Mechanism-based toxicity

Side effects commonly arise from exaggerated effects at the primary target (mechanism-based toxicity), problems with dosing, prolonged use, or cytotoxicity (i.e.,... 

Quality candidates for risk for QT disturbance and potential mutagenicity ancillary pharmacology Early ID of potential structural- mechanism-based toxicity... 

Mechanism-based toxicity studies for drug development... 

Fig. 3. A mechanism-based toxicity (MBT) curation tool was divided into four panels with (a) general information, (b) metabolism of the molecule, (c) biological data, and (d) toxicity data. The general information panel describes the structure, IUPAC name, smiles of the molecule, and the information on metabolites, their structures and any references. The panel on metabolism describes the toxicity information on individual metabolites and the references from which the information was curated. Biological data give the information on which protein or cells or organs get affected and the measurement of the effect. Toxicity panel gives the information on the molecule as well as the metabolites effect on the species, exposure times, measurement type and their values, effects, and the references.

This book brings together the expertise of leading scientists from around the world on the complex toxicology of anticholinesterase compounds (Organophosphates and Carbamates). It provides the most up-to-date and in-depth knowledge on various aspects of OP and CM compounds, including their use, classiHcation, mechanism-based toxicity, and prophylactic and therapeutic measurements. 

The subject of non-equilibrium situations such as pseudo-irreversible inhibition in drug design has been reviewed by Dr David Swinney, who concluded that first, in the absence of mechanism-based toxicity, drug mechanisms that create transitions to a non-equilibrium state will be more efficient second, in the presence of mechanism-based toxicity, biochemical mechanisms that maintain equilibrium to achieve a tolerable balance between efficacy and toxicity are desired. Non-equilibrium states, of course, include slow-off rate and irreversible inhibition. 

This molecular mechanism is part of what makes the glycopepcide class attractive as antibacterial agents. The interaction with the precursor is highly specific, and as no eukaryotic analog of o-alanyDo-alanine is present in mammalian cells, no basis for mechanism-based toxicity is present. The mechanism also seems to be one for which mutational resistance should be relatively difficult to achieve, as the D-alanyl-D-alanine-con-taining pentapeptide is the result of several synthetic steps in precursor formation, and it is involved in several steps of wall synthesis. 

---