Interaction of benzocaine with model membranes

We measured the absorption properties, water solubility and partition coefficients (P) between n-octanol, egg phosphatidylcholine (EPC) liposomes and erythrocyte ghosts/water for benzocaine (BZC), an ester-type always uncharged local anesthetic. The interaction of BZC with EPC liposomes was followed using Electron Paramagnetic Resonance, with spin labels at different positions in the acyl chain (5, 7, 12, 16-doxylstearic acid methyl ester). Changes in lipid organization upon BZC addition allowed the determination of P values, without phase separation. The effect of BZC in decreasing membrane organization (maximum of 11.6% at approx. 0.8:1 BZC:EPC) was compared to those caused by the local anesthetics tetracaine and lidocaine. Hemolytic tests revealed a biphasic (protective/inductive) concentration-dependent hemolytic effect for BZC upon rat erythrocytes, with an effective BZC:lipid molar ratio in the membrane for protection (Re-PROT), onset of hemolysis (Re-SAT) and 100% membrane solubilization (Re-SOL) of 1.0:1, 1.1:1 and 1.3:1, respectively. The results presented here reinforce the importance of considering hydrophobic interactions in the interpretation of the effects of anesthetics on membranes. (C) 2000 Elsevier Science B.V. All rights reserved.874170021322

Spectroscopic evidence for a preferential location of lidocaine inside phospholipid bilayers

We examined the effect of uncharged lidocaine on the structure and dynamics of egg phosphatidylcholine (EPC) membranes at pH 10.5 in order to assess the location of this local anesthetic in the bilayer. Changes in the organization of small unilamellar vesicles were monitored either by electron paramagnetic resonance (EPR)-in the spectra of doxyl derivatives of stearic acid methyl esters labeled at different positions in the acyl chain (5-, 7-, 12- and 16-MeSL)-or by fluorescence, with pyrene fatty-acid (4, 6-, 10- and 16-Py) probes. The largest effects were observed with labels located at the upper positions of the fatty-acid acyl-chain. Dynamic information was obtained by H-1-NMR. Lidocaine protons presented shorter longitudinal relaxation times (T,) values due to their binding, and consequent immobilization to the membrane. In the presence of lidocaine the mobility of all glycerol protons of EPC decreased, while the choline protons revealed a higher degree of mobility, indicating a reduced participation in lipid-lipid interactions. Two-dimensional Nuclear Overhauser Effect experiments detected contacts between aromatic lidocaine protons and the phospholipid-choline methyl group. Fourier-transform infrared spectroscopy spectra revealed that lidocaine changes the access of water to the glycerol region of the bilayer. A 'transient site' model for lidocaine, preferential location in EPC bilayers is proposed. The model is based on the consideration that insertion of the bulky aromatic ring of the anesthetic into the glycerol backbone region causes a decrease in the mobility of that EPC region (T-1 data) and an increased mobility of the acyl chains (EPR and fluorescence data). (C) 2002 Elsevier Science B.V. All rights reserved.99322924

Computational analysis and physico-chemical characterization of an inclusion compound between praziquantel and methyl-beta-cyclodextrin for use as an alternative in the treatment of schistosomiasis

Schistosomiasis is still an endemic disease in many regions, with 250 million people infected with Schistosoma and about 500,000 deaths per year. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment, however it is classified as Class II in the Biopharmaceutics Classification System, as its low solubility hinders its performance in biological systems. The use of cyclodextrins is a useful tool to increase the solubility and bioavailability of drugs. The aim of this work was to prepare an inclusion compound of PZQ and methyl-beta-cyclodextrin (MeCD), perform its physico-chemical characterization, and explore its in vitro cytotoxicity. SEM showed a change of the morphological characteristics of PZQ:MeCD crystals, and IR data supported this finding, with changes after interaction with MeCD including effects on the C-H of the aromatic ring, observed at 758 cm(-1). Differential scanning calorimetry measurements revealed that complexation occurred in a 1:1 molar ratio, as evidenced by the lack of a PZQ transition temperature after inclusion into the MeCD cavity. In solution, the PZQ UV spectrum profile in the presence of MeCD was comparable to the PZQ spectrum in a hydrophobic solvent. Phase solubility diagrams showed that there was a 5.5-fold increase in PZQ solubility, and were indicative of a type A(L) isotherm, that was used to determine an association constant (K(a)) of 140.8 M(-1). No cytotoxicity of the PZQ:MeCD inclusion compound was observed in tests using 3T3 cells. The results suggest that the association of PZQ with MeCD could be a good alternative for the treatment of schistosomiasis.7041671192