Toxic off-target

Intercellular Signaling Pathway Toxicity (off-target) Inflammatory... 

Eedorov Y, Anderson EM, Birmingham A, Reynolds A, KarpUow J, Robinson K, Leake D, Marshall WS, Khvorova A (2006) Off-target effects by siRNA can induce toxic phenotype. RNA 12 1188-1196... 

Compound related includes drug metabolism and pharmacokinetics (DMPK), safety (off-target toxicity) and selectivity, and formulation and synthesis (cost of goods)... 

A number of commercial antibody-based microarrays for multiplexed cytokines analysis are now available (Beckman Coulter BD Biosciences Panom-ics Pierce S S Zyomyx and others). Cytokines are essentially biomarkers of cell injury, inflammation, and apoptosis. They are released by cells in culture in response to drug action (Turtinen et al., 2004) or are elevated in serum in various disease states. Moreover, numerous cytokines are involved in cellular response and many serve as dual effectors (Asao and Fu, 2000). As a result, anticytokine microarrays are being evaluated in drug discovery for off-target toxicity testing to replace standard ELISA plate formats. 

While the above examples focus on safety matters associated with pharmacological off-targets, it has to be emphasized that the knowledge of physicochemical properties of compounds is equally important at any phase of drug discovery. For example, poor solubility and permeability can prevent decent exposure and extensive hepatic metabolism might create inactive or toxic metabolites. 

Off-target pharmacology Evaluation of interaction of compound with a wide range of receptors and enzymes and proteins indicates that higher reactivity is assodated with higher potential for toxicity... 

Some of the challenges in performing efficient transfection are as described in detail in the chapter, to reduce toxicity, achieve higher efficiency without deleterious manipulation of gene expression machinery, reduce lipid-induced off target effects, and interferon responses. The procedure of transfection is still relatively poorly understood and the challenges posed to the researcher are still daunting at times. The objective of this chapter is to equip the user with vital information to enhance the success of transfection experiments. 

Tissue cross-reactivity studies for monoclonal antibody products were originally intended to explore off-target tissue binding. Studies have thus been used to screen candidates to avoid off-target binding. As stated in ICH S6, an animal species that does not express the desired epitope may be of some relevance for assessing toxicity if comparable unintentional tissue cross-reactivity to... 

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