Manoj Varshney

Scavenging nanoparticles: an emerging treatment for local anesthetic toxicity.

e i o t g s a r i n a r i d t o t o r t c dreaded complication of local anesthetic use in regional anesthesia is systemic toxicity from nintentional intravascular local anesthetic injecion. Although systemic toxic reactions are not ommon after peripheral nerve block, 7.5 to 20 vents per 10, 000 in adults,1 they can be lifehreatening and resistant to treatment.2-6 Recent ata from an American Society of Anesthesiology losed Claims Project demonstrate that unintenional intravenous local anesthetic injection was the econd largest category of block-related regional nesthesia claims that resulted in death or brain amage.7 The manifestations of local anesthetic toxicity ange from local neurotoxic and myotoxic reactions o cardiovascular collapse and coma. Central nerous system toxicity presents as a spectrum that ncludes shivering, muscle twitching, tonic-clonic eizures, hypoventilation, and respiratory arrest.8 ardiovascular toxicity primarily manifests as arhythmias and myocardial depression.9-14 Local ansthetic overdose can cause a variety of arrhythias, including atrial and ventricular conduction elays, complete heart block, asystole, ventricular ctopy, ventricular tachycardia, torsades de pointes, nd ventricular fibrillation.8,15 The molecular mechanisms whereby local aneshetics exert their toxic effects have not been fully stablished and are likely complex in nature. Ex-

A Physiologically-Based Pharmacokinetic Model of Drug Detoxification by Nanoparticles

Nanoparticles (NPs) may be capable of reversing the toxic effects of drug overdoses in humans by adsorbing/absorbing drug molecules. This paper develops a model to include the kinetic effects of treating drug overdoses by NPs. Depending on the size and the nature of the NPs, they may either pass through the capillary walls and enter the tissue space or remain only inside the capillaries and other blood vessels; models are developed for each case. Furthermore, the time scale for equilibration between the NP and the blood will vary with the specific type of NP. The NPs may sequester drug from within the capillaries depending on weather this time scale is larger or smaller than the residence time of blood within the capillary. Models are developed for each scenario. The results suggest that NPs are more effective at detoxification if they are confined to the blood vessels and do not enter the tissues. The results also show that the detoxification process is faster if drug uptake occurs within the capillaries. The trends shown by the model predictions can serve as useful guides in the design of the optimal NP for detoxification.

Surfactant-Mediated Fabrication of Optical Nanoprobes

Modern bio-imaging techniques often employ contrast agents to improve the image quality and also toprovide specific information about anatomical structure and/or the function of biological systems. Quantumdots, fluorescent dye-doped silica and gold nanoparticles are important examples of new nanoparticulate-basedimaging agents that have overcome many of the limitations of conventional contrast media such as organicdyes. These agents have the ability to provide enhanced photostability and sensitivity in combination withsufficient in vitro and in vivo stability. Surfactant-mediated methods are one of the most versatile strategiesfor synthesizing nanosized contrast agents. Microemulsion-mediated synthesis, in particular, offers a widelyapplicable approach to produce a variety of engineered optical nanoprobes presenting good control overnanoparticle size, design and robust surface derivatization. Herein the authors provide a review ofsurfactant chemistry and strategies, with a particular focus on microemulsions, for generating luminescentnanoprobes, such as quantum dots, fluorescent silica and gold nanoparticles for bioimaging applications.

Thromboelastographic and pharmacokinetic profiles of micro- and macro-emulsions of propofol in swine.

Purpose. Compared with traditional macroemulsion propofol formulations currently in clinical use, microemulsion formulations of this common intravenous anesthetic may offer advantages. The pharmacokinetics and coagulation effects as assessed by thromboelastography of these formulations were characterized in swine. Methods. Yorkshire swine (20–30 kg, either sex, n=15) were sedated, anesthetized with isoflurane, and instrumented to obtain a tracheostomy, internal jugular access and carotid artery catheterization. Propofol (2 mg/kg, 30 s) was administered as a macroemulsion (10 mg/ml; Diprivan®; n=7) or a custom (2 mg/kg, 30 s) microemulsion (10 mg/ml; n=8). Arterial blood specimens acquired pre‐ and post‐injection (1 and 45 min) were used for thromboelastography. Arterial blood specimens (n=12 samples/subject, 60 min) were serially collected, centrifuged and analysed with solid‐phase extraction with UPLC to determine propofol plasma concentrations. Non‐compartmental pharmacokinetic analysis was applied to plasma concentrations. Results. No changes were noted in the thromboelastographic R time (p=0.74), K time (p=0.41), α angle (p=0.97), or maximal amplitude (p=0.71) for either propofol preparation. Pharmacokinetic parameters k (p=0.45), t1/2 (p=0.26), Co (p=0.89), AUC0−∞ (p=0.23), CL (p=0.14), MRT (p=0.47), Vss (p=0.11) of the two formulations were not significantly different. Conclusion. The microemulsion and macroemulsion propofol formulations had similar pharmacokinetics and did not modify thromboelastographic parameters in swine. Copyright

Injectable Nanoparticle Technology for In Vivo Remediation of Overdosed Toxins

Internal and external exposure to excess amounts of natural and synthetic chemicals, including some therapeutics, can be reversed if general or selective antidotes are available. The focus of the present study-in-progress is to synthesize, characterize and evaluate the biological effectiveness of several types of injectable dispersed phases having potential for binding and deactivating some lipophilic molecules that when taken internally in excess cause cardiac failure. The types of dispersed phases under investigation are 1) microemulsions, 2)microgels, 3)porous nanoparticles, 4)nanotubes, 5)core-shell nanoparticles and 6)nanoparticles with toxin receptors covalently attached to their surfaces. in this chapter only types 1), 3) and 6) will be discussed. Biocompatible oil-in-water microemulsions stabilized by co-surfactants have been prepared which are stable in blood and capable of quickly absorbing quantities of bupivacaine, cocaine and amitriptyline. Silica particles to be used for reference purposes have been synthesized with pores templated for bupivacaine and will be evaluated for adsorption capacity. Silica nanoparticles with attached dinitrobenzoyl or cyclodextrin binding receptors show rapid and high yield binding by aromatic π-π complexation or by cavity penetration, respectively. BET, HPLC, NMR, SEM, TEM and TGA data have been obtained to support the chemical conclusions. Bioassays have been performed using EKG/QRS and TEG techniques.