By J. Thomas August (Eds.)
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Pharmacokinetics has advanced from its foundation right into a advanced self-discipline with a number of subspecialties and functions in sufferer administration, drug improvement, and regulatory matters. This growth has made it tricky for anybody person to develop into a full-fledged professional in all components. gratifying the necessity for a wide-ranging consultant to the numerous present subspecialties during this box, Pharmacokinetics in Drug Discovery and improvement information the several parts within the box delivering the fitting complete, easy accessibility textual content and reference.
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Similarly, oxidation of the phosphorothioate backbone to the natural phosphodiester structure would also yield nonmutagenic (and probably nontoxic) metabolites. Finally, it is possible that phosphorothioate bonds could be hydrolyzed slowly, releasing nucleoside phosphorothioates 28 Stanley T. Crooke that presumably would be rapidly oxidized to natural (nontoxic)nucleoside phosphates. However, oligonucleotides with modified bases, backbones, or both may pose different risks. 3. In Vivo The acute 50% lethal dose (LD,,) in mice of all phosphorothioate oligonucleotides tested to date is in excess of 500 mg/kg (D.
M. Crooke, 1993b; S. T. Crooke, 1993). Polynucleotides and other polyanions have been shown to cause release of cytokines (Colby, 1971). , 1991). , 1992). In the latter study, the oligonucleotides that displayed natural killer (NK) cell-stimulating activity contained specific palindromic sequences and tended to be guanosine rich. Collectively, these observations indicate that nucleic acids may have broad immunostimulatory activity. It has been shown that phosphorothioate oligonucleotides stimulate B lymphocyte proliferation in a mouse splenocyte preparation (analogous t o bacterial DNA) (Psietsky and Reich, 1993), and the response may underlie the observations of lymphoid hyperplasia in the spleen and lymph nodes of rodents caused by repeated administration of these compounds (see Section V,F,3).
The effects of these modifications on cellular uptake have been assessed by means of fluorescent, or radiolabeled, oligonucleotides or by measurement of pharmacological activities. From the perspective of medicinal chemistry, few systematic studies have been performed. , 1991). A cholesterol modification was reported to be more effective at enhancing uptake than the other substituents. It also seems likely that the effects of various conjugates on cellular uptake may be affected by the cell type and target studied.
Advances in Pharmacology by J. Thomas August (Eds.)