The synthesis of TNF may be inhibited at the transcriptional level by antisense to either TNF or NF-kappa B 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-kappa B 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-kappa B at 100 mcg, (3) CNI-1493 1mg kg(-1) plus antisense kappa to NF-at 100 mg kg(-1) and (4) CNI-1493 200 mg kg(-1) plus anti-sense oligomer to NF-kappa B 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-kappa B inhibited TNF 41% greater that CNI alone and 51% greater than antisense oligomers to NF-kappa B alone at 4 h after endotoxin administration. Survival at 5 days with CNI alone was 0%, 20% with antisense oligomers to NF-kappa B 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.