Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo.

Mycophenolic acid, a selective inhibitor of the de novo synthesis of guanosine nucleotides in T and B lymphocytes, has been proposed to inhibit human immunodeficiency virus (HIV) replication in vitro by depleting the substrate (guanosine nucleotides) for reverse transcriptase. Here we show that mycophenolic acid induced apoptosis and cell death in a large proportion of activated CD4+ T cells, thus indicating that it may inhibit HIV infection in vitro by both virological mechanisms and immunological mechanisms (depletion of the pool of activated CD4+ T lymphocytes). Administration of mycophenolate mophetil, the ester derivate of mycophenolic acid, to HIV-infected subjects treated with anti-retroviral therapy and with undetectable viremia resulted in the reduction of the number of dividing CD4 + and CD8+ T cells and in the inhibition of virus isolation from purified CD4+ T-cell populations. Based on these results, the potential use of mycophenolate mophetil in the treatment of HIV infection deserves further investigation in controlled clinical trials.

Synthesis and anticancer activity of long-chain isonicotinic ester ligand-containing arene ruthenium complexes and nanoparticles

Arene ruthenium complexes containing long-chain N-ligands L1 = NC5H4-4-COO-C6H4-4-O-(CH2)9-CH3 or L2 = NC5H4-4-COO-(CH2)10-O-C6H4-4-COO-C6H4-4-C6H4-4-CN derived from isonicotinic acid, of the type [(arene)Ru(L)Cl2] (arene = C6H6, L = L1: 1; arene = p-MeC6H4Pr i , L = L1: 2; arene = C6Me6, L = L1: 3; arene = C6H6, L = L2: 4; arene = p-MeC6H4Pr i , L = L2: 5; arene = C6Me6, L = L2: 6) have been synthesized from the corresponding [(arene)RuCl2]2 precursor with the long-chain N-ligand L in dichloromethane. Ruthenium nanoparticles stabilized by L1 have been prepared by the solvent-free reduction of 1 with hydrogen or by reducing [(arene)Ru(H2O)3]SO4 in ethanol in the presence of L1 with hydrogen. These complexes and nanoparticles show a high anticancer activity towards human ovarian cell lines, the highest cytotoxicity being obtained for complex 2 (IC50 = 2 μM for A2780 and 7 μM for A2780cisR)

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Clinical pharmacokinetics of mycophenolic acid and its metabolites in solid organ transplant recipient

Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressant mycophenolic acid (MPA), is widely used for maintenance immunosuppressive therapy and prevention of renal allograft rejection in renal transplant recipients.MPA inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme involved in the “de novo” synthesis of purine nucleotides, thus suppressing both T-cell and B-cell proliferation. MPA shows a complex pharmacokinetics with considerable interand intra- patient by between- and within patient variabilities associated to MPA exposure. Several factors may contribute to it. The pharmacokinetic modeling according to the population pharmacokinetic approach with the non-linear mixed effects models has shown to be a powerful tool to describe the relationships between MMF doses and the MPA exposures and also to identify potential predictive patients’ demographic and clinical characteristics for dose tailoring during the post-transplant immunosuppresive treatment.

Poly(beta,L-malic acid)Doxorubicin ionic complex: A pH-dependent delivery system.

Poly(ß,L-malic acid) (PMLA) was made to interact with the cationic anticancer drug Doxorubicin (DOX) in aqueous solution to form ionic complexes with different compositions and an efficiency near to 100%. The PMLA/DOX complexes were characterized by spectroscopy, thermal analysis, and scanning electron microscopy. According to their composition, the PMLA/DOX complexes spontaneously self-assembled into spherical micro or nanoparticles with negative surface charge. Hydrolytic degradation of PMLA/DOX complexes took place by cleavage of the main chain ester bond and simultaneous release of the drug. In vitro drug release studies revealed that DOX delivery from the complexes was favored by acidic pH and high ionic strength

Self-condensation of n-(N-propyl)butanimine: NMR and mass spectral analyses and investigation by theoretical calculation

The stability of N-propylbutanimine (1) was investigated under different experimental conditions. The acid-catalyzed self-condensation that produced the E-enimine (4) and Z-inimine (5) was studied by experimental analyses and theoretical calculations. Since the calculations for the energy of 5 indicated that it had a lower energy than 4, yet 4 was the principal product, the self-condensation of 1 must be kinetically controlled.

Alkaline earth layered benzoates as reusable heterogeneous catalysts for the methyl esterification of benzoic acid

This paper describes the synthesis and characterization of layered barium, calcium and strontium benzoates and evaluates the potential of these materials as catalysts in the synthesis of methyl benzoate. The methyl esterification of benzoic acid was investigated, where the effects of temperature, alcohol:acid molar ratio and amount of catalyst were evaluated. Ester conversions of 65 to 70% were achieved for all the catalysts under the best reaction conditions. The possibility of recycling these metallic benzoates was also demonstrated, evidenced by unaltered catalytic activity for three consecutive reaction cycles.

FAST GC-FID METHOD FOR MONITORING ACIDIC AND BASIC CATALYTIC TRANSESTERIFICATION REACTIONS IN VEGETABLE OILS TO METHYL ESTER BIODIESEL PREPARATION

A fast gas chromatography with a flame ionisation detector (GC-FID) method for the simultaneous analysis of methyl palmitate (C16:0), stearate (C18:0), oleate (C18:1), linoleate (C18:2) and linolenate (C18:3) in biodiesel samples was proposed. The analysis was conducted in a customised ionic-liquid stationary-phase capillary, SLB-IL 111, with a length of 14 m, an internal diameter of 0.10 mm, a film thickness of 0.08 µm and operated isothermally at 160 °C using hydrogen as the carrier gas at a rate of 50 cm s-1 in run time about 3 min. Once methyl myristate (C14:0) is present lower than 0.5% m/m in real samples it was used as an internal standard. The method was successful applied to monitoring basic and acidic catalysis transesterification reactions of vegetable oils such as soybean, canola, corn, sunflower and those used in frying process.

