Brazilian Journal of Anesthesiology
https://bjan-sba.org/article/doi/10.1590/S0034-70942006000500007
Brazilian Journal of Anesthesiology
Scientific Article

Mistura com excesso enantiomérico de 50% (S75-R25) de bupivacaína complexada com ciclodextrinas e anestesia por via subaracnóidea em ratos

Complexation of 50% enantiomeric excess (S75-R25) bupivacaine with cyclodextrins and spinal block anesthesia in rats

Daniele Ribeiro de Araujo; Angélica de Fátima de Assunção Braga; Carolina Morales Moraes; Leonardo Fernandes Fraceto; Eneida de Paula

http://dx.doi.org/10.1590/S0034-70942006000500007 Braz J Anesthesiol, vol.56, n5, p.495-506, 2006
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Resumo

JUSTIFICATIVA E OBJETIVOS: Com a finalidade de prolongar a duração de ação e reduzir a toxicidade sistêmica, têm-se desenvolvido formulações de anestésicos locais (AL) complexados com ciclodextrinas (CD). Este estudo realizou a caracterização físico-química e avaliou, em ratos, os efeitos dos complexos de inclusão de bupivacaína racêmica (S50-R50) e da mistura com excesso enantiomérico de 50% (S75-R25) de bupivacaína com hidroxipropil-betaciclodextrina (HP-beta-CD), comparando-os com as soluções atualmente utilizadas na clínica. MÉTODO: Os complexos de inclusão de S75-R25 em HP-beta-CD (razão molar 1:1) foram caracterizados por estudos de solubilidade de fases variando-se as concentrações de HP-beta-CD e a temperatura. Determinaram-se as constantes de afinidade (K) pela HP-beta-CD e os parâmetros termodinâmicos para a complexação. Os bloqueios motor e sensitivo foram avaliados, por meio da administração subaracnóidea das formulações na concentração clínica de 0,5%. RESULTADOS: A formação de complexos de inclusão foi observada pelo aumento da solubilidade aquosa do AL sob diferentes temperaturas e concentrações de HP-beta-CD. Os testes in vivo mostraram que S50-R50HP-beta-CD e S75-R25HP-beta-CD reduziram a latência (p < 0,001) sem alterar o tempo de recuperação do bloqueio motor, tempo para efeito máximo e efeito total dos fármacos. Além disso, ambas as formulações aumentaram a intensidade (1,5 vez, p < 0,001) e prolongaram a duração da analgesia, com relação aos fármacos livres. CONCLUSÕES: Os complexos S50-R50HP-beta-CD e S75-R25HP-beta-CD potencializaram o bloqueio nervoso diferencial, podendo ser utilizados para reduzir a freqüência de administrações ou a dose de AL para indução de um mesmo efeito. A formulação contendo a mistura com excesso enantiomérico de 50% (S75-R25) de bupivacaína mostrou-se interessante no desenvolvimento de formulações seguras e úteis para o tratamento da dor aguda no período pós-operatório.

Palavras-chave

ANESTÉSICOS, Local, ANIMAIS

Abstract

BACKGROUND AND OBJECTIVES: In order to prolong the action and reduce systemic toxicity, formulations of local anesthetic (LA) complexed with cyclodextrins (CD) have been developed. This study determined the physical-chemical characterization and evaluated the effects of inclusion complexes of racemic bupivacaine (S50-R50) and 50% enantiomeric excess (S75-R25) bupivacaine with hydroxypropil-beta-cyclodextrin (HP-beta-CD) in rats, and comparing them with the solutions currently used in the clinical practice. METHODS: Inclusion complexation of S75-R25 with HP-beta-CD (equimolar ratio 1:1) was characterized by phase-solubility studies varying the concentrations of HP-beta-CD and the temperature. Affinity constants (K) for HP-beta-CD and the thermodynamic parameters for complexation were determined. Motor and sensitive anesthesias were evaluated through the subarachnoid administration of the formulations in the concentration of 0.5%. RESULTS: Inclusion complexation was observed through the increase in aqueous solubility of LA in different temperatures and concentrations of HP-beta-CD. The in vivo tests demonstrated that S50-R50HP-beta-CD and S75-R25HP-beta-CD reduced latency (p < 0.001) without changing the recovery time of the motor block, time for maximal effect, and total effect of the drugs. Besides, both formulations increased the intensity (1.5 times, p < 0.001) and prolonged the duration of analgesia compared to the free drugs. CONCLUSIONS: The complexes S50-R50HP-beta-CD and S75-R25HP-beta-CD potentiated the differential nervous block, and can be used to reduce the frequency of administration or the dose of the LA to induce the same effect. The formulation containing enantiomeric excess (S75-R25) bupivacaine showed to be interesting in the development of safer formulations, and useful for the treatment of acute pain in the postoperative period.

