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.
Mayumi
T
T
Department of Emergency Medicine, Nagoya University School of Medicine, Japan. mtoshi@med.nagoya-u.ac.jp
Takezawa
J
J
Takahashi
H
H
Kuwayama
N
N
Fukuoka
T
T
Shimizu
K
K
Yamada
K
K
Kondo
S
S
Aono
K
K
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