Comparative analysis of the trypanocidal activity and chemical properties of E-lychnophoric acid and its derivatives using theoretical calculations

E-Lychnophoric acid 1, its derivative ester 2 and alcohol 3 killed 100% of trypomastigote blood forms of Trypanosoma cruzi at the concentrations of 13.86, 5.68, and 6.48 µg/mL, respectively. Conformational distribution calculations (AM1) of 1, 2 and 3 gave minimum energies for the conformers a, b, c, and d, which differ from each other only in the cyclononene ring geometry. Calculations (DFT/BLYP/6-31G*) of geometry optimization and chemical properties were performed for conformers of 1, 2, and 3. The theoretical results were numerically compared to the trypanocidal activity. Calculated values of atomic charge, orbital population, and vibrational frequencies showed that the C-4-C-5 pi-endocyclic bond does not affect the trypanocidal activity of the studied compounds. Nevertheless, the structure of the group at C-4 strongly influences the activity. However, the theoretical results indicated that the intra-ring (C-1 and C-9) and pi-exocycle (C-8 and C-14) carbons of caryophyllene-type structures promote the trypanocidal activity of these compounds.

Flavianate, an amino acid precipitant, is a competitive inhibitor of trypsin at pH 3.0

Textile dyes bind to proteins leading to selective co-precipitation of a complex involving one protein molecule and more than one dye molecule of opposite charge in acid solutions, in a process of reversible denaturation that can be utilized for protein fractionation. In order to understand what occurs before the co-precipitation, a kinetic study using bovine ß-trypsin and sodium flavianate was carried out based on reaction progress curve techniques. The experiments were carried out using a-CBZ-L-Lys-p-nitrophenyl ester as substrate which was added to 50 mM sodium citrate buffer, pH 3.0, containing varying concentrations of ß-trypsin and dye. The reaction was recorded spectrophotometrically at 340 nm for 30 min, and the families of curves obtained were analyzed simultaneously by fitting integrated Michaelis-Menten equations. The dye used behaved as a competitive inhibitor of trypsin at pH 3.0, with Ki = 99 µM; kinetic parameters for the substrate hydrolysis were: Km = 32 µM, and kcat = 0.38/min. The competitive character of the inhibition suggests a specific binding of the first dye molecule to His-57, the only positively charged residue at the active site of the enzyme.

Effect of dietary fat saturation on lipid metabolism, arachidonic acid turnover and peritoneal macrophage oxidative stress in mice

We investigated the effects of a saturated fat diet on lipid metabolism and arachidonic acid (AA) turnover in mouse resident peritoneal macrophages. The pro-oxidative effect of this diet was also studied. Female C57BL/6 mice were weaned at 21 days of age and assigned to either the experimental diet containing coconut oil (COCO diet), or the control diet containing soybean oil as fat source (10 mice per group). The fat content of each diet was 15% (w/w). Mice were fed for 6 weeks and then sacrificed. The concentration of total lipids, triglycerides, (LDL + VLDL)-cholesterol, thiobarbituric acid-reactive substances (TBARS) and reduced glutathione were increased in the plasma of mice fed the COCO diet, without changes in phospholipid or total cholesterol concentrations compared to control. The concentrations of total cholesterol, free and esterified cholesterol, triglycerides, and TBARS were increased in the macrophages of COCO-fed mice, while the content of total phospholipids did not change. The phospholipid composition showed an increase of phosphatidylcholine and a decrease of phosphatidylethanolamine. The [³H]-AA distribution in the phospholipid classes showed an increase in phosphatidylcholine and phosphatidylethanolamine. Incorporation of [³H]-cholesterol into the macrophages of COCO-fed mice and into the cholesterol ester fraction was increased. The COCO diet did not affect [³H]-AA uptake but induced an increase in [³H]-AA release. The COCO diet also enhanced AA mobilization induced by lipopolysaccharide. These results indicate that the COCO diet, high in saturated fatty acids, alters the lipid metabolism and AA turnover of peritoneal macrophages in female mice and also produces a significant degree of oxidative stress.

Aryl hydroxamic acid analogues as potential therapeutic agents /

A new synthetic pathway to analogues of the aglucones of naturally occurring cyclic hydroxamic acids (2,4-dihydroxy-l,4-benzoxazin-3-ones) has been developed. The new pathway involves the coupling of substituted nitrophenols wdth /-propyl-abromo- O-methoxymethylglycolate. These materials were reductively cyclised to reveal the hydroxamic acid functionality. Removal of the C-2 0-methoxymethyl protecting group was achieved chemoselectively using boron trichloride. The analogue 7-methoxy-2,4-dihydroxy-l,4-benzoxazin-3-one (DIMBOA) was assayed with papain and a semilog plot of activity of papain in the presence of excess DIMBOA was found to be linear. A single exponential equation was suggested as the model for kinetic analysis. '^ Nuclear magnetic resonance (NMR) spectra of a couple of hydroxamates were acquired as reference standards for future mechanistic studies of these compounds as thiol protease inhibitors. A 10% '^-labeled sample ofDIMBOA was also prepared for future mechanistic studies using NMR techniques.