Safety and tolerability of repeated administration of pyridoxal 2-chlorobenzoyl hydrazone in rabbits
Identifieur interne : 001E38 ( Main/Exploration ); précédent : 001E37; suivant : 001E39Safety and tolerability of repeated administration of pyridoxal 2-chlorobenzoyl hydrazone in rabbits
Auteurs : M. Sterba [République tchèque] ; T. Simunek [République tchèque] ; Y. Mazurová ; M. Adamcová ; O. Popelová ; J. Kaplanová [République tchèque] ; P. Ponka [Canada] ; V. Gersl [République tchèque]Source :
- Human and Experimental Toxicology [ 0960-3271 ] ; 2005-11.
English descriptors
- Teeft :
- Animal behaviour, Anova, Antioxidant effects, Biochem cell biol, Biochem pharmacol, Biochemical parameters, Blood pressure, Blue trichrome, Body weight gain, Cardiac, Cardiac damage, Cardiac troponin, Castle hill, Charles university, Chelation, Chelator, Chelators, Control group, Control vehicle, Cremophor, Czech republic, Detection limit, Eosinophilic cytoplasm, Essential interface, Fifth administration, First administration, Gross changes, Haematological, Haematological analyses, Haematological parameters, Heart rate, Highest dose, Histopathological, Histopathological examination, Hradec, Hradec kralove, Hradec krdlove, Hydrazone, Hypertransfused rats, Inconsistent changes, Initial values, Invasive haemodynamic measurements, Iron chelation, Iron chelator, Iron chelators, Iron overload, Isonicotinoyl, Isovolumic phase, Novel iron chelator, Physiological limits, Plasma biochemistry, Plasma concentrations, Ponka, Premature deaths, Present study, Promising drug, Pyridoxal, Pyridoxal hydrazone, Pyridoxal isonicotinoyl hydrazone, Pyridoxal isonicotinoyl hydrazone analogs, Radioiron excretion, Reversible changes, Safety pharmacology, Significant changes, Software chart, Statistical significance, Sterba, Tolerability, Total plasma protein, Troponin, Vehicle group, Vehicle groups, Ventricular ejection fraction, Whole study.
Abstract
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.
Url:
DOI: 10.1191/0960327105ht571oa
Affiliations:
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<front><div type="abstract" xml:lang="en">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.</div>
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