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Cardiovascular Research 2007 74(3):480-486; doi:10.1016/j.cardiores.2007.02.017
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Copyright © 2007, European Society of Cardiology

Rescue of amitriptyline-intoxicated hearts with nanosized vesicles

Anand Babu Dhanikula, Daniel Lamontagne and Jean-Christophe Leroux*

Canada Research Chair in Drug Delivery, Faculty of Pharmacy, University of Montreal, C.P. 6128 Succ. Centre-ville, Montreal, QC, Canada H3C 3J7

* Corresponding author. Tel.: +1 514 343 6455; fax: +1 514 343 6871. Email address: jean-christophe.leroux{at}umontreal.ca

Objective: Amitriptyline, one of the most prescribed antidepressants, is reported to claim a large number of human lives due to drug overdose related cardiac arrest. Although amitriptyline poisoning has long been recognized as a frequent and serious fatality in the medical field, few efforts have been made to devise methods for treating its toxicity. To address this issue, phospholipid-based nanosized vesicles (spherulites) were employed to reverse the cardiotoxicity induced by amitriptyline in an isolated heart perfusion model.

Methods: The ability of spherulites to efficiently take up amitriptyline was first established in vitro in protein free and albumin-containing buffers. Vesicles bearing an internal pH of 3.0 or 7.4 were then infused into amitriptyline pre-intoxicated isolated rat hearts, and changes in coronary perfusion pressure (CPP), the first derivative of left ventricular pressure (dP/dt max) and heart rate were monitored. Control hearts received no vesicles.

Results: Based on the recoveries in CPP observed, the efficacies of the formulations were ranked as follows: control=pH 7.4-spherulites<pH 3.0-spherulites; whereas the ranking for the recoveries in heart rate was: control<pH 7.4-spherulites<pH 3.0-spherulites. The significantly faster and higher recoveries in pH 3.0- vs. 7.4-spherulite-treated hearts demonstrated the importance of pH-gradient formulation for efficient extraction of tissue-bound amitriptyline.

Conclusion: These data suggest that spherulites have a protective effect against acute cardiovascular failure following intoxication with amitriptyline and possibly other cardiotoxic drugs. It appears that the beneficial effects derived from the formulation infusion involved restoration of both haemodynamic and metabolic oxygen demands on the heart.

KEYWORDS Conduction block; Heart failure; Phospholipids; Sudden death

Time for primary review 26 days


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