betadex and Cardiotoxicity

The aim of this study was to investigate the efficacy of 2-hydroxypropyl-beta-cyclodextrin (HPBCD) as an antidotal treatment for the in vivo cardiovascular effects of amitriptyline poisoning. Experiments were carried out on 33 Wistar rats. To evaluate cardiovascular effects of HPBCD, rats were infused with dextrose or HPBCD. In the poisoning model, amitriptyline (0.94 mg/kg/min) was infused until the mean arterial blood pressure (MAP) dropped to 50 % of the baseline. Following amitriptyline infusion, dextrose, low-dose HPBCD (4.19 mg/kg/min), or high-dose HPBCD (16.76 mg/kg/min) was infused, and MAP, heart rate (HR), and electrocardiogram were recorded for 60 min. Hearts were examined for tissue damage and apoptosis. HPBCD infusion alone did not yield significant difference for MAP, HR, QRS duration, QT interval, and cardiac tissue damage when compared to dextrose (p > 0.05). In the poisoning model, MAP and HR decreased, while QRS duration and QT interval prolonged significantly following amitriptyline infusion (p < 0.0167). Dextrose, low-dose HPBCD, and high-dose HPBCD infusion similarly corrected MAP, HR, QRS duration, and QT interval values at the end-experiment time point (p > 0.05). Histological scores for tissue damage and apoptosis showed no significant difference between the groups (p > 0.05). Based on our results, HPBCD did not show cardiovascular toxicity, while it was not more effective than dextrose for the treatment of amitriptyline poisoning. Further antidotal studies of cyclodextrins with higher doses and/or binding affinities are needed for poisonings.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Amitriptyline; Animals; Antidotes; Apoptosis; Arterial Pressure; beta-Cyclodextrins; Cardiotoxicity; Cardiovascular Diseases; Chelating Agents; Disease Models, Animal; Electrocardiography; Glucose; Heart Rate; Hemodynamics; Male; Rats, Wistar; Time Factors

To date, improving oral bioavailability of water-soluble drugs with poor membrane permeability is still challenging. An example of this includes doxorubicin hydrochloride (DOX·HCl), a widely used chemotherapeutic. We therefore developed a novel DOX·HCl-loaded polymersome (Ps-DOX·HCl) self-assembled by amphiphilic β-cyclodextrin-centered triarm star polymer (mPEG(2k)-PLA(3k))3-CD with the considerable drug loading capability. Using Madin-Darby canine kidney (MDCK) cells trans-well models, it was found that the cellular uptake and absorptive transport of DOX·HCl was significantly increased and the efflux was attenuated when delivered through polymersomes than free drugs. This phenomenon was further verified in mechanistic studies, which was attributed to the change in membrane transport pathway from paracellular route (free DOX·HCl) to active transcellular transport (drug-loaded polymersomes). Moreover, in vivo pharmacokinetic studies in mice demonstrated a significant increase in the oral bioavailability of Ps-DOX·HCl compared with free DOX·HCl (7.32-fold), as well as extended half-life (8.22-fold). This resulted in a substantial anticancer efficacy against mouse sarcoma 180 (S180) tumor in vivo. The cardiotoxicity, which is intrinsically induced by DOX·HCl, and toxicity toward gastrointestinal tissues were avoided according to histological studies. These findings indicate that (mPEG(2k)-PLA(3k))3-CD copolymer displays great potential as a vehicle for the effective oral delivery of water-soluble drugs with low permeability.

Topics: Administration, Oral; Animals; Antibiotics, Antineoplastic; beta-Cyclodextrins; Cardiotoxicity; Cell Line, Tumor; Dogs; Doxorubicin; Drug Carriers; Female; Hydrophobic and Hydrophilic Interactions; Madin Darby Canine Kidney Cells; Mice; Mice, Inbred ICR; Polyesters; Polyethylene Glycols; Tissue Distribution

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.. 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.. 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 < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. SBE-β-CD alone evoked a mild cardiodepressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μmol/L; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05).. A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac toxicity in rat isolated heart while SBE-β-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardiotoxicity, and the beneficial effects may involve mitochondrial lipid processing.

Topics: Animals; Arrhythmias, Cardiac; beta-Cyclodextrins; Bupivacaine; Cardiotoxicity; Cocaine; Coronary Circulation; Depression, Chemical; Fat Emulsions, Intravenous; Heart; Heart Rate; Male; Myocardial Contraction; Rats; Rats, Sprague-Dawley