Effects of slow-releasing colistin microspheres on endotoxin-induced sepsis.
Lipopolysaccharide (LPS) is a major contributing factor to endotoxic shock. Colistin specifically binds to LPS. However, it has the disadvantages that adverse reactions are common and it has a short half-life. To overcome these disadvantages, we prepared slow-releasing colistin microspheres and examined the efficacy of these colistin microspheres in a mouse model of endotoxin-induced sepsis. We prepared the colistin microspheres using poly-lactic-co-glycolic acid. For acute toxicity investigations, mice were overdosed with colistin sulfate or colistin microspheres. The group administered with colistin microspheres was associated with less acute toxicity and fewer nephrotoxic changes on histopathological examination compared to the group administered with colistin sulfate alone. For pharmacokinetic analysis, mice were subcutaneously administered with colistin microspheres or colistin sulfate alone. The plasma concentration of colistin was higher in the colistin microspheres group than in the colistin sulfate group at 12 and 24 h after administration. Moreover, mice were intraperitoneally injected with LPS and then immediately subcutaneously administered with blank microspheres, colistin microspheres or colistin sulfate alone. The levels of endotoxin in the sera and cytokine in the spleens were then measured. A significant reduction in the serum endotoxin level in the colistin microspheres group was observed at 24 h. The reduced endotoxin levels in the sera were correlated with the lower cytokine levels in the spleens of mice treated with colistin microspheres. Our results suggest that the use of colistin microspheres may help to maintain a higher colistin concentration in blood, reduce the levels of endotoxin and cytokines in endotoxin-induced sepsis, and lead to decreased toxicity.
Department of Microbiology and Infectious Diseases, Toho University School of Medicine, 5-21-16 Omori-nishi, Ota-ku, Tokyo, 143-8540, Japan.
Yuta
Y
Nanjo
Yoshikazu
Y
Ishii
Soichiro
S
Kimura
Toshiro
T
Fukami
Masahiro
M
Mizoguchi
Toyofumi
T
Suzuki
Kazuo
K
Tomono
Yoshikiyo
Y
Akasaka
Toshiharu
T
Ishii
Kazuhisa
K
Takahashi
Kazuhiro
K
Tateda
Keizo
K
Yamaguchi
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D003091:Colistin / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004731:Endotoxins / Q000097:blood; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008863:Microspheres; D012772:Shock, Septic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology
D000900:Anti-Bacterial Agents; D003692:Delayed-Action Preparations; D004731:Endotoxins; D008070:Lipopolysaccharides; D003091:Colistin