number of types of control oligonucleotides have been used including randomized oligonu-cleotides. Unfortunately, we know little to nothing about the potential biological effects of such "controls" and the more complicated a biological system arid test, the more likely that "control" oligonucleotides may have activities that complicate interpretations. Thus, when a control oligonucleotide displays a surprising activity, the mechanism of that activity should be explored carefully before concluding that the effects of the "control oligonucleotide" prove that the activity of the putative antisense oligonucleotide are not the result of an antisense mechanism.
3.1.8 Kinetics of Effects. Many rate constants may affect the activities of antisense oligonucleotides, such as the rate of synthesis and degradation of the target RNA and its protein; the rates of uptake into cells; the rates of distribution, extrusion, and metabolism of an oligonucleotide in cells; and similar pharmacokinetic considerations in animals. Fortunately, in the past several years, many more careful dose-response and kinetic studies have been reported and in general they demonstrated a relatively slow onset of action and a duration of response consistent with the elim-. ination rates of the drugs tested (see below).
Nevertheless, more careful kinetic studies are required and more rational in vitro and in vivo dose schedules must be developed.
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