In vivo toxicity of foscarnet and zidovudine given alone or in combination.
The toxicities of foscarnet (PFA) and zidovudine (AZT) given alone or in combination have been investigated in mice. PFA administered at a dose of 500 mg/kg/day and AZT at a dose of 400 mg/kg/day for 17 days caused clear hematotoxicity and nephrotoxicity. Each drug alone showed little hematotoxicity, but using a combination of both drugs significantly and dramatically decreased RBC (approximately 50%), Hb (approximately 43%), and hematocrit (approximately 43%) and increased platelets (approximately 45%) on Day 11 of treatment. It seems that there is a synergistic or at least an additive effect between PFA and AZT in terms of red blood cell toxicity. Surprisingly, AZT significantly increased serum creatinine levels on Days 5 and 11 of treatment (up to 40% increase), whereas PFA was less toxic (only approximately 17% increase on Day 5 of treatment). Using a combination of the two drugs, PFA seems to reduce the nephrotoxic effect of AZT on Day 11 of treatment. None of the treatments had any effect on BUN. At a lower dose level of 340 mg PFA/kg/day and 270 mg AZT/kg/day for 15 days there was hematotoxicity (much less evident than that at the higher dose level), but no nephrotoxicity. Electron microscopic examination of the renal cortex of animals from the experiments testing the higher dose levels revealed a clear vacuolization in proximal tubules and necrosis of mitochondria in distal tubules. These effects were more striking with the combination and less evident with PFA or AZT alone. In conclusion, even though we have used a high dose of AZT, there was synergistic/additive hematotoxicity. The combination was less nephrotoxic, only on Day 11 of treatment, than either of these agents used alone although histopathology, at the time of euthanization, showed more severe damage.
Omar
R F
RF
Centre de Recherche en Infectiologie, Centre Hospitalier de l'Université Laval, Ste-Foy, Québec, Canada.
Gourde
P
P
Désormeaux
A
A
Tremblay
M
M
Beauchamp
D
D
Bergeron
M G
MG
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D017245:Foscarnet / Q000008:administration & dosage / Q000633:toxicity*; D006402:Hematologic Diseases / Q000139:chemically induced; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D015388:Organelles / Q000187:drug effects / Q000648:ultrastructure; D015215:Zidovudine / Q000008:administration & dosage / Q000633:toxicity*
D000998:Antiviral Agents; D017245:Foscarnet; D015215:Zidovudine