Effects of 2-HYDROXYPROPYl-beta-cyclodextrin on cardiovascular signs of amitriptyline poisoning in A rat model

Objective: The aim of this study is to investigate the efficacy of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) as an antidotal treatment modality for the cardiovascular toxic effects of amitriptyline poisoning in a rat model. Methods: Experiments were carried out on 33 male Wistar rats (280-300 g). To evaluate cardiovascular effects of HPBCD alone, rats were infused with dextrose (5%, n=7) or HPBCD (16.76 mg/kg/min, n=6) via a jugular vein for 15 minutes. Arterial pressure via a carotid artery cannulation and electrocardiography data were recorded for 60 minutes. Mean arterial blood pressure (MAP), heart rate (HR), QRS duration, and QT interval values were measured for baseline, end-dextrose or -HPBCD infusion, and end-experiment timepoints (60 min). In the poisoning model, amitriptyline HCl (0.94 mg/kg/min) was infused via a jugular vein until the MAP dropped to the 50% of the baseline. Following amitriptyline infusion, dextrose (5%, n=6), low-dose HPBCD (4.19 mg/kg/min, 1:1 molar ratio, n=7), or high-dose HPBCD (16.76 mg/kg/min, 1:4 molar ratio, n=7) was infused via femoral vein for the same amount of time of amitriptyline infusion. MAP, HR, QRS duration, and QT interval were measured for baseline, end-amitriptyline infusion, end-dextrose or -HPBCD infusion, and end-experiment timepoints (60 min). Hearts were excised at the end-experiment timepoint and examined with hematoxylin-eosin and Masson's trichrome stainings and activated caspase-3 immunohistochemistry for determination and scoring of tissue damage and apoptosis of cardiomyocytes, respectively. Results: Baseline MAP, HR, QRS duration, and QT interval were similar in all groups (p>0.05, for all parameters). HPBCD infusion alone did not yield statistically significant difference for MAP, HR, QRS duration, QT interval, and histological scores for tissue damage and apoptosis when compared to dextrose in either group (p>0.05, for all parameters). In the amitriptyline poisoning model, MAP and HR values decreased while QRS duration and QT interval prolonged significantly following the amitriptyline infusion (p<0.0167, for all parameters in all groups). Dextrose, low-dose HPBCD, and high-dose HPBCD infusion similarly corrected MAP, HR, QRS, and QT values to the baseline at the end-experiment timepoint (p<0.0167, except for MAP value in low-dose HPBCD group) without significant difference between groups (p>0.05, for all parameters). Histological scores for tissue damage and apoptosis showed no statistically significant difference in dextrose, low-dose HPBCD, and high-dose HPBCD groups (p>0.05, for both comparisons). One rat in dextrose group and one in high-dose HPBCD group died after the end of dextrose or HPBCD infusion. Conclusion: Based on our results, HPBCD did not show cardiovascular toxicity while it was no more effective than dextrose for the treatment of cardiovascular toxic effects of amitriptyline poisoning in rats.