Does routine follow up after head injury help? A randomised controlled trial

Excess surfactant present in emulsions can influence the rates of transport of incorporated drugs by micellar solubilization, alteration of the partitioning process and by drug-surfactant complexation. Cetyltrimethylammonium bromide (CTAB), a cationic surfactant was selected to investigate these phenomena as it forms relatively stable mineral oil-water (O-W) emulsions and has the potential for ionic interaction. Phenylazoaniline, benzocaine, benzoic acid and phenol were chosen as model drugs for this study. The emulsion critical micelle concentration (CMC) for CTAB determined using a combination of a membrane equilibrium technique and surface-tension measurement was 1.0% w/v in 10% v/v% O-W emulsion systems. Ionic interaction between model drugs and surfactants and drug hydrophobicity affected their transport rates in the emulsion systems. The transport rates of the lipophilic drugs (benzocaine and phenylazoaniline) and the ionized hydrophillic drug (benzoic acid, pH 7.0) in the emulsion systems increased with increasing CTAB concentration up to 0.5% w/v micellar concentration and then decreased at higher concentrations. The rate of transport of phenol was not affected by the presence of micellar phase. Ionic interaction between surfactant and model drugs affected transport rates of model drugs in emulsion systems. The micellar phase was considered to affect the overall transport rates of model drugs.     

Intestinal water and solute absorption studies: comparison of in situ perfusion with chronic isolated loops in rats

The effects of lumenal glucose on jejunal water transport and the influence of glucose-induced water absorption on solute uptake from single-pass perfusions are compared in anesthetized rats in situ and isolated chronic loops in unanesthetized rats in vivo. While the magnitudes of solute membrane permeabilities are consistently higher in the chronic loop system, the effects on water transport and its promotion of jejunal solute uptake are comparable between the two experimental systems. The effect of glucose-induced water absorption on the enhanced/baseline jejunal uptake ratio of the hydrophilic drug, acetaminophen, is greater than that for the lipophilic drug, phenytoin, in both experimental systems. The fact that chronic loop effective solute permeabilities were equivalent to solute membrane permeabilities in situ is consistent with greater lumenal fluid mixing in vivo. In addition, in situ body temperature affects the uptake of phenytoin but not acetaminophen, water, or glucose. This suggests that active and paracellular solute transport is not compromised in situ, while membrane partitioning and diffusion of lipophilic species are more sensitive to experimental conditions.     

Microencapsulation in yeast cells

A method for encapsulating high concentrations of essential oils into bakers' yeast (Saccharomyces cerevisiae) is described. The process involves mixing an aqueous suspension of yeast and an essential oil, which allows the oil to pass freely through the cell wall and membrane and remain passively within the cell. Oil droplets sequestered within the cell were clearly visible using confocal microscopy. Transmission electron microscopy demonstrated that the cell wall and membrane remain intact during the process. Cells quickly lost viability during the process and it appeared unnecessary for the cells to be viable for the process to occur. Encapsulated oil was recovered from the cells using a water/ethanol extraction procedure and analysed by gas chromatography. No significant differences were noted between encapsulated and unencapsulated oil profiles. The rate of permeation of oil into the yeast cells was found to increase significantly at higher temperatures due to the phase transition of the lipid membrane. The rates at which different essential oils permeated the cell varied considerably due to variations in terpene chemistry. The encapsulation of straight chain hydrocarbons highlighted the effects of molecular size, shape and the presence of hydroxl groups on the process. The process occurs by passive diffusion as a result of hydrophobic flavour components partitioning into the cell membrane and intracellular lipid. This paper briefly reviews the patented literature and reports some of the initial observations of the transport mechanisms involved during the accumulation of essential oils by yeast cells.     

Diffusion and Sorption of Hexachlorobenzene in Sediments and Saturated Soils

In order to understand the transport and fate of hydrophobic organic chemicals (HOCs) in consolidated sediments and saturated soils, long-term (up to 512 d), one-dimensional, time-dependent diffusion experiments were done with a representative HOC, hexachlorobenzene (HCB), in three different sediments and soils. In addition, long-term HCB partitioning experiments in suspended sediments at high concentrations and tritiated water diffusion experiments in consolidated sediments were done in order to more accurately interpret the HCB diffusion experiments. Numerical models were used to analyze the results. Good agreement between the experimental data and calculated results was obtained. Despite the length of the experiments, the experimental results demonstrate that the HCB in the consolidated sediments was far from a steady-state chemical equilibrium. Experiments and theoretical results also indicate that the assumption of local chemical equilibrium was not valid, and sorption rates must therefore be considered for a valid analysis of transport.     

