraz. Different grapevine tissues had a similar pattern of rotundone production at different grape developmental stages. In the individual vine shoots, non-grape tissues contained higher concentrations and amounts of rotundone compared to berries, which showed that non-grape tissues were the larger pool of rotundone within the plant. This study confirmed the local production of rotundone in individual tissues and ruled out the possibility of phloem translocation of rotundone between different tissues. In addition, other terpenes, including one monoterpenoid (geraniol) and six sesquiterpenes (clovene, α-ylangene, β-copaene, α-muurolene, δ-cadinene, and cis/trans-calamenene) were, for the first time, detected in the ethylenediaminetetraacetic acid-facilitated petiole phloem exudates, with their originality unconfirmed. Unlike other herbivore-induced terpenes, herbivorous activity had limited influences on the concentration of rotundone in grapevine leaves. PMID:27446104

  10. Comparative studies on the distribution of rhodanese in different tissues of domestic animals.

    Science.gov (United States)

    Aminlari, M; Gilanpour, H

    1991-01-01

    1. The activity of rhodanese in different tissues of some domestic animals was measured. 2. Rhodanese was present in all tissues studied. 3. The activity of rhodanese in most tissues of sheep was higher than other animals studied. 4. In sheep and cattle the epithelium of rumen, omasum and reticulum were the richest sources of rhodanese. Significant activity of rhodanese was also present in liver and kidney. 5. In camel the liver contained the highest level of rhodanese followed by lung and rumen epithelium. Camel liver contained a third of the activity of sheep liver. 6. Equine liver had a third of the activity of sheep liver. Other tissues showed low levels of rhodanese activity. 7. Dog liver contained only 4% of the activity of sheep liver. In this animal, brain was the richest source of rhodanese. 8. The results are discussed in terms of efficacy of different tissues of animals in cyanide detoxification.

  11. Species distribution and drug susceptibility of candida in clinical isolates from a tertiary care centre at Indore

    Directory of Open Access Journals (Sweden)

    N Pahwa

    2014-01-01

    Full Text Available Background: The incidence of fungal infections has increased significantly, contributing to morbidity and mortality. This is caused by an alarming increase in infections with multi-drug resistant bacteria leading to overuse of broad-spectrum antimicrobials, which lead to overgrowth of Candida, thus enhancing its opportunity to cause disease. Candida are major human fungal pathogens that cause both mucosal and deep tissue infections. Objective : The aim of our study was to identify the distribution of Candida species among clinical isolates and their sensitivity pattern for common antifungal drugs. Materials and Methods : Two hundred and thirty-seven different clinical isolates of Candida were collected from patients visiting to a tertiary care centre of Indore from 2010 to 2012. Identification of Candida species as well as antifungal sensitivity testing was performed with Vitek2 Compact (Biomerieux France using vitek 2 cards for identification of yeast and yeast like organisms (ID-YST cards. Antifungal susceptibility testing was performed with Vitek2 "Fungal Susceptibility Card (AST YS01 kits respectively. Results : We found that the non-albicans Candida were more prevalent than Candida albicans in paediatric (60 year patients than other age group (4-18, 19-60 years patients and also in intensive care unit (ICU patients as compared to out patient department (OPD patients. Resistance rates for amphotericin B, fluconazole, flucytosine, itraconazole, and voriconazole were 2.9%, 5.9%, 0.0%, 4.2% and 2.5%%, respectively. All the strains of C. krusei were found resistant to fluconazole with intermediate sensitivity to flucytosine. Conclusion: Species-level identification of Candida and their antifungal sensitivity testing should be performed to achieve better clinical results.

  12. Automated Liquid Microjunction Surface Sampling-HPLC-MS/MS Analysis of Drugs and Metabolites in Whole-Body Thin Tissue Sections

    Energy Technology Data Exchange (ETDEWEB)

    Kertesz, Vilmos [ORNL; Van Berkel, Gary J [ORNL

    2013-01-01

    A fully automated liquid extraction-based surface sampling system utilizing a commercially available autosampler coupled to high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) detection is reported. Discrete spots selected for droplet-based sampling and automated sample queue generation for both the autosampler and MS were enabled by using in-house developed software. In addition, co-registration of spatially resolved sampling position and HPLC-MS information to generate heatmaps of compounds monitored for subsequent data analysis was also available in the software. The system was evaluated with whole-body thin tissue sections from propranolol dosed rat. The hands-free operation of the system was demonstrated by creating heatmaps of the parent drug and its hydroxypropranolol glucuronide metabolites with 1 mm resolution in the areas of interest. The sample throughput was approximately 5 min/sample defined by the time needed for chromatographic separation. The spatial distributions of both the drug and its metabolites were consistent with previous studies employing other liquid extraction-based surface sampling methodologies.

  13. Comparative tissue distribution and excretion of orally administered [3H]diacetoxyscirpenol (anguidine) in rats and mice

    International Nuclear Information System (INIS)

    Wang, J.S.; Busby, W.F. Jr.; Wogan, G.N.

    1990-01-01

    A quantitative comparison of tissue distribution and excretion of an orally administered sublethal dose of [3H]diacetoxyscirpenol (anguidine) was made in rats and mice 90 min, 24 hr, and 7 days after treatment. Total recoveries of 95-100% were obtained. Approximately 90% of the dose was excreted in urine and feces during the first 24 hr with a feces:urine ratio of about 1:4.5 in both species. Carcass and tissue radioactivity dropped rapidly during the first 24 hr but remained relatively constant at low, but detectable, levels over the course of the experiment. Few substantive interspecies differences were noted in tissue distribution. At 90 min the highest percentage of dose was in tissues involved in sequestering diacetoxyscirpenol because of high body water/lipid content or the absorption, metabolism, or excretion of the toxin. The rank order of these tissues was generally stable over the course of the experiment. When data were expressed as specific radioactivity instead, the carcass and skin dropped from the top rank tissues at 90 min and were replaced by the spleen and cecum. At 24 hr and 7 days the top-ranked order of tissues shifted to include organs associated with trichothecene-induced toxicity such as the lymphohematopoietic system (spleen, thymus, and femur bone marrow), heart, and testis (in mouse) as well as the cecum and large intestine. In addition, the rate of loss of radioactivity with time generally did not decrease as rapidly in these target organs as observed in liver, kidney, skin, and carcass. Brain radioactivity, though very low, also diminished relatively slowly. Significant differences in specific radioactivity which did occur between the rat and mouse tended to occur in target organs and with the higher levels present in the mouse. These data were discussed in terms of interspecies differences in lethality and target organ toxicity

  14. Errors in estimating neutron quality factor using lineal energy distributions measured in tissue-equivalent proportional counters

    International Nuclear Information System (INIS)

    Borak, T.B.; Stinchcomb, T.G.

    1982-01-01

    Neutron dose equivalent is obtained from quality factors which are defined in terms of LET. It is possible to estimate the dose averaged quality factor, antiQ, directly from distributions in lineal energy, y, that are measured in tissue-equivalent proportional counters. This eliminates a mathematical transformation of the absorbed dose from D(y) to D(L). We evaluate the inherent error in computing Q from D(y) rather than D(L) for neutron spectra below 4 MeV. The effects of neutron energy and simulated tissue diameters within a gas cavity are examined in detail. (author)

  15. Chemical and structural investigation of lipid nanoparticles: drug-lipid interaction and molecular distribution

    Energy Technology Data Exchange (ETDEWEB)

    Anantachaisilp, Suranan; Smith, Siwaporn Meejoo [Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400 (Thailand); Treetong, Alongkot; Ruktanonchai, Uracha Rungsardthong [National Nanotechnology Center, National Science and Technology Development Agency, 111 Thailand Science Park, Paholyothin Road, Klong 1, Klong Luang, Pathumthani 12120 (Thailand); Pratontep, Sirapat [College of KMITL Nanotechnology, King Mongkut' s Institute of Technology Ladkrabang, Bangkok (Thailand); Puttipipatkhachorn, Satit, E-mail: uracha@nanotec.or.th [Department of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400 (Thailand)

    2010-03-26

    Lipid nanoparticles are a promising alternative to existing carriers in chemical or drug delivery systems. A key challenge is to determine how chemicals are incorporated and distributed inside nanoparticles, which assists in controlling chemical retention and release characteristics. This study reports the chemical and structural investigation of {gamma}-oryzanol loading inside a model lipid nanoparticle drug delivery system composed of cetyl palmitate as solid lipid and Miglyol 812 as liquid lipid. The lipid nanoparticles were prepared by high pressure homogenization at varying liquid lipid content, in comparison with the {gamma}-oryzanol free systems. The size of the lipid nanoparticles, as measured by the photon correlation spectroscopy, was found to decrease with increased liquid lipid content from 200 to 160 nm. High-resolution proton nuclear magnetic resonance ({sup 1}H-NMR) measurements of the medium chain triglyceride of the liquid lipid has confirmed successful incorporation of the liquid lipid in the lipid nanoparticles. Differential scanning calorimetric and powder x-ray diffraction measurements provide complementary results to the {sup 1}H-NMR, whereby the crystallinity of the lipid nanoparticles diminishes with an increase in the liquid lipid content. For the distribution of {gamma}-oryzanol inside the lipid nanoparticles, the {sup 1}H-NMR revealed that the chemical shifts of the liquid lipid in {gamma}-oryzanol loaded systems were found at rather higher field than those in {gamma}-oryzanol free systems, suggesting incorporation of {gamma}-oryzanol in the liquid lipid. In addition, the phase-separated structure was observed by atomic force microscopy for lipid nanoparticles with 0% liquid lipid, but not for lipid nanoparticles with 5 and 10% liquid lipid. Raman spectroscopic and mapping measurements further revealed preferential incorporation of {gamma}-oryzanol in the liquid part rather than the solid part of in the lipid nanoparticles. Simple models

  16. Chemical and structural investigation of lipid nanoparticles: drug-lipid interaction and molecular distribution

    Science.gov (United States)

    Anantachaisilp, Suranan; Meejoo Smith, Siwaporn; Treetong, Alongkot; Pratontep, Sirapat; Puttipipatkhachorn, Satit; Rungsardthong Ruktanonchai, Uracha

    2010-03-01

    Lipid nanoparticles are a promising alternative to existing carriers in chemical or drug delivery systems. A key challenge is to determine how chemicals are incorporated and distributed inside nanoparticles, which assists in controlling chemical retention and release characteristics. This study reports the chemical and structural investigation of γ-oryzanol loading inside a model lipid nanoparticle drug delivery system composed of cetyl palmitate as solid lipid and Miglyol 812® as liquid lipid. The lipid nanoparticles were prepared by high pressure homogenization at varying liquid lipid content, in comparison with the γ-oryzanol free systems. The size of the lipid nanoparticles, as measured by the photon correlation spectroscopy, was found to decrease with increased liquid lipid content from 200 to 160 nm. High-resolution proton nuclear magnetic resonance (1H-NMR) measurements of the medium chain triglyceride of the liquid lipid has confirmed successful incorporation of the liquid lipid in the lipid nanoparticles. Differential scanning calorimetric and powder x-ray diffraction measurements provide complementary results to the 1H-NMR, whereby the crystallinity of the lipid nanoparticles diminishes with an increase in the liquid lipid content. For the distribution of γ-oryzanol inside the lipid nanoparticles, the 1H-NMR revealed that the chemical shifts of the liquid lipid in γ-oryzanol loaded systems were found at rather higher field than those in γ-oryzanol free systems, suggesting incorporation of γ-oryzanol in the liquid lipid. In addition, the phase-separated structure was observed by atomic force microscopy for lipid nanoparticles with 0% liquid lipid, but not for lipid nanoparticles with 5 and 10% liquid lipid. Raman spectroscopic and mapping measurements further revealed preferential incorporation of γ-oryzanol in the liquid part rather than the solid part of in the lipid nanoparticles. Simple models representing the distribution of γ-oryzanol and

  17. Chemical and structural investigation of lipid nanoparticles: drug-lipid interaction and molecular distribution

    International Nuclear Information System (INIS)

    Anantachaisilp, Suranan; Smith, Siwaporn Meejoo; Treetong, Alongkot; Ruktanonchai, Uracha Rungsardthong; Pratontep, Sirapat; Puttipipatkhachorn, Satit

    2010-01-01

    Lipid nanoparticles are a promising alternative to existing carriers in chemical or drug delivery systems. A key challenge is to determine how chemicals are incorporated and distributed inside nanoparticles, which assists in controlling chemical retention and release characteristics. This study reports the chemical and structural investigation of γ-oryzanol loading inside a model lipid nanoparticle drug delivery system composed of cetyl palmitate as solid lipid and Miglyol 812 as liquid lipid. The lipid nanoparticles were prepared by high pressure homogenization at varying liquid lipid content, in comparison with the γ-oryzanol free systems. The size of the lipid nanoparticles, as measured by the photon correlation spectroscopy, was found to decrease with increased liquid lipid content from 200 to 160 nm. High-resolution proton nuclear magnetic resonance ( 1 H-NMR) measurements of the medium chain triglyceride of the liquid lipid has confirmed successful incorporation of the liquid lipid in the lipid nanoparticles. Differential scanning calorimetric and powder x-ray diffraction measurements provide complementary results to the 1 H-NMR, whereby the crystallinity of the lipid nanoparticles diminishes with an increase in the liquid lipid content. For the distribution of γ-oryzanol inside the lipid nanoparticles, the 1 H-NMR revealed that the chemical shifts of the liquid lipid in γ-oryzanol loaded systems were found at rather higher field than those in γ-oryzanol free systems, suggesting incorporation of γ-oryzanol in the liquid lipid. In addition, the phase-separated structure was observed by atomic force microscopy for lipid nanoparticles with 0% liquid lipid, but not for lipid nanoparticles with 5 and 10% liquid lipid. Raman spectroscopic and mapping measurements further revealed preferential incorporation of γ-oryzanol in the liquid part rather than the solid part of in the lipid nanoparticles. Simple models representing the distribution of γ-oryzanol and

  18. Specialty pharmacies and other restricted drug distribution systems: financial and safety considerations for patients and health-system pharmacists.