Keywords

ANESTHETICS, Local, ANIMALS

References

Covino BG. Pharmacology of local anaesthetic agents. Br J Anaesth. 1986;58:701-716.

Simonetti MPB, Valinetti EA, Ferreira FM. Avaliação da atividade anestésica local da S(-) bupivacaína: estudo experimental in vivo em nervo isquiático de rato. Rev Bras Anestesiol. 1997;47:425-434.

Fromming KH, Szejtli J. Topics in Inclusion Science Cyclodextrins in Pharmacy, Hungria. Kluwer Academic Publishers. 1994:33-34.

Gould S, Scott RC. 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD): a toxicology review. Food Chem Toxicol. 2005:1451-1459.

Szejtli J. Medicinal applications of cyclodextrins. Med Res Rev. 1994;14:353-386.

Araujo DR, Pinto LMA, Braga AFA. Formulações de anestésicos locais de liberação controlada: aplicações terapêuticas. Rev Bras Anestesiol. 2003;53:663-671.

Dollo G, Le Corre P, Chevanne F. Inclusion complexation of amide-type local anesthetics with beta-cyclodextrin and derivates. I: Physicochemical characterization. Int J Pharm. 1996;131:219-228.

Dollo G, Le Corre P, Chevanne F. Inclusion complexation of amide-type local anesthetics with beta-cyclodextrin and derivates. II. Evaluation of affinity constants and in vitro transfer rate constants. Int J Pharm. 1996;136:65-74.

Dollo G, Thompson DO, Le Corre P. Inclusion complexation of amide-type local anesthetics with beta-cyclodextrin and derivates. III. Biopharmaceutics of bupivacaine-SBE7-beta-CD complex following percutaneous sciatic nerve administration in rabbits. Int J Pharm. 1998;164:11-19.

Dollo G, Le Corre P, Freville JC. Biopharmaceutics of local anesthetic-cyclodextrin complexes following loco-regional administration. Ann Pharm Fr. 2000;58:425-432.

Estebe JP, Ecoffey C, Dollo G. Bupivacaine pharmacokinetics and motor blockade following epidural administration of the bupivacaine-sulphobutylether 7-b-cyclodextrin complex in sheep. Eur J Anaesthesiol. 2002;19:308-310.

Araujo DR, Pinto LMA, Braga AFA. Sistemas de liberação controlada com bupivacaína racêmica (S50-R50) e mistura enantiomérica de bupivacaína (S75-R25): efeitos da complexação com ciclodextrinas no bloqueio do nervo isquiático em camundongos. Rev Bras Anestesiol. 2005;55:316-328.

Higuchi T, Connors KA. Phase-solubility techniques. Adv Anal Chem Instr. 1965;4:117-212.

de Paula E, Schreier S. Use of a novel method for determination of partition coefficients to compare the effect of local anesthetics on membrane structure. Biochim Biophys Acta. 1995;1240:25-33.

Ravelet C, Ravel A, Grosset C. Stoichiometry and formation constants of six PAHs with g-Ciclodextrin, determined by HPLC using a cyano stacionary phase. J Liq Chrom Relat Technol. 2002;25:421-432.

Ismaili L, Andre C, Nicod L. Chromatographic determination of the association constants between Psorasolen derivatives and modified beta-cyclodextrin: effect of sucrose as a co-enhancer association agent. J Liq Chrom Relat Technol. 2003;26:871-882.

Gazpio C, Sanchez M, Garcia-Zubiri . HPLC and Solubility study of the interaction between pindolol and cyclodextrins. J Pharm Biomed Anal. 2005;9:487-492.

Mestre C, Pelissier T, Fialip J. A method to perform direct transcutaneous intrathecal injection in rats. J Pharm Toxic Meth. 1994;32:197-200.

Feldman HS, Covino BG. Comparative motor-blocking effects of bupivacaine and ropivacaine, a new amino amide local anesthetic, in the rat and dog. Anesth Analg. 1988;67:1047-1052.

Randall LO, Selitto JJ. A method for measurement of analgesic activity of inflamed tissue. Archiv Int Pharmacodyn. 1957:409-419.

Zar JH. Biostatistical Analysis. 1996:180-216.

Bibby D, Davies NM, Tucker IG. Mechanisms by which cyclodextrins modify drug release from polymeric drug delivery systems. Int J Pharmac. 2000;197:1-11.

Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nature Reviews. 2004;3:1023-1035.

Kuzma PJ, Kline MD, Calkins MD. Progress in the development of ultra-long-acting local anesthetics. Reg Anesth. 1997;22:543-551.

Boersma FP, Meert TF, Vercauteren M. Spinal sufentanil in rats: part I: epidural versus intrathecal sufentanil and morphine. Acta Anaesthesiol Scand. 1992;36:187-192.

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