Characterization of partitioning behavior of cephalosporins using microemulsion and micellar electrokinetic chromatography

Electrokinetic chromatography (EKC) was introduced to determine the partitioning behavior of various cephalosporins (cefpim, cefpirom, cefaloridin, cefaclor, cephalexin, cefuroxim, cefotaxim) in microemulsions (ME) and micellar (MC) systems. The partitioning behavior of cephalosporins in microemulsions was characterized calculating the capacity factor. The required parameters for the determination of the capacity factor (micro(aq) and micro-me are the electrophoretic mobilities of the solutes in the aqueous phase and the microemulsion phase, micro(eff) is the effective mobility in the microemulsion solution) were measured by EKC using cationic and anionic microemulsion systems consisting of the surfactants/n-heptane/1-butanol/10 mM phosphate buffer solution, pH 7.0. Electrokinetic chromatography was shown to be a useful method to quantify the partitioning behavior of drugs in oil/water microemulsion. The logarithm of the capacity factor was correlated with the logarithm of the 1-octanol/water partitioning coefficients.     

A two-phase model for controlled drug release from biphasic polymer hydrogels

A comprehensive two phase model is developed to describe the sustained release of a solute or drug from a biphasic hydrogel substrate. Such a material consists of a continuous hydrophilic phase (polymer backbone in water) and a dispersion of spherical microdomains made of the hydrophobic side chains of the polymer organised in a micelle like fashion. The solute or drug is assumed to be encapsulated within the dispersed microdomains, and to diffuse from the interior to the surface of the microdomain where it exchanges following a Langmuir isotherm. Mass transfer to the bulk phase occurs by desorption of the drug from the surface through a driving force that is proportional to the difference of surface and bulk concentration. Accordingly the drug is released to the surroundings by diffusion through the bulk. Depending on the values of the Langmuir constant and assuming well stirred behaviour in the interior of the microdomain, the present model results in either of the two asymptotic models developed in previous studies. The results of a parametric study show that the desired steady state flux of a specific drug to the surroundings may be obtained given appropriate values of structural properties of the material. This conclusion is further supported when using this model to simulate earlier experimental results. The polymer structural properties can be manipulated easily during the fabrication of dispersed-phase networks, as indicated by preliminary experiments.     

The absence of stereoselective P-glycoprotein-mediated transport of R/S-verapamil across the rat jejunum

We have studied the potential stereoselective transport and metabolism of R/S-verapamil in rat jejunum, in-situ. A regional single-pass perfusion of the rat jejunum was performed on 24 rats in six separate groups. The effective permeability (Peff) was assessed for three different concentrations of verapamil, 4, 40 and 400 mg L(-1). The Peff of each enantiomer was also determined at 400 mg L(-1) when chlorpromazine (10 mM) was added to the perfusion solution. Two other groups of rats received R/S-verapamil as an intravenous infusion and the intestinal secretion and metabolism were studied by simultaneously perfusing the jejunum with a control or with chlorpromazine (10 mM) added. The concentrations in the outlet perfusate of each enantiomer of verapamil and norverapamil were assayed with HPLC. R/S-Verapamil is a high permeability drug in the proximal rat small intestine throughout the luminal concentration range studied and complete intestinal absorption was expected. There was an increase of Peff from 0.42 x 10(-4) cm s(-1) to 0.80 x 10(-4) cm s(-1) (P < 0.05) at concentrations from 4 to 400 mg L(-1), respectively. The observed concentration-dependent jejunal Peff and fraction absorbed (P < 0.05) of R/S-verapamil is consistent with the saturation of an efflux mechanism. When chlorpromazine (a P-glycoprotein inhibitor/substrate) was added the jejunal Peff increased to 1.47 x 10(-4) cm s(-1). There was no difference between the Peff of the two enantiomers in any of these experiments. The efflux of R/S-norverapamil into the rat jejunum was high after intravenous administration of R/S-verapamil, suggesting extensive metabolism in the enterocyte. In conclusion, both R/S-verapamil enantiomers are P-glycoprotein substrates, but there is no stereoselective transport of R/S-verapamil in the rat jejunum. The results also suggests that R/S-norverapamil is formed inside the enterocytes.     

