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Area Product (area + product)

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Medical Sciences42%

Selected Abstracts

Decrease in Tumor Apparent Permeability-Surface Area Product to a MRI Macromolecular Contrast Medium Following Angiogenesis Inhibition with Correlations to Cytotoxic Drug Accumulation

MICROCIRCULATION, Issue 5 2004
HEIKE E. DALDRUP-LINK
ABSTRACT Background: New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (KPS) in tumors to a macromolecular contrast medium (MMCM), to follow changes in KPS induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin. Methods: Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)30) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate KPS. These estimates of KPS were correlated with cytotoxic drug accumulations in the tumors. Results: Anti-VEGF treatment reduced KPS to MMCM in tumor tissue from 0.013 mL h,1 cm,3 (n = 9) at baseline to 0.003 mL h,1 cm,3 (n = 9) 24 h later (p < .05). The KPS values correlated significantly (r2 = .78; p < .0001) with the tumor cisplatin accumulation. No correlation (r2 = .001; p = .89) was found between KPS and tumor accumulation of the substantially smaller 5-FU molecule. Conclusions: MMCM-enhanced MRI can be used to detect and estimate changes in KPS to this contrast agent following a single dose of anti-VEGF antibody. The decline in KPS induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration. [source]

Ionization-specific prediction of blood,brain permeability

JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 1 2009
Kiril Lanevskij
Abstract This study presents a mechanistic QSAR analysis of passive blood,brain barrier permeability of drugs and drug-like compounds in rats and mice. The experimental data represented in vivo log,PS (permeability-surface area product) from in situ perfusion, brain uptake index, and intravenous administration studies. A data set of 280 log,PS values was compiled. A subset of 178 compounds was assumed to be driven by passive transport that is free of plasma protein binding and carrier-mediated effects. This subset was described in terms of nonlinear lipophilicity and ionization dependences, that account for multiple kinetic and thermodynamic effects: (i) drug's kinetic diffusion, (ii) ion-specific partitioning between plasma and brain capillary endothelial cell membranes, and (iii) hydrophobic entrapment in phospholipid bilayer. The obtained QSAR model provides both good statistical significance (RMSE,<,0.5) and simple physicochemical interpretations (log,P and pKa), thus providing a clear route towards property-based design of new CNS drugs. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:122,134, 2009 [source]

Decrease in Tumor Apparent Permeability-Surface Area Product to a MRI Macromolecular Contrast Medium Following Angiogenesis Inhibition with Correlations to Cytotoxic Drug Accumulation

MICROCIRCULATION, Issue 5 2004
HEIKE E. DALDRUP-LINK
ABSTRACT Background: New strategies for cancer therapy include the combination of angiogenesis inhibitors with cytotoxins. However, angiogenesis inhibitors may alter tumor microvessel structure and transendothelial permeability thereby reducing tumoral delivery of cytotoxic agents. The aim of this study was to estimate quantitatively the apparent permeability-surface area product (KPS) in tumors to a macromolecular contrast medium (MMCM), to follow changes in KPS induced by antibodies to vascular endothelial growth factor (anti-VEGF), and to correlate the findings with tumor accumulation of cisplatin, a highly protein-bound cytotoxin, and 5-fluorouracil (5-FU), a small unbound cytotoxin. Methods: Dynamic MRI enhanced with a MMCM (albumin-(Gd-DTPA)30) was analyzed using a two-compartment tumor tissue model (plasma and interstitial water) to quantitatively estimate KPS. These estimates of KPS were correlated with cytotoxic drug accumulations in the tumors. Results: Anti-VEGF treatment reduced KPS to MMCM in tumor tissue from 0.013 mL h,1 cm,3 (n = 9) at baseline to 0.003 mL h,1 cm,3 (n = 9) 24 h later (p < .05). The KPS values correlated significantly (r2 = .78; p < .0001) with the tumor cisplatin accumulation. No correlation (r2 = .001; p = .89) was found between KPS and tumor accumulation of the substantially smaller 5-FU molecule. Conclusions: MMCM-enhanced MRI can be used to detect and estimate changes in KPS to this contrast agent following a single dose of anti-VEGF antibody. The decline in KPS induced by this inhibitor of angiogenesis is associated with reduced tumor concentration of a protein-bound cytotoxin, similar in molecular weight to the contrast agent. MRI assays of microvascular status as performed here may be useful to clinically monitor responses to anti-angiogenesis drugs and to optimize the choice and timing of cytotoxic drug administration. [source]

A study of dislocation contribution from the temperature dependence of zero-bias resistance-area product of long-wavelength n-on-p mercury cadmium telluride diodes

PHYSICA STATUS SOLIDI (A) APPLICATIONS AND MATERIALS SCIENCE, Issue 2 2006
Vishnu Gopal
Abstract A study of the contribution of dislocations to the zero-bias resistance,area product (R0A) of long-wavelength infrared n-on-p mercury cadmium telluride (HgCdTe) diodes has been carried out from the modelling of the temperature dependence of R0A product of diodes fabricated in a material of known dislocation density. The capture probabilities of electrons and holes relevant to the modelling of the effect of dislocations in p-type HgCdTe have been thus evaluated. The general applicability of these parameters has been further verified by using them to model the temperature variation of the R0A of the diodes reported by other groups. Results of the present study show that dislocations degrade the impedance of HgCdTe diodes at low temperatures on account of their shunt-resistance behavior rather than the commonly accepted dislocation-assisted tunnelling mechanism. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source]

