Prevention of lethality and suppression of proinflammatory cytokines in experimental septic shock by microencapsulated CNI-1493.
CNI-1493, a newly developed, water-soluble tetravalent guanylhydrazone, is a powerful inhibitor of tumor necrosis factor (TNF) and interleukin-1 (IL-1) synthesis. Microencapsulation of drugs into microcapsules that target macrophages has improved the effectiveness of both TNF and IL-1 neutralizing antibodies in experimental models of septic shock. It is the purpose of this study to determine if microencapsulation of CNI-1493 will improve cytokine inhibition. CNI-1493 was microencapsulated using albumin into 1 microm spheres. Comparable amounts of CNI-1493 in solution and in microencapsulated form were added to 1 ml aliquots of whole blood along with 100 ng of endotoxin. TNF and IL-1 were measured by ELISA. Microencapsulated CNI-1493 was also given to rats with endotoxic shock (15 mg/kg Escherichia coli endotoxin) and rats with peritonitis induced by peritoneally injecting 10(10) CFU E. coli. Equivalent amounts of encapsulated and solution CN I-493 were given intravenously. Endotoxin 15 mg/kg was also given to rats 6 and 24 h after a dose of encapsulated CNI-1493 to determine the duration of action of encapsulated drug. The microencapsulated CNI-1493 produced significantly greater inhibition of TNF and IL-1 at all doses in the whole blood model. There was significantly improved survival and cytokine inhibition in the endotoxic shock model as well as the peritonitis model in rats treated with microencapsulated CNI-1493. There was also 83% survival in rats given endotoxin 24 h after a dose of encapsulated CNI-1493. From these data, we conclude that CNI-1493 is a potent inhibitor of cytokine production and is greatly potentiated by microencapsulation, which transports the drug to macrophages.
D'Souza
M J
MJ
Department of Pharmaceutical Sciences, Southern College of Pharmacy, Mercer University, Atlanta, GA 30341, USA.
Oettinger
C W
CW
Milton
G V
GV
Tracey
K J
KJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D003864:Depression, Chemical; D004195:Disease Models, Animal; D004339:Drug Compounding; D019446:Endotoxemia / Q000188:drug therapy; D004927:Escherichia coli Infections / Q000188:drug therapy; D006835:Hydrazones / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008863:Microspheres; D010538:Peritonitis / Q000188:drug therapy; D051381:Rats; D012772:Shock, Septic / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006835:Hydrazones; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines