Pyridoxal isonicotinoyl hydrazone (PIH) and its analogs as protectants against anthracycline-induced cardiotoxicity.
The risk of cardiotoxicity is the main drawback of anthracycline antibiotics. However, these drugs remain among the most effective and frequently used anti cancer drugs. In this study we aimed to assess the cardioprotective effects of aroylhydrazone iron (FE) chelators: pyridoxal isonicotinoyl hydrazone (PIH) and its two analogs: salicyladehyde isonicotinoyl hydrazone (SIH) and pyridoxal o-chlorbenzoyl hydrazone (o-108). In rabbits, chronic treatment with daunorubicin (DAU) (3 mg/kg weekly for 10 weeks) induced mortality (33%) as well as left ventricular (LV) dysfunction. Co-administrations of PIH (25 mg/kg, i.p.), SIH hydrochloride [1 mg/kg, iv] as well as o-108 (10 mg/kg, i.p.), fully prevented premature deaths and most of the DAU-induced functional impairments were significantly suppressed. However, when 2- to 2.5-fold higher doses of the chelators were used, they led to rather paradoxical and mostly negative results regarding both cardioprotection and overall mortality.
Simunek
Tomas
T
Charles University Prague, Faculty of Pharmacy, Hradec Kralove, Czech Republic. simunekt@faf.cuni.cz
Sterba
Martin
M
Popelova
Olga
O
Kaiserova
Helena
H
Potacova
Anna
A
Adamcova
Michaela
M
Mazurova
Yvona
Y
Ponka
Premysl
P
Gersl
Vladimir
V
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D003630:Daunorubicin / Q000008:administration & dosage / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced* / Q000401:mortality / Q000517:prevention & control*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D007538:Isoniazid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D011730:Pyridoxal / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D011817:Rabbits
D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D007502:Iron Chelating Agents; D011730:Pyridoxal; C021079:pyridoxal isonicotinoyl hydrazone; D007538:Isoniazid; D003630:Daunorubicin