    Science.gov (United States)

    Kirschenbaum, Bonnie E

    2009-12-15

    To discuss the role of restricted drug distribution systems in the implementation of risk evaluation and mitigation strategies (REMS), health-system pharmacists' concerns associated with the use of specialty pharmacies and other restricted drug distribution systems, reimbursement policies for high-cost specialty drugs, supply chain models for traditional and specialty drugs, and emerging trends in the management of and reimbursement for specialty pharmaceuticals. Restricted drug distribution systems established by pharmaceutical manufacturers, specialty pharmacies, or other specialty suppliers may be a component of REMS, which are required by the Food and Drug Administration for the management of known or potential serious risks from certain drugs. Concerns of health-system pharmacists using specialty suppliers include access to pharmaceuticals, operational challenges, product integrity, financial implications, continuity of care, and patient safety. An ambulatory care patient taking a specialty drug product from home to a hospital outpatient clinic or inpatient setting for administration, a practice known as "brown bagging," raises concerns about product integrity and institutional liability. An institution's finances, tolerance for liability, and ability to skillfully manage the processes involved often determine its choice between an approach that prohibits brown bagging but is costly and one that permits the practice under certain conditions and is less costly. The recent shift from a traditional supply chain model to a specialty pharmacy supply chain model for high-cost pharmaceuticals has the potential to increase pharmaceutical costs for health systems. A dialogue is needed between health-system pharmacists and group purchasing organizations to address the latter's role in mitigating the financial implications of this change and to help clarify the safety issues. Some health plans have shifted part of the cost of expensive drugs to patients by establishing a

  19. Distribution of 238Pu in tissues of fish from the canal in Miamisburg, Oho

    International Nuclear Information System (INIS)

    Kennedy, C.W.; Bartelt, G.E.

    1978-01-01

    The 238 Pu concentrations of varous tissues were measured for seven species of freshwater fish from an ecosystem containing elevated levels of 238 Pu. The highest levels of 238 Pu were found in the gastrointestinal tracts and gills, while the lowest levels were found in muscle tissue. A rapid uptake of 238 Pu was observed for hatchery bluegills introduced into this system. High plutonium concentrations in the gastrointestinal tracts and gills suggest that these organs are potential uptake sites. The presence of 238 Pu in certain tissues (liver, gonads, bone, and muscle) indicates that there is a translocation of 238 Pu from the uptake sites

  20. Attitudes towards drug-eluting stent use and the distribution of motivation type among interventional cardiologists.

    Science.gov (United States)

    Qian, Feng; Phelps, Charles E; Ling, Frederick S; Hannan, Edward L; Veazie, Peter J

    2012-06-01

    The safety of drug-eluting stent (DES) use was called into question in 2006. However, the attitudes towards DES use after DES safety concerns were expressed and the distribution of chronic motivation type among interventional cardiologists are unknown. This study aims to examine the current attitudes towards DES use among interventional cardiologists and to investigate the distribution of chronic motivation type among these doctors. A questionnaire survey of interventional cardiologists was conducted in New York State from October 2008 to April 2009. The questionnaire included face valid items to measure the attitudes towards DES use, valid Regulatory Focus Questionnaire to measure the chronic motivation type, and items collecting demographic information. A total of 119 valid responses were received (response rate: 47%). There were no statistically significant differences regarding the demographic factors between the respondents and the non-respondents. The vast majority of interventional cardiologists (92%) agreed that 'DES is a revolutionary technology' and that 'DES use will increase in the future' (70%). The chronic motivation type of the respondents was predominantly sensitive to positive outcomes (89%). Interventional cardiologists had a very positive attitude regarding DES technology and predicted future growth of DES use. The vast majority of interventional cardiologists were found to be concerned about achieving positive outcomes and wanted to prevent errors of omission. To the best of our knowledge, this is the first study to report the distribution of chronic motivation type among doctors. © 2011 Blackwell Publishing Ltd.

  1. Tissue-engineered cartilaginous constructs for the treatment of caprine cartilage defects, including distribution of laminin and type IV collagen.

    Science.gov (United States)

    Jeng, Lily; Hsu, Hu-Ping; Spector, Myron

    2013-10-01

    The purpose of this study was the immunohistochemical evaluation of (1) cartilage tissue-engineered constructs; and (2) the tissue filling cartilage defects in a goat model into which the constructs were implanted, particularly for the presence of the basement membrane molecules, laminin and type IV collagen. Basement membrane molecules are localized to the pericellular matrix in normal adult articular cartilage, but have not been examined in tissue-engineered constructs cultured in vitro or in tissue filling cartilage defects into which the constructs were implanted. Cartilaginous constructs were engineered in vitro using caprine chondrocyte-seeded type II collagen scaffolds. Autologous constructs were implanted into 4-mm-diameter defects created to the tidemark in the trochlear groove in the knee joints of skeletally mature goats. Eight weeks after implantation, the animals were sacrificed. Constructs underwent immunohistochemical and histomorphometric evaluation. Widespread staining for the two basement membrane molecules was observed throughout the extracellular matrix of in vitro and in vivo samples in a distribution unlike that previously reported for cartilage. At sacrifice, 70% of the defect site was filled with reparative tissue, which consisted largely of fibrous tissue and some fibrocartilage, with over 70% of the reparative tissue bonded to the adjacent host tissue. A novel finding of this study was the observation of laminin and type IV collagen in in vitro engineered cartilaginous constructs and in vivo cartilage repair samples from defects into which the constructs were implanted, as well as in normal caprine articular cartilage. Future work is needed to elucidate the role of basement membrane molecules during cartilage repair and regeneration.

  2. Thermal distribution in biological tissue at laser induced fluorescence and photodynamic therapy

    Science.gov (United States)

    Krasnikov, I. V.; Seteikin, A. Yu.; Drakaki, E.; Makropoulou, M.

    2012-03-01

    Laser induced fluorescence spectroscopy and photodynamic therapy (PDT) are techniques currently introduced in clinical applications for visualization and local destruction of malignant tumours as well as premalignant lesions. During the laser irradiation of tissues for the diagnostic and therapeutic purposes, the absorbed optical energy generates heat, although the power density of the treatment light for surface illumination is normally low enough not to cause any significantly increased tissue temperature. In this work we tried to evaluate the utility of Monte Carlo modeling for simulating the temperature fields and the dynamics of heat conduction into the skin tissue under several laser irradiation conditions with both a pulsed UV laser and a continuous wave visible laser beam. The analysis of the results showed that heat is not localized on the surface, but it is collected inside the tissue. By varying the boundary conditions on the surface and the type of the laser radiation (continuous or pulsed) we can reach higher than normal temperature inside the tissue without simultaneous formation of thermally damaged tissue (e.g. coagulation or necrosis zone).

  3. Analysis of skin tissues spatial fluorescence distribution by the Monte Carlo simulation

    International Nuclear Information System (INIS)

    Churmakov, D Y; Meglinski, I V; Piletsky, S A; Greenhalgh, D A

    2003-01-01

    A novel Monte Carlo technique of simulation of spatial fluorescence distribution within the human skin is presented. The computational model of skin takes into account the spatial distribution of fluorophores, which would arise due to the structure of collagen fibres, compared to the epidermis and stratum corneum where the distribution of fluorophores is assumed to be homogeneous. The results of simulation suggest that distribution of auto-fluorescence is significantly suppressed in the near-infrared spectral region, whereas the spatial distribution of fluorescence sources within a sensor layer embedded in the epidermis is localized at an 'effective' depth

  4. Analysis of skin tissues spatial fluorescence distribution by the Monte Carlo simulation

    Energy Technology Data Exchange (ETDEWEB)

    Churmakov, D Y [School of Engineering, Cranfield University, Cranfield, MK43 0AL (United Kingdom); Meglinski, I V [School of Engineering, Cranfield University, Cranfield, MK43 0AL (United Kingdom); Piletsky, S A [Institute of BioScience and Technology, Cranfield University, Silsoe, MK45 4DT (United Kingdom); Greenhalgh, D A [School of Engineering, Cranfield University, Cranfield, MK43 0AL (United Kingdom)

    2003-07-21

    A novel Monte Carlo technique of simulation of spatial fluorescence distribution within the human skin is presented. The computational model of skin takes into account the spatial distribution of fluorophores, which would arise due to the structure of collagen fibres, compared to the epidermis and stratum corneum where the distribution of fluorophores is assumed to be homogeneous. The results of simulation suggest that distribution of auto-fluorescence is significantly suppressed in the near-infrared spectral region, whereas the spatial distribution of fluorescence sources within a sensor layer embedded in the epidermis is localized at an 'effective' depth.

  5. Analysis of skin tissues spatial fluorescence distribution by the Monte Carlo simulation

    Science.gov (United States)

    Y Churmakov, D.; Meglinski, I. V.; Piletsky, S. A.; Greenhalgh, D. A.

    2003-07-01

    A novel Monte Carlo technique of simulation of spatial fluorescence distribution within the human skin is presented. The computational model of skin takes into account the spatial distribution of fluorophores, which would arise due to the structure of collagen fibres, compared to the epidermis and stratum corneum where the distribution of fluorophores is assumed to be homogeneous. The results of simulation suggest that distribution of auto-fluorescence is significantly suppressed in the near-infrared spectral region, whereas the spatial distribution of fluorescence sources within a sensor layer embedded in the epidermis is localized at an `effective' depth.

  6. Non-invasive assessment of distribution volume ratios and binding potential: tissue heterogeneity and interindividually averaged time-activity curves

    Energy Technology Data Exchange (ETDEWEB)

    Reimold, M.; Mueller-Schauenburg, W.; Dohmen, B.M.; Bares, R. [Department of Nuclear Medicine, University of Tuebingen, Otfried-Mueller-Strasse 14, 72076, Tuebingen (Germany); Becker, G.A. [Nuclear Medicine, University of Leipzig, Leipzig (Germany); Reischl, G. [Radiopharmacy, University of Tuebingen, Tuebingen (Germany)

    2004-04-01

    Due to the stochastic nature of radioactive decay, any measurement of radioactivity concentration requires spatial averaging. In pharmacokinetic analysis of time-activity curves (TAC), such averaging over heterogeneous tissues may introduce a systematic error (heterogeneity error) but may also improve the accuracy and precision of parameter estimation. In addition to spatial averaging (inevitable due to limited scanner resolution and intended in ROI analysis), interindividual averaging may theoretically be beneficial, too. The aim of this study was to investigate the effect of such averaging on the binding potential (BP) calculated with Logan's non-invasive graphical analysis and the ''simplified reference tissue method'' (SRTM) proposed by Lammertsma and Hume, on the basis of simulated and measured positron emission tomography data [{sup 11}C]d-threo-methylphenidate (dMP) and [{sup 11}C]raclopride (RAC) PET. dMP was not quantified with SRTM since the low k {sub 2} (washout rate constant from the first tissue compartment) introduced a high noise sensitivity. Even for considerably different shapes of TAC (dMP PET in parkinsonian patients and healthy controls, [{sup 11}C]raclopride in patients with and without haloperidol medication) and a high variance in the rate constants (e.g. simulated standard deviation of K {sub 1}=25%), the BP obtained from average TAC was close to the mean BP (<5%). However, unfavourably distributed parameters, especially a correlated large variance in two or more parameters, may lead to larger errors. In Monte Carlo simulations, interindividual averaging before quantification reduced the variance from the SRTM (beyond a critical signal to noise ratio) and the bias in Logan's method. Interindividual averaging may further increase accuracy when there is an error term in the reference tissue assumption E=DV {sub 2}-DV ' (DV {sub 2} = distribution volume of the first tissue compartment, DV &apos

  7. A biomimetic physiological model for human adipose tissue by adipocytes and endothelial cell cocultures with spatially controlled distribution

    International Nuclear Information System (INIS)

    Yao, Rui; Zhang, Renji; Lin, Feng; Du, Yanan; Luan, Jie

    2013-01-01

    An in vitro model that recapitulates the characteristics of native human adipose tissue would largely benefit pathology studies and therapy development. In this paper, we fabricated a physiological model composed of both human adipocytes and endothelial cells with spatially controlled distribution that biomimics the structure and composition of human adipose tissue. Detailed studies into the cell–cell interactions between the adipocytes and endothelial cells revealed a mutual-enhanced effect which resembles the in vivo routine. Furthermore, comparisons between planar coculture and model coculture demonstrated improved adipocyte function as well as endothelial cell proliferation under the same conditions. This research provided a reliable model for human adipose tissue development studies and potential obesity-related therapy development. (paper)

  8. Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients.

    Science.gov (United States)

    Douet, Jean Y; Lacroux, Caroline; Aron, Naima; Head, Mark W; Lugan, Séverine; Tillier, Cécile; Huor, Alvina; Cassard, Hervé; Arnold, Mark; Beringue, Vincent; Ironside, James W; Andréoletti, Olivier

    2017-06-01

    In the United-Kingdom, ≈1 of 2,000 persons could be infected with variant Creutzfeldt-Jakob disease (vCJD). Therefore, risk of transmission of vCJD by medical procedures remains a major concern for public health authorities. In this study, we used in vitro amplification of prions by protein misfolding cyclic amplification (PMCA) to estimate distribution and level of the vCJD agent in 21 tissues from 4 patients who died of clinical vCJD and from 1 asymptomatic person with vCJD. PMCA identified major levels of vCJD prions in a range of tissues, including liver, salivary gland, kidney, lung, and bone marrow. Bioassays confirmed that the quantitative estimate of levels of vCJD prion accumulation provided by PMCA are indicative of vCJD infectivity levels in tissues. Findings provide critical data for the design of measures to minimize risk for iatrogenic transmission of vCJD.

  9. Elucidation of Arctigenin Pharmacokinetics and Tissue Distribution after Intravenous, Oral, Hypodermic and Sublingual Administration in Rats and Beagle Dogs: Integration of In Vitro and In Vivo Findings

    Directory of Open Access Journals (Sweden)

    Jie Li

    2017-06-01

    Full Text Available Although arctigenin (AG has diverse bioactivities, such as anti-oxidant, anti-inflammatory, anti-cancer, immunoregulatory and neuroprotective activities, its pharmacokinetics have not been systematically evaluated. The purpose of this work was to identify the pharmacokinetic properties of AG via various experiments in vivo and in vitro. In this research, rats and beagle dogs were used to investigate the PK (pharmacokinetics, PK profiles of AG with different drug-delivery manners, including intravenous (i.v, hypodermic injection (i.h, and sublingual (s.l administration. The data shows that AG exhibited a strong absorption capacity in both rats and beagle dogs (absorption rate < 1 h, a high absorption degree (absolute bioavailability > 100%, and a strong elimination ability (t1/2 < 2 h. The tissue distributions of AG at different time points after i.h showed that the distribution of AG in rat tissues is rapid (2.5 h to reach the peak and wide (detectable in almost all tissues and organs. The AG concentration in the intestine was the highest, followed by that in the heart, liver, pancreas, and kidney. In vitro, AG were incubated with human, monkey, beagle dog and rat liver microsomes. The concentrations of AG were detected by UPLC-MS/MS at different time points (from 0 min to 90 min. The percentages of AG remaining in four species’ liver microsomes were human (62 ± 6.36% > beagle dog (25.9 ± 3.24% > rat (15.7 ± 9% > monkey (3.69 ± 0.12%. This systematic investigation of pharmacokinetic profiles of arctigenin (AG in vivo and in vitro is worthy of further exploration.

