Local anesthetics (LAs) reversibly prevent impulse transmission in nerves by voltage-, time- and frequency-dependent blockade of sodium channel conductance (I-Na). These pharmacological actions underlie the therapeutic use of LAs in clinical care to provide regional anesthesia (e.g., epidural blockade) for patients undergoing surgical procedures or childbirth. However, inadvertent intravascular injection or overdose may lead to undesired INa blockade in other tissues (e.g., heart, central nervous system) and thereby cause potentially life threatening adverse events (e.g., cardiac arrest, seizures). Although seizure activity and respiratory depression caused by LA overdose are potentially life threatening, these events can be readily treated with antiepileptic medications and controlled artificial ventilation, respectively. Of equal or greater importance, few options (e.g., ACLS) currently exist for treatment of cardiac toxicity caused by intravascular injection. For these reasons, an agent or technique allowing rapid, efficacious treatment of the cardiac effects of LA toxicity would be useful. The objectives of this grant are to generate the knowledge necessary to create agents specifically designed to treat patients suffering from the toxic effects of LAs. Recent advances in particle science engineering now afford new and exciting opportunities to develop highly effective therapeutic strategies aimed at successfully treating drug poisonings. Specifically, the recent advent of nanotechnology with its tremendous potential to solve major biomedical problems now offers unparalleled opportunities to solve the problem of LA toxicity. Four types of biocompatible and biodegradable nanoparticles (NPs) with 10-100 nm diameter will be synthesized by colleagues in the NSF Engineering Research Center for Particle Science and Technology for detoxification of LAs. These NPs will rely on absorption (microemulsions), adsorption (electron acceptor), or both mechanisms (2 types of """"""""smart"""""""" microemulsions) to reduce the free concentration of LA in various media and decrease the biological effects of LA in tissues and intact organisms. The NPs will be studied to 1) detail the physicochemical characterization of the NP-LA interaction (Objective A), and 2) determine whether the cardiotoxic effects of LAs can be attenuated by NPs in biological systems (Objective B). This highly multidisciplinary project spanning organic chemistry, engineering, and medicine contains two objectives and three specific aims:
Specific Aim #1 : Determine the extraction efficiency of NPs to remove LAs from simple (normal saline) and complex (human plasma and blood) media. Optimize LA extraction efficiency of the various NPs.
Specific Aim #2 : Determine the molecular mechanisms whereby the different types of NPs can efficiently extract LAs.
Specific Aim #3 : Determine the effectiveness of nanoparticles to attenuate or reverse the cardiotoxic effects of LAs at three functional levels: 1) single cell (ventricular myocytes), 2) tissue (isolated hearts), and 3) intact rat (closed chest).
| Varshney, Manoj; Morey, Timothy E; Shah, Dinesh O et al. (2004) Pluronic microemulsions as nanoreservoirs for extraction of bupivacaine from normal saline. J Am Chem Soc 126:5108-12 |
