Synergism in survival to endotoxic shock in rats given microencapsulated CNI-1493 and antisense oligomers to NF-kappaB.

The synthesis of TNF may be inhibited at the transcriptional level by antisense to either TNF or NF-kappaB or at the post-transcriptional level by CNI-1493, a guanylhydrazone compound which inhibits p38 MAP kinase activity. Previous studies have demonstrated that targeting macrophages and other phagocytic cells by intracellular drug delivery using albumin microcapsules containing either antisense oligomers to NF-kappaB or CNI-1493 greatly enhances intracellular drug concentration and survival in both endotoxic shock and sepsis models. It is the purpose of this study to determine if microencapsulated drugs acting at different stages in the synthesis of TNF are synergistic. Four groups of 10 rats each were given 15 mg kg(-1) of E.coli endotoxin and treated with (1) CNI-1493 1 mg kg(-1), (2) antisense oligomers to NF-kappaB at 100 mcg, (3) CNI-1493 1 mg kg(-1) plus antisense kappa to NF- at 100 mg kg(-1) and (4) CNI-1493 200 mg kg(-1) plus antisense oligomer to NF-kappaB at 200 mg kg(-1). TNF and IL1 were measured by ELISA at 4, 8, 24 and 48 h. The rats were observed for 5 days. The combination of CNI-1493 and antisense oligomers to NF-kappaB inhibited TNF 41% greater that CNI alone and 51% greater than antisense oligomers to NF-kappaB alone at 4 h after endotoxin administration. Survival at 5 days with CNI alone was 0%, 20% with antisense oligomers to NF-kappaB and 60% with the combination. In conclusion, synergism in survival occurs using microencapsulated drugs acting at different points in the synthesis of TNF was demonstrated using an in-vivo model of endotoxic shock. Both the amount of TNF inhibition and the mortality were significantly improved with combination therapy. Multiple drugs acting at different sites in the synthesis of TNF may be useful in the treatment of disease states characterized by pro-inflammatory cytokine release.