  10. Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering.

    Science.gov (United States)

    Yao, Qingqing; Liu, Yangxi; Selvaratnam, Balaranjan; Koodali, Ranjit T; Sun, Hongli

    2018-04-09

    Controlled delivery systems play a critical role in the success of bone morphogenetic proteins (i.e., BMP2 and BMP7) for challenged bone repair. Instead of single-drug release that is currently and commonly prevalent, dual-drug delivery strategies are highly desired to achieve effective bone regeneration because natural bone repair process is driven by multiple factors. Particularly, angiogenesis is essential for osteogenesis and requires more than just one factor (e.g., Vascular Endothelial Growth Factor, VEGF). Therefore, we developed a novel mesoporous silicate nanoparticles (MSNs) incorporated-3D nanofibrous gelatin (GF) scaffold for dual-delivery of BMP2 and deferoxamine (DFO). DFO is a hypoxia-mimetic drug that can activate hypoxia-inducible factor-1 alpha (HIF-1α), and trigger subsequent angiogenesis. Sustained BMP2 release system was achieved through encapsulation into large-pored MSNs, while the relative short-term release of DFO was engineered through covalent conjugation with chitosan to reduce its cytotoxicity and elongate its half-life. Both MSNs and DFO were incorporated onto a porous 3D GF scaffold to serve as a biomimetic osteogenic microenvironment. Our data indicated that DFO and BMP2 were released from a scaffold at different release rates (10 vs 28 days) yet maintained their angiogenic and osteogenic ability, respectively. Importantly, our data indicated that the released DFO significantly improved BMP2-induced osteogenic differentiation where the dose/duration was important for its effects in both mouse and human stem cell models. Thus, we developed a novel and tunable MSNs/GF 3D scaffold-mediated dual-drug delivery system and studied the potential application of the both FDA-approved DFO and BMP2 for bone tissue engineering. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Kinetics of tissue distribution and elimination of 4,4'-methylene bis(2-chloroaniline) in rats

    Energy Technology Data Exchange (ETDEWEB)

    Tobes, M.C.; Brown, L.E.; Chin, B.; Marsh, D.D. (Michigan Univ., Ann Arbor (USA). Medical Center)

    1983-06-01

    The tissue distribution kinetics and elimination of 4,4'-methylene bis(2-chloroaniline) (MBOCA) in rats was studied after a single dose of (/sup 14/C)MBOCA (0.49 mg/kg body weight, i.v.). The highest concentrations of radioactivity were in the small intestine, liver, adipose, lung, kidney, skin, and adrenals. For most tissues, a rapid decrease in radioactivity was followed by a slower decrease except for the small intestine, adipose and skin which demonstrated transient increases. Subcellular distribution in liver at 1 h showed radioactivity in all cell fractions. Although very lipophilic, (/sup 14/C)MBOCA was completely eliminated within 48 h with the major route via the feces (73.4%).

  12. Spatial distribution patterns of energy deposition and cellular radiation effects in lung tissue following simulated exposure to alpha particles

    International Nuclear Information System (INIS)

    Hofmann, W.; Crawford-Brown, D.J.

    1990-01-01

    Randomly oriented sections of rat tissue have been digitised to provide the contours of tissue-air interfaces and the locations of individual cell nuclei in the alveolated region of the lung. Sources of alpha particles with varying irradiation geometries and densities are simulated to compute the resulting random pattern of cellular irradiation, i.e. spatial coordinates, frequency, track length, and energy of traversals by the emitted alpha particles. Probabilities per unit track lengths, derived from experimental data on in vitro cellular inactivation and transformation, are then applied to the results of the alpha exposure simulations to yield an estimate of the number of both dead and viable transformed cells and their spatial distributions. If lung cancer risk is linearly related to the number of transformed cells, the carcinogenic risk for hot particles is always smaller than that for a uniform nuclide distribution of the same activity. (author)

  13. Drug choice, spatial distribution, HIV risk, and HIV prevalence among injection drug users in St. Petersburg, Russia

    Directory of Open Access Journals (Sweden)

    Shaboltas Alla V

    2009-07-01

    Full Text Available Abstract Background The HIV epidemic in Russia has been driven by the unsafe injection of drugs, predominantly heroin and the ephedrine derived psychostimulants. Understanding differences in HIV risk behaviors among injectors associated with different substances has important implications for prevention programs. Methods We examined behaviors associated with HIV risk among 900 IDUs who inject heroin, psychostimulants, or multiple substances in 2002. Study participants completed screening questionnaires that provided data on sociodemographics, drug use, place of residence and injection- and sex-related HIV risk behaviors. HIV testing was performed and prevalence was modeled using general estimating equation (GEE analysis. Individuals were clustered by neighborhood and disaggregated into three drug use categories: Heroin Only Users, Stimulant Only Users, and Mixed Drug Users. Results Among Heroin Only Users, younger age, front/backloading of syringes, sharing cotton and cookers were all significant predictors of HIV infection. In contrast, sharing needles and rinse water were significant among the Stimulant Only Users. The Mixed Drug Use group was similar to the Heroin Only Users with age, front/back loading, and sharing cotton significantly associated with HIV infection. These differences became apparent only when neighborhood of residence was included in models run using GEE. Conclusion The type of drug injected was associated with distinct behavioral risks. Risks specific to Stimulant Only Users appeared related to direct syringe sharing. The risks specific to the other two groups are common to the process of sharing drugs in preparation to injecting. Across the board, IDUs could profit from prevention education that emphasizes both access to clean syringes and preparing and apportioning drug with these clean syringes. However, attention to neighborhood differences might improve the intervention impact for injectors who favor different drugs.

  14. C-Psilocin tissue distribution in pregnant rats after intravenous administration

    Directory of Open Access Journals (Sweden)

    Francis C.P. Law

    2014-06-01

    Full Text Available Background: Many species of hallucinogenic mushrooms have been found in the genus Psilocybe. The main psychoactive chemicals of Psilocybe mushrooms are psilocin and its phosphoryloxy derivative, psilocybin. In addition to its psychedelic effects, psilocybin is an effective agent to lift the mood of depressed patients with terminal cancers. Objective: To study the dispositional kinetics of 14C-psilocin in pregnant rats after intravenous injection, to calculate tissue dose surrogates i.e., tissue 14C concentration and area under the concentration-time curve using the experimental data, to quantify trans-placental passage of psilocin and/or its metabolites, and to identify new psilocin metabolite(s in rat urine. Methods: A group of 15 pregnant Wistar rats weighing between 0.30-0.36 kg was used in the study. Each rat was given a single dose of 7.5 mg/kg 14C-psilocin i.v. Three rats were randomly selected and sacrificed at 0.5, 1.0, 2.0, 4.0, and 8.0 hr post-dosing. The maternal and fetal tissues were quickly removed and the radioactivity in these tissues determined by liquid scintillation counting. In a separate study, urine samples were collected from 6 male Wistar rats after administering 15 mg/kg of unlabeled psilocin i.p. The urine samples were collected and extracted by chloroform-methanol (9:1 v/v and analyzed using a gas chromatograph/mass spectrometer. Results: 14C-Psilocin crossed the placental barrier of pregnant rats readily after i.v. administration; maternal tissue 14C concentrations were found to be much higher than those in fetal tissues. The areas under the curve for maternal tissues also were much higher than the fetal tissues. In general, maternal tissues could be divided into the fast eliminating organ group, which included the brain (elimination half-life 13 hr. A new psilocin metabolite tentatively identified as dihydroxyindoleacetic acid was found in the urine. Conclusion: Our study showed that psilocin readily crossed the

  15. Study of Different Tissue Density Effects on the Dose Distribution of a 103Pd Brachytherapy Source Model MED3633

    Directory of Open Access Journals (Sweden)

    Ali Asghar Mowlavi

    2010-09-01

    Full Text Available Introduction: Clinical application of encapsulated radioactive brachytherapy sources has a major role in cancer treatment. In the present research, the effects of different tissue densities on the dose distribution of a 103Pd brachytherapy source in a spherical phantom of 50 cm radius have been studied. Material and Methods: As is well known, absorbed dose in tissue depends to its density, but this difference is not clear in measurements. Therefore, we applied the MCNP code to evaluate the effect of density on the dose distribution. 103Pd brachytherapy sources are used to treat prostate, breast and other cancers. Results: Absorbed dose has been calculated and presented around a source placed in the center of the phantom for different tissue densities. Also, we derived anisotropy and radial dose functions and compared our Monte Carlo results with experimental results of Rivard and Li et al. for F(1, θ and g(r in 1.040 g/cm3 tissue. Conclusion: The results of this study show that relative dose variations around the source center are very considerable at different densities, because of the presence of a photoabsorber (Au-Cu alloy in the source core. Dose variation exceeds 80% at the point (Z = 2.4 mm, Y = 0 mm. Computed values of anisotropy and radial dose functions are in good agreement with the experimental results of Rivard and Li et al.

  16. The distribution of diisopropylfluorophosphate (DFP) in tissues of animals polluted with the labeled preparate 23P (DF32P)

    International Nuclear Information System (INIS)

    Lis, T.; Mierzejewski, J.

    1977-01-01

    The distribution of diisopropylfluorophosphate (DFP) in organs and tissues of pigs and guinea-pigs with the acute alimentary intoxication with DF 32 P was determined by the use of a scintillic registration method. Radioactivity revealed all the samples studied. The most pronounced radioactivity was noted in lymph nodes, spleen and liver of guinea-pigs, and in kidneys, liver and spleen of pigs. (author)

  17. Evaluation of stability and size distribution of sunflower oil-coated micro bubbles for localized drug delivery.

    Science.gov (United States)

    Filho, Walter Duarte de Araujo; Schneider, Fábio Kurt; Morales, Rigoberto E M

    2012-09-20

    Micro bubbles were initially introduced as contrast agents for ultrasound examinations as they are able to modify the signal-to-noise ratio in imaging, thus improving the assessment of clinical information on human tissue. Recent developments have demonstrated the feasibility of using these bubbles as drug carriers in localized delivery. In micro fluidics devices for generation of micro bubbles, the bubbles are formed at interface of liquid gas through a strangulation process. A device that uses these features can produce micro bubbles with small size dispersion in a single step. A T-junction micro fluidic device constructed using 3D prototyping was made for the production of mono dispersed micro bubbles. These micro bubbles use sunflower oil as a lipid layer. Stability studies for micro bubbles with diameters different generated from a liquid phase of the same viscosity were conducted to evaluate whether micro bubbles can be used as drug carriers. The biocompatibility of coating layer, the ability to withstand environmental pressure variations combined with echogenicity, are key factors that they can safely play the role of drug transporters. The normal distribution curve with small dispersion of the diameter of bubbles validates the process of generating micro bubbles with low value of variation coefficient, i.e., 0.381 at 1.90%. The results also showed the feasibility of using sunflower oil as the lipid matrix with stable population of bubbles over 217 minutes for micro bubbles with an average diameter of 313.04 μm and 121 minutes for micro bubbles with an average diameter of 73.74 μm, considering bubbles with air as gaseous phase. The results indicate that the micro fluidic device designed can be used for producing micro bubbles with low variation coefficient using sunflower oil as a coating of micro bubbles. These carriers were stable for periods of time that are long enough for clinical applications even when regular air is used as the gas phase. Improved

  18. Evaluation of stability and size distribution of sunflower oil-coated micro bubbles for localized drug delivery

    Directory of Open Access Journals (Sweden)

    Filho WalterDuartedeAraujo

    2012-09-01

    Full Text Available Abstract Background Micro bubbles were initially introduced as contrast agents for ultrasound examinations as they are able to modify the signal-to-noise ratio in imaging, thus improving the assessment of clinical information on human tissue. Recent developments have demonstrated the feasibility of using these bubbles as drug carriers in localized delivery. In micro fluidics devices for generation of micro bubbles, the bubbles are formed at interface of liquid gas through a strangulation process. A device that uses these features can produce micro bubbles with small size dispersion in a single step. Methods A T-junction micro fluidic device constructed using 3D prototyping was made for the production of mono dispersed micro bubbles. These micro bubbles use sunflower oil as a lipid layer. Stability studies for micro bubbles with diameters different generated from a liquid phase of the same viscosity were conducted to evaluate whether micro bubbles can be used as drug carriers. The biocompatibility of coating layer, the ability to withstand environmental pressure variations combined with echogenicity, are key factors that they can safely play the role of drug transporters. Results The normal distribution curve with small dispersion of the diameter of bubbles validates the process of generating micro bubbles with low value of variation coefficient, i.e., 0.381 at 1.90%. The results also showed the feasibility of using sunflower oil as the lipid matrix with stable population of bubbles over 217 minutes for micro bubbles with an average diameter of 313.04 μm and 121 minutes for micro bubbles with an average diameter of 73.74 μm, considering bubbles with air as gaseous phase. Conclusion The results indicate that the micro fluidic device designed can be used for producing micro bubbles with low variation coefficient using sunflower oil as a coating of micro bubbles. These carriers were stable for periods of time that are long enough for clinical

  19. Alkylation of human hair keratin for tunable hydrogel erosion and drug delivery in tissue engineering applications.

    Science.gov (United States)

    Han, Sangheon; Ham, Trevor R; Haque, Salma; Sparks, Jessica L; Saul, Justin M

    2015-09-01

    Polymeric biomaterials that provide a matrix for cell attachment and proliferation while achieving delivery of therapeutic agents are an important component of tissue engineering and regenerative medicine strategies. Keratins are a class of proteins that have received attention for numerous tissue engineering applications because, like other natural polymers, they promote favorable cell interactions and have non-toxic degradation products. Keratins can be extracted from various sources including human hair, and they are characterized by a high percentage of cysteine residues. Thiol groups on reductively extracted keratin (kerateine) form disulfide bonds, providing a more stable cross-linked hydrogel network than oxidatively extracted keratin (keratose) that cannot form disulfide crosslinks. We hypothesized that an iodoacetamide alkylation (or "capping") of cysteine thiol groups on the kerateine form of keratin could be used as a simple method to modulate the levels of disulfide crosslinking in keratin hydrogels, providing tunable rates of gel erosion and therapeutic agent release. After alkylation, the alkylated kerateines still formed hydrogels and the alkylation led to changes in the mechanical and visco-elastic properties of the materials consistent with loss of disulfide crosslinking. The alkylated kerateines did not lead to toxicity in MC3T3-E1 pre-osteoblasts. These cells adhered to keratin at levels comparable to fibronectin and greater than collagen. Alkylated kerateine gels eroded more rapidly than non-alkylated kerateine and this control over erosion led to tunable rates of delivery of rhBMP-2, rhIGF-1, and ciprofloxacin. These results demonstrate that alkylation of kerateine cysteine residues provides a cell-compatible approach to tune rates of hydrogel erosion and therapeutic agent release within the context of a naturally-derived polymeric system. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  20. Changes in the content of edible and non-edible components and distribution of tissue components in cockerels and capons

    International Nuclear Information System (INIS)

    Zawacka, M.; Gesek, M.; Michalik, D.; Murawska, D.

