Safety and tolerability of repeated administration of pyridoxal 2-chlorobenzoyl hydrazone in rabbits.
Recently, pyridoxal 2-chlorobenzoyl hydrazone (o-108) has been identified as an effective iron chelator [Link et al., Blood 2003; 101: 4172-79]. Since chronic treatment would be necessary in its potential indications, in the present study, the safety and tolerability of this agent after repeated administration was determined. Three doses of o-108 (25, 50, 100 mg/kg, in 10% Cremophor EL) were administered intraperitoneally, once weekly, for 10 weeks to three groups (n=5 each) of Chinchilla male rabbits. The effects on biochemical, haematological and cardiovascular parameters were examined during the experiment; histopathological examination was performed at the end of the experiment. Results were compared with control (saline 2 mL/kg, n=11) and vehicle groups (10% Cremophor EL, 2 mL/kg, n=12). No premature deaths occurred; the well-being of animals was evidenced by their body weight gain, although lower gain was observed with the highest dose (100 mg/kg). Significant elevations of cardiac troponin T plasma concentrations were observed with the highest dose of o-108, but no abnormalities were found in the cardiovascular function and only minor and inconsistent changes in haematological and biochemical parameters were observed. Histopathological examinations of selected organs revealed only weak and reversible changes through all studied groups. Thus, the data from this study suggest that o-108 remains a promising drug from the standpoint of the possibility of its repeated administration and warrants further investigation.
Sterba
M
M
Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Czech Republic. sterbam@lfhk.cuni.cz
Simůnek
T
T
Mazurová
Y
Y
Adamcová
M
M
Popelová
O
O
Kaplanova
J
J
Ponka
P
P
Gersl
V
V
D000818:Animals; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004798:Enzymes / Q000097:blood; D006835:Hydrazones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D008855:Microscopy, Electron, Scanning; D011730:Pyridoxal / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D011817:Rabbits; D013997:Time Factors; D014018:Tissue Distribution; D020107:Troponin T / Q000097:blood
D004798:Enzymes; D006835:Hydrazones; D007502:Iron Chelating Agents; D020107:Troponin T; C507461:pyridoxal 2-chlorobenzoyl hydrazone; D011730:Pyridoxal