Modeling Uncoupled Solute Transport in Natural Organic Matter Size Fractionation by Ultrafiltration

Physicochemical separation of organic macrosolutes and colloidal particles is routinely required during the analysis of natural, waste, and process waters derived from aquatic and terrestrial environmental samples. This study was conducted to demonstrate the utility of a two-parameter nonlinear permeation coefficient model (PCM) in describing the uncoupled transport of solutes in dilute heterogeneous solutions subjected to batch ultrafiltration (UF). The PCM was used in conjunction with natural organic matter (NOM) permeate data for a natural water and six hydrophobic and hydrophilic subfractions to determine permeation coefficients p and NOM concentrations Cr0 with apparent molecular weight less than membrane specific cutoff values of moderately hydrophilic YC/YM series Amicon? UF membranes. Experimentally measured permeation coefficients p determined for the whole water were found to correlate well with composite permeation coefficients p? calculated using a mass-fraction weighted average of individual NOM subfraction permeation coefficient values. Correlation of experimentally measured and calculated permeation coefficient values (p and p?) indicated that the PCM can adequately describe uncoupled transport of chemically distinct solute fractions during batch UF of heterogeneous dilute solutions.     

Kinetics of anthracycline accumulation in multidrug-resistant tumor cells: relationship to drug lipophilicity and serum albumin binding

A multidrug-resistant Ehrlich ascites tumor cell line (EHR2/DNR+) was used to examine the membrane transport kinetics of lipophilic anthracycline derivatives in the presence of serum albumin. We present a model for theoretical data analysis with consideration of drug-albumin complex formation. For a set of five derivatives (doxorubicin, daunorubicin, 4-demethoxydaunorubicin, 4'-deoxy-4'-iododoxorubicin, and 13-dihydro-4'-deoxy-4'-iododoxorubicin), data were given on the rates of diffusional drug uptake, and membrane permeability coefficients of the noncharged molecules were estimated. Both the initial rates and the steady-state levels of drug uptake were found to decrease by addition of BSA at concentrations ranging from 5 to 75 mg/mL. For each drug, this effect of serum albumin could be accounted for by the altered distribution between free and protein-bound drug molecules in the bulk aqueous medium. A good fit of theoretical accumulation curves to the experimental data was obtained. It was concluded that a mathematical simulation method makes it possible to predict the uptake characteristics of lipophilic anthracycline compounds into tumor cells under serum conditions.     

Na+,K+-ATPase was found to be the membrane component responsible for the hydrophobic behavior of the brain membrane tubulin

We have previously described that the tubulin isolated from brain membranes as a hydrophobic compound by partitioning into Triton X-114 is a peripheral membrane protein [corrected]. The hydrophobic behavior of this tubulin is due to its interaction with membrane protein(s) and the interaction occurs principally with the acetylated tubulin isotype. In the present work we identified the membrane protein that interacts with tubulin as the Na+,K+-ATPase alpha subunit by amino acid sequencing. Using purified brain Na+,K+-ATPase we were able to isolate part of the total hydrophilic tubulin as a hydrophobic compound which contains a high proportion of the acetylated tubulin isotype.     

乳状液膜法迁移及分离钼（Ⅵ）的研究

采用仲胺N7207为流动载体，兰113A为表面活性剂、煤油为膜溶剂、NaOH作内相试剂的乳状液膜体系迁移分离Mo（Ⅵ）。研究了其迁移机理，确定了适宜的制乳、迁移分离等有关条件。在所筛选的制乳及迁移分离条件下，迁移分离含Mo(Ⅵ）100mg/L的水样，迁移率达98．0％以上。     

Energetics and mechanism of drug transport mediated by the lactococcal multidrug transporter LmrP

The gene encoding the secondary multidrug transporter LmrP of Lactococcus lactis was heterologously expressed in Escherichia coli. The energetics and mechanism of drug extrusion mediated by LmrP were studied in membrane vesicles of E. coli. LmrP-mediated extrusion of tetraphenyl phosphonium (TPP+) from right-side-out membrane vesicles and uptake of the fluorescent membrane probe 1-[4-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene (TMA-DPH) into inside-out membrane vesicles are driven by the membrane potential (Deltapsi) and the transmembrane proton gradient (DeltapH), pointing to an electrogenic drug/proton antiport mechanism. Ethidium bromide, a substrate for LmrP, inhibited the LmrP-mediated TPP+ extrusion from right-side-out membrane vesicles, showing that LmrP is capable of transporting structurally unrelated drugs. Kinetic analysis of LmrP-mediated TMA-DPH transport revealed a direct relation between the transport rate and the amount of TMA-DPH associated with the cytoplasmic leaflet of the lipid bilayer. This observation indicates that drugs are extruded from the inner leaflet of the cytoplasmic membrane into the external medium. This is the first report that shows that drug extrusion by a secondary multidrug resistance (MDR) transporter occurs by a "hydrophobic vacuum cleaner" mechanism in a similar way as was proposed for the primary lactococcal MDR transporter, LmrA.     

