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By J. Thomas August (Eds.)

ISBN-10: 0120329417

ISBN-13: 9780120329410

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Therapeutic Index In Fig. 2, an attempt to put the toxicities and their dose-response relationships in a therapeutic context is shown. This is particularly important because considerable confusion has arisen concerning the potential utility of phosphorothioate oligonucleotides for selected therapeutic purposes deriving from unsophisticated interpretation of toxicological data. 2 mg/kg over 2 hr) FIGURE 2 Plasma concentrations of ISIS 2302 at which various activities are observed. These concentrations are determined by extracting plasma and analyzing by capillary gel electrophoresis and represent intact ISIS 2302.

Crooke and Lebleu, 1993, for reviews). 5"C less per nucleotide than that for a corresponding phosphodiester oligodeoxynucleotide. This reduction in T, per nucleotide is virtually independent of the number of phosphorothioate units substituted for phosphodiesters. O°C, depending on sequence. Compared with RNA and RNA duplex formation, a phos- 14 Stanley T. 2"C lower per unit (Freier, 1993). , 1992). , 1992; Freier, 1993). Association rates to structured RNA targets can vary from l o 2 to lo8M-' sec-', depending on the structure of the RNA, site of binding in the structure, and other factors (Freier, 1993).

Leeds, unpublished observations). Distribution of phosphorothioate oligonucleotides from blood after absorption or intravenous administration is extremely rapid. , 1991; Iversen, 1991). Blood and plasma clearance is multiexponential, with a terminal elimination half-life from 40 to 60 hr in all species except humans. In humans, the terminal elimination half-life may be somewhat longer (S. T. , 1994). Phosphorothioates distribute broadly to all peripheral tissues. , 1993, 1994). No evidence of significant penetration of the blood-brain barrier has been reported.

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Advances in Pharmacology by J. Thomas August (Eds.)

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