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Unfortunately, other symptoms of septic shock, such as low blood
pressure and high plasma glucose levels, were still detectable. Rats
treated with compound
83
showed all of the symptoms of septic shock to
some extent. Although these model dimer analogues were less potent
LPS antagonists
in vitro
compared to β-PGG, they appeared to exhibit
more promising activity with live rats. Perhaps this improvement was
simply a consequence of the fact that the dimer species do not induce
secretion of IL-1β in and of themselves. Future work may include the
search for more powerful antagonists of lipid A using these novel
dimeric tannin analogues as lead compounds.
30
25
20
TNF
α
(ng/mL)
15
10
LPS only
LPS + Analogue 83
LPS + Analogue 86
5
0
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rat specimen
Fig. 6.26 Inhibition of LPS-stimulated TNFα secretion in live rats (at 90 min) by the
dimeric tannin analogues
83
and
86
.
6.6 Conclusion
At present, all of the approved anti-TNFα drugs are proteins and given
the general disadvantages of peptide-based drugs such as poor biological
stability, mandatory subcutaneous or intravenous administration, and
high costs to manufacture, small molecules remain very attractive
alternatives. Dimeric ellagitannin analogues, with their inherently low
toxicity, promising antagonistic action, and novel structures, might
represent interesting leads for further development as an anti-sepsis
therapy. In a different vein, ellagitannins such as agrimoniin, oenothein
B, and coriariin A have documented tumoricidal activities against
numerous cancer xenograft models. These tannin species appear to
