A Study of Potential Toxic Effects After Repeated 10-Week Administration of a New Iron Chelator – Salicylaldehyde Isonicotinoyl Hydrazone (SIH) to Rabbits

Abstract

Salicylaldehyde Isonicotinoyl Hydrazone (SIH) – a Pyridoxal Isonicotinoyl Hydrazone (PIH) analogue – is an effective iron chelator with antioxidant and antimalarial effects, as documented in numerous in vitro studies. However, no toxicological data obtained from in vivo studies have been made available yet. In this study, the potential toxic effects of repeated administration of SIH (50 mg/kg, once weekly, 10 weeks, i.p.), partially dissolved in a 10 % Cremophor solution, on various biochemical, haematological, and cardiovascular parameters and on morphology of selected tissues were investigated in rabbits. The obtained values were compared with data from the control (saline, 1 ml/kg, i.v.) and the Cremophor (10 % Cremophor solution, 2 ml/kg, i.p.) groups. In this study, SIH did not induced marked signs of toxicity: No premature deaths occurred, the body weight increase was comparable with the control and Cremophor groups. Only few and mild changes in some biochemical and haematological parameters could be determined, most of them were noticed also in the control or Cremophor groups. The morphological changes in the kidney were mild and did not manifest in the biochemical examination. The cardiac function was also not affected markedly – the values of left ventricular ejection fraction and systolic time interval did not differ from the values of control group. Only an increased left ventricular contractility (dP/dtmax) was noticed in the SIH group at the end of the experiment as compared to the controls (13354±1191 vs. 9339±647 mmHg/s, resp.). These results seem to be promising from the standpoint of possible clinical use of SIH.

Iron homeostasis and eye disease

“…SIH is a highly lipophilic chelator and as a result has increased cell permeability. A number of studies have demonstrated that SIH may have a role in mitigating oxidative-stress induced damage to cardiomyocytes[146-148]. In our studies, SIH protects cultured RPE cells against hydrogen peroxide toxicity [149].…”

Comparison of various iron chelators and prochelators as protective agents against cardiomyocyte oxidative injury

“…Indeed, SIH has previously shown the best “therapeutic” ratio of inherent toxicity and cytoprotective efficiency against diverse ROS-mediated injuries (H 2 O 2 , tert -butyl hydroperoxide, catecholamines and their oxidation products) when compared with other Fe chelators, including the clinically-approved agents DFO, ICL670A or L1 [16, 17]. Of note, SIH has a very favorable in vivo toxicological profile, as it was well tolerated and induced no histopathological signs of organ toxicity or changes of biochemical and hematological parameters following its 10-week repeated administration to rabbits [51]. …”

LC–UV/MS methods for the analysis of prochelator—Boronyl salicylaldehyde isonicotinoyl hydrazone (BSIH) and its active chelator salicylaldehyde isonicotinoyl hydrazone (SIH)

“…Marked protective potential of SIH has been also shown in anthracycline cardiotoxicity both in vitro using neonatal cardiomyocytes [9] and in vivo in a chronic model of daunorubicin-induced heart failure in rabbits [10]. Importantly, good inherent tolerability and low toxicity profile of SIH have been demonstrated following its 10-weeks repeated administration to rabbits [11]. …”