The effect of amiodarone pretreatment on survival of mice with cocaine toxicity

Abstract

Introduction: Cocaine is a common drug of abuse and use has been associated with ventricular dysrhythmias. Published guidelines suggest that amiodarone is the first line antidysrhythmic for ventricular tachycardia and fibrillation. However, the effects amiodarone in the setting of cocaine toxicity are unknown and unstudied. The purpose of this study was to evaluate the safety and efficacy of amiodarone pretreatment in a murine model of acute cocaine toxicity.Methods: This was a randomized, blinded, placebo controlled investigation using male CF-1 mice weighing 29-37 g. First, the safety of an intraperitoneal dose of amiodarone (40 mg/kg) was confirmed in 5 mice. Second, based on preliminary investigations, an approximate intraperitoneal LD 50 dose of cocaine (110 mg/kg) was identified and used as the cocaine dose in this study. Animals were then randomized to 2 groups. The control group received 0.5 mL of intraperitoneal 0.9% saline 30 minutes before cocaine. The study group received 40 mg/kg of intraperitoneal amiodarone (40 mg/kg) 30 minutes before cocaine. A blinded observer monitored mice for 2 hours after cocaine administration.Results: No mice in the amiodarone-only group developed any signs of toxicity or died. In the saline ϩ cocaine group 31/32 (96.9%; 95% CI 83.8 to 99.9) mice seized with a median time to seizure of 2.5 minutes, and 23/32 (71.9%; 95% CI 52.3 to 86.3) died with a median time to death of 5.5 minutes. In the amiodarone ϩ cocaine group 31/33 (93.9%; 95% CI 79.0 to 99.3) mice seized with a median time to seizure of 2.0 minutes, and 24/33 (72.7%; 95% CI 54.5 to 86.7) died with a median time to death of 6.0 minutes. All animals that died did so within 9 minutes. The difference in the proportion of animals dying in the amiodarone ϩ cocaine group compared to the saline ϩ cocaine group was 0.008 (Ϫ21 to 22%).Conclusions: In this study, pretreatment with amiodarone in cocaine poisoned mice resulted in no change in seizure incidence or mortality. However, definite conclusions about the reason for these findings cannot be drawn from this model.

Treatment of patients with cocaine‐induced arrhythmias: bringing the bench to the bedside

“…All IA and IC anti-arrhythmic agents are contraindicated. Although not definitive, early investigation of the use of amiodarone in cocaine toxic animals has not been encouraging [32].…”

“…As mentioned previously, data suggest safety and efficacy of lidocaine in humans [29], contraindications exist for b-adrenergic antagonists, and both type IA and IC antiarrhythmic agents. Although data on amiodarone are not supportive, evidence of harm is also lacking [32].The use of magnesium is interesting, but unsupported by any human data.…”

Administration of ziprasidone for 10 days increases cocaine toxicity in mice

“…We identified this dose of cocaine as an LD50 in a previous experiment in this mouse strain, and have successfully used it several times to produce mortality between 50% and 70%. 10,12 We believe that the lower mortality in the placebo group observed in this study is because the animals were handled daily during the experiments. Unpredictable stress increases the behavioral effects of cocaine, and this may translate into increased toxic effects.…”

Case files of the Medical Toxicology Fellowship at the Toxikon Consortium in Chicago: Cocaine-associated wide-complex dysrhythmias and cardiac arrest— treatment nuances and controversies

“…While experience with using lidocaine may exist, literature support of its use in the patient with cocaineinduced wide-complex dysrhythmias is sparse at best [15,28]. Amiodarone has not been proven to be a viable alternative to sodium bicarbonate or lidocaine, possesses promiscuous pharmacological activity, and cannot be generally recommended for cocaine-associated dysrhythmias in the absence of data supporting its safety and efficacy [1,30].…”

“…Since amiodarone blocks ␤-adrenergic receptors in addition to sodium, potassium, and calcium channels, theoretical concerns exist regarding its safety in the setting of cocaine exposure [1]. A recent randomized, controlled mouse study utilizing relatively high-dose intraperitoneal cocaine (110 mg/kg) failed to demonstrate any difference in seizure incidence or mortality following amiodarone pretreatment (40 mg/kg) [30].…”