FABIANO YOKAICHIYA
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Artigo IPEN-doc 27384 Capsaicin-cyclodextrin complex enhances mepivacaine targeting and improves local anesthesia in inflamed tissues2020 - COUTO, VERONICA M.; OLIVEIRA-NASCIMENTO, LAURA de; CABEÇA, LUIZ F.; GERALDES, DANILO C.; COSTA, JULIANA S.R.; RISKE, KARIN A.; FRANZ-MONTAN, MICHELLE; YOKAYCHIYA, FABIANO; FRANCO, MARGARETH K.K.D.; PAULA, ENEIDA deAcidic environments, such as in inflamed tissues, favor the charged form of local anesthetics (LA). Hence, these drugs show less cell permeation and diminished potency. Since the analgesic capsaicin (CAP) triggers opening of the TRPV1 receptor pore, its combination with LAs could result in better uptake and improved anesthesia. We tested the above hypothesis and report here for the first time the analgesia effect of a two-drug combination (LA and CAP) on an inflamed tissue. First, CAP solubility increased up to 20 times with hydroxypropyl-beta-cyclodextrin (HP-β-CD), as shown by the phase solubility study. The resulting complex (HP-β-CD-CAP) showed 1:1 stoichiometry and high association constant, according to phase-solubility diagrams and isothermal titration calorimetry data. The inclusion complex formation was also confirmed and characterized by differential scanning calorimetry (DSC), X-ray diffraction, and 1H-NMR. The freeze-dried complex showed physicochemical stability for at least 12 months. To test in vivo performance, we used a pain model based on mouse paw edema. Results showed that 2% mepivacaine injection failed to anesthetize mice inflamed paw, but its combination with complexed CAP resulted in pain control up to 45 min. These promising results encourages deeper research of CAP as an adjuvant for anesthesia in inflamed tissues and cyclodextrin as a solubilizing agent for targeting molecules in drug delivery.Artigo IPEN-doc 26865 Complexation of the local anesthetic pramoxine with hydroxypropyl-beta-cyclodextrin can improve its bioavailability2020 - BEZAMAT, JULIANA M.; YOKAICHIYA, FABIANO; FRANCO, MARGARETH K.K.D.; CASTRO, SIMONE R.; PAULA, ENEIDA de; CABEÇA, LUIS F.Local anesthetics are widely used in clinical procedures, to eliminate pain during/after invasive procedures. A wide range of drug delivery systems has been developed to improve the effect of local anesthetics and/or to reduce their toxicity. Pramoxine (PMX) is a topical anesthetic agent with an unusual (morpholine ring) structure and low solubility (ca. 3 mM at pH 7.4). In this work, a novel formulation was devised for PMX in hydroxypropyl- β-cyclodextrin (HP-β-CD). Host-guest inclusion complex was prepared by the co-solubilization method, with complexation kinetics of 10 h, and 1:1 PMX/HP-β-CD stoichiometry. Complexation promoted 14-fold increase in the solubility of PMX. X-ray diffraction measurements revealed loss of the crystalline PMX pattern in the presence of HP-β-CD, an indication of inclusion complexation. Using 1H NMR (DOSY) experiments the association constant of PMX to HP-β-CD (Ka = 923.1 mol/L) was determined, while nuclear Overhauser (ROESY) analysis confirmed the formation of PMX/HP-β-CD inclusion complex, by detection of spatial proximities between hydrogens from PMX aromatic ring and cyclodextrin's cavity. In two in vitro toxicity models (mouse 3T3 fibroblasts in culture and red blood cells hemolysis) pramoxine toxicity was significantly reduced upon complexation into HP-β-CD. These results point out PMX/HP-β-CD as a promising pharmaceutical formulation to improve the bioavailability of pramoxine, allowing its application beyond topical anesthesia.Artigo IPEN-doc 21224 Clonidine complexation with hydroxypropyl-beta-cyclodextrin: From physico-chemical characterization to in vivo adjuvant effect in local2016 - BRAGA, M.A.; MARTINI, M.F.; PICKHOLZ, M.; YOKAICHIYA, F.; FRANCO, MARGARETH K.K.D.; CABEÇA, L.F.; GUILHERME, V.A.; SILVA, C.M.G.; LIMIA, C.E.G.; PAULA, E. de