Disproportional effects of Igf2 knockout on placental morphology and diffusional exchange characteristics in the mouse

THE JOURNAL OF PHYSIOLOGY, Issue 20 2008
P. M. Coan
Both complete knockout of the Igf2 gene (Igf2null+/,) and knockout of its placental specific transcript alone (Igf2P0+/,) lead to fetal growth restriction in mice. However, in the Igf2null+/, this growth restriction occurs concurrently in gestation with placental growth restriction, whereas, placental growth restriction precedes fetal growth restriction in the Igf2P0+/, mouse. Previous studies have shown that the Igf2P0+/, placenta has proportionate reductions in its cellular compartments and its diffusional exchange characteristics. Yet, nothing is known about the structural development or diffusional exchange characteristics of the Igf2null+/, mouse. Hence, this study compares the structural properties (using stereology) and diffusional exchange characteristics (using measurement of permeability,surface area product, P.S, of three inert hydrophilic tracers) of the Igf2null+/, and the Igf2P0+/, placenta to identify the role of Igf2 in the development of the labyrinthine exchange membrane and its functional consequences. Our data show disproportionate effects of complete Igf2 ablation on the compartments of the placenta, not seen when the placental-specific transcript alone is deleted. Furthermore, although the theoretical diffusing capacity (calculated from the stereological data) of the Igf2null+/, placenta was reduced relative to control, there was no effect of the complete knockout on permeability surface area available for small hydrophilic tracers. This is in contrast to the Igf2P0+/, placenta, where theoretical diffusion capacity and P.S values were reduced similarly. Total ablation of the Igf2 gene from the fetoplacental unit in the mouse therefore results in a disproportionate growth of placental compartments whereas, deleting the placental specific transcript of Igf2 alone results in proportional placental growth restriction. Thus, placental phenotype depends on the degree of Igf2 gene ablation and the interplay between placental and fetal Igf2 in the mouse. [source]

Role of villus microcirculation in intestinal absorption of glucose: coupling of epithelial with endothelial transport

THE JOURNAL OF PHYSIOLOGY, Issue 2 2003
J. R. Pappenheimer
Capillaries in jejunal villi can absorb nutrients at rates several hundred times greater (per gram tissue) than capillaries in other tissues, including contracting skeletal muscle and brain. We here present an integrative hypothesis to account for these exceptionally large trans-endothelial fluxes and their relation to epithelial transport. Equations are developed for estimating concentration gradients of glucose across villus capillary walls, along paracellular channels and across subjunctional lateral membranes of absorptive cells. High concentrations of glucose discharged across lateral membranes to subjunctional intercellular spaces are delivered to abluminal surfaces of villus capillaries by convection-diffusion in intercellular channels without significant loss of concentration. Post-junctional paracellular transport thus provides the series link between epithelial and endothelial transport and makes possible the large trans-endothelial concentration gradients required for absorption to blood. Our analysis demonstrates that increases of villus capillary blood flow and permeability-surface area product (PS) are essential components of absorptive mechanisms: epithelial transport of normal digestive loads could not be sustained without concomitant increases in capillary blood flow and PS. The low rates of intestinal absorption found in anaesthetised animals may be attributed to inhibition of normal villus microvascular responses to epithelial transport. [source]

Effect of macrolide antibiotics on uptake of digoxin into rat liver

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 3 2007
Suwako Ito
Abstract The objective of this study was to examine the effect of macrolide antibiotics, clarithromycin, erythromycin, roxithromycin, josamycin and azithromycin, on the hepatic uptake of digoxin. The uptake of [3H]digoxin was studied in rats in vivo, using the tissue-sampling single-injection technique, and in isolated rat hepatocytes in vitro. The uptake of [3H]digoxin into rat hepatocytes was concentration-dependent with a Michaelis constant (Km) of 445 nM. All the macrolide antibiotics inhibited the uptake of [3H]digoxin into rat hepatocytes in a concentration-dependent manner. However, clarithromycin did not affect the in vivo hepatic uptake of digoxin in rats. The in vivo permeability,surface area product of digoxin for hepatic uptake (PSinf) was estimated to be 12.5 ml/min/g liver from the present in vitro data, which is far larger than the hepatic blood flow rate (1.4 ml/min/g liver). Macrolide antibiotics at clinically relevant concentrations inhibit digoxin uptake by rat hepatocytes in vitro, but not in vivo, probably because hepatic uptake of digoxin in rats is blood flow-limited. Clinically observed digoxin,macrolide interaction in humans could be due to macrolide inhibition of hepatic digoxin uptake, if the uptake is permeation-limited. Copyright © 2007 John Wiley & Sons, Ltd. [source]