Intracellular target site

Two mechanisms are operating alone or in concert to minimize the antibiotic concentration at the intracellular target site Downregulation of the expression of the pore proteins, also called porins, and upregulation of one or a set of several unspecific efflux pumps. However, the impact of these mechanisms on the resistance is low, since due to the essential function of porins for uptake of nutrients their reduction is limited and to avoid disturbances of membrane integrity due to extensive oveiproduction of mdr efflux pumps these are subjected a strict regulation. 

Finally, it has to be mentioned that LPA also has an intracellular target site, which is the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy). LPA competes for thiazolidinedione binding and activates PPARy-dependent gene transcription. Thereby, LPA induced neointima formation in a rat carotid artery model. 

By nature, the nucleic acid therapeutics have a high negative charge density and are enzymatically labile hydrophilic biomacromolecules thus, efficient delivery of these therapeutics faces similar challenges as the peptide and protein therapeutics. Irrespective of whether the nucleus (in the case of DNA delivery) or the cytoplasm (e.g., for siRNA delivery) of the cell is the intracellular target site, protection and targeting approaches are required to efficiently deliver the drug. 

Membrane transport of toxic heavy metals not only controls their access to intracellular target sites but also helps to determine their uptake, distribution, and excretion from the body. The critical role of membranes in the toxicology of metals has attracted the attention of many investigators, and extensive information has been collected on the mechanisms of metal transfer across membranes. Characteristics of metal transport in different cells (see also Part II, Chapter 4), or even on opposite sides of the same cell, or under different physiological conditions, are not identical, and no unitary hypothesis has been formulated until now to explain this process in all cells (Foulkes 2000). 

Metal ions can protect phosphines against oxidation until they reach intracellular target sites. Evidently, a fine balance between kinetic and thermodynamic stability of the M-P bonds needs to be achieved Pt(II)dppe complexes appear to be inactive, Cu(I), Ag(I) and Au(I) dppe complexes are active. Complexes such as [Au(dppe)2]Cl possess enough kinetic lability in the Au-P bonds to react via a ring-opening mechanism. 

Further therapeutic benefit can be gained by ensuring that the chelating agent is delivered to target sites at an appropriate concentration, rate and duration. Ideally for maximal chelation, a drug must be present within the body at both a reasonable concentration and length of time to ensure interception of iron from either extracellular or intracellular iron pools. Compounds with short plasma half lives are thus likely to be less effective due to the limited pool of chelatable iron present within the body at any one time. 

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