Efficacy of treatment with the iron (III) complex of diethylenetriamine pentaacetic acid in mice and primates inoculated with live lethal dose 100 Escherichia coli.
The iron (III) complex of diethylenetriamine pentaacetic acid (DTPA iron [III]) protected mice and baboons from the lethal effects of an infusion with live LD100 Escherichia coli. In mice, optimal results were obtained when DTPA iron (III) was administered two or more hours after infection. Prevention of death occurred in spite of the fact that the adverse effects of TNF-alpha were well underway in the mouse model. The half-life of DTPA iron (III) was 51 +/- 9 min in normal baboons; primary clearance was consistent with glomerular filtration. In septic baboons, survival was observed after administration of two doses of DTPA iron (III) at 2.125 mg/kg, the first one given before, or as late as 2 h after, severe hypotension. Administration of DTPA iron (III) did not alter mean systemic arterial pressure, but did protect baboons in the presence of high levels of TNF-alpha and free radical overproduction. Furthermore, exaggerated production of nitric oxide was attenuated. The mechanism of protection with DTPA iron (III) is not obvious. Because of its ability to interact in vitro with free radicals, its poor cell permeability, and its short half-life, we postulate that DTPA iron (III) and/or its reduced form may have protected the mice and baboons by sequestration and subsequent elimination of free radicals (including nitric oxide) from their systems.
Molina
L
L
Glaxo-Wellcome Inc., Research Triangle Park, North Carolina 27709, USA.
Studenberg
S
S
Wolberg
G
G
Kazmierski
W
W
Wilson
J
J
Tadepalli
A
A
Chang
A C
AC
Kosanke
S
S
Hinshaw
L
L
D000818:Animals; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000145:classification; D004927:Escherichia coli Infections / Q000188:drug therapy*; D016166:Free Radical Scavengers; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D010215:Papio; D004369:Pentetic Acid / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012703:Serotyping; D012772:Shock, Septic / Q000188:drug therapy*; D016019:Survival Analysis
D016166:Free Radical Scavengers; D009566:Nitrates; D009573:Nitrites; D004369:Pentetic Acid