    2018-01-01

    The aim of this study was to determine the effects of castration and age on the content of edible and non-edible components, and the distribution of tissue components in the carcasses of cockerels and capons. The study was conducted on 200 birds (Green-legged Partridge), divided into two sex categories (with 5 replications per group and 20 birds per replication), raised to 28 wk of age. At 8 wk of age, 100 birds were surgically castrated and afterwards at 12 wk of age and at four-wk intervals, 10 intact cockerels and 10 capons were selected randomly and slaughtered. Cockerels, compared with capons, were characterized by a higher proportion of edible components at 24 and 28 wk of age, and a more desirable carcass tissue composition due to a higher content of lean meat in total body weight (BW). Capons had higher abdominal fat content than cockerels, which resulted in a higher percentage of non-edible components in their BW at 24 and 28 wk of age. Differences in the distribution of lean meat in the carcass were noted from 20 wk of age in both castrated and intact birds. The content of breast muscles increased in capons, and the content of leg muscles (thigh and drumstick) increased in cockerels. The results of this study indicate that in view of the optimal lean meat content of the carcass and the optimal distribution of major tissue components, Green-legged Partridge capons should be fattened for a maximum period of 24 wk.

  1. Prevalence and tissue distribution of Besnoitia darlingi cysts in the Virginia opossum (Didelphis virginiana) in Michigan.

    Science.gov (United States)

    Elsheikha, Hany M; Mansfield, Linda S; Fitzgerald, Scott D; Saeed, Mahdi A

    2003-08-14

    Specimens of Virginia opossums (Didelphis virginiana) in Michigan were examined over 1 year to document the presence of Besnoitia darlingi cysts. Cyst morphology, prevalence, seasonal variation, and tissue sites of isolation were studied. Histology and ultrastructural features of the detected cysts and bradyzoites were consistent with B. darlingi. In the opossums, B. darlingi had intracellular tissue cysts. Tissue cysts had a mean diameter of 560 microm and were separated from the host tissue by a thick (5-20 microm) cyst wall. Overall prevalence of B. darlingi cysts in opossums was 10.9% (15/137). Variations in the prevalence were detected during spring (3/17; 17.6%), summer (10/34; 29.4%), and fall (2/60; 3.3%). No cysts were detected in the specimens examined during winter (0/26; 0%). Numerous B. darlingi cysts were detected in ears, conjunctiva, tongue, abdominal muscles, diaphragm, stomach, heart, liver, kidney, lung, and spleen. Cysts were detected mainly in adult female opossums that were debilitated. Ear was the most frequent organ from which the cysts were reported (10/15; 66.7%) when compared individually with other body tissues (P<0.05).

  2. Correlation between CT numbers and tissue parameters needed for Monte Carlo simulations of clinical dose distributions

    Science.gov (United States)

    Schneider, Wilfried; Bortfeld, Thomas; Schlegel, Wolfgang

    2000-02-01

    We describe a new method to convert CT numbers into mass density and elemental weights of tissues required as input for dose calculations with Monte Carlo codes such as EGS4. As a first step, we calculate the CT numbers for 71 human tissues. To reduce the effort for the necessary fits of the CT numbers to mass density and elemental weights, we establish four sections on the CT number scale, each confined by selected tissues. Within each section, the mass density and elemental weights of the selected tissues are interpolated. For this purpose, functional relationships between the CT number and each of the tissue parameters, valid for media which are composed of only two components in varying proportions, are derived. Compared with conventional data fits, no loss of accuracy is accepted when using the interpolation functions. Assuming plausible values for the deviations of calculated and measured CT numbers, the mass density can be determined with an accuracy better than 0.04 g cm-3 . The weights of phosphorus and calcium can be determined with maximum uncertainties of 1 or 2.3 percentage points (pp) respectively. Similar values can be achieved for hydrogen (0.8 pp) and nitrogen (3 pp). For carbon and oxygen weights, errors up to 14 pp can occur. The influence of the elemental weights on the results of Monte Carlo dose calculations is investigated and discussed.

  3. Controlled destruction and temperature distributions in biological tissues subjected to monoactive electrocoagulation.

    Science.gov (United States)

    Erez, A; Shitzer, A

    1980-02-01

    An analysis of the temperature fields developed in a biological tissue undergoing a monoactive electrical coagulating process is presented, including thermal recovery following prolonged heating. The analysis is performed for the passage of alternating current and assumes a homogeneous and isotropic tissue model which is uniformly perfused by blood at arterial temperature. Solution for the one-dimensional spherical geometry is obtained by a Laplace transform and numerical integrations. Results obtained indicate the major role which blood perfusion plays in determining the effects of the coagulating process; tissue temperatures and depth of destruction are drastically reduced as blood perfusion increases. Metabolic heat generation rate is found to have negligible effects on tissue temperatures whereas electrode thermal inertia affects temperature levels appreciably. However, electrodes employed in practice would have a low thermal inertia which might be regarded as zero for all practical purposes. It is also found that the depth of tissue destruction is almost directly proportional to the electrical power and duration of application. To avoid excessively high temperatures and charring, it would be advantageous to reduce power and increase the time of application. Results of this study should be regarded as a first approximation to the rather complex phenomena associated with electrocoagulation. They may, nevertheless, serve as preliminary guidelines to practicing surgeons applying this technique.

  4. Simulation study of pO2 distribution in induced tumour masses and normal tissues within a microcirculation environment.

    Science.gov (United States)

    Li, Mao; Li, Yan; Wen, Peng Paul

    2014-01-01

    The biological microenvironment is interrupted when tumour masses are introduced because of the strong competition for oxygen. During the period of avascular growth of tumours, capillaries that existed play a crucial role in supplying oxygen to both tumourous and healthy cells. Due to limitations of oxygen supply from capillaries, healthy cells have to compete for oxygen with tumourous cells. In this study, an improved Krogh's cylinder model which is more realistic than the previously reported assumption that oxygen is homogeneously distributed in a microenvironment, is proposed to describe the process of the oxygen diffusion from a capillary to its surrounding environment. The capillary wall permeability is also taken into account. The simulation study is conducted and the results show that when tumour masses are implanted at the upstream part of a capillary and followed by normal tissues, the whole normal tissues suffer from hypoxia. In contrast, when normal tissues are ahead of tumour masses, their pO2 is sufficient. In both situations, the pO2 in the whole normal tissues drops significantly due to the axial diffusion at the interface of normal tissues and tumourous cells. As the existence of the axial oxygen diffusion cannot supply the whole tumour masses, only these tumourous cells that are near the interface can be partially supplied, and have a small chance to survive.

  5. Distribution of phospholipase C isozymes in various rat tissues and cultured cells

    International Nuclear Information System (INIS)

    Suh, P.G.; Ryu, S.H.; Choi, W.C.; Lee, K.Y.; Rhee, S.G.

    1987-01-01

    Monoclonal antibodies prepared against PLC-I or PLC-II enzyme did not cross-react with the other. Using a pair of antibodies which recognizes 2 different antigenic sites on the same molecule, radioimmunoassays were developed for the quantitation of PLC-I and PLC-II in homogenates of various tissues and cultured cells, prepared by homogenization in a 2 M KCl buffer. The contents of PLC enzymes were measured in 19 rat tissues, in human platelets and in 17 cultured cells. Results indicate that the concentration of PLC-I and PLC-II is very high in brain, PLC-I is localized mainly in brain and partly in seminal vesicles, PLC-II is found in most tissues and cells. PLC-I is highly localized even in brain: 5 different neuroblastoma did not contain PLC-I while 2 glioma and 1 astrocytoma contained significant amounts

  6. Distribution of enrofloxacin in intestinal tissue and contents of healthy pigs after oral and intramuscular administrations

    DEFF Research Database (Denmark)

    Wiuff, C.; Lykkesfeldt, J.; Aarestrup, Frank Møller

    2002-01-01

    The concentration of enrofloxacin in plasma, intestinal tissue, lymph nodes and intestinal contents was investigated in healthy pigs after oral (p.o.) and intramuscular (i.m.) administration of a single dose of 2.5 mg/kg bw. Tissue and content samples were collected from jejunum, ileum, caecum...... administration, and maximum concentrations in tissue and plasma were determined later than after i.m. administration. No difference between route of administration was observed in the intestinal content. Enrofloxacin concentrations in faeces during a 5-day dosing regimen with i.m. and p.o. administration were....... On the basis of these results it was concluded that in order to ensure an immediate high concentration of enrofloxacin, and thereby avoid an initial selection for resistant mutants, the intramuscular route seems to be preferable to the oral route....

  7. Relationship between 578-nm (copper vapor) laser beam geometry and heat distribution within biological tissues

    Science.gov (United States)

    Ilyasov, Ildar K.; Prikhodko, Constantin V.; Nevorotin, Alexey J.

    1995-01-01

    Monte Carlo (MC) simulation model and the thermoindicative tissue phantom were applied for evaluation of a depth of tissue necrosis (DTN) as a result of quasi-cw copper vapor laser (578 nm) irradiation. It has been shown that incident light focusing angle is essential for DTN. In particular, there was a significant rise in DTN parallel to elevation of this angle up to +20 degree(s)C and +5 degree(s)C for both the MC simulation and tissue phantom models, respectively, with no further increase in the necrosis depth above these angles. It is to be noted that the relationship between focusing angles and DTN values was apparently stronger for the real target compared to the MC-derived hypothetical one. To what extent these date are applicable for medical practice can be evaluated in animal models which would simulate laser-assisted therapy for PWS or related dermatologic lesions with converged 578 nm laser beams.

  8. Tissue distribution and deposition pattern of a cellulosic parenchyma-specific protein from cassava roots

    Directory of Open Access Journals (Sweden)

    Petrônio A.S. Souza

    1998-06-01

    Full Text Available A protein with a molecular mass of 22kDa was purified from the cellulosic parenchyma of cassava roots. The amino acid composition of the protein was determined and antibodies generated against the purified protein were used to show that the concentration of the protein remains unchanged during root "tuber" formation. By using a tissue printing technique, as well as western blot, it was shown that the cellulosic parenchyma was the only root tissue in which the protein was deposited.

  9. Drug-induced perturbations in the in vivo distribution of oncological radiotracers

    International Nuclear Information System (INIS)

    Wiebe, L.I.; Knaus, E.E.

    1986-01-01

    Nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), a watersoluble form of the nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR) was administered by i.v. injection to normal mice and BDF 1 mice with implanted Lewis Lung carcinomas. Tritiated 5-Fluoro-2'-deoxyuridine ( 3 H-FUdR) was injected either alone 10 min before, 10 min after, 60 min after, or simultaneously with the transport inhibitor. Tissue distributions of tritium were determined after intervals of 1, 2 and 4 h. The per cent of injected radioactivity (% dose) in liver and kidney was increased by all NBMPR-P protocols. No statistically significant changes in the distribution of radioactivity in tumor, spleen, marrow or blood were induced by doses of NBMPR-P. Elevated levels of tritium radioactivity in blood were accompanied by similar increases in renal and hepatic radioactivity. There was no evidence to suggest that any advantage would be gained by using NBMPR-P treatment in conjunction with radiolabelled FUdR for tumor diagnosis. (author)

  10. Determination and correlation of spatial distribution of trace elements in normal and neoplastic breast tissues evaluated by μ-XRF

    International Nuclear Information System (INIS)

    Silva, M.P.; Oliveira, M.A.; Poletti, M.E.

    2012-01-01

    Full text: Some trace elements, naturally present in breast tissues, participate in a large number of biological processes, which include among others, activation or inhibition of enzymatic reactions and changes on cell membranes permeability, suggesting that these elements may influence carcinogenic processes. Thus, knowledge of the amounts of these elements and their spatial distribution in normal and neoplastic tissues may help in understanding the role of these elements in the carcinogenic process and tumor progression of breast cancers. Concentrations of trace elements like Ca, Fe, Cu and Zn, previously studied at LNLS using TXRF and conventional XRF, were elevated in neoplastic breast tissues compared to normal tissues. In this study we determined the spatial distribution of these elements in normal and neoplastic breast tissues using μ-XRF technique. We analyzed 22 samples of normal and neoplastic breast tissues (malignant and benign) obtained from paraffin blocks available for study at the Department of Pathology HC-FMRP/USP. From the blocks, a small fraction of material was removed and subjected to histological sections of 60 μm thick made with a microtome. The slices where placed in holder samples and covered with ultralen film. Tissue samples were irradiated with a white beam of synchrotron radiation. The samples were positioned at 45 degrees with respect to the incident beam on a table with 3 freedom degrees (x, y and z), allowing independent positioning of the sample in these directions. The white beam was collimated by a 20 μm microcapillary and samples were fully scanned. At each step, a spectrum was detected for 10 s. The fluorescence emitted by elements present in the sample was detected by a Si (Li) detector with 165 eV at 5.9 keV energy resolution, placed at 90 deg with respect to the incident beam. Results reveal that trace elements Ca-Zn and Fe-Cu could to be correlated in malignant breast tissues. Quantitative results, achieved by Spearman

  11. A tissue-engineered gastric cancer model for mechanistic study of anti-tumor drugs

    International Nuclear Information System (INIS)

    Gao, Ming; Cai, Yiting; Wu, Wei; Shi, Yazhou; Fei, Zhewei

    2013-01-01

    The use of the traditional xenograft subcutaneous tumor model has been contested because of its limitations, such as a slow tumorigenesis, inconsistent chemotherapeutic results, etc. In light of these challenges, we aim to revamp the traditional model by employing an electrospun scaffold composed of polydioxanone, gelatin and elastin to boost the tumorigenesis. The scaffold featured a highly porous microstructure and successfully supported the growth of tumor cells in vitro without provoking apoptosis. In vivo studies showed that in the scaffold model the tumor volume increased by 43.27% and the weight by 75.58%, respectively, within a 12-week period. In addition, the scaffold model saw an increase of CD24 + and CD44 + cells in the tumor mass by 42% and 313%, respectively. The scaffolding materials did not lead to phenotypic changes during the tumorigenesis. Thereafter, in the scaffold model, we found that the chemotherapeutic regimen of docetaxel, cisplatin and fluorouracil unleashed a stronger capability than the regimen comprising cisplatin and fluorouracil to deplete the CD44 + subpopulation. This discovery sheds mechanistic lights on the role of docetaxel for its future chemotherapeutic applications. This revamped model affords cancer scientists a convenient and reliable platform to mechanistically investigate the chemotherapeutic drugs on gastric cancer stem cells. (paper)

  12. Herbicide-induced experimental variegate porphyria in mice: tissue porphyrinogen accumulation and response to porphyrogenic drugs.

