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Cardiac Depression Induced by Cocaine or Cocaethylene are Alleviated by Lipid Emulsion More Effectively Than by Sulfobutylether β-Cyclodextrin
- Publication Year :
- 2015
-
Abstract
- Objectives Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (SBE-β-CD; Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. Methods For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (–dP/dtmax), rate-pressure product (RPP = heart rate × LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 μmol/L) and cocaethylene (10, 30, and 50 μmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-β-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. Results Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and –dP/dtmaxabs (p
- Subjects :
- Male
Fat Emulsions, Intravenous
medicine.drug_class
Beta-Cyclodextrins
Pharmacology
Article
Rats, Sprague-Dawley
chemistry.chemical_compound
Cocaethylene
Cocaine
Heart Rate
Coronary Circulation
medicine
Animals
Cardiotoxicity
Local anesthetic
business.industry
beta-Cyclodextrins
Arrhythmias, Cardiac
Heart
General Medicine
medicine.disease
Bupivacaine
Myocardial Contraction
Rats
chemistry
Anesthesia
Depression, Chemical
Toxicity
Emergency Medicine
Benzoylecgonine
Cocaine intoxication
Ecgonine
business
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....411cd6b5d243fb7233c0dea9a82b0480