2/4/Al cell

Tavelin, S., Taipalensuu, J., Hallboeoek, F., Vellonen, K.-S., Moore, V. and Artursson, P. (2003) An improved cell culture model based on 2/4/Al cell monolayers for studies of intestinal drug transport characterization of transport routes. Pharmaceutical Research, 20, 373-381. 

Al cells paracellular and both active and passive transcellular transport... 

This comparison revealed that the transport characteristics of most compounds were well-predicted in all three models. However, HDM failed, as expected, to predict the absorption characteristics of both carrier-mediated and paracel-lularly transported compounds the two cell lines predicted most compounds equally well, but 2/4/Al cells showed slightly better prediction, suggesting that the paracellular component of drug transport is more important than expected (Matsson et al. 2005). 

The paracellular permeation pathway in the intestinal cell monolayer models is often limited. Therefore these models are not suitable for predicting permeability of paracellularly absorbed compounds. The average pore radius in Caco-2 cells (<6 A) is more representative of the colon than the small intestine (8-13 A)and paracellular transport can be up to 100-fold lower in Caco-2 cells than in the small intestine. Investigation of a rat intestinal cell line 2/4/Al, which forms polarized cell mono-layers and has an average pore radius (9 A) more representative of the small intestine, showed improved prediction of oral absorption for incompletely absorbed drugs [24, 25]. 

In addition it was also suggested that cell lines that have limited expression of transporters (e.g., 2/4/Al) are of use in understanding passive permeability. Saturation of transporters or inhibition can also be used to understand the contribution of passive permeation and active transport. 

Pictures of blood cells taken in a transmission acoustic microscope were shown in Fig. 2.4. Blood cells have since been studied in a more modern reflection microscope at 0.8 GHz and 1.6 GHz (Schenk et al. 1988). Like the pictures of cells from the tadpole heart endothelia, the pictures showed differences in topography, density, elasticity, and absorption revealing effects of haemoglobin content and details of the cell cytoskeleton. 

Recently, Matsson et al. compared artificial membranes (hexadecane-membranes HDM) with 2 different cell monolayer models [i.e., the rat fetal duodenal cell line (2/4/Al) and the commonly used Caco-2 cell line] with respect to their potential for predicting the fraction absorbed in man they also successfully built a computer-aided prediction model of drug permeability using the same compound data set (Matsson et al., 2005). The three methods describe the importance of different pathways ... 

Exposure of Sprague-Dawley male rats to radon at cumulative doses as low as 100 WLM resulted in an increase in sister chromatid exchanges (SCEs) in bone marrow by 600 days post-exposure (Poncy et al. 1980). At 750 days post-exposure, the number of SCEs reached 3.21 per cell. The SCEs in the 500 and 3,000 WLM groups reached constant values of 3.61 and 4.13 SCEs per cell. In the high-dose group (6,000 WLM), SCEs continued to increase from 100 to 200 days after exposure, reaching a mean value of 3.5 SCE per cell. In controls SCEs were constant with age (2.4 per cell). 

Measurements of metabolite concentrations in muscle fibers before and after fatiguing stimulation have shown that ATP decreases from 6 to 4.6 mM and PCr decreases from 35 to 2.4 mM with a calculated increase in Pj from 3 to 38 mM (Dawson et al., 1978 Nassar-Gentina et al., 1978). The free ADP concentration was calculated to increase from 30 to 200 pM. At the same time pH decreased from 7.0 to 6.5 (Dawson et al., 1978 Juel, 1988 Westerblad and Lannergren, 1988). The effect of these metabolic changes has been studied in skinned muscle fibers, i.e., fibers in which the cell membrane has been removed. The skinning of the fibers... 

Neurological effects related to cholinesterase depression occurred in seven children acutely exposed to methyl parathion by inhalation as well as orally and dermally (Dean et al. 1984). The children were admitted to a local hospital with signs and symptoms of lethargy, increased salivation, increased respiratory secretions, and miosis. Two of the children were in respiratory arrest. Two children died within several days of each other. All of the children had depressed plasma and erythrocyte cholinesterase levels (Table 3-2). These effects are similar to those occurring in methyl parathion intoxication by other routes (see Sections 3.2.2.4 and 3.2.3.4). Three adults exposed in the same incident had normal plasma (apart from one female) and red blood cell cholinesterase, and urinary levels of 4-nitrophenol (0.46-12.7 ppm) as high as some of the ill children. 

Flax seeds were placed for germination on moist paper for three days at 22°C and in the dark then, the plantlets were transferred under continuous white light on a liquid culture medium, as previously described [6], Suspension-cultured cells of flax were obtained from hypocotyl-derived calli as described by Schaumann et al. [4] and cultured on a medium described by Murashige and Skoog [7] containing kinetin (0.75 mg 1 ) and 2-4 D (0.2 mg 1 ). 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

The metabolism of pentafluoro-, pentachloro-, and pentabromophenol by Mycobacterium fortuitum strain CG-2 is initiated by a monooxygenase that carries out hydroxylation at the para position (Uotila et al. 1992). Cell extracts of Rhodococcus chiorophenoiicus Mycobacterium chlorophenolicunt) strain PCP-1 in the presence of a reductant transformed tetrafluoro-, tetrachloro-, and tetrabromohydroquinone to 1,2,4-trihydroxybenzene by reactions that clearly involve both hydrolytic and reductive loss of fluorine (Uotila et al. 1995). 

A thiazole core has also been utilised by Solvay Pharmaceuticals [309] in the search for a novel bioisosterie replacement of the rimonabant (382) pyrazole core. The affinity of several compounds for the human CBi receptor was determined in transfected CHO cells using tritium-labelled CP 55940. Antagonism was determined in the same cell line by WIN 55212-2-induced release of arachidonic acid. The pK[ of (456) was found to be 6.9, while the p 2 value was measured as 8.7. A series of six 1,2,4-triazole analogues has been prepared by Jagerovic et al. [310], via their corresponding A-acylbenzamides (Table 6.39). 

Tilton B, Ho L, Oberlin E, et al. Signal transduction by CXC chemokine receptor 4. Stromal cell-derived factor 1 stimulates prolonged protein kinase B and extracellular signal-regulated kinase 2 activation in T lymphocytes. J Exp Med 2000 192(3) 313-324. 

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