    Science.gov (United States)

    Krijt, J; Stranska, P; Maruna, P; Vokurka, M; Sanitrak, J

    1997-01-01

    Administration of oxadiazon or oxyfluorfen (1000 ppm in the diet) to male BALB/c mice for 9 days resulted in experimental porphyria, resembling the acute phase of human variegate porphyria. Urinary concentrations of 5-aminolevulinic acid and porphobilinogen reached 1500 and 3000 mumol/L, respectively. Both herbicides caused a decrease of protoporphyrinogen oxidase activity in liver and kidney. Brain protoporphyrinogen oxidase activity was not altered. Liver and kidney porphyrin content increased to 11 and 17 nmol/g, respectively (control mice, 2 nmol/g). Over 50% of liver and kidney porphyrins were in the reduced (porphyrinogen) form. Bile of oxadiazon-treated mice contained 700 nmol/mL of protoporphyrinogen (control mice, 15 nmol/mL). Porphyrin content of the trigeminal nerve increased from 1 nmol/g in control animals to 11 nmol/g in oxadiazon-treated animals, suggesting a possible contribution of peripheral nerve porphyrins to porphyric neuropathy. Mice treated with 125 ppm of oxadiazon in the diet for 9 days excreted moderately elevated levels of porphobilinogen in urine (control mice, less than 50 mumol/L; treated mice, 330 mumol/L). Administration of phenobarbital or phenytoin (single injections on days 7, 8, and 9) increased the urinary porphobilinogen concentration to 3500 mumol/L. This response to porphyrogenic drugs resembles the response observed in human acute porphyrias.

  13. Elemental distribution and sample integrity comparison of freeze-dried and frozen-hydrated biological tissue samples with nuclear microprobe

    Energy Technology Data Exchange (ETDEWEB)

    Vavpetič, P., E-mail: primoz.vavpetic@ijs.si [Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana (Slovenia); Vogel-Mikuš, K. [Biotechnical Faculty, Department of Biology, University of Ljubljana, Jamnikarjeva 101, SI-1000 Ljubljana (Slovenia); Jeromel, L. [Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana (Slovenia); Ogrinc Potočnik, N. [Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana (Slovenia); FOM-Institute AMOLF, Science Park 104, 1098 XG Amsterdam (Netherlands); Pongrac, P. [Biotechnical Faculty, Department of Biology, University of Ljubljana, Jamnikarjeva 101, SI-1000 Ljubljana (Slovenia); Department of Plant Physiology, University of Bayreuth, Universitätstr. 30, 95447 Bayreuth (Germany); Drobne, D.; Pipan Tkalec, Ž.; Novak, S.; Kos, M.; Koren, Š.; Regvar, M. [Biotechnical Faculty, Department of Biology, University of Ljubljana, Jamnikarjeva 101, SI-1000 Ljubljana (Slovenia); Pelicon, P. [Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana (Slovenia)

    2015-04-01

    The analysis of biological samples in frozen-hydrated state with micro-PIXE technique at Jožef Stefan Institute (JSI) nuclear microprobe has matured to a point that enables us to measure and examine frozen tissue samples routinely as a standard research method. Cryotome-cut slice of frozen-hydrated biological sample is mounted between two thin foils and positioned on the sample holder. The temperature of the cold stage in the measuring chamber is kept below 130 K throughout the insertion of the samples and the proton beam exposure. Matrix composition of frozen-hydrated tissue is consisted mostly of ice. Sample deterioration during proton beam exposure is monitored during the experiment, as both Elastic Backscattering Spectrometry (EBS) and Scanning Transmission Ion Microscopy (STIM) in on–off axis geometry are recorded together with the events in two PIXE detectors and backscattered ions from the chopper in a single list-mode file. The aim of this experiment was to determine differences and similarities between two kinds of biological sample preparation techniques for micro-PIXE analysis, namely freeze-drying and frozen-hydrated sample preparation in order to evaluate the improvements in the elemental localisation of the latter technique if any. In the presented work, a standard micro-PIXE configuration for tissue mapping at JSI was used with five detection systems operating in parallel, with proton beam cross section of 1.0 × 1.0 μm{sup 2} and a beam current of 100 pA. The comparison of the resulting elemental distributions measured at the biological tissue prepared in the frozen-hydrated and in the freeze-dried state revealed differences in elemental distribution of particular elements at the cellular level due to the morphology alteration in particular tissue compartments induced either by water removal in the lyophilisation process or by unsatisfactory preparation of samples for cutting and mounting during the shock-freezing phase of sample preparation.

  14. Drug loaded homogeneous electrospun PCL/gelatin hybrid nanofiber structures for anti-infective tissue regeneration membranes.

    Science.gov (United States)

    Xue, Jiajia; He, Min; Liu, Hao; Niu, Yuzhao; Crawford, Aileen; Coates, Phil D; Chen, Dafu; Shi, Rui; Zhang, Liqun

    2014-11-01

    Infection is the major reason for guided tissue regeneration/guided bone regeneration (GTR/GBR) membrane failure in clinical application. In this work, we developed GTR/GBR membranes with localized drug delivery function to prevent infection by electrospinning of poly(ε-caprolactone) (PCL) and gelatin blended with metronidazole (MNA). Acetic acid (HAc) was introduced to improve the miscibility of PCL and gelatin to fabricate homogeneous hybrid nanofiber membranes. The effects of the addition of HAc and the MNA content (0, 1, 5, 10, 20, 30, and 40 wt.% of polymer) on the properties of the membranes were investigated. The membranes showed good mechanical properties, appropriate biodegradation rate and barrier function. The controlled and sustained release of MNA from the membranes significantly prevented the colonization of anaerobic bacteria. Cells could adhere to and proliferate on the membranes without cytotoxicity until the MNA content reached 30%. Subcutaneous implantation in rabbits for 8 months demonstrated that MNA-loaded membranes evoked a less severe inflammatory response depending on the dose of MNA than bare membranes. The biodegradation time of the membranes was appropriate for tissue regeneration. These results indicated the potential for using MNA-loaded PCL/gelatin electrospun membranes as anti-infective GTR/GBR membranes to optimize clinical application of GTR/GBR strategies. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. SU-E-T-409: Evaluation of Tissue Composition Effect On Dose Distribution in Radiotherapy with 6 MV Photon Beam of a Medical Linac

    Energy Technology Data Exchange (ETDEWEB)

    Ghorbani, M; Tabatabaei, Z; Noghreiyan, A Vejdani [Mashhad University of Medical Sciences, Mashhad (Iran, Islamic Republic of); Meigooni, A Soleimani [Comprehensive Cancer Center of Nevada, Las Vegas, NV (United States)

    2015-06-15

    Purpose: The aim of this study is to evaluate soft tissue composition effect on dose distribution for various soft tissues and various depths in radiotherapy with 6 MV photon beam of a medical linac. Methods: A phantom and Siemens Primus linear accelerator were simulated using MCNPX Monte Carlo code. In a homogeneous cubic phantom, six types of soft tissue and three types of tissue-equivalent materials were defined separately. The soft tissues were muscle (skeletal), adipose tissue, blood (whole), breast tissue, soft tissue (9-component) and soft tissue (4-component). The tissue-equivalent materials included: water, A-150 tissue-equivalent plastic and perspex. Photon dose relative to dose in 9-component soft tissue at various depths on the beam’s central axis was determined for the 6 MV photon beam. The relative dose was also calculated and compared for various MCNPX tallies including,F8, F6 and,F4. Results: The results of the relative photon dose in various materials relative to dose in 9-component soft tissue and using different tallies are reported in the form of tabulated data. Minor differences between dose distributions in various soft tissues and tissue-equivalent materials were observed. The results from F6 and F4 were practically the same but different with,F8 tally. Conclusion: Based on the calculations performed, the differences in dose distributions in various soft tissues and tissue-equivalent materials are minor but they could be corrected in radiotherapy calculations to upgrade the accuracy of the dosimetric calculations.

  16. Study of the equivalent dose distribution in organs and tissues using periapical odontological radiography

    International Nuclear Information System (INIS)

    Santos, H.F.S.; Cipeli, J.F.; Fortes, M.A.B.; Federico, C.A.

    2017-01-01

    In this article presents a study of the doses obtained in periapical odontological radiography in main tissues of the head, using thermoluminescent dosemeters of type TLD-700H applied to a anthropomorphic simulator. The results indicate that the skin and salivary glands received the highest doses and the risk of calculated injury was 1.44 x 10 -6 Sv -1 per radiograph

  17. Tissue distribution of metals in white-fronted geese and spot-billed ducks from Korea.

    Science.gov (United States)

    Kim, Jungsoo; Oh, Jong-Min

    2013-07-01

    This study presents concentrations of Fe, Zn, Mn, Cu, Pb and Cd in livers, kidneys, muscles and bones of white-fronted geese Anser albifrons (geese) and spot-billed ducks Anas poecilorhyncha (ducks). Iron in livers, kidneys and muscles, Zn in muscles, Mn and Cd in every tissue, Cu in livers, muscles and bones and Pb in bones differed between species, and there were significant differences among tissues in both species. Essential elements such as Fe, Zn, Mn and Cu concentrations were within the background levels. Lead concentrations in livers of 7 of 14 geese and 7 of 19 ducks and in bones of 4 of 19 ducks exceeded background concentrations for waterfowl (5 μg/g dw for the liver, 10 μg/g dw for the bone). Almost all samples of both species had the background Cd concentrations in the liver (33 of 33 geese and ducks) and kidney (14 geese and 18 ducks). Tissue concentrations of Cd were greater in geese than ducks. In contrast, tissue concentrations of Pb in bones were greater in ducks than in geese. These different trends for Cd and Pb reflect a short and/or long term difference in exposure and degree of accumulation of these metals.

  18. Comparative distributions of alkaline earths and Pb among tissues of marine plants and animals

    International Nuclear Information System (INIS)

    Burnett, M.W.; Settle, D.M.; Patterson, C.C.

    1978-01-01

    Lead, barium, strontium and calcium were studied by isotope dilution, clean-lab techniques in both a marine and a terrestrial ecosystem. Analyses for Pb and Ba are difficult since their concentrations range down to the ng g -1 level in plant and animal tissue. Experimental details are given. Results are presented and discussed. (U.K.)

  19. Tracheal CT morphology: correlation with distribution and extent of thoracic adipose tissue

    Energy Technology Data Exchange (ETDEWEB)

    Ap Dafydd, Derfel [Imperial College Healthcare NHS Trust, Department of Radiology, Charing Cross Hospital, London (United Kingdom); Desai, Sujal R. [King' s College Hospital NHS Foundation Trust, King' s College London, King' s Health Partners, London (United Kingdom); Gordon, Fabiana; Copley, Susan J. [Imperial College, London (United Kingdom)

    2016-10-15

    To evaluate the relationship between adipose tissue measurements and anterior bowing of the posterior tracheal wall in a large nonselected group of patients undergoing CT pulmonary angiography (CTPA). Consecutive patients undergoing CTPA over a 4-month period were analyzed retrospectively. Using an adapted scoring system (posterior bowing, flattening, mild/moderate or severe anterior bowing of the posterior tracheal membrane), the axial morphology and cross-sectional area of the trachea at the narrowest point and 1 cm above the aortic arch were evaluated. Measurements of adipose tissue were taken (anterior mediastinal fat width, sagittal upper abdominal diameter and subcutaneous fat thickness at the level of the costophrenic angle). Relationships between tracheal morphology and measurements of adipose tissue were analyzed. 296 patients were included (120 males, 176 females, mean age 59 years, range 19-90). Severe anterior bowing of the posterior tracheal wall correlated with increasing sagittal upper abdominal diameter (p = 0.002). Mild/moderate and severe anterior bowing of the posterior tracheal wall correlated with increasing mediastinal fat width (p = 0.000 and p = 0.031, respectively). Tracheal cross-sectional area was inversely correlated with increasing subcutaneous fat thickness (p = 0.022). The findings demonstrate a statistically significant relationship between CT tracheal morphology and adipose tissue measurements in a large nonselected population. (orig.)

  20. Preclinical pharmacokinetics, tissue distribution and plasma protein binding of sodium (±-5-bromo-2-(α-hydroxypentyl benzoate (BZP, an innovative potent anti-ischemic stroke agent

    Directory of Open Access Journals (Sweden)

    Xin Tian

    2016-08-01

    Full Text Available Sodium (±-5-bromo-2-(α-hydroxypentyl benzoate (BZP is a potential cardiovascular drug and exerts potent neuroprotective effect against transient and long-term ischemic stroke in rats. BZP could convert into 3-butyl-6-bromo-1(3H-isobenzofuranone (Br-NBP in vitro and in vivo. However, the pharmacokinetic profiles of BZP and Br-NBP still have not been evaluated. For the purpose of investigating the pharmacokinetic profiles, tissue distribution and plasma protein binding of BZP and Br-NBP, a rapid, sensitive and specific method based on liquid chromatography coupled to mass spectrometry (LC-MS/MS has been developed for determination of BZP and Br-NBP in biological samples. The results indicated that BZP and Br-NBP showed a short elimination half-life, and pharmacokinetic profile in rats (3, 6 and 12 mg/kg; i.v. and beagle dogs (1, 2 and 4 mg/kg; i.v.gtt were obtained after single dosing of BZP. After multiple dosing of BZP, there was no significant accumulation of BZP and Br-NBP in the plasma of rats and beagle dogs. Following i.v. single dose (6 mg/kg to rats, BZP and Br-NBP were distributed rapidly into all tissues examined, with the highest concentrations of BZP and Br-NBP in lung and kidney, respectively. The brain distribution of Br-NBP in middle cerebral artery occlusion (MCAO rats was more than in normal rats (P<0.05. The plasma protein binding degree of BZP at three concentrations (8000, 20000 and 80000 ng/mL from rat, beagle dog and human plasma were 98.1~98.7%, 88.9~92.7% and 74.8%~83.7% respectively. In conclusion, both BZP and Br-NBP showed short half-life, good dose-linear pharmacokinetic profile, wide tissue distribution and different degree protein binding to various species plasma. This was the first preclinical pharmacokinetic investigation of BZP and Br-NBP in both rats and beagle dogs, which provided vital guidance for further preclinical research and the subsequent clinical trials.

