In Vitro Compound Preselection

From both an ethical and an economic point of view, the selection of compounds for testing of compounds in vivo should be carefully made. The entire process of a medicinal chemistry program should carefully integrate the later stages of in vivo testing. Prior to the initiation of animal experiments, and in particular, long-term efficacy studies, a set of information is needed. In vitro experiments should utilize thoroughly characterized tumor cell lines that have the capacity to form tumors in vivo. Proof of mechanism in vitro should be convincing with demonstration of target inhibition/activation consistent with inhibition of proliferation or another marker of tumor inhibition; however, this is may be done using techniques not involving small molecules (antisense, small interfering RNA, transient transfection using dominant-negative genes, etc.). Compounds should be selected based on adequate in vitro evidence of activity and selectivity for the proposed target, and suitable physicochemical properties. When possible, knowledge of the duration of effect after removal of the compound should be available and may be useful in planning administration regimens. Information on stability in plasma, plasma protein binding, and metabolic stability of the compound in microsomes is needed if compounds are to be compared and prediction of likely clinical utility made. In vitro pharmacokinetic (PK) data could also be included in the preselection criteria; for example, using CaCo-2 cells to select compounds for increased oral bioavailability (50). As part of the in vitro screening process, some indication of the toxicity of the compound inhibition of proliferation against tumor/normal cell lines not expressing/overexpressing target or bearing wild-type form. Observations giving early indications of toxicity should be incorporated into in vivo preclinical efficacy testing (51).

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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