title: Improvement of tetracaine antinociceptive effect by inclusion in cyclodextrins.
abstract: Local anesthetics (LA) are among the most important pharmacological compounds used to attenuate or eliminate pain. However, systemic toxicity is still a limitation for LA application, especially for ester-type drugs, such as tetracaine (TTC) that presents poor chemical stability (due to hydrolysis by plasma esterases). Several approaches have been used to improve LA pharmaceutical properties, including the employment of drug-delivery systems. Here we used beta-cyclodextrin (β-CD) or hydroxypropyl-beta-cyclodextrin (HP-β-CD) to develop two new TTC formulations (TTC:β-CD and TTC:HP-β-CD). The inclusion complexes formation, in a 1:1 stoichiometry, was confirmed by differential scanning calorimetry, X-ray diffraction, UV-VIS absorption and fluorescence. Nuclear magnetic resonance (DOSY experiments) revealed that TTC association with HP-β-CD is stronger (Ka=1200 mol/L(-1)) than with β-CD (Ka=845 mol/L(-1)). Moreover, nuclear Overhauser effect (NOE) experiments provided information on the topology of the complexes, where TTC aromatic ring is buried inside the CD hydrophobic cavity. In vitro tests with 3T3 fibroblast cells culture revealed that complexation decreased TTC cytotoxicity. In addition, the total analgesic effect of TTC, tested in rats through the infraorbital nerve test, was improved in 36% with TTC:β-CD and TTC:HP-β-CD. In conclusion, these formulations presented potential for future clinical use, by reducing the toxicity and increasing the antinociceptive effect of tetracaine.
authors: Department of Biochemistry, Institute of Biology, State University of Campinas, (Unicamp) Campinas, SP, Brazil.
authors: Roberta Aline
authors: RA
authors: Franco de Lima
authors: Marcelo Bispo
authors: MB
authors: de Jesus
authors: Cíntia Maria
authors: CM
authors: Saia Cereda
authors: Giovana Radomille
authors: GR
authors: Tofoli
authors: Luis Fernando
authors: LF
authors: Cabeça
authors: Irineu
authors: I
authors: Mazzaro
authors: Leonardo Fernandes
authors: LF
authors: Fraceto
authors: Eneida
authors: E
authors: de Paula
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D013748:Tetracaine / Q000008:administration & dosage* / Q000737:chemistry; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D000700:Analgesics; D003505:Cyclodextrins; D013748:Tetracaine