Action of deferoxamine against Pneumocystis carinii.
We found earlier that deferoxamine (DFO), a drug used for treatment of iron overload, is active against a rat model of Pneumocystis carinii pneumonia (PCP). We had assumed a mode of action by deprivation of nutritional iron; however, data here show that DFO penetrates P. carinii, causing irreversible damage, thus indicating a different mode of action. Penetration was demonstrated by showing DFO uptake by high-pressure liquid chromatography analysis. By using calcein-AM as an indicator, exposure to DFO was shown to cause a reduction in P. carinii cytoplasmic free iron. Exposure to >or=100 microM DFO for >or=8 h in vitro caused growth to cease and cell numbers to decline over several days. This direct and irreversible damage to P. carinii led to the prediction that infrequent delivery of DFO to the lungs via an aerosol would be an effective treatment in the animal model of PCP. This prediction was confirmed by demonstrating that a once-a-week aerosol treatment of rats was 100% effective both as a prophylactic and as a curative treatment in a rat model of PCP.
Clarkson
A B
AB
Department of Medical and Molecular Parasitology, New York University School of Medicine, New York, New York 10016, USA. clarka01@nyu.edu
Turkel-Parrella
D
D
Williams
J H
JH
Chen
L C
LC
Gordon
T
T
Merali
S
S
D000336:Aerosols; D000818:Animals; D002614:Chelating Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003593:Cytoplasm / Q000378:metabolism; D003676:Deferoxamine / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D007501:Iron / Q000378:metabolism; D011010:Pneumocystis / Q000187:drug effects* / Q000378:metabolism; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy / Q000382:microbiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000336:Aerosols; D002614:Chelating Agents; D007501:Iron; D003676:Deferoxamine