Drug targeting using low density lipoprotein (LDL): physicochemical factors affecting drug loading into LDL particles

Low density lipoprotein (LDL) has been found suitable as a targeting carrier for cytotoxic drugs. However, higher drug loading into LDL particles without disrupting their native integrity remains a major obstacle. The purpose of this study is to investigate the different physicochemical factors that may affect drug loading and to characterize LDL-drug conjugates. Doxorubicin (Dox) and 3', 5'-O-dipalmitoyl-5-iodo-2'-deoxyuridine (dpIUdR) were used as reference cytotoxic drugs. Drugs were loaded into LDL particles using the dry film method with or without surfactants, liposomal and the direct addition method. The effects of incubation temperature, time and stoichiometry of LDL-drug conjugates on drug loading were investigated. The LDL-drug conjugates were evaluated for their stability and characterized by differential scanning calorimetry (DSC), denatured gel (SDS-PAGE), and electron microscopy (EM). We have suitably incorporated 45+/-10 Dox and 150+/-25 dpIUdR molecules/LDL particle. A seven-fold increase in Dox incorporation was achieved with the liposomal preparation compared to the dry film method. A 4- to 6-h incubation at 37 degreesC was suitable to restore the native structure of LDL particles. No apo B fragmentation of LDL particles was noted on denatured gel. DSC studies showed no change in the Tm of the LDL and the LDL-drug conjugates. An increase in particle size of LDL-dpIUdR, not LDL-Dox was observed in EM compared to the native LDL which may be related to higher incorporation of dpIUdR. The results indicate that physicochemical factors significantly affect drug loading efficiency and may need to be considered to optimize drug incorporation into LDL particles.     

Comments on `A Lyapunov function of two-dimensional linear systems'

The authors show that the function introduced in the above-titled paper by H. Mahgoub and R. Carroll (ibid., vol. AC-31, p.170-172, (1986)) is not a Lyapunov function for a discrete 2-D system     

N-methyl-D-aspartate antagonists, glutamate release inhibitors, 4-aminopyridine at neuromuscular transmission

GLP-1, an incretin hormone of the enteroinsular axis with insulinotropic and glucagonostatic activity, is secreted after nutrient ingestion. GLP-1 is mainly produced by intestinal L-cells in the lower gastrointestinal tract (GIT); simple carbohydrates are absorbed in the upper GIT and alpha-glucosidase inhibition leads to augmented and prolonged GLP-1 release in normal subjects. In a cross-over study, 100 mg acarbose or placebo was administered simultaneously with 100 g sucrose to 11 hyperglycaemic Type 2 diabetic patients poorly controlled with diet and sulphonylureas. Plasma levels of GLP-1, insulin, C-peptide, glugacon, GIP, glucose and H2-exhalation were measured over 6 h. Differences in the integrated responses over the observation period were evaluated by repeated measurement analysis of variance with fasting values used as covariates. With acarbose, sucrose reached the colon 60-90 min after ingestion as indicated by a significant increment in breath hydrogen exhalation (p = 0.005). After an early GLP-1 increment 15 min after sucrose under both conditions, GLP-1 release was prolonged in the acarbose group (p = 0.001; significant from 210 to 360 min.). Initially (0-150 min), glucose (p = 0.001), insulin (p = 0.001), and GIP (p < 0.001) were suppressed by acarbose, whereas later there were no significant differences. Glucagon levels were higher with acarbose in the last 3 h of the 6 h observation period (p = 0.02). We conclude that in hyperglycaemic Type 2 diabetic patients, ingestion of acarbose with a sucrose load leads to elevated and prolonged GLP-1 release.     

An expert system to automate timing design

Presents a novel approach for automating the timing design of interfaces between VLSI chips in microcomputer systems. The Prolog-based expert system, called TDS (for timing design system), incorporates the heuristic knowledge of the hardware designer. TDS is a rule-based system that interprets the specification sheets of VLSI chips and can synthesize, diagnose, and verify timing charts at the expert's level. The system uses a functional model based on timing specifications, not the structural information. TDS can model other interfaces that are based on timing specifications, such as standard bus interfaces     

Determination of cadmium and selected micronutrients in commonly used and traded medicinal plants in Turkey

