Low-dose intramuscular polymyxin B improves survival of septic rats.
Polymyxin B (PLB) is a cationic antibiotic that also stoichiometrically neutralizes the lipid A moiety of endotoxin. We examined effects of a small dose of PLB on the mortality of rats with cecal ligation and puncture, on LPS-stimulated nitric oxide (NO) production, and on tumor necrosis factor alpha (TNF alpha) production by isolated rat Kupffer cells.


METHODS
In vivo studies: Cecal ligation and puncture (CLP) was performed under anesthesia in 28 rats. One hour after CLP, either 600 U/kg of PLB or saline was administered intramuscularly every 6 h (PLB group: n = 12; control group: n = 16). Plasma endotoxin was measured at 3 and 24 h after the CLP by the Endospecy test. This was compared with survival.


METHODS
Kupffer cells were isolated from the normal rat liver. The cells were incubated with LPS or LPS + PLB. After 24 h, NO and TNF alpha content were measured using the Griess and ELISA methods, respectively.


RESULTS
Low dose PLB significantly decreased the endotoxin levels at both 3 and 24 h (5.5 +/- 2.1 pg/mL vs. 32.8 +/- 3.6 at 3 h; 26.1 +/- 6.1 vs. 49.1 +/- 5.6 at 24 h (p < .05) after CLP. PLB significantly improved survival of CLP rats (68.8% in the control group vs. 100% in the PLB treated group on 3 days after CLP, p < .001). PLB also attenuated NO and TNF alpha production from the Kupffer cells.


CONCLUSIONS
Intramuscular PLB administered in low doses may improve the mortality of sepsis.
Department of Emergency Medicine, Nagoya University School of Medicine, Japan. mtoshi@med.nagoya-u.ac.jp
T
T
Mayumi
J
J
Takezawa
H
H
Takahashi
N
N
Kuwayama
T
T
Fukuoka
K
K
Shimizu
K
K
Yamada
S
S
Kondo
K
K
Aono
D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000097:blood; D066298:In Vitro Techniques; D007273:Injections, Intramuscular; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood / Q000187:drug effects; D008026:Ligation; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011112:Polymyxin B / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004731:Endotoxins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D011112:Polymyxin B