The Various Modes of Action

The rifamycins, streptovaricins and tolypomycins are very effective antibacterial agents. They all inhibit the synthesis of RNA by inactivating the DNA-dependent RNA polymerase. This effect occurs at low concentrations (0.01 jug/ml, 10-8 M) and is highly specific. It is the most thoroughly investigated and clearly defined biological action of the ansamycins. 

Maytansine and related compounds inhibit cell division in sea urchin eggs at concentrations of 0.04 j/g/ml (6 x 10-8 M), possibly by interfering with the polymerization of tubulin. This effect bears some resemblance to the action of the vinca alkaloids such as vincristine. Maytansine inhibits the growth of KB cells at levels of 10 5 fig/ml. 

Clear evidence exists to prove that ansamycins such as rifampicin have no effect on eukaryotic RNA polymerases, be they of nuclear, mitochondrial or chloroplastic 

As has already been mentioned, some lipophilic rifamycins and some strepto-varicins and geldanamycins affect the growth of cells transformed by RNA tumour viruses or the RNA-dependent DNA polymerase (reverse transcriptase) characteristic of these viruses. Again, high drug concentrations are needed to produce an effect and only partial, but never absolute, selectivity of enzyme inhibition has been found. 

Effects on DNA viruses and larger infectious agents belonging to the genus of Chlamydiae  

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With the great diversity of chemicals and the various modes of action, it is very likely that scaling (extrapolating) equations like Equation 1 will differ for different chemicals. Thus, decisions on how genetic-risk estimates are to be extrapolated to man will have to be made in different ways for different chemicals. This point of view is reflected, at least implicitly, in the recently published EPA proposed guidelines for mutagenicity risk assessments.4... 

The various modes of action provide the basis for the following therapeutic indications of ornithine aspartate ... 

The various modes of action of F as an anticaries agent have been discussed in detail elsewhere [20,21], The delivery and retention of F at, or close to, the site of action is regarded as an important feature of the successful application of the agent [22, 23], In particular, the maintenance of an elevated, even if low, F concentration adjacent to the tooth surface has long been believed to be the key to achieve optimal caries control [24],... 

Defining the mode of action to be modeled is the first step in QSAR generation (McKinney et al. 2000). Chapter 1 covers broadly the various modes of action. The class of relevant toxicants and candidate explanatory variables (descriptors) are identified once the mode of action is defined. Previous chapters describe the potential explanatory variables for metal ions. The final step in QSAR development is the generation of quantitative means for selecting and relating the explanatory variable(s) to the effect of interest. The purpose of this chapter is to provide essential details about this last step. 

In the stabilization of PVC, the principal mode of action of the various stabilizer systems has been explained in terms of the Frye and Horst mechanism, i.e., substitution of labile chlorines by more stable groups. Evidence for other actions, such as HCl neutralization, addition to polyene sequences, and bimetallic complex formation have also been given. Despite the wide acceptance of the Frye and Horst mechanism, researchers have frequently contended that this could not be the dominant mechanism in the stabilization of PVC. 

The significance of mirex residues in various tissues is unresolved, as is the exact mode of action of mirex and its metabolites. Minchew et al. (1980) and others indicated that mirex is a neurotoxic agent, with a mode of action similar to that of other chlorinated hydrocarbon insecticides, such as DDT. In studies with crayfish and radiolabeled mirex, mirex toxicosis was associated with neurotoxic effects that included hyperactivity, uncoordinated movements, loss of equilibrium, and... 

Transcriptional repression by DNA methylation is achieved by various modes of action. In one such mechanism, DNA methylation simply inhibits the binding of a transcription factor [17[. By a more complex means of action, a number of DNA methyl-binding proteins potentiate transcriptional silencing. In some cases, binding is accompanied by the action of an associated histone-modifying enzyme. 

Hardening can be achieved by subjecting gelatin to heat or suitable radiation, or by the addition of chemical reagents. A variety of inorganic and organic hardeners have been used including heterocyclic compounds with various modes of action. 

This chapter provides some new views on theoretical concepts that are in use in mixture studies, such as the ecological equivalent of the mode of action, which is the ecological mode of action, and the introduction of the mixed-mechanism problems and mixed-mechanism models for cases in which various types of compounds affect the exposed biota. It is argued that the conceptual approaches in mixture studies should further address environmental-chemical interactions, toxicokinetic and toxi-codynamic interactions, and ecological interactions. 

Our current understanding of mixture extrapolation is based on simple pharmacodynamic concepts of noninteractive joint action, such as simple similar action and simple independent action, with the associated extrapolation models concentration addition and response addition. These models are used for various types of extrapolations. Although mode of action is important when considering possible mixture interactions and extrapolations, the concept of the ecological mode of action needs to be expanded, as was also concluded for extrapolation across levels of biological organization. Mixture extrapolation should consider environmental (matrix)-chemical... 

Although various catalytic mechanisms have been proposed based on these results, the definite mode of action was derived mainly from recent X-ny structural analysis data. 

Chapter 5 discusses the different pesticide classification schemes, the different methods used to estimate their toxicity, and the specific mode of action of the different chemical groups of pesticides. This chapter also discusses the three main functional groups of pesticides (insecticides, herbicides, and fungicides) and the characteristics of various products in each group. 

Potassium restriction was also associated with sodium retention and with calcium depletion in various studies. The converse is also true, giving one good explanation as to why potassium works so well. The mineral causes the body to excrete more sodium in the urine, the same mode of action achieved with antihypertensive drugs called thiazide diuretics. Potassium seems to correct salt sensitivity as well. 

The relationship between a chemical s structure and its biological action has been studied extensively for over a century (16). In cases where there is not a complete understanding of the mechanism/mode of action or where the influence of functional groups is not known or obvious, there is a vast body of knowledge on how different structural features within a class of chemicals may correlate with various levels of hazard. Structure-activity relations (SAR) or their mathematical treatment. Quantitative SAR (QSAR) have been developed for myriad endpoints including cancer, developmental and reproductive effects, aquatic toxicity, boiling points, water solubility and many others hazard endpoints. An instructor therefore has many opportunities to incorporate the concept of SAR at several points in the curriculum. 

In two overviews the results of various clinical and efficacy trials were summarized (3,4) and the safety, immunogenicity, and efficacy of the vaccine were under-hned. The authors considered that the intravector mode of action of the vaccine was unique and opened the door to a new method of preventing insect-borne illnesses in humans. 

Fig. 10. Schematic representation of the thyiakoid membrane and various modes of action by uncoupiers, energy-transfer inhibitors, and protonophores.

The possible modes of action of indomethacin remain to be a subject of active interest. As a reference compound it has been found to be active in most of the in vitro and in vivo assays mentioned above. While none of these can be considered as the primary mode of action, certainly several are contributory. An earlier report of kallikrein inhibition was not confirmed.The suggestion37 that the antiinflammatory activity of indomethacin may be due to the displacement of tissue-bound corticosteroid has also been disputed. 3 The distribution cind metabolism of indomethacin in various species have been reported in detail39, and a number of long-term clinical studies have been published. 3... 

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