1234 www.anesthesia-analgesia.org November 2012 • Volume 115 • Number 5 DOI: B upivacaine (BVC) and ropivacaine (RVC) are local anesthetics widely used in surgical procedures world- wide. 1,2 In current clinical practice there is a need for local anesthetics whose action is long-lasting and which present low systemic uptake to minimize any toxic side effects. 3,4 Drug delivery systems can be used to prolong the duration of action and reduce the toxicity of local anes- thetics, since because they enable the controlled release of the anesthetic molecules. Local anesthetics carried in drug delivery systems such as cyclodextrins have been used as potential new formulations for pain treatment. 5,6 In previous studies by other workers 7,8 and by our own research group, 9–11 the inclusion of BVC or RVC in hydroxypropyl-β-cyclodextrin (HP-β-CD) increased the anesthetic effect after injection in the subarachnoid space or after sciatic nerve blockade, compared to plain solu- tions at the same concentration. However, for the devel- opment of new pharmaceutical formulations, such as the BVC-hydroxypropyl-β-cyclodextrin inclusion complex (BVC HP-β-CD ) or the RVC-hydroxypropyl-β-cyclodextrin inclusion complex (RVC HP-β-CD ), an assessment of toxicity is essential to provide the fundamental information required to ensure their safe application. The aims of this study were therefore to: (1) evaluate the cytotoxicity of the new local anesthetic formulations, BVC HP-β-CD and RVC HP-β-CD , in primary Schwann cell cultures; (2) evaluate their local neurotoxicity by histopathological analysis of rat sciatic nerve after intraneural injection; and From the *Department of Biochemistry, Institute of Biology, State University of Campinas, Campinas, SP, Brazil; †Laboratory of Molecular Biology and Pharmacology, São Francisco University, Bragança Paulista, SP, Brazil; ‡Department of Basic Sciences, Federal University of Jequitinhonha and Mucuri Valleys, Diamantina, Minas Gerais, Brazil; §Department of Anatomy, Celular Biology, Physiology and Biophysics, Institute of Biology, State University of Campinas, Campinas, SP, Brazil; ‖Department of Histology and Embryology, Institute of Biology, State University of Campinas, Campinas, SP, Brazil; and ¶Human and Natural Sciences Center, Federal University of ABC, Santo André, SP, Brazil. Accepted for publication June 12, 2012. This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (São Paulo, Brazil) [06/00121-9 and 07/55189-0]. The authors declare no conlicts of interest. This report was previously presented, in part, at the XXVII and XXIX Annual Congress of the European Society of Regional Anaesthesia (September 24–27, 2008, Italy; September, 8–11, 2010, Portugal); 36th Controlled Release Society Annual Meeting and Exposition (July 18–22, 2009, Copenhagen, Denmark). Reprints will not be available from the authors. Address correspondence to Cintia Maria Saia Cereda, PhD, Department of Biochemistry, Institute of Biology, State University of Campinas (UNICAMP), P.O. Box 6109, CEP 13083–862, Campinas, SP, Brazil. Address e-mail to cscereda@gmail.com. Copyright © 2012 International Anesthesia Research Society DOI: 10.1213/ANE.0b013e318266f3d9 Local Neurotoxicity and Myotoxicity Evaluation of Cyclodextrin Complexes of Bupivacaine and Ropivacaine Cintia Maria Saia Cereda, PhD,* Giovana Radomille Tofoli, PhD,† Luiz Gabriel Maturana, MSc,‡ Amauri Pierucci, PhD,‡ Lazaro Alessandro Soares Nunes, PhD,* Michelle Franz-Montan, PhD,* Alexandre Leite Rodrigues de Oliveira, PhD,§ Sarah Arana, PhD,|| Daniele Ribeiro de Araujo, PhD,¶ and Eneida de Paula, PhD* BACKGROUND: Bupivacaine (BVC) and ropivacaine (RVC) are local anesthetics widely used in surgical procedures. In previous studies, inclusion complexes of BVC or RVC in hydroxypropyl-β- cyclodextrin (HP-β-CD) increased differential nervous blockade, compared to the plain anesthetic solutions. In this study we evaluated the local neural and muscular toxicity of these new formula- tions containing 0.5% BVC or RVC complexed with HP-β-CD (BVC HP-β-CD and RVC HP-β-CD ). METHODS: Schwann cell viability was assessed by determination of mitochondrial dehydroge- nase activity, and histopathological evaluation of the rat sciatic nerve was used to identify local neurotoxic effects (48 hours and 7 days after the treatments). Evaluations of serum creatine kinase levels and the histopathology of rat gastrocnemius muscle (48 hours after treatment) were also performed. RESULTS: Schwann cell toxicity evaluations revealed no signiicant differences between com- plexed and plain local anesthetic formulations. However, use of the complexed local anesthetics reduced serum creatine kinase levels 5.5-fold, relative to the plain formulations. The differences were signiicant at P < 0.05 (BVC) and P < 0.01 (RVC). The histopathological muscle evaluation showed that differences between groups treated with local anesthetics (BVC or RVC) and their respective complexed formulations (BVC HP-β-CD or RVC HP-β-CD ) were signiicant (P < 0.05). CONCLUSIONS: We concluded that the new formulations presented a lower myotoxicity and a similar cytotoxic effect when compared to plain local anesthetic solutions. (Anesth Analg 2012;115:1234–41) Section Editor: Terese T. Horlocker Regional Anesthesia