  1. Bioprinting cell-laden matrigel for radioprotection study of liver by pro-drug conversion in a dual-tissue microfluidic chip

    International Nuclear Information System (INIS)

    Snyder, J E; Hamid, Q; Wang, C; Chang, R; Sun, W; Emami, K; Wu, H

    2011-01-01

    The objective of this paper is to introduce a novel cell printing and microfluidic system to serve as a portable ground model for the study of drug conversion and radiation protection of living liver tissue analogs. The system is applied to study behavior in ground models of space stress, particularly radiation. A microfluidic environment is engineered by two cell types to prepare an improved higher fidelity in vitro micro-liver tissue analog. Cell-laden Matrigel printing and microfluidic chips were used to test radiation shielding to liver cells by the pro-drug amifostine. In this work, the sealed microfluidic chip regulates three variables of interest: radiation exposure, anti-radiation drug treatment and single- or dual-tissue culture environments. This application is intended to obtain a scientific understanding of the response of the multi-cellular biological system for long-term manned space exploration, disease models and biosensors.

  2. Bioprinting cell-laden matrigel for radioprotection study of liver by pro-drug conversion in a dual-tissue microfluidic chip

    Energy Technology Data Exchange (ETDEWEB)

    Snyder, J E; Hamid, Q; Wang, C; Chang, R; Sun, W [Department of Mechanical Engineering, Drexel University, Philadelphia, PA 19104 (United States); Emami, K; Wu, H, E-mail: sunwei@drexel.edu, E-mail: weisun@tsinghua.edu.cn [Radiation Biophysics Lab, NASA Johnson Space Center, Houston, TX 77586 (United States)

    2011-09-15

    The objective of this paper is to introduce a novel cell printing and microfluidic system to serve as a portable ground model for the study of drug conversion and radiation protection of living liver tissue analogs. The system is applied to study behavior in ground models of space stress, particularly radiation. A microfluidic environment is engineered by two cell types to prepare an improved higher fidelity in vitro micro-liver tissue analog. Cell-laden Matrigel printing and microfluidic chips were used to test radiation shielding to liver cells by the pro-drug amifostine. In this work, the sealed microfluidic chip regulates three variables of interest: radiation exposure, anti-radiation drug treatment and single- or dual-tissue culture environments. This application is intended to obtain a scientific understanding of the response of the multi-cellular biological system for long-term manned space exploration, disease models and biosensors.

  3. Receptor model for the molecular basis of tissue selectivity of 1,4-dihydropyridine calcium channel drugs

    Science.gov (United States)

    Langs, David A.; Strong, Phyllis D.; Triggle, David J.

    1990-09-01

    Our analysis of the solid state conformations of nifedipine [dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinecarboxylate] and its 1,4-dihydropyridine (1,4-DHP) analogues produced a cartoon description of the important interactions between these drugs and their voltage-dependent calcium channel receptor. In the present study a molecular-level detailed model of the 1,4-DHP receptor binding site has been built from the published amino acid sequence of the 215-1 subunit of the voltage-dependent calcium channel isolated from rabbit skeletal muscle transverse tubule membranes. The voltage-sensing component of the channel described in this work differs from others reported for the homologous sodium channel in that it incorporates a water structure and a staggered, rather than eclipsed, hydrogen bonded S4 helix conformation. The major recognition surfaces of the receptor lie in helical grooves on the S4 or voltagesensing α-helix that is positioned in the center of the bundle of transmembrane helices that define each of the four calcium channel domains. Multiple binding clefts defined by Arg-X-X-Arg-P-X-X-S `reading frames' exist on the S4 strand. The tissue selectivity of nifedipine and its analogues may arise, in part, from conservative changes in the amino acid residues at the P and S positions of the reading frame that define the ester-binding regions of receptors from different tissues. The crystal structures of two tissue-selective nifedipine analogues, nimodipine [isopropyl (2-methoxyethyl) 1,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] and nitrendipine [ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinecarboxylate] are reported. Nimodipine was observed to have an unusual ester side chain conformation that enhances the fit to the proposed ester-sensing region of the receptor.

  4. TU-F-18C-05: Evaluation of a Method to Calculate Patient-Oriented MGD Coefficients Using Estimates of Glandular Tissue Distribution

    International Nuclear Information System (INIS)

    Porras-Chaverri, M; Galavis, P; Bakic, P; Vetter, J

    2014-01-01

    Purpose: Evaluate mammographic mean glandular dose (MGD) coefficients for particular known tissue distributions using a novel formalism that incorporates the effect of the heterogeneous glandular tissue distribution, by comparing them with MGD coefficients derived from the corresponding anthropomorphic computer breast phantom. Methods: MGD coefficients were obtained using MCNP5 simulations with the currently used homogeneous assumption and the heterogeneously-layered breast (HLB) geometry and compared against those from the computer phantom (ground truth). The tissue distribution for the HLB geometry was estimated using glandularity map image pairs corrected for the presence of non-glandular fibrous tissue. Heterogeneity of tissue distribution was quantified using the glandular tissue distribution index, Idist. The phantom had 5 cm compressed breast thickness (MLO and CC views) and 29% whole breast glandular percentage. Results: Differences as high as 116% were found between the MGD coefficients with the homogeneous breast core assumption and those from the corresponding ground truth. Higher differences were found for cases with more heterogeneous distribution of glandular tissue. The Idist for all cases was in the [−0.8 − +0.3] range. The use of the methods presented in this work results in better agreement with ground truth with an improvement as high as 105 pp. The decrease in difference across all phantom cases was in the [9 − 105] pp range, dependent on the distribution of glandular tissue and was larger for the cases with the highest Idist values. Conclusion: Our results suggest that the use of corrected glandularity image pairs, as well as the HLB geometry, improves the estimates of MGD conversion coefficients by accounting for the distribution of glandular tissue within the breast. The accuracy of this approach with respect to ground truth is highly dependent on the particular glandular tissue distribution studied. Predrag Bakic discloses current

  5. Rat fetuin: distribution of protein and mRNA in embryonic and neonatal rat tissues

    DEFF Research Database (Denmark)

    Terkelsen, O B; Jahnen-Dechent, W; Nielsen, Henrik

    1998-01-01

    Fetuin is a serum protein widely distributed in the animal kingdom and found in all mammalian species so far investigated. It is mainly a fetal protein, in the sense that the highest concentrations are found in serum and body fluids of embryos and fetuses. In order to elucidate possible biological......-nucleotides-long digoxigenin-labeled riboprobe. Fetuin was unevenly distributed in all organ systems during development, with the most pronounced expression at E 10Fetuin is a serum protein widely distributed in the animal kingdom and found in all mammalian species so far investigated. It is mainly a fetal...

  6. [Distributions of H3K27me3 and its modification enzymes in different tissues of mice].

    Science.gov (United States)

    Wang, Yuying; Wang, Xinli; Zhang, Ran; Zhang, Zhiyan; Wang, Yu; Yang, Bo; Wang, Guanjie; Zhang, Xin; Ma, Fuhao; Xu, Hongye; Wu, Xiaohui; Zhang, Feng; Li, Qing

    2017-11-01

    Objective To investigate the levels of trimethylated histone 3 at lysine residue 27 (H3K27me3) and its modification enzymes Zeste gene enhancer homolog 2 (EZH2), lysine-specific demethylase 6B (Kdm6B/JMJD3) and lysine-specific demethylase 6A (Kdm6A/UTX) in tissues and organs of 7-day and 2-month postnatal mice. Methods Immunohistochemistry was used to detect the expressions of H3K27me3 and its modification enzymes EZH2, JMJD3 and UTX in the brain, salivary glands, back fat, thymus, lung, heart, stomach, intestines, liver, testes, and skin of 7-day and 2-month mice. Real-time quantitative PCR was used to confirm the results. The relationships between H3K27me3 and its modification enzymes were analyzed statistically. Results Immunohistochemistry showed H3K27me3 persistently present in all examined tissues of 7-day and 2-month mice. EZH2 was persistently expressed in the brain, heart, liver, and skin of 7-day and 2-month mice, but only expressed in the salivary glands, adipose tissues, thymus, lung, intestines, and testes of 2-month mice. JMJD3 was expressed in the brain, salivary glands, adipose tissues, lung, heart, stomach, intestines, testes, skin of 7-day mice, but was not expressed in the lung, adipose tissues and stomach of 2-month mice. UTX was expressed in the brain, salivary glands, adipose tissues, lung, heart, testes, skin of 7-day mice, but only expressed in the testes of 2-month mice. Most mRNA of H3K27 modification enzymes were moderately or highly expressed as their immunohistochemical results were positive. Conclusion There was H3K27me3 persistently present in the all examined tissues at different stages. EZH2 was mostly expressed in the brain, salivary glands, adipose tissues, thymus, lung, heart, intestines, liver, testes and skin of 2-month-old mice. JMJD3 and UTX were mostly expressed in the brain, salivary glands, adipose tissues, lung, heart, skin and testes of 7-day-old mice. No significant association was found between the distribution of H3K

  7. Tissue distributions of radiopharmaceuticals labeled with positron emitters and problems in relating them to human studies

    International Nuclear Information System (INIS)

    Christman, D.R.

    1980-01-01

    This paper discusses a few specific examples of organ distributions involving positron-emitting nuclides intended to illustrate some specific points in this area. In particular, work with 2-fluoro-2-deoxyglucose will be discussed in some detail, and its distribution in the body compared with the closely related (chemically but not biologically) 3-fluoro-3-deoxyglucose and 1- 11 C-2-deoxyglucose. Other compounds labeled with these two nuclides, and with 13 N and 15 O will also be discussed

  8. Hyaluronic acid based hydrogel system for soft tissue regeneration and drug delivery

    Science.gov (United States)

    Jha, Amit Kumar

    the gels. Human MSCs were undifferentiated during the early time points of culture, however differentiated into osteoblast phenotype after 28 days of culture. In summary, the HA-based hydrogel matrices are hierarchically structured, mechanically robust and enzymatically stable, capable of mediating cellular functions through the spatial and temporal presentation of defined biological cues. These hydrogel systems are promising candidates for soft tissue regeneration.

  9. Maternal transfer of dechloranes and their distribution among tissues in contaminated ducks.

    Science.gov (United States)

    Wu, Ping-Fan; Yu, Lian-Lian; Li, Long; Zhang, Yun; Li, Xing-Hong

    2016-05-01

    The tissue concentrations of dechlorane plus and its analogues were determined in ducks collected from several e-waste recycling villages of Taizhou, China. Compared with the published literature, the relatively high concentrations of these compounds were detected in ducks, indicating serious DP contamination. Since both the duck meat and eggs were important components for diet, this result reminded us of keeping a watchful eye on human dietary exposure to DP and its analogues in this study area. The wet-weight concentrations of DP and its analogues were significantly related to tissue lipid content (p ducks. On the basis of lipid adjustment, the significantly lower levels in brain than those in liver and blood, displayed the occurrence of liver sequestration and blood-brain barrier to DP and its analogues in the duck (p ducks. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    International Nuclear Information System (INIS)

    Tamura, Akitoshi; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-01-01

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  11. Oral administration of drugs with hypersensitivity potential induces germinal center hyperplasia in secondary lymphoid organ/tissue in Brown Norway rats, and this histological lesion is a promising candidate as a predictive biomarker for drug hypersensitivity occurrence in humans

    Energy Technology Data Exchange (ETDEWEB)

    Tamura, Akitoshi, E-mail: akitoshi-tamura@ds-pharma.co.jp; Miyawaki, Izuru; Yamada, Toru; Kimura, Juki; Funabashi, Hitoshi

    2013-08-15

    It is important to evaluate the potential of drug hypersensitivity as well as other adverse effects during the preclinical stage of the drug development process, but validated methods are not available yet. In the present study we examined whether it would be possible to develop a new predictive model of drug hypersensitivity using Brown Norway (BN) rats. As representative drugs with hypersensitivity potential in humans, phenytoin (PHT), carbamazepine (CBZ), amoxicillin (AMX), and sulfamethoxazole (SMX) were orally administered to BN rats for 28 days to investigate their effects on these animals by examinations including observation of clinical signs, hematology, determination of serum IgE levels, histology, and flow cytometric analysis. Skin rashes were not observed in any animals treated with these drugs. Increases in the number of circulating inflammatory cells and serum IgE level did not necessarily occur in the animals treated with these drugs. However, histological examination revealed that germinal center hyperplasia was commonly induced in secondary lymphoid organs/tissues in the animals treated with these drugs. In cytometric analysis, changes in proportions of lymphocyte subsets were noted in the spleen of the animals treated with PHT or CBZ during the early period of administration. The results indicated that the potential of drug hypersensitivity was identified in BN rat by performing histological examination of secondary lymphoid organs/tissues. Data obtained herein suggested that drugs with hypersensitivity potential in humans gained immune reactivity in BN rat, and the germinal center hyperplasia induced by administration of these drugs may serve as a predictive biomarker for drug hypersensitivity occurrence. - Highlights: • We tested Brown Norway rats as a candidate model for predicting drug hypersensitivity. • The allergic drugs did not induce skin rash, whereas D-penicillamine did so in the rats. • Some of allergic drugs increased

  12. A Topographical Atlas of Shiga Toxin 2e Receptor Distribution in the Tissues of Weaned Piglets

    Directory of Open Access Journals (Sweden)

    Daniel Steil

    2016-11-01

    Full Text Available Shiga toxin (Stx 2e of Stx-producing Escherichia coli (STEC is the primary virulence factor in the development of pig edema disease shortly after weaning. Stx2e binds to the globo-series glycosphingolipids (GSLs globotriaosylceramide (Gb3Cer, Galα1-4Galβ1-4Glcβ1-1Cer and globotetraosylceramide (Gb4Cer, GalNAcβ1-3Galα1-4Galβ1-4Glcβ1-1Cer, the latter acting as the preferential Stx2e receptor. We determined Stx receptor profiles of 25 different tissues of a male and a female weaned piglet using immunochemical solid phase binding assays combined with mass spectrometry. All probed tissues harbored GSL receptors, ranging from high (category I over moderate (category II to low content (category III. Examples of Gb4Cer expression in category I tissues are small intestinal ileum, kidney pelvis and whole blood, followed by colon, small intestinal duodenum and jejunum belonging to category II, and kidney cortex, cerebrum and cerebellum as members of category III organs holding true for both genders. Dominant Gb3Cer and Gb4Cer lipoforms were those with ceramides carrying constant sphingosine (d18:1 and a variable C16:0, C22:0 or C24:1/C24:0 fatty acid. From the mapping data, we created a topographical atlas for Stx2e receptors in piglet tissues and organs, which might be helpful to further investigations on the molecular and cellular mechanisms that underlie infections of Stx2e-producing STEC in pigs and their zoonotic potential for humans.

