Pharmacology and toxicology of a new aqueous formulation of intravenous amiodarone (Amio-Aqueous) compared with Cordarone IV.
Hypotension is the most frequent adverse event reported with intravenous amiodarone (Cordarone IV). The hypotension has been attributed to the vasoactive solvents of the formulation, polysorbate 80 and benzyl alcohol, both known to exhibit negative inotropy and hypotensive effect. A new aqueous formulation of intravenous amiodarone (Amio-Aqueous) does not contain vasoactive excipients and may be less toxic and cause less hypotension than Cordarone IV. This hypothesis was tested in a series of animal studies with direct comparison of Amio-Aqueous and Cordarone IV. All studies were performed on Sprague-Dawley rats. The acute toxicology study showed that both LD50 and LD100 were 30% greater for Amio-Aqueous than for Cordarone. At the dose at which all animals expired on Cordarone, 50% of animals were still alive on Amio-Aqueous. The study on myocardial contractility showed that Amio-Aqueous was a far less negative inotropic than Cordarone IV (P < 0.001). Amio Aqueous did not have an effect on contractility at 5- and 10-mg/kg dose levels while Cordarone resulted in a 25% (P < 0.01) and 29% (P < 0.002) decrease, respectively. The study on arterial blood pressure showed that Cordarone caused a significant decrease in blood pressure at each of the 3, 5, 10, and 20 mg/kg doses (P < 0.05 to P < 0.001) while Amio-Aqueous did not. The study on the antiarrhythmic effects showed comparable efficacy for both formulations. In conclusion, Cordarone IV was more toxic and caused significant hypotension and negative inotropy while Amio-Aqueous lacked the hypotensive and cardiotoxic properties of Cordarone. Therefore, Amio-Aqueous is a safer alternative than the standard formulation.
Somberg
John C
JC
Rush University, and the American Institute of Therapeutics, 21 North Skokie Valley Highway, Lake Bluff, IL 60044, USA. jsomberg@rush.edu
Cao
Wei
W
Cvetanovic
Ivana
I
Ranade
Vasant
V
Molnar
Janos
J
D000638:Amiodarone / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D007022:Hypotension / Q000139:chemically induced*; D007262:Infusions, Intravenous; D007928:Lethal Dose 50; D009200:Myocardial Contraction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D000638:Amiodarone