Eradication of Barrett''s mucosa with argon plasma coagulation and acid suppression: immediate and mid term results

Microcapsules are used for the formulation of drug controlled release and drug targeting dosage forms. Encapsulated hydrophobic drugs are often applied as their solutions in plant oils. The uptake of the oils in the complex coacervate microcapsules can be improved by the addition of surfactants. In this study, soybean, olive and peanut oils were chosen as the representatives of plant oils. The well characterized complex coacervation of gelatin and acacia has been used to produce the microcapsules. The amount of encapsulated oil has been determined gravimetrically. The encapsulation of the oils was high (75-80%). When the surfactants with HLB values from 1.8 to 6.7 were used, the amount of encapsulated oil was high (65-85%). A significant decrease of the oil content in the microcapsules was found when Tween 61 with HLB = 9.6 had been added into the mixture. No oil was found inside the microcapsules from the coacervate emulsion mixture containing Tween 81 (HLB = 10) and Tween 80 (HLB = 15), respectively. The results of the experiment confirm the dependence of hydrophobic substance encapsulation on the HLB published recently for Squalan.     

Modeling the route of administration-based enhancement in the brain delivery of EAB 515, studied by microdialysis

EAB 515 (S-alpha-amino-5-phosphonomethyl[1,1'biphenyl]-3-propanoic acid) is an extremely hydrophilic N-methyl-D-aspartate antagonist. It shows marked CNS activity, in that it is a potent neuroprotector in models of cerebral ischemia, and also demonstrates social and non-social behavioral alteration following systemic administration in animals. Because of its high degree of ionization at physiologic pH, one would not expect appreciable brain uptake of EAB 515 across tight junctions of the blood-brain barrier. This is in contrast to its pharmacologic effect as well as brain/plasma ratios measured during systemic administration in rats. These observations lead us to investigate other transport pathways that might account for its brain uptake. Such mechanistic information is imperative in rational drug delivery and drug design strategies. Upon intracerebroventricular administration, the observed steady-state cortical extracellular fluid concentrations of EAB 515 were over 100-fold higher than those observed following intravenous administration, when normalized for the dosing rate. This increased distribution into the brain, based upon the route of administration, suggests the transport of drug directly between the cerebrospinal fluid and the brain extracellular space. The parameters of the model that adequately describes the data obtained from the two routes of administration in individual animals were estimated. The clinical significance of these results is in the use of intracerebroventricular administration for enhanced brain delivery of hydrophilic drugs that poorly cross the blood-brain barrier.     

Drug excretion mediated by a new prototype of polyspecific transporter

Cationic drugs of different types and structures (antihistaminics, antiarrhythmics, sedatives, opiates, cytostatics and antibiotics, for example) are excreted in mammals by epithelial cells of the renal proximal tubules and by hepatocytes in the liver. In the proximal tubules, two functionally disparate transport systems are involved which are localized in the basolateral and luminal plasma membrane and are different from the previously identified neuronal monoamine transporters and ATP-dependent multidrug exporting proteins. Here we report the isolation of a complementary DNA from rat kidney that encodes a 556-amino-acid membrane protein, OCT1, which has the functional characteristics of organic cation uptake over the basolateral membrane of renal proximal tubules and of organic cation uptake into hepatocytes. OCT1 is not homologous to any other known protein and is found in kidney, liver and intestine. As OCT1 translocates hydrophobic and hydrophilic organic cations of different structures, it is considered to be a new prototype of polyspecific transporters that are important for drug elimination.     

Does fluid flow across the intestinal mucosa affect quantitative oral drug absorption? Is it time for a reevaluation?