  13. Serum Adipokines and Adipose Tissue Distribution in Rheumatoid Arthritis and Ankylosing Spondylitis. A Comparative Study

    OpenAIRE

    Toussirot, Éric; Grandclément, Émilie; Gaugler, Béatrice; Michel, Fabrice; Wendling, Daniel; Saas, Philippe; Dumoulin, Gilles

    2013-01-01

    Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are inflammatory rheumatic diseases that may modify body composition. Adipose tissue has the ability to release a wide range of products involved in physiologic functions, but also in various pathological processes, including the inflammatory/immune response. RA and AS are both associated with the development of cardiovascular complications. It is has been established that central/abdominal, and particularly intra-abdominal or visceral...

  14. Serum adipokines and adipose tissue distribution in rheumatoid arthritis and ankylosing spondylitis. A comparative study.

    OpenAIRE

    ERIC eTOUSSIROT; Emilie eGrandclement; Beatrice eGaugler; Fabrice eMichel; daniel eWendling; Philippe eSaas; Gilles eDumoulin; cic ebt

    2013-01-01

    Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are inflammatory rheumatic diseases that may modify body composition. Adipose tissue has the ability to release a wide range of products involved in physiologic functions, but also in various pathological processes, including the inflammatory/immune response. RA and AS are both associated with the development of cardiovascular complications. It is has been established that central/abdominal and particularly intra-abdominal or visceral ...

  15. Adjustment methodology for preliminary study on the distribution of bone tissue boron. Potential therapeutic applications

    International Nuclear Information System (INIS)

    Brandizzi, D; Dagrosa, A; Carpano, M.; Olivera, M. S.; Nievas, S; Cabrini, R.L.

    2013-01-01

    Boron is an element that has an affinity for bone tissue and represents a considered element in bone health . Other boron compounds are used in the Boron Neutron Capture Therapy (BNCT ) in the form of sodium borocaptate (BSH ) and borono phenylalanine (BPA). The results of clinical trials up to date are encouraging but not conclusive . At an experimental level , some groups have applied BNCT in osteosarcomas . We present preliminary methodological adjustments for the presence of boron in bone. (author)

  16. Vasoactive intestinal polypeptide (VIP) tissue distribution in the rat as measured by radioimmunoassay and by radioreceptorassay

    International Nuclear Information System (INIS)

    Besson, J.; Dupont, C.; Laburthe, M.; Bataille, D.; Rosselin, G.

    1977-01-01

    A new radioimmunoassay which allows the measurement of the rat vasoactive intestinal polypeptide, was performed. VIP is present in the whole digestive tract of rat, mainly between the duodenum and the colon. 1.5% of the total VIP is present in brain. The VIP-like immunoreactivity appears to correspond to biologically active molecule since a radioreceptorassay using liver plasma membranes as the target tissue, gives the same results as the radioimmunoassay [fr

  17. Uptake and Tissue Distribution of Pharmaceuticals and Personal Care Products in Wild Fish from Treated-Wastewater-Impacted Streams.

    Science.gov (United States)

    Tanoue, Rumi; Nomiyama, Kei; Nakamura, Haruna; Kim, Joon-Woo; Isobe, Tomohiko; Shinohara, Ryota; Kunisue, Tatsuya; Tanabe, Shinsuke

    2015-10-06

    A fish plasma model (FPM) has been proposed as a screening technique to prioritize potential hazardous pharmaceuticals to wild fish. However, this approach does not account for inter- or intraspecies variability of pharmacokinetic and pharmacodynamic parameters. The present study elucidated the uptake potency (from ambient water), tissue distribution, and biological risk of 20 pharmaceutical and personal care product (PPCP) residues in wild cyprinoid fish inhabiting treated-wastewater-impacted streams. In order to clarify the uncertainty of the FPM for PPCPs, we compared the plasma bioaccumulation factor in the field (BAFplasma = measured fish plasma/ambient water concentration ratio) with the predicted plasma bioconcentration factor (BCFplasma = fish plasma predicted by use of theoretical partition coefficients/ambient water concentration ratio) in the actual environment. As a result, the measured maximum BAFplasma of inflammatory agents was up to 17 times higher than theoretical BCFplasma values, leading to possible underestimation of toxicological risk on wild fish. When the tissue-blood partition coefficients (tissue/blood concentration ratios) of PPCPs were estimated, higher transportability into tissues, especially the brain, was found for psychotropic agents, but brain/plasma ratios widely varied among individual fish (up to 28-fold). In the present study, we provide a valuable data set on the intraspecies variability of PPCP pharmacokinetics, and our results emphasize the importance of determining PPCP concentrations in possible target organs as well as in the blood to assess the risk of PPCPs on wild fish.

  18. The analysis for energy distribution and biological effects of the clusters from electrons in the tissue equivalent material

    International Nuclear Information System (INIS)

    Zhang Wenzhong; Guo Yong; Luo Yisheng; Wang Yong

    2004-01-01

    Objective: To study energy distribution of the clusters from electrons in the tissue equivalent material, and discuss the important aspects of these clusters on inducing biological effects. Methods: Based on the physical mechanism for electrons interacting with tissue equivalent material, the Monte Carlo (MC) method was used. The electron tracks were lively simulated on an event-by-event (ionization, excitation, elastic scattering, Auger electron emission) basis in the material. The relevant conclusions were drawn from the statistic analysis of these events. Results: The electrons will deposit their energy in the form (30%) of cluster in passing through tissue equivalent material, and most clusters (80%) have the energy amount of more than 50 eV. The cluster density depends on its diameter and energy of electrons, and the deposited energy in the cluster depends on the type and energy of radiation. Conclusion: The deposited energy in cluster is the most important factor in inducing all sort of lesions on DNA molecules in tissue cells

  19. Distribution of animal drugs between skim milk and milk fat fractions in spiked whole milk: Understanding the potential impact on commercial milk products

    Science.gov (United States)

    Seven animal drugs [penicillin G (PENG), sulfadimethoxine (SDMX), oxytetracycline (OTET), erythromycin (ERY), ketoprofen (KETO), thiabendazole (THIA) and ivermectin (IVR)] were used to evaluate drug distribution between milk fat and skim milk fractions of cow milk. Greater than 90% of radioactivity...

  20. Distribution of chloramphenicol to tissues, plasma and urine in pigs after oral intake of low doses.

    Science.gov (United States)

    Aspenström-Fagerlund, Bitte; Nordkvist, Erik; Törnkvist, Anna; Wallgren, Per; Hoogenboom, Ron; Berendsen, Bjorn; Granelli, Kristina

    2016-09-01

    Toxic effects of chloramphenicol in humans caused the ban for its use in food-producing animals in the EU. A minimum required performance level (MRPL) was specified for chloramphenicol at 0.3 μg kg(-1) for various matrices, including urine. In 2012, residues of chloramphenicol were found in pig urine and muscle without signs of illegal use. Regarding its natural occurrence in straw, it was hypothesised that this might be the source, straw being compulsory for use as bedding material for pigs in Sweden. Therefore, we investigated if low daily doses of chloramphenicol (4, 40 and 400 μg/pig) given orally during 14 days could result in residues in pig tissues and urine. A dose-related increase of residues was found in muscle, plasma, kidney and urine (showing the highest levels), but no chloramphenicol was found in the liver. At the lowest dose, residues were below the MRPL in all tissues except in the urine. However, in the middle dose, residues were above the MRPL in all tissues except muscle, and at the highest dose in all matrices. This study proves that exposure of pigs to chloramphenicol in doses occurring naturally in straw could result in residues above the MRPL in plasma, kidney and especially urine.

  1. Heavy metal distribution in organic and siliceous marine sponge tissues measured by square wave anodic stripping voltammetry.

    Science.gov (United States)

    Illuminati, S; Annibaldi, A; Truzzi, C; Scarponi, G

    2016-10-15

    May sponge spicules represent a "tank" to accumulate heavy metals? In this study we test this hypothesis determining the distribution of Cd, Pb and Cu concentrations between organic and siliceous tissues in Antarctic Demospongia (Sphaerotylus antarcticus, Kirkpatrikia coulmani and Haliclona sp.) and in the Mediterranean species Petrosia ficiformis. Results show that although, in these sponges, spicules represent about 80% of the mass content, the accumulation of pollutant is lower in the spicules than in the corresponding organic fraction. The contribution of tissues to the total sponge content of Cd, Pb and Cu is respectively 99%, 82% and 97% for Antarctic sponges and 96%, 95% and 96% for P. ficiformis, similar in polar and temperate organisms. These results pave the way to a better understanding of the role of marine sponges in uptaking heavy metals and to their possible use as monitor of marine ecosystems, recommend by the Water Framework Directive. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. In vivo study on influence of the heterogeneity of tissues in the dose distribution in high energy X ray therapy

    International Nuclear Information System (INIS)

    Aldred, M.A.

    1987-01-01

    Several authors investigated the effect of the heterogeneity of tissue in the dose distribution in a radiation-therapy. Practically all of them carried out ''in vitro'' measurements using a solid body immersed in a water phantom, in order to simulate the inhomogeneity, such as bone, air cavity, etc. In the present work, ''in vivo'' measurements were performed utilizing thermoluminescent dosimeters, whose appropriateness and convenience are well known. Eight patients at Instituto de Radioterapia Oswaldo Cruz were selected, that were under irradiation treatments in their pelvic region. The ratio between body entry radiation dose and the corresponding exit dose, when compared to the same ratio for a homogeneous phantom, gives the influence of the heterogeneity of the tissue the radiation crosses. The results found in those eight patients have shown that ''in vivo'' measurements present a ratio about 8% smaller that in homogeneous phantom case. (author) [pt

  3. Changes in collagenous tissue microstructures and distributions of cathepsin L in body wall of autolytic sea cucumber (Stichopus japonicus).

    Science.gov (United States)

    Liu, Yu-Xin; Zhou, Da-Yong; Ma, Dong-Dong; Liu, Yan-Fei; Li, Dong-Mei; Dong, Xiu-Ping; Tan, Ming-Qian; Du, Ming; Zhu, Bei-Wei

    2016-12-01

    The autolysis of sea cucumber (Stichopus japonicus) was induced by ultraviolet (UV) irradiation, and the changes of microstructures of collagenous tissues and distributions of cathepsin L were investigated using histological and histochemical techniques. Intact collagen fibers in fresh S. japonicus dermis were disaggregated into collagen fibrils after UV stimuli. Cathepsin L was identified inside the surface of vacuoles in the fresh S. japonicus dermis cells. After the UV stimuli, the membranes of vacuoles and cells were fused together, and cathepsin L was released from cells and diffused into tissues. The density of cathepsin L was positively correlated with the speed and degree of autolysis in different layers of body wall. Our results revealed that lysosomal cathepsin L was released from cells in response to UV stimuli, which contacts and degrades the extracellular substrates such as collagen fibers, and thus participates in the autolysis of S. japonicus. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Calculation of dose distribution for 252Cf fission neutron source in tissue equivalent phantoms using Monte Carlo method

    International Nuclear Information System (INIS)

    Ji Gang; Guo Yong; Luo Yisheng; Zhang Wenzhong

    2001-01-01

    Objective: To provide useful parameters for neutron radiotherapy, the author presents results of a Monte Carlo simulation study investigating the dosimetric characteristics of linear 252 Cf fission neutron sources. Methods: A 252 Cf fission source and tissue equivalent phantom were modeled. The dose of neutron and gamma radiations were calculated using Monte Carlo Code. Results: The dose of neutron and gamma at several positions for 252 Cf in the phantom made of equivalent materials to water, blood, muscle, skin, bone and lung were calculated. Conclusion: The results by Monte Carlo methods were compared with the data by measurement and references. According to the calculation, the method using water phantom to simulate local tissues such as muscle, blood and skin is reasonable for the calculation and measurements of dose distribution for 252 Cf

  5. Fluid distribution and tissue thickness changes in 29 men during 1 week at moderate altitude (2,315 m).

    Science.gov (United States)

    Gunga, H C; Kirsch, K; Baartz, F; Steiner, H J; Wittels, P; Röcker, L

    1995-01-01

    To quantify fluid distribution at a moderate altitude (2,315 m) 29 male subjects were studied with respect to tissue thickness changes [front (forehead), sternum, tibia], changes of total body water, changes of plasma volume, total protein concentrations (TPC), colloid osmotic pressure (COP), and electrolytes. Tissue thickness at the forehead showed a significant increase from 4.14 mm to 4.41 mm 48 h after ascent to the Rudolfshuette (2,315 m) (P Rudolf-shuette in Saalfelden (744 m) COP was back to the control values. The TPC also showed an initial drop from 7.75 g.dl-1 to 7.48 g.dl-1 after 48 h at altitude and remained below the control value during the whole week (P < 0.01). It seems from our study that even with exposure to moderate altitude measurable fluid shifts to the upper part of the body occurred which were detected by our ultrasound method.

  6. Probability distribution of dose rates in the body tissue as a function of the rhytm of Sr90 administration and the age of animals

    International Nuclear Information System (INIS)

    Rasin, I.M.; Sarapul'tsev, I.A.

    1975-01-01

    The probability distribution of tissue radiation doses in the skeleton were studied in experiments on swines and dogs. When introducing Sr-90 into the organism from the day of birth till 90 days dose rate probability distribution is characterized by one, or, for adult animals, by two independent aggregates. Each of these aggregates correspond to the normal distribution law

  7. Ex vivo investigation of ocular tissue distribution following intravitreal administration of connexin43 mimetic peptide using the microdialysis technique and LC-MS/MS.

    Science.gov (United States)

    Bisht, Rohit; Mandal, Abhirup; Rupenthal, Ilva D; Mitra, Ashim K

    2016-12-01

    This study aimed to develop and evaluate an ex vivo eye model for intravitreal drug sampling and tissue distribution of connexin43 mimetic peptide (Cx43MP) following intravitreal injection using the microdialysis technique and LC-MS/MS. An LC-MS/MS method was developed, validated, and applied for quantification of Cx43MP in ocular tissues. Microdialysis probes were calibrated for in vitro recovery studies. Bovine eyes were fixed in a customized eye holder and after intravitreal injection of Cx43MP, microdialysis probes were implanted in the vitreous body. Vitreous samples were collected at particular time intervals over 24 h. Moreover, 24 and 48 h after intravitreal injection ocular tissues were collected, processed, and analyzed for Cx43MP concentrations using LC-MS/MS. The LC-MS/MS method showed good linearity (r 2  = 0.9991). The mean percent recovery for lower (LQC), medium (MQC), and higher quality control (HQC) (0.244, 3.906, and 125 μg/mL) was found to be 83.83, 84.92, and 94.52, respectively, with accuracy ranges between 96 and 99 % and limits of detection (LOD) and quantification (LOQ) of 0.122 and 0.412 μg/mL. The in vitro recovery of the probes was found to be over 80 %. As per microdialysis sample analysis, the Cx43MP concentration was found to increase slowly in the vitreous body up to 16 h and thereafter declined. After 48 h, the Cx43MP concentration was higher in vitreous, cornea, and retina compared to lens, iris, and aqueous humor. This ex vivo model may therefore be a useful tool to investigate intravitreal kinetics and ocular disposition of therapeutic molecules after intravitreal injection.

