Efficacy, toxicity, and pharmacokinetics of pentoxifylline and its analogs in experimental Staphylococcus aureus infections.
Pentoxifylline (PTX), a drug that improves neutrophil function in vitro, has been shown to protect neonatal mice against death from experimental staphylococcal infection in vivo at a dose of 50 mg/kg. Using a total of 774 neonatal mice, the effects of various doses of PTX were examined and compared with the effects of three analogs: HWA-448, HWA-285, and A81-3138. A subcutaneous abscess was induced with 10(8) Staphylococcus aureus, and drug or saline was given daily subcutaneously from 2 days before to 4 days after infection. Noninfected animals (given saline without S. aureus) had 0% mortality (0 of 66), and infected animals without drug (given saline) had a mortality of 70% (161 of 231). PTX and HWA-448 showed the greatest protection among the drugs tested at 15 mg/kg with mortality rates of 27 and 38%, respectively (Kaplan-Meier method, P = 0.0001 and 0.0004, respectively). HWA-285 was most protective at 25 mg/kg (mortality, 45%; P = 0.0046) and A81-3138 was most protective in animals at 15 mg/kg (mortality, 42%; P = 0.0045). PTX, HWA-448, HWA-285, and A81-3138 at doses of 200, 100, 100, and 50 to 75 mg/kg, respectively, were toxic as shown by worsened weight loss and increased mortality in animals when compared with infected animals without drug. PTX and its analogs decrease mortality from experimental infections at lower doses but are toxic at higher doses. Pharmacokinetic characteristics of the drugs were similar except that HWA-285 produced lower concentrations in serum and A81-3138 showed a dose-dependent kinetics (longer half-life at a higher dose).
Maderazo
E G
EG
Department of Medicine, Hartford Hospital, Connecticut 06115-0729.
Breaux
S
S
Woronick
C L
CL
Krause
P J
PJ
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000378:metabolism; D013805:Theobromine / Q000031:analogs & derivatives*; D015431:Weight Loss / Q000187:drug effects
D013805:Theobromine; D010431:Pentoxifylline