Lipopolyamines as a therapeutic strategy in experimental Gram-negative bacterial sepsis.
Lipopolyamines are a class of polycationic amphiphilic compounds that have been shown to bind with high affinity to polyanionic macromolecules, including both DNA and bacterial lipopoly-saccharide (LPS). One of these compounds, termed DOSPER (1,3-di-oleoyloxy-2-(6-carboxyl-spermyl)- propylamide), is non-cytotoxic and has been shown to inhibit LPS-mediated cytokine release and lethality in endotoxin challenge models. In the study reported here, the activity of DOSPER was tested in neutropenic rats with invasive Gram-negative bacteremia caused by Pseudomonas aeruginosa. DOSPER alone was ineffective (0/8) at influencing mortality, but provided a significant survival advantage if administered in combination with a bactericidal antibiotic, ceftazidime (10/12; P<0.05). Ceftazidime alone was partially protective (6/12) while the control group had no survivors (0/8). DOSPER administration markedly reduced circulating endotoxin levels (P<0.01) and interleukin-6 levels (P<0.05) but had no significant effect on bacteremia and bacterial concentrations of P. aeruginosa in liver or spleen tissue. Lipopolyamines may be potentially valuable as a therapeutic adjunct in treatment of Gram-negative bacterial sepsis.
Opal
S M
SM
Brown University School of Medicine, Infectious Disease Division, Memorial Hospital of Rhode Island, Pawtucket, RI, USA. Steven_Opal@brown.edu
Palardy
J E
JE
Parejo
N
N
Morrison
D C
DC
D000818:Animals; D016470:Bacteremia; D002442:Ceftazidime / Q000008:administration & dosage / Q000627:therapeutic use*; D002511:Cephalosporins / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage / Q000627:therapeutic use*; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy*; D009503:Neutropenia / Q000188:drug therapy; D051381:Rats; D018805:Sepsis / Q000188:drug therapy*; D016019:Survival Analysis
C118665:1,3-dioleoyloxy-2-(6-carboxyspermyl)propylamide; D002511:Cephalosporins; D005229:Fatty Acids, Monounsaturated; D002442:Ceftazidime