title: Treatment of calcium channel blocker-induced cardiovascular toxicity with drug scavenging liposomes.
abstract: Calcium channel blocker (CCB) overdose is potentially lethal. Verapamil and diltiazem are particularly prone to acute toxicity due to their dual effect on cardiac and vascular tissues. Unfortunately, conventional decontamination measures are ineffective in accelerating blood clearance and, to date, few efforts have been made to develop antidotes. To address the issue, injectable long-circulating liposomes bearing a transmembrane pH-gradient are proposed as efficient detoxifying agents of CCB poisoning. By scavenging the drug in situ, these circulating nanocarriers can restrict its distribution in tissues and hinder its pharmacological effect. In vitro, we showed that liposomes stability in serum and their ability to sequester CCBs could be finely-tuned by modulating their internal pH, surface charge, and lipid bilayer structure. Subsequently, we verified their efficacy in reversing the cardiovascular effects of verapamil in rats implanted with telemetric pressure/biopotential transmitters. In animals orally intoxicated to verapamil, an intravenous injection of the liposomal antidote rapidly attenuated the reduction in blood pressure. Areas under diastolic, systolic, and mean pressures curves were significantly reduced by up to 60% and the time to hemodynamic recovery was shortened from 19 to only 11 h. These findings confirm the protective effect of pH-gradient liposomes against cardiovascular failure after CBB intoxication, and endorse their potential as efficient, versatile antidotes.
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Forster
authors.forename: Paola
authors.initials: P
authors.lastname: Luciani
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Leroux
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000633:toxicity*; D002319:Cardiovascular System / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology; D004110:Diltiazem / Q000633:toxicity; D004337:Drug Carriers; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007275:Injections, Intravenous; D007700:Kinetics; D008081:Liposomes / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014700:Verapamil / Q000633:toxicity
chemical_list: D002121:Calcium Channel Blockers; D004337:Drug Carriers; D008081:Liposomes; D014700:Verapamil; D004110:Diltiazem