Blood-brain barrier artificial

Reichel, A., Begley, D. J. Potential of immobilized artificial membranes for predicting drug penetration across the blood-brain barrier. Pharm. Res. 1998, 35,1270-1274. 

BBB PAMPA Blood brain barrier parallel artificial membrane permeability assay... 

Considering the spatial geometry of cerebral capillaries and capillary blood flow, a number of dynamic models of the blood-brain barrier have been developed, in which endothelial cells are cultured inside a permeable tube, the outer surface of which is coated with astrocytes. Supply of the cells with nutrients and artificial blood flow are maintained by using a peristaltic pump system [112, 113]. 

The rather time- and cost-expensive preparation of primary brain microvessel endothelial cells, as well as the limited number of experiments which can be performed with intact brain capillaries, has led to an attempt to predict the blood-brain barrier permeability of new chemical entities in silico. Artificial neural networks have been developed to predict the ratios of the steady-state concentrations of drugs in the brain to those of the blood from their structural parameters [117, 118]. A summary of the current efforts is given in Chap. 25. Quantitative structure-property relationship models based on in vivo blood-brain permeation data and systematic variable selection methods led to success rates of prediction of over 80% for barrier permeant and nonper-meant compounds, thus offering a tool for virtual screening of substances of interest [119]. 

Garg P, Verma J (2006) In silico prediction of blood-brain barrier permeability An artificial neural network model. J Chem Inf Model 46 289-297... 

Fu XC, Wang GP, Liang WQ, Yu QS (2004) Predicting blood-brain barrier penetration of drugs using an artificial neural network. Pharmazie 59 126-130. 

Di, L., Kerns, E.H., Fan, K., McConnell, O.J. and Carter, G.T. (2003) High throughput artificial membrane permeability assay for blood-brain barrier. European Journal of Medicinal Chemistry, 38, 223-232. 

On the other hand, PAMPA is a purely artificial method and PAMPA membranes do not reassemble real lipid bilayer structures as barriers for permeation but much thicker barriers. The thickness and material of the supporting PVDF filters also influences artificially the permeation of compounds depending on the lipophilicity of the compounds more than the thin polycarbonate filter does in CACo2 experiments. Also the best choice of membrane constituents for PAMPA experiments is still under investigation and it seems that it will depend a lot on the goal of the PAMPA experiment which membrane is used (e.g. blood brain barrier permeation or intestinal absorption). One has to take into account that PAMPA today is a summary term on a lot of different methods applied in different laboratories using different membrane constituents, sink conditions, permeation times etc., which makes inter laboratory comparison difficult. 

The blocking action could also be implemented by administration of an enzyme or a catalytic antibody (regarded as an artificial enzyme) that not only binds but also accelerates cocaine metabolism and thereby frees itself for further binding [16-25]. Usually, a pharmacokinetic agent would not be expected to across the blood-brain barrier and thus would itself have no direct pharmacodynamic action, such as abuse liability [5]. 

Cucullo, L., Oby, E., Hallene, K, Aumayr, B., Rapp, E.. and (anigro, D. (2006) Artificial blood-brain barrier, in Blood-Brain Barriers (eds R. Dermietzel. D.C. Spray, and M. Nedergaard), Wiley-VCH Verlag GmbH, Weinheim,... 

Many organizations use colon adenocarcinoma (Caco-2) for detailed study of permeability however, this method can be resource intensive. Parallel artificial-membrane permeability (PAMPA) [19] has proven to be a reliable predictor of passive transcellular permeability for intestinal absorption prediction. It is also useful to interpret results of cell-based discovery assays, in which cell-membrane permeability is limiting. Finally, pTf provides insight into the pH dependence of solubility and permeability. It can be measured [20] or calculated to get an understanding of the regions of the intestine in which the compound will be best absorbed, as well as to anticipate the effect of pH on solubility and pemieability. Permeability at the blood-brain barrier (BBB) also can be rapidly profiled [21]. 

Similar concerns have been voiced regarding the safety of the acidic amino acid Asp in the artificial sweetener aspartame (L-aspartyl-L-phenylalanine methylester). As with MSG, however, the homeostatic mechanisms regulating plasma Asp levels following Asp consumption do not allow for large increases in plasma Asp that could alter CNS function. In fact, the concern regarding the safety of aspartame results from the other amino acid phenylalanine, which much more readily crosses the blood-brain barrier and can alter CNS function. This is especially important for people who unknowingly are heterozygous for phenylketonuria (2). 

LNAA supplementation targeting the blood-brain barrier was first suggested as an alternative therapy over 40 years ago [27], In artificially induced hyperphenylalaninemic rats, LNAA supplementation resulted in lower brain phenylalanine concentrations but no change in serum phenylalanine concentrations. Conclusions from this study were the basis for considering the use of increasing LNAA to compete with phenylalanine as an alternative nutrition management tool in individuals with PKU. 

Yoon CH, Kim SJ, Shin BS, Lee KC, and Yoo SD (2006) Rapid screening of blood-brain barrier penetration of drugs using immobilized artificial membrane phosphatidylcholine column chromatography J Biomol Screen 11 13-20. 

The use of a faster-growing cell line, MDCK (Madin-Darby canine kidney) cells, appears to be a good replacement for Caco-2 cells (Irvine et al. 1999). The parallel artificial membrane permeation assay (PAMPA) is a rapid in vitro assay, in which transcellular permeation is evaluated (Kansy et al. 1998). PAMPA may also be used to predict oral absorption, blood-brain barrier penetration, and human skin permeability (Fujikawa et al. 2007) by using QSAR models. To our knowledge, neither PAMPA, Caco-2 cell monolayers nor MDCK cells have been used to examine the absorption/permeability of the pyrethroids. The advantages and limitations of the Caco-2 model were reviewed by Artursson et al. (1996) and Delie and Rubas (1997). 

PAMPA Parallel Artificial Membrane Permeability Assay is a method which determines the permeability of substances from a donor compartment, through a Upid-infused artificial membrane into an acceptor compartment. PAMPA models regularly exhibit a high degree of correlation with permeation across a variety of barriers including Caco-2 cultmes, the G1 tract, blood-brain barriers and skin... 

From a methodological point of view, tite PAMPA-BBB system is quite simple. The lipids, dissolved in dodecane, are soaked with a filter mounted in a two-compartment chamber. The drug is added to the donor compartment (which can be either the upper or lower chamber), and its passage through the artificial membrane is measured in the acceptor compartment (Fig. 14.17). A standard compound with well-characterized permeability proper-hes (e.g., verapamil) is tested in parallel. Compounds that readily cross the blood-brain barrier have an in vitro permeability (P,) > 2.7 10" cm s in the PAMPA assay. On the opposite, drugs with low blood-brain barrier permeation have a < 0.710 cm s". Beside... 

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