Publications

Abstract Cardiovascular complications associated with 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse have increasingly been reported. The indirect effect of MDMA mediated by a sustained high level of circulating biogenic amines may contribute to the cardiotoxic effects, but other factors, like the direct toxic effects of MDMA and its metabolites in cardiac cells, remain to be investigated. Thus, the objective of the present in vitro study was to evaluate the potential cardiotoxic effects of MDMA and its major metabolites 3,4-methylenedioxyamphetamine (MDA), N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA), and alpha-methyldopamine (alpha-MeDA) using freshly isolated adult rat cardiomyocytes. The cell suspensions were incubated with these compounds in the final concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 mM for 4 h. alpha-MeDA, N-Me-alpha-MeDA, and their respective aminochromes (oxidation products) were quantified in cell suspensions by HPLC-DAD. The toxic effects were evaluated at hourly intervals for 4 h by measuring the percentage of cells with normal morphology, glutathione (GSH), and glutathione disulfide (GSSG); intracellular Ca2+, ATP, and ADP; and the cellular activities of glutathione peroxidase, glutathione reductase, and glutathione-S-transferase. No toxic effects were found after exposure of rat cardiomyocytes to MDMA or MDA at any of the tested concentrations for 4 h. In contrast, their catechol metabolites N-Me-alpha-MeDA and alpha-MeDA induced significant toxicity in rat cardiomyocytes. The toxic effects were characterized by a loss of normal cell morphology, which was preceded by a loss of GSH homeostasis due to conjugation of GSH with N-Me-alpha-MeDA and alpha-MeDA, sustained increase of intracellular Ca2+ levels, ATP depletion, and decreases in the antioxidant enzyme activities. The oxidation of N-Me-alpha-MeDA and alpha-MeDA into the toxic compounds N-methyl-alpha-methyldopaminochrome and alpha-methyldopaminochrome, respectively, was also verified in cell suspensions incubated with these MDMA metabolites. The results obtained in this study provide evidence that the metabolism of MDMA into N-Me-alpha-MeDA and alpha-MeDA is required for the expression of MDMA-induced cardiotoxicity in vitro, being N-Me-alpha-MeDA the most toxic of the studied metabolites.

Abstract The present work reports a vibrational spectroscopic study of several beta-methyl-beta-nitrostyrene derivatives, which are important intermediates in the synthesis of illicit amphetamine-like drugs, such as 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), p-methoxyamphetamine (PMA) and 4-methylthioamphetamine (4-MTA). A complete conformational analysis of 3,4-methylenedioxy-beta-methyl-beta-nitrostyrene (3,4-MD-MeNS), 4-methoxy-beta-methyl-beta-nitrostyrene (4-MeO-MeNS), 4-methylthio-beta-methyl-beta-nitrostyrene (4-MeS-MeNS), was carried out by Raman spectroscopy coupled to ab initio MO calculations - both complete geometry optimisation and harmonic frequency calculation. The Raman spectra show characteristic features of these precursors, which allow their ready differentiation and identification. It was verified that the conformational behaviour of these systems is mainly determined by the stabilising effect of pi-electron delocalisation.

Abstract The standard (pdegrees = 0.1 MPa) molar enthalpy of formation of crystalline 2-hydroxypyridine N-oxide was measured, at T = 298.15 K, by static bomb calorimetry and the standard molar enthalpy of sublimation, at T = 298.15 K, was obtained using Calvet microcalorimetry. These values were used to derive the standard molar enthalpy of formation of 2-hydroxypyridine N-oxide in gaseous phase, and to evaluate the dissociation enthalpy of the N-O bond. Additionally, high-level density functional theory calculations using the B3LYP hybrid exchange-correlation energy functional have been performed for the three isomers of hydroxypyridine N-oxide in order to confirm the experimental trend for the dissociation enthalpy of the (N-O) bond.

Abstract The standard (p(o) = 0.1 MPa) molar energies of combustion in oxygen, at T = 298.15 K, of four 1,3-benzodioxole derivatives ( sesamol, piperonyl alcohol, piperonylic acid and homopiperonylic acid) were measured by static bomb calorimetry. The values of the standard molar enthalpies of sublimation, at T = 298.15 K, were derived from vapour pressure - temperature measurements using the Knudsen effusion technique. Combining these results the standard molar enthalpies of formation of the compounds, in the gas phase, at T = 298.15 K, have been calculated: sesamol (- 325.7 +/- 1.9) kJ mol(-1); piperonyl alcohol (- 329.0 +/- 2.0) kJ mol(-1); piperonylic acid ( - 528.9 +/- 2.6) kJ mol(-1) and homopiperonylic acid (- 544.5 +/- 2.9) kJ mol(-1). The most stable geometries of all the compounds were obtained using the density functional theory with the B3LYP functional and two basis sets: 6-31G** and 6-311G**. The nonplanarity of the molecules was analyzed in terms of the anomeric effect, which is believed to arise from the interaction between a nonbonded oxygen p orbital and the empty orbital sigma*(co) involving the other oxygen atom. Calculations were performed to obtain estimates of the enthalpies of formation of all the benzodioxoles using appropriate isodesmic reactions. There is a perfect agreement between theoretical and experimental results.

