Novel serine-based gemini surfactants as chemical permeation enhancers of local anesthetics: A comprehensive study on structure-activity relationships, molecular dynamics and dermal delivery.

This work aims at studying the efficacy of a series of novel biocompatible, serine-based surfactants as chemical permeation enhancers for two different local anesthetics, tetracaine and ropivacaine, combining an experimental and computational approach. The surfactants consist of gemini molecules structurally related, but with variations in headgroup charge (nonionic vs. cationic) and in the hydrocarbon chain lengths (main and spacer chains). In vitro permeation and molecular dynamics studies combined with cytotoxicity profiles were performed to investigate the permeation of both drugs, probe skin integrity, and rationalize the interactions at molecular level. Results show that these enhancers do not have significant deleterious effects on the skin structure and do not cause relevant changes on cell viability. Permeation across the skin is clearly improved using some of the selected serine-based gemini surfactants, namely the cationic ones with long alkyl chains and shorter spacer. This is noteworthy in the case of ropivacaine hydrochloride, which is not easily administered through the stratum corneum. Molecular dynamics results provide a mechanistic view of the surfactant action on lipid membranes that essentially corroborate the experimental observations. Overall, this study suggests the viability of these serine-based surfactants as suitable and promising delivery agents in pharmaceutical formulations.

Lysine-based surfactants as chemical permeation enhancers for dermal delivery of local anesthetics.

The aim of this study is to investigate the efficacy of new, biocompatible, lysine-based surfactants as chemical permeation enhancers for two different local anesthetics, tetracaine and ropivacaine hydrochloride, topically administered. Results show that this class of surfactants strongly influences permeation, especially in the case of the hydrophilic and ionized drug, ropivacaine hydrochloride, that is not easily administered through the stratum corneum. It is also seen that the selected permeation enhancers do not have significant deleterious effects on the skin structure. A cytotoxicity profile for each compound was established from cytotoxicity studies. Molecular dynamics simulation results provided a rationale for the experimental observations, introducing a mechanistic view of the action of the surfactants molecules upon lipid membranes.

Effect of cyclodextrins and pH on the permeation of tetracaine: supramolecular assemblies and release behavior.

This work provides a new insight on fundamental principles of the interaction mechanism between two forms of tetracaine - a potent local anesthetic - both in neutral (TC) and ionized (TC(+)) states, with beta- (ß-CD) and hydroxypropyl-beta-cyclodextrin (HP-ß-CD), and how such interactions affect the transport of tetracaine, at different concentrations, across a model membrane. The kinetics and mechanism of TC release from HPMC gels is also evaluated giving an insight on the role of cyclodextrin on the tetracaine transport. HPLC, fluorescence and NMR spectroscopies provided solid physicochemical knowledge of these systems and in vitro studies were performed to obtain relevant data on the transport and mechanism parameters. HPLC and fluorescence spectroscopy data revealed that tetracaine interacts with both cyclodextrins on a 1:1 stoichiometry but it is observed that neutral tetracaine forms more stables complexes (ca. 1050 M(-1) for both cyclodextrins) than in its ionized form (628 and 337 M(-1) for ß-CD and HP-ß-CD respectively). Despite of that, no host-guest interactions take place as seen by ROESY. This study clearly demonstrates that both forms of tetracaine are successfully released from the formulations at a controlled rate, following a Super-Case transport mechanism and the transport of tetracaine can be tuned by using cyclodextrins.

Geophysical technique and groundwater monitoring to detect leachate contamination in the surrounding area of a landfill--Londrina (PR--Brazil).

The aim of the present study was to define leachate plume by using two techniques: geophysical and groundwater sampling in order to evaluate groundwater contamination. After performing a topographic survey and using geophysics, the leachate plume was identified. With this data, the wells for groundwater monitoring were located. Groundwater samples were analyzed for: COD, BOD, pH, alkalinity, conductivity, TKN and heavy metals. Through the electroresistivity method it was possible to define the shape of plume contamination. This method was important to locate the groundwater monitoring wells. The results of the physicochemical parameters showed the suitability of the geophysical study. The highest values of electric conductivity and alkalinity correspond to the wells located in the area interpreted as contaminated by leachate in the map of the resistivity. Even with seasonal variations, BOD values are low if compared to Brazilian environmental regulations, but COD values are higher up to 40 times the values of BOD. The concentrations of Ni, Zn, Cd and Cu in the groundwater are below the limits established by the potable water quality standards in Brazil, except for Pb whose concentration in groundwater were higher if compared to Brazilian legislation.

Delivery of daunorubicin to cancer cells with decreased toxicity by association with a lipidic nanoemulsion that binds to LDL receptors.

A lipidic nanoemulsion termed LDE concentrates in neoplastic cells after injection into the bloodstream and thus can be used as a drug carrier to tumour sites. The chemotherapeutic agent daunorubicin associates poorly with LDE; the aim of this study was to clarify whether the derivatization of daunorubicin by the attachment of an oleyl group increases the association with LDE, and to test the cytotoxicity and animal toxicity of the new preparation. The association of oleyl-daunorubicin (oDNR) to LDE showed high yield (93 +/- 2% and 84 +/- 4% at 1:10 and 1:5 drug:lipid mass, respectively) and was stable for at least 20 days. Association with oDNR increased the LDE particle diameter from 42 +/- 4 nm to 75 +/- 6 nm. Cytotoxicity of LDE-oDNR was reduced two-fold in HL-60 and K-562 cell lines, fourteen-fold in B16 cells and nine-fold in L1210 cells when compared with commercial daunorubicin. When tested in mice, LDE-oDNR showed remarkable reduced toxicity (maximum tolerated dose > 253 micromol kg(-1), compared with <3 micromol kg(-1) for commercial daunorubicin). At high doses, the cardiac tissue of LDE-oDNR-treated animals had much smaller structural lesions than with commercial daunorubicin. LDE-oDNR is therefore a promising new preparation that may offer superior tolerability compared with commercial daunorubicin.

Effects on Walker 256 tumour of carmustine associated with a cholesterol-rich microemulsion (LDE).

A cholesterol-rich microemulsion that binds to low-density lipoprotein (LDL) receptors (LDE), after injection into the bloodstream, concentrates in neoplastic tissues that over-express those receptors. LDE can thus serve as a vehicle for drug targeting. It was shown that carmustine side effects are pronouncedly reduced when the drug is associated with LDE in cancer patients. In this study, the therapeutic action of LDE associated with carmustine was compared with that of the non-associated drug in rats implanted with Walker 256 tumour. The toxicity and anti-tumour activity in rats treated with either free carmustine or carmustine associated with LDE and in control rats treated with saline solution were determined after a single intraperitoneal injection. The LD90 (90% lethal dose) of LDE-carmustine was 77 mg kg(-1) and of free carmustine was 44 mg kg(-1), indicating that LDE decreases toxicity. LDE-carmustine was able to decrease tumour mass at a lower dose level than free carmustine. Tumour regression time was shorter in LDE-carmustine- than in free carmustine-treated animals. Therefore, this study shows that the association of carmustine with LDE increases the therapeutic index of carmustine.