PURPOSE: Hydrophilic and charged solutes have a lower membrane permeability which is due to a lower partition into the lipid membrane (low solubility in the membrane phase) and/or a slower transcellular diffusion coefficient. They are therefore anticipated to be absorbed through the paracellular route, which is a consequence of diffusion and a convective volume flow through the water-filled intercellular space. METHODS: Two approaches have been used to investigate the mechanisms underlying the paracellular drug transport across the intestinal mucosa: (a) including water transport by exposing the apical side of the epithelium with a hypotonic solution, and (b) stimulated paracellular transport by widening of tight junction and increased water absorption as a consequence of the sodium-coupled transport of nutrients. RESULTS: Among the first studies that recognized this fluid flux dependent transmucosal transport of drugs, was one published by Oschenfahrt & Winne in 1973 and the one by Kitazawa et al. in 1975. During the last two decades the importance of this paracellular route for drug delivery have been explored in vitro and in situ. CONCLUSIONS: The limits concerning molecular weight, shape, ionization and the effect of physiological stimulants, such as luminal concentrations of nutrients, osmolality and motility, are currently under investigation. However, recently published in vivo human data by ourselves and others indicate that the promising results obtained in vitro and in situ for various hydrophilic compounds might not be valid in quantitative aspects in humans, especially not for drugs with a molecular weight over 200.     

Modeling Water Movement and Flux from Membrane Pervaporation Systems for Wastewater Microirrigation

A mathematical model to predict the performance of a membrane pervaporation unit directly placed in the soil to reuse wastewater for agricultural microirrigation was presented. The model was formulated by combining the solution–diffusion and the resistance-in-series model for mass transport across the membrane thickness, the Richard’s equation for soil water movement and the van Genuchten function for soil hydraulic properties to predict the water permeate flux for different types of test soil over a wide range of process operating conditions. Its applicability was assessed by comparing to the experimental data collected using both hollow fiber (HF) bundles and corrugated sheets (CS) membrane modules made of a hydrophilic dense polymer. A good agreement was observed between the model predictions and the experimental measurements. Further analysis concluded that the water permeate flux were mainly controlled by the porosity, the particle-size distribution, and the residual water of the soil. The overall mass transfer resistances were estimated to be 1.2×1014 and 5.6×1013?s?Pa/m for the HF and CS modules buried in loam soil, respectively, which are different from those measured in sweeping air pervaporation tests. The soil resistance for water transport was 7.1×1013?s?Pa/m. It is believed that the model could be a valuable tool to refine the design and optimize the operation of the proposed membrane pervaporation system.     

Evaluation of process parameters involved in chitosan microsphere preparation by the o/w/o multiple emulsion method

Chitosans are interesting biopolymers largely studied for applications in the medical and pharmaceutical fields. In this work, an o/w/o multiple emulsion technique was used for the preparation of hydrophobic drug loaded microspheres. Moreover, the influence of critical variables (concentration of acetic acid in the polymer solution and drug-polymer ratio) on microsphere morphology and drug content was evaluated. Two chitosans of different molecular weights and deacetylation degree were employed; ketoprofen, a non-steroidal anti- inflammatory drug, was chosen as the hydrophobic model drug. The multiple emulsion method produced well-formed microspheres with good yields. Acetic acid concentration in the polymeric solutions influenced particle size and drug content of the microspheres. The highest drug encapsulation efficiencies were obtained for the lowest theoretical drug/chitosan ratio.     

Intestinal permeability in patients with Crohn''s disease and ulcerative colitis and their first degree relatives

A method has been devised for predicting the ability of drugs to cross the blood-brain barrier. The criteria depend on the amphiphilic properties of a drug as reflected in its surface activity. The assessment was made with various drugs that either penetrate or do not penetrate the blood-brain barrier. The surface activity of these drugs was quantified by their Gibbs adsorption isotherms in terms of three parameters: (i) the onset of surface activity, (ii) the critical micelle concentration, and (iii) the surface area requirement of the drug at the air/water interface. A calibration diagram is proposed in which the critical micelle concentration is plotted against the concentration required for the onset of surface activity. Three different regions are easily distinguished in this diagram: a region of very hydrophobic drugs which fail to enter the central nervous system because they remain adsorbed to the membrane, a central area of less hydrophobic drugs which can cross the blood-brain barrier, and a region of relatively hydrophilic drugs which do not cross the blood-brain barrier unless applied at high concentrations. This diagram can be used to predict reliably the central nervous system permeability of an unknown compound from a simple measurement of its Gibbs adsorption isotherm.