Cultural models

With few exceptions, information on the anticonvulsant pharmacology of specific ion channel subunits analyzed in expression systems is scarce. Hitherto, a first understanding of the mechanism of action of most antiepileptic dtugs has evolved from analyses of somatic ion channel pharmacology either in isolated neurons from human or rodent neurons, or cell culture models. 

Collins, A., Gentner, D. (1987). How people construct mental models. In D. Holland N. Quinn (Eds.), Cultural models in language and thought (Vol. 1, pp. 243-265). New York University of Cambridge. 

Hoschele D (2006) Cell culture models for the investigation of NRTI-induced mitochondrial toxicity. Relevance for the prediction of clinical toxicity. Toxicol In Vitro 20(5) 535-546 Itescu S, Brancato LJ et al (1989) A sicca syndrome in HIV infection association with HLA-DR5 and CDS lymphocytosis. Lancet 2(8661) 466 68 Itescu S, Brancato LJ et al (1990) A diffuse infiltrative CDS lymphocytosis syndrome in human immunodeficiency virus (HIV) infection a host immune response associated with HLA-DR5. Ann Intern Med 112(1) 3-10... 

LIU Y and HU m (2002) Absorption and metabolism of flavonoids in the caco-2 cell culture model and a perfused rat intestinal model. Drug Metab Dispos. 30 (4) 370-77. 

In this model, no attempt is made to reproduce the in vivo physiochemical conditions occurring in the lumen of the human small intestine during digestion. This cell culture model only provides information about the intestinal absorption and metabolism processes of the compound. Using this cell culture system in con-... 

Liu, C.S., Glahn, R.P., and Liu R.H., Assessment of carotenoid bioavailability of whole foods using a Caco-2 cell culture model coupled with an in vitro digestion, J. Agric. Food Chem., 52, 4330, 2004. 

Garrett, D.A., Failla, M.L., and Sarama, R.J., Estimation of carotenoid bioavailability from fresh stir-fried vegetables using an in vitro digestion/Caco-2 cell culture model, J. Nutr. Biochem., 11, 574, 2000. 

Hetem, S., Jowett, A. K. Ferguson, M. W. (1989). Biocompatibility of a posterior composite and dental cements using a new organ culture model. Journal of Dentistry, 17, 155-61. 

Whereas the relationship of solute permeability with lipophilicity has been studied in a large number of in vivo systems (including intestinal absorption models [54,55], blood-brain [56 58] and blood nerve [59] barrier models, and cell culture models [60 62], to name just a few), numerous in vitro model systems have been developed to overcome the complexity of working with biological membranes [63-66]. Apart from oil-water systems that are discussed here, the distribution of a solute between a water phase and liposomes is... 

Once potent ligands for a viral protein are identified, further advancement depends on demonstrating activity in cells. Unfortunately, reproducible in vitro viral replication assays for HCV have not been reported. There are scattered reports that a very low level of genome replication, or even virus production, can be observed under certain circumstances [56]. However, recently specific sequences yielding relatively reproducible replication, at consistently detectable levels have been reported [57]. In the coming years these may allow routine assays suitable for compound evaluation to be developed, but to date drug discovery must rely on other cell culture models. 

Durham HD, Roy J, Dong L, Figlewicz DA. Aggregation of mutant Cu/ Zn superoxide dismutase proteins in culture model of ALS. J Neuropathol Exp Neurol 1997 56 523-530. 

Astashkina, A., Mann, B. Grainger, D. W. A critical evaluation of in vitro cell culture models for high-throughput drug screening and toxicity. Pharmacol. Ther. 134, 82-106 (2012). 

Table 2 Most Commonly Used Cell Culture Models for Measuring Transcellular Flux... 

Kim DC, PS Burton, RT Borchardt. (1993). A correlation between the permeability characteristics of a series of peptides using an in vitro cell culture model (Caco-2) and those using an in situ perfused rat ileum model of the intestinal mucosa. Pharm Res 10 1710-1714. 

Tififany-Castiglioni E. 1993. Cell culture models for lead toxicity in neuronal and glial cells. Neurotoxicology 14 513-536. 

Carotenoid absorption and metabolism have been comprehensively reviewed (Erdman et al., 1993 Parker, 1996 van Vliet, 1996 Furr and Clark, 1997 Yeum and Russell, 2002) and this chapter will focus only on recent advances in these areas. A particular emphasis will be placed on studies that used in vitro and cell culture models as tools to understand better the mechanisms of absorption on the molecular level. 

Pade, V., Stavchansky, S., Estimation of the relative contribution of the transcellular and paracellular pathway to the transport of passively absorbed drugs in the Caco-2 cell culture model, Pharm. Res. 1997, 34, 1210-1215. 

Another limitation is that there is no quantitative relationship between active drug transport in the cell culture models and in vivo e.g. [92, 93]. The reason may be that the expression level of the transporter in Caco-2 cells is not comparable to that in vivo or that there is a difference in effective surface area (see Section 4.3.2.2 below). One solution to this problem is to determine the apparent transport constants, Km and Vmax, for each transporter and subsequently, to determine a scaling factor. However, this is not readily done. In addition these studies are further complicated by the lack of specific substrates. For example, there are almost no specific substrates for the drug efflux transporters [18]. Therefore, other epithelial... 

Tavelin, S., J. Taipalensuu, F. Hallbook, K. Vellonen, V. Moore, and P. Artursson. An Improved Cell Culture Model Based on 2/4/A1 Cell Monolayers for Studies of Intestinal Drug Transport. Characterization of Transport Routes., Pharm. Res. 2003, 20, 373-381. 

For the different purposes presented here, cell culture models can provide the basis of screening, biopharmaceutical assessments, and evaluations for mechanistic purposes and some considerations for optimal and rational design are discussed below. 

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