Acute and Transient Toxicities

6.8.3.1.1 Complement Activation. Rapid infusion of phosphorothioate oligodeoxynucle-

otides to nonhuman primates can result in cardiovasulcar collapse (266-268). These hemodynamic effects are associated with complement activation, but complement activation is necessary but not sufficient to produce the observed cardiovascular effects (for review, see Ref. 169). The other factors contributing to cardivascular collapse are not yet fully elucidated. However, it has been suggested that dosing monkeys that are restrained may result in exacerbating cardiovascular events. Activation of the complement cascade, attributed to activation of the alternate pathway, is relatively insensitive to sequence, but is absolutely related to peak plasma concentration (269). The threshold concentration for activation of complement in the monkey is 40-50 ¡xg/mL phosphorothioate oligodeoxynucleotide and, once the threshold is reached, variable but potentially dangerous levels of complement activation are observed.

Studies in humans have avoided peak plasma concentrations that would induce complement. However, it appears that monkeys are substantially more sensitive than humans to complement activation. A comparison of the effects on complement activation in human vs. monkey serum demonstrates a dramatic difference. In monkey serum, phos-phorothioate oligodeoxynucleotides activate complement in a concentration-dependent fashion. It human serum, complement activation is actually inhibited at higher concentrations of oligonucleotide (169). This is thought to be attributable to the sensitivity of human serum to inhibition of complement activators. The mechanism of complement activation is currently believed to be attributable to an interaction with factor H (169). These effects can be reduced by chemical modifications and formulations that reduce plasma protein binding (169).

6.8.3.1.2 Inhibition of Clotting. In all species studies, phosphorothioate oligodeoxy-nucleotides induce a transient, apparently self-limited, peak plasma concentration-related inhibition of clotting, manifested as an increase in activated partial thromboplastin time (aPTT) (270-273).Increases in aPTTare minimally affected by sequence, although the effects are directly proportional to the length of the phosphorothioate oligodeoxynucleotide (169). The mechanism of aPTT increase appears to be an interaction with the intrinsic tenase complex (274, 275). This interaction is complex and involves effects on multiple clotting factors including factors Villa, IXa, and X. The effects on clotting are transient, appear to be self-limited, and have not resulted in bleeding diatheses in either animals or humans. Effects on clotting can be ameliorated by chemical modifications such as 2'-0-meth-oxyethyl substitution (169).

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