Amphiphiles drugs

Sofer A, Futerman AH. Cationic amphiphilic drugs inhibit the internalization of cholera toxin to the Golgi apparatus and the subsequent elevation of cyclic AMP. J Biol Chem 1995 270(20) 12117-12122. 

As cationic amphiphilic drugs, p-blockers can exert a membrane-stabilizing effect, as evidenced by the ability of the more lipophilic congeners to inhibit Na+-channel function and impulse conduction in cardiac tissues. At the usual therapeutic dosage, the high concentration required for these effects will not be reached. 

The basic principle is shared by several methods In chromatographic or electrophoretic systems where the liposomes (vesicles) are immobilized, pseudostationary, or carried by an electroendosmotic flow, migrating amphiphilic drug molecules partition between the water outside the liposomes, the lipid bilayer of the liposome, and the aqueous compartment within the liposome (Fig. 3). In all cases the migration rate basically reflects the par-... 

Toxicophore analysis Evaluation of chemical moieties historically associated with safety issues, for example, genotoxidly, cationic amphiphilic drugs and phosphohpidosis, tertiary amines that are charge neutral at physiologic pH and vacuohzation... 

Fatty acid beta-oxidation Inhibition by valproate, tetracyclines, nonsteroidal antiinflammatory drugs, antianginal cationic amphiphilic drugs, female sex hormones, CoA depleters such as valproate and salicylate... 

There are specific fiuorescent dyes for specific pathologies created by specific drug classes, such as phospholipidosis from cationic amphiphilic drugs [18, 19], mitochondrial DNA depletion by nucleoside reverse transcriptase inhibitors that also inhibit mitochondrial DNA polymerase gamma and redox cyclers that produce reactive oxygen species. The complex mechanism of statin-induced toxicity is demonstrated vith early sublethal effects on apoptosis, mitochondrial function and calcium homeostasis [20]. 

Haupft, R. and Mohr, K. (1985). In uence of cationic amphiphilic drugs on the phase transition temperature of phospholipids with different polar headgrou ochim. Biophys. Acta, 814, 156-162. 

For the medicinal chemist it is of interest to note that such phenomena, i.e. phase separation and domain formation, can also be induced in artificial membranes by cationic amphiphilic drugs. An increase in the microheterogeneity of biological membranes and in consequence a decisive change in membrane function in a defined area must, therefore, be considered. It is mediated through indirect physicochemical interaction with amphiphilic drags. 

Also, it is not the overall lipophilicity of a drug molecule determined in octanol-buffer that is important, but the 3-D distribution pattern of lipophilicity on the surface of the molecule, which may generate a hydrophobic-hydrophilic dipole. Such a dipole can determine the specific interaction and orientation of an amphiphilic drug in a highly structured biological membrane. This includes domain formation and accumulation, change in drug conformation, and so forth. All this is... 

Tab. 3.10 Effect of different cationic amphiphilic drugs on the phase transition temperature Tt of liposomes from different phospholipids. (Reprinted from Tab. 1 of ref. 53, with permission from Elsevier Science)...

The larger partition coefficient into lipids is because only the neutral form can efficiently partition into octanol. Ordered phospholipid bilayers can, however, take up both forms neutral and charged. The influence of anionic and cationic charge on the ability of amphiphilic drugs to partition and bind to DPPC liposomes was investigat-... 

The influence of a series of 12 cationic amphiphilic drugs, including anesthetics, an-tiarrhythmics, and psychotropic agents, has been studied on the binding equilibrium of [3H]-ouabain to membrane suspensions of guinea-pig myocardium. The binding of 3H-labeled ouabain to cardiac Na+,K+-ATPase is a method used to characterize the interaction between cardiac glycosides and their receptor. 

It has commonly been assumed that transfer processes can be modeled in terms of simple bulk-phase thermodynamics. However, in many circumstances this assumption seems to be incorrect. Bulk thermodynamics cannot be applied when the solutes (especially amphiphilic drugs) partition into amphiphilic aggregates such as bilayer membranes. It is important to remember that a bilayer consisting of phospholipids is a solvent with an interfacial phase and a high surface/volume ratio. 

David, S.A., Bechtel, B., Annaiah, C., Mathan, V.I., Balaram, P. Interaction of cationic amphiphilic drugs with lipid A Implications for development of endotoxin antagonists. Biochim Biophys Acta 1212 (1994) 167-175. 

Fatouros, D. G, and Antimisiaris, S. G. (2002), Effect of amphiphilic drugs on the stability and zeta-potential of their liposome formulations A study with prednisolone, diazepam and griseofulvin, J. Coll. Interf. Sci., 251, 271-277. 

Mohr, K. and Struve, M., Differential influence of aruonic and cationic charge on the ability of amphiphilic drugs to interact with DPPC-liposomes, Biochem. Pharmacol., 41, 961,1991. 

Grage, S.L. Gauger, D.R. Selle, C. Pohle, W. Richter, W. Ulrich, A.S. The amphiphilic drug flufenamic acid can induce a hexagonal phase in DMPC a solid-state P-and F-NMR study. Phys. Chem. Chem. Phys. 2000, 2 (20), 4574-4579. 

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