BACKGROUND: Medicinal plants commonly used and traded in Turkey were monitored for their cadmium and selected micronutrient (copper, iron, manganese and zinc) content. RESULTS: Cadmium was not detected in any sample of licorice extract, linden flowers or nettle leaves. However, in the rest of the samples, cadmium was found in the range of 7–126 µg kg^?1, with the highest concentration in chamomile leaf. Of all the monitored trace elements, the highest concentration found was 520 mg kg^?1 iron in zahter. The highest copper, manganese and zinc concentrations were found in rose hips (24 mg kg^?1), Turkish oregano (58 mg kg^?1) and zahter (50 mg kg^?1), respectively. CONCLUSION: The results of the present study reveal that cadmium and trace element concentrations in medicinal plants commonly used as traditional medicines in Turkey are well below the critical levels. Copyright © 2007 Society of Chemical Industry     

DETERMINATION OF COPPER(II) IN NATURAL WATERS BY EXTRACTION USING N-O-VANILLIDINE-2-AMINO-P-CRESOL AND FLAME ATOMIC ABSORPTION SPECTROMETRY

A simple and accurate solvent extraction method was developed for the separation and preconcentration of trace levels of copper(II) in water using N-o-vanillidine-2-amino-p-cresol prior to its determination using flame atomic absorption spectrometry. Analytical parameters such as the pH of the aqueous phase, extraction time, concentration of the reagent, concentration of the nitric acid back extraction agent, volumes of aqueous phase and back extraction agent, and concomitant ions on the extraction yield of the copper(II) were investigated and optimized. Under the optimal conditions, the detection limit (3σ) was 0.61 µ g L^?1 for a 25 mL blank solution, yielding a preconcentration factor of 12.5. The method was succesfully applied to the determination of copper(II) in tap water, river water, and seawater. The accuracy of the method was verified by analyzing two certified reference materials and spiked water samples. The results obtained were in agreement with the certified values and the recoveries for spiked water samples were between 98 and 112%.     

Benders Decomposition Algorithms for Two Variants of the Single Allocation Hub Location Problem

Networks and Spatial Economics - The hub location problem (HLP) is a special type of the facility location problem with numerous applications in the airline industry, postal services, and computer...     

Passenger Flow Prediction Based on Newly Adopted Algorithms

Passenger flow forecasting is an essential part of transportation systems. Neural networks in the transportation field have been applied to passenger demand prediction. In this paper, we developed two hybrid methods, known as parlimentary optimization algorithm-artificial neural network (POA-ANN), and intelligent water drops algorithm-ANN (IWD algorithm-ANN). In addition, we applied the proposed algorithms to illustrate the effect of precise prediction for passenger queues. We mainly focus on predicting passenger demand by comparing the genetic algorithm-ANN (GA-ANN) with POA-ANN and IWD-ANN. The results of prediction methods suggest that both POA-ANN and IWD-ANN provide a better forecasting performance, which is obtained via mean square error (MSE), than GA-ANN in the field of passenger flow prediction. This study illustrates that the newly adopted algorithms exhibit good performance for passenger prediction.     

Alanine containing porous beads for mercury removal from artificial solutions

N‐methacryloyl‐(L )‐alanine (MALA) was synthesized by using methacryloyl chloride and alanine as a metal‐complexing ligand or comonomer. Spherical beads with an average diameter of 150–200 μm were obtained by suspension polymerization of MALA and 2‐hydroxyethyl methacrylate (HEMA) conducted in an aqueous dispersion medium. Poly(HEMA–MALA) beads were characterized by SEM, swelling studies, surface area measurement, and elemental analysis. Poly(HEMA–MALA) beads have a specific surface area of 68.5 m²/g. Poly(HEMA–MALA) beads with a swelling ratio of 63%, and containing 247 μmol MALA/g were used in the removal of Hg²⁺ from aqueous solutions. Adsorption equilibrium was achieved in about 60 min. The adsorption of Hg²⁺ ions onto PHEMA beads was negligible (0.3 mg/g). The MALA incorporation into the polymer structure significantly increased the mercury adsorption capacity (168 mg/g). Adsorption capacity of MALA containing beads increased significantly with pH. The adsorption of Hg²⁺ ions increased with increasing pH and reached a plateau value at around pH 5.0. Competitive heavy metal adsorption from aqueous solutions containing Cd²⁺, Cu²⁺, Pb²⁺, and Hg²⁺ was also investigated. The adsorption capacities are 44.5 mg/g for Hg²⁺, 6.4 mg/g for Cd²⁺, 2.9 mg/g for Pb²⁺, and 2.0 mg/g for Cu²⁺ ions. These results may be considered as an indication of higher specificity of the poly(HEMA–MALA) beads for the Hg²⁺ comparing to other ions. Consecutive adsorption and elution operations showed the feasibility of repeated use for poly(HEMA–MALA) chelating beads. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 1222–1228, 2006