  8. Identification and verification of critical performance dimensions. Phase 1 of the systematic process redesign of drug distribution.

    Science.gov (United States)

    Colen, Hadewig B; Neef, Cees; Schuring, Roel W

    2003-06-01

    Worldwide patient safety has become a major social policy problem for healthcare organisations. As in other organisations, the patients in our hospital also suffer from an inadequate distribution process, as becomes clear from incident reports involving medication errors. Medisch Spectrum Twente is a top primary-care, clinical, teaching hospital. The hospital pharmacy takes care of 1070 internal beds and 1120 beds in an affiliated psychiatric hospital and nursing homes. In the beginning of 1999, our pharmacy group started a large interdisciplinary research project to develop a safe, effective and efficient drug distribution system by using systematic process redesign. The process redesign includes both organisational and technological components. This article describes the identification and verification of critical performance dimensions for the design of drug distribution processes in hospitals (phase 1 of the systematic process redesign of drug distribution). Based on reported errors and related causes, we suggested six generic performance domains. To assess the role of the performance dimensions, we used three approaches: flowcharts, interviews with stakeholders and review of the existing performance using time studies and medication error studies. We were able to set targets for costs, quality of information, responsiveness, employee satisfaction, and degree of innovation. We still have to establish what drug distribution system, in respect of quality and cost-effectiveness, represents the best and most cost-effective way of preventing medication errors. We intend to develop an evaluation model, using the critical performance dimensions as a starting point. This model can be used as a simulation template to compare different drug distribution concepts in order to define the differences in quality and cost-effectiveness.

  9. 10 CFR 32.72 - Manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing...

    Science.gov (United States)

    2010-01-01

    ... radioactive drug; and the shielding provided by the packaging to show it is appropriate for the safe handling... constructed of lead, glass, plastic, or other material, of a radioactive drug to be transferred for commercial...

  10. Changes in the content of edible and non-edible components and distribution of tissue components in cockerels and capons

    Directory of Open Access Journals (Sweden)

    Magdalena Zawacka

    2018-04-01

    Full Text Available The aim of this study was to determine the effects of castration and age on the content of edible and non-edible components, and the distribution of tissue components in the carcasses of cockerels and capons. The study was conducted on 200 birds (Green-legged Partridge, divided into two sex categories (with 5 replications per group and 20 birds per replication, raised to 28 wk of age. At 8 wk of age, 100 birds were surgically castrated and afterwards at 12 wk of age and at four-wk intervals, 10 intact cockerels and 10 capons were selected randomly and slaughtered. Cockerels, compared with capons, were characterized by a higher proportion of edible components at 24 and 28 wk of age, and a more desirable carcass tissue composition due to a higher content of lean meat in total body weight (BW. Capons had higher abdominal fat content than cockerels, which resulted in a higher percentage of non-edible components in their BW at 24 and 28 wk of age. Differences in the distribution of lean meat in the carcass were noted from 20 wk of age in both castrated and intact birds. The content of breast muscles increased in capons, and the content of leg muscles (thigh and drumstick increased in cockerels. The results of this study indicate that in view of the optimal lean meat content of the carcass and the optimal distribution of major tissue components, Green-legged Partridge capons should be fattened for a maximum period of 24 wk.

  11. Radioactivity in the pelagic fish. I. Distribution of radioactivity in various tissues of fish

    Energy Technology Data Exchange (ETDEWEB)

    Amano, K; Yamada, K; Bito, M; Takase, A; Tanaka, S

    1955-01-01

    Pelagic fishes caught after an atomic explosion experiment at Bikini Atolls in the Pacific were examined by radiochemical techniques. Generally the radioactivity was large in liver, kidney, gall bladder and heart, and then in pyloric ceca, stomach, intestine, and gonad; there was little activity in skin, bone, and muscles. This order varied with species. Large radioactivity of the stomach contents did not necessarily mean large activity in the tissues, indicating considerable participation of diffusion of sea water into the fish body. Muscles from various sites showed slight difference in the activity. The dark muscle, however, showed several times as large activity as ordinary muscle.

  12. Effects of heat stress on dynamic absorption process, tissue distribution and utilization efficiency of vitamin C in broilers

    International Nuclear Information System (INIS)

    Liu Guohua; Chen Guosheng; Cai Huiyi

    1998-01-01

    The experiment was conducted to determine the effects of heat stress on ascorbic acid nutritional physiology of broilers with radioisotope technology. 3 H-Vc was fed to broilers and then the blood, liver, kidney, breast muscle, and excreta were sampled to determine the dynamic absorption process, the tissue distribution and the utilization efficiency of vitamin C. The results indicated that the absorption, metabolism and mobilization of supplemented vitamin C in broilers with heat stress was faster than that in broilers without heat stress. However, the utilization efficiency of supplemented vitamin C in broilers with heat stress was not higher than that of broilers without heat stress

  13. Cloning, characterization and tissue distribution of the rat ATP-binding cassette (ABC) transporter ABC2/ABCA2.

    OpenAIRE

    Zhao, L X; Zhou, C J; Tanaka, A; Nakata, M; Hirabayashi, T; Amachi, T; Shioda, S; Ueda, K; Inagaki, N

    2000-01-01

    The ABC1 (ABCA) subfamily of the ATP-binding cassette (ABC) transporter superfamily has a structural feature that distinguishes it from other ABC transporters. Here we report the cloning, molecular characterization and tissue distribution of ABC2/ABCA2, which belongs to the ABC1 subfamily. Rat ABC2 is a protein of 2434 amino acids that has 44.5%, 40.0% and 40.8% identity with mouse ABC1/ABCA1, human ABC3/ABCA3 and human ABCR/ABCA4 respectively. Immunoblot analysis showed that proteins of 260 ...

  14. Investigations of some elements distribution in dental tissues by INAA as a function of ecological and some other parameters

    International Nuclear Information System (INIS)

    Draskovic, R.J.; Jacimovic, Lj.; Stojicevic, M.; Pajic, P.; Filipovic, V.

    1982-01-01

    Distribution of some elements (Hg, Zn, Sb, Co and Sc) in dental tissues (enamel, dentine, pulp) has been investiaated by instrumental neutron activation analysis (INAA). Teeth samples were taken from patients living in different regions (mine and mineralized areas, plain), taking into account the following parameters: ecological conditions, age of patients, stomatological operations and use of local cosmetic preparations containig mercury. Samples of vegetation (beech, moss, pine) from two locations belonging to regions of mineralized areas also were analyzed. Results of our investigations are presented and discussed. (author)

  15. 14C2H4: distribution of 14C-labeled tissue metabolites in pea seedlings

    International Nuclear Information System (INIS)

    Giaquinta, R.; Beyer, E. Jr.

    1977-01-01

    The 14 C-metabolite distribution pattern following 14 C 2 H 4 metabolism in intact pea seedlings (Pisum sativum L.) was determined under various conditions. After a 24 hr exposure to 14 C 2 H 4 , the majority of 14 C-metabolites were water-soluble (60-70%) with lesser amounts in the protein (10-15%), lipid (1%), and insoluble (1-2%) fractions. Ion exchange chromatography of the water-soluble components into basic, neutral, and acidic fractions revealed a 50:40:10 distribution, respectively. Chromatography of the neutral fraction revealed two regions of radioactivity (Rf=0.38) and 0.63 which did not cochromatograph with twenty-two known sugars or neutral metabolites. Chromatograms of the basic fraction contained 3 regions of radioactivity. Similar distribution patterns were noted when 14 C 2 H 4 exposure was followed by a 6 hr air chase or when 5% CO 2 , an antagonist of ethylene action, was present during the exposure. Marked differences in the 14 C-metabolite distribution patterns were obtained when 14 CO 2 was substituted for 14 C 2 H 4 . These results indicate that the metabolic pathway involved in ethylene metabolism is different from that involved in intermediately carbon metabolism. (auth.)

  16. Distribution of polyethylene wear particles and bone fragments in periprosthetic tissue around total hip joint replacements

    Czech Academy of Sciences Publication Activity Database

    Zolotarevova, E.; Entlicher, G.; Pavlova, Ewa; Šlouf, Miroslav; Pokorný, D.; Veselý, F.; Gallo, J.; Sosna, A.

    2010-01-01

    Roč. 6, č. 9 (2010), s. 3595-3600 ISSN 1742-7061 R&D Projects: GA MŠk 2B06096 Institutional research plan: CEZ:AV0Z40500505 Keywords : joint replacement * polyethylene * wear particles distribution Subject RIV: CD - Macromolecular Chemistry Impact factor: 4.824, year: 2010

  17. Composition and distribution of cell wall phenolic compounds in flax (Linum usitatissimum L.) stem tissues

    NARCIS (Netherlands)

    Gorshkova, T.A.; Salnikov, V.V.; Pogodina, N.M.; Chemikosova, S.B.; Yablokova, E.V.; Ulanov, A.V.; Ageeva, M.V.; Dam, van J.E.G.; Lozovaya, V.V.

    2000-01-01

    Cell wall phenolic compounds were analysed in xylem and bast fibre-rich peels of flax stems by biochemical, histochemical and ultrastructural approaches. Localization of cell wall phenolics by the enzyme-gold method using laccase revealed several gold particle distribution patterns. One of the major

  18. Quantitative evaluation of peptide analogue distribution in mouse tissue using 3D computer modelling

    DEFF Research Database (Denmark)

    Jensen, Casper Bo

    histology sections. The work demonstrates the use of automated image analysis based on image registration to quantify LSFM data of the peptide brain distribution following peripheral administration. The methodology was expanded during the PhD work to also include study of receptor mapping and brain...

  19. 41 CFR 102-41.230 - May SASPs pick up or store donated drug paraphernalia in their distribution centers?

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false May SASPs pick up or store donated drug paraphernalia in their distribution centers? 102-41.230 Section 102-41.230 Public Contracts and Property Management Federal Property Management Regulations System (Continued) FEDERAL...

  20. 41 CFR 105-74.210 - To whom must I distribute my drug-free workplace statement?

    Science.gov (United States)

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false To whom must I distribute my drug-free workplace statement? 105-74.210 Section 105-74.210 Public Contracts and Property Management Federal Property Management Regulations System (Continued) GENERAL SERVICES ADMINISTRATION...

  1. Effect of low to normal dietary phosphorus levels on zinc metabolism and tissue distribution in calves

    International Nuclear Information System (INIS)

    Laflamme, D.P.; Miller, W.J.; Neathery, M.W.; Gentry, R.P.; Blackmon, D.M.; Logner, K.R.; Fielding, A.S.

    1985-01-01

    Sixteen 10-wk-old, phosphorus (P)-depleted Holstein bull calves were fed for 6 wk a control diet containing .08% P or P-supplemented diets containing .14, .20 or .32% P with supplemental P from two sources (CDP and Dynafos). The diets contained .45, .56, .66 and .87% Ca. After 5 wk of the experiment, the calves were dosed orally with 65 Zn, and daily total fecal collections were initiated. At the end of the experimental period, the calves were killed and tissue samples were taken for total Zn and 65 Zn analyses. Growth, feed intake and feed efficiency improved with increasing dietary P levels. Level of dietary P and Ca had little or no effect on total Zn content of rib, tibia, liver, heart, kidney, muscle or blood. Likewise, 65 Zn absorption and content in most tissues were not affected. The results do not preclude the possibility of some minor effects of P levels on Zn metabolism. However, it is apparent that when adequate Zn is fed, any effects are likely to be of little or no practical importance

  2. Distribution of dearomatised white spirit in brain, blood, and fat tissue after repeated exposure of rats

    DEFF Research Database (Denmark)

    Lof, A.; Lam, Henrik Rye; Gullstrand, E.

    1999-01-01

    Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg....../l), or 800 p.p.m. (4.58 mg/l) of dearomatised white spirit, 6 hr/day, 5 days/week up to 3 weeks. Five rats from each group were sacrificed immediately after the exposure for 1, 2, or 3 weeks and 2, 4, 6, or 24 hr after the end of 3 weeks' exposure. After 3 weeks of exposure the concentration of total white...... spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure...

  3. Distribution of the Most Common Genetic Variants Associated with a Variable Drug Response in the Population of the Republic of Macedonia

    Directory of Open Access Journals (Sweden)

    Nestorovska Kapedanovska A.

    2014-12-01

    Full Text Available Genetic variation in the regulation, expression and activity of genes coding for Phase I, Phase II drug metabolizing enzymes (DMEs and drug targets, can be defining factors for the variability in both the effectiveness and occurrence of drug therapy side effects. Information regarding the geographic structure and multi-ethnic distribution of clinically relevant genetic variations is becoming increasingly useful for improving drug therapy and explaining inter-individual and inter-ethnic differences in drug response.

  4. A new Monte Carlo program for calculations of dose distributions within tissue equivalent phantoms irradiated from π--meson beams

    International Nuclear Information System (INIS)

    Przybilla, G.

    1980-11-01

    The present paper reports on the structure and first results from a new Monte Carlo programme for calculations of energy distributions within tissue equivalent phantoms irradiated from π - -beams. Each pion or generated secondary particle is transported until to the complete loss of its kinetic energy taking into account pion processes like multiple Coulomb scattering, pion reactions in flight and absorption of stopped pions. The code uses mainly data from experiments, and physical models have been added only in cases of lacking data. Depth dose curves for a pensil beam of 170 MeV/c within a water phantom are discussed as a function of various parameters. Isodose contours are plotted resulting from a convolution of an extended beam profile and the dose distribution of a pencil beams. (orig.) [de

  5. Distribution of obestatin and ghrelin in human tissues: immunoreactive cells in the gastrointestinal tract, pancreas, and mammary glands

    DEFF Research Database (Denmark)

    Grönberg, Malin; Tsolakis, Apostolos V; Magnusson, Linda

    2008-01-01

    Obestatin and ghrelin are two peptides derived from the same prohormone. It is well established that ghrelin is produced by endocrine cells in the gastric mucosa. However, the distribution of human obestatin immuno