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An effect of oligonucleotide administration on platelets is something that has been observed for PS ODNs in mice and correlated with splenomegaly associated with the proinflammatory effects [10]. Some transient effects on platelet count in patients in clinical trials with PS ODNs also have been reported [77–80].
The observation of thrombocytopenia for 2 -MOE viagra online in rodents is far less than observed with PS ODNs, consistent with the lower degree of splenomegaly [12]. Still, there is at least one 2 -MOE ASO that has produced decrease in platelet count both in monkey and man [48].
Thrombocytopenia in both species was dose-dependent and transient. The cause of the decrease in platelet count in the clinical cases for both PS ODNs and 2 -MOE viagra online are not considered to be related to splenomegaly, but could nonetheless be related to some increase in proinflammatory cytokines.
It is possible that these cytokines or chemokines may have secondary effects on platelet production or platelet sequestration. For example, IL-10 has been associated with mild and transient underproduction of platelets in people [81]. This effect on platelets has not been a common observation with 2 -MOE ASOs, but is a parameter that should be closely monitored for novel oligonucleotides.
The most common and well-studied of the hybridization-independent effects associated with viagra online administration is the tendency to stimulate a proinflammatory reaction [10,82]. However, while this is appropriately considered a class effect, the degree of proinflammatory effect depends on several variables, and so the context of the type of oligonucleotide is very important to consider.
There are a number of factors that influence the potency of the proinflammatory effects, including oligonucleotide sequence, base modifications, and backbone chemistry, which are discussed in more detail below. The most extreme example of the proinflammatory effects is the class of oligonucleotide aptamers containing specific sequence motifs designed to produce a shift toward Th1-type immunity for therapeutic purposes [18]. These so-called immunomodulatory oligonucleotides have been studied in great detail and are reviewed specifically in Chapter 27. This review will focus on the effect and consequence of proinflammatory effects associated with antisense oligonucleotides, which differ in meaningful way from the immunomodulatory oligonucleotides.
It is known that the basis for the sequence specificity of this effect are specific motifs in the oligonucleotides that closely mimic bacterial DNA, and are therefore recognized by pathogenassociated molecular pattern (PAMP) receptors of the innate immune system to activate B cells, monocytes, macrophages, and dendritic cells [83,84]. As it turns out, a sequence motif as simple as a Cytosine-Guanosine (CpG) dimer flanked by two 5 -purine and two 3 -pyrimidines is sufficient to be recognized by these PAMPs as bacterial-like in rodents [85].
The basis for this recognition is the under representation of the CpG dimers in mammalian DNA [85]. As a result, the design of antisense oligonucleotides has been greatly influenced by the emergence of the immunomodulatory oligonucleotides. Without this knowledge, early antisense inhibitors, such as GEM 91, fomivirsen, and others contained CpG dimers, and although they did not contain the optimal flanking sequences, they were relatively effective proinflammatory agents [60,86–88]. These effects were the basis of some speculating that the pharmacologic effects of these compounds were not mediated by antisense activity [89–91].
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