Abstract In this work, the gas-phase homolytic N-H bond dissociation enthalpy (BDE) was investigated for a large series of molecules containing at least one N-H bond by means of accurate density-functional theory calculations. The molecules studied belong to different classes of compounds, namely, amines, amides and anilines, amino acids, phenoxazines, indolamines, and other compounds of general interest, such as anti-inflammatory drugs. To achieve these purposes, the (RO)B3LYP/6-311+G(2d,2p)//(U)B3LYP/6-31G* level of theory was used. The calculated gas-phase N-H BDEs, at T = 298.15 K, are in the range 499.6-203.9 kJ/mol, for purine and HNO, respectively. Further, the calculated BDEs are in excellent agreement with a significant number of available experimental BDEs. Solvent effects were also taken in account, and rather significant differences are found among N-H BDEs computed in the gas phase and in heptane, DMSO, or water.

Abstract The standard (pdegrees = 0.1 MPa) molar enthalpies of formation of the crystalline complexes bis[N-(N",N"-diethylaminothiocarbonyl)benzamidinato]nickel(II), {Ni(datb)(2)}, and bis[N-(N",N"-diethylaminothiocarbonyl)-N'-phenylbenzamidinato]nickel(II), {Ni(datpb)(2)}, were determined, at T = 298.15 K, by high precision solution-reaction calorimetry. [GRAPHICS] From the obtained results, the metal-ligand exchange enthalpies in the crystalline phase were derived. The enthalpy of a hypothetical metal-ligand exchange reaction in the crystalline phase was derived, thus allowing a discussion of the energetics of complexation in comparison with known crystal-structural parameters.

Abstract The amphetamine designer drugs 3,4-methylenedioxymethamphetamine (MDMA or "ecstasy") and its N-demethylated analogue 3,4-methylenedioxyamphetamine (MDA or "love") have been extensively used as recreational drugs of abuse. MDA itself is a main MDMA metabolite. MDMA abuse in humans has been associated with numerous reports of hepatocellular damage. Although MDMA undergoes extensive hepatic metabolism, the role of metabolites in MDMA-induced hepatotoxicity remains unclear. Thus, the aim of the present study was to evaluate the effects of MDA and alpha-methyldopamine (alpha-MeDA), a major metabolite of MDA, in freshly isolated rat hepatocyte suspensions. The cells were incubated with MDA or alpha-MeDA at final concentrations of 0.1, 0.2, 0.4, 0.8, or 1.6 mM for 3 h. The toxic effects induced following incubation of hepatocyte suspensions with these metabolites were evaluated by measuring cell viability, the extent of lipid peroxidation, levels of glutathione (GSH) and glutathione disulfide (GSSG), the formation of GSH conjugates, and the activities of GSSG reductase (GR), GSH peroxidase (GPX), and GSH S-transferase (GST). MDA induced a concentration- and time-dependent GSH depletion, but had a negligible effect on lipid peroxidation, cell viability, or on the activities of GR, GPX, and GST. In contrast, alpha-MeDA (1.6 mM, 3 h) induced a marked depletion of GSH accompanied by a loss on cell viability, and decreases in GR, GPX and GST activities, although no significant effect on lipid peroxidation was found. For both metabolites, GSH depletion was not accompanied by increases in GSSG levels; rather, 2-(glutathion-S-yl)-alpha-MeDA and 5-(glutathion-S-yl)-alpha-MeDA were identified by HPLC-DAD/EC within cells incubated with MDA or alpha-MeDA. The results provide evidence that one of the early consequences of MDMA metabolism is a disruption of thiol homeostasis, which may result in loss of protein function and the initiation of a cascade of events leading to cellular damage.

Abstract Fluorocarbons are attracting much attention nowadays because of their unique properties, which may provide interesting applications in areas as wide as environmental, biomedical and material science. However, the behavior of these compounds is not well understood and only scattered data can be found in the open literature and company technical reports. In this work, three important properties of perfluoro-n-octane were experimentally determined: the liquid density, the vapor pressure and the oxygen solubility. Liquid density was measured, in the temperature range between 288 and 313 K with a vibrating tube densimeter and vapor pressure was measured with an apparatus based on the static method up to 333 K. The solubility of oxygen in perfluoro-n-octane, in the temperature range between 288 and 313 K and at pressures close to atmospheric, was determined experimentally with a precision apparatus based on the saturation method at constant pressure. Experimental solubility data, density and vapor pressure were correlated with the soft-SAFT EoS.

Abstract The standard (pdegrees = 0.1 MPa) molar enthalpies of combustion in oxygen of three crystalline N-benzoylthiocarbamic-O-alkylesters, PhCONHCSOR, R = Et (Hbtcee), n-Bu (Hbtcbe), n-Hex (Hbtche), were measured at T = 298.15 K by rotating bomb calorimetry. The standard molar enthalpies of sublimation of the three compounds were measured using Calvet microcalorimetry. These values were used to derive the standard molar enthalpies of formation of the compounds in their crystalline and gaseous phases, respectively. [GRAPHIC]

Abstract The standard (p(0) = 0.1 MPa) molar enthalpies of combustion, in oxygen, of three crystalline N-thiocarbamoylbenzamidines, PhCRNCSNEt2, R = -NH2 (DATB), -NEt2 (DATDB), -NHPh (DATPB), were measured at T = 298.15 K by rotating bomb calorimetry. The standard molar enthalpies of sublimation of the three compounds were measured by Calvet microcalorimetry. These values were used to derive the standard molar enthalpies of formation of the compounds in their crystalline and gaseous phases, respectively. [GRAPHICS]