Long-Term Effectiveness, Safety and Tolerability of Fingolimod in Patients with Multiple Sclerosis in Real-World Treatment Settings in France: The VIRGILE Study.

Introduction: It is important to confirm the effectiveness and tolerability of disease-modifying treatments for relapsing-remitting multiple sclerosis (RRMS) in real-world treatment settings. This prospective observational cohort study (VIRGILE) was performed at the request of the French health authorities. The primary objective was to evaluate the effectiveness of fingolimod 0.

Discovery of isatin and 1H-indazol-3-ol derivatives as d-amino acid oxidase (DAAO) inhibitors.

d-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d-serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1H-indazol-3-ol derivatives and nanomolar inhibitors were identified.

The janus facet of nanomaterials.

Application of nanoscale materials (NMs) displays a rapidly increasing trend in electronics, optics, chemical catalysis, biotechnology, and medicine due to versatile nature of NMs and easily adjustable physical, physicochemical, and chemical properties. However, the increasing abundance of NMs also poses significant new and emerging health and environmental risks. Despite growing efforts, understanding toxicity of NMs does not seem to cope with the demand, because NMs usually act entirely different from those of conventional small molecule drugs.

Role of the conformational flexibility of evodiamine in its binding to protein hosts: a comparative spectroscopic and molecular modeling evaluation with rutaecarpine.

Spectroscopic studies combined with computational analysis indicate the inherent conformational flexibility of the β-carbolin derivative evodiamine (EVD) featured with diverse pharmacological activities. Qualitative evaluation of the circular dichroism (CD) spectra of EVD enantiomers complemented with quantum chemical calculations reveals a chiral exciton signature that can be assigned to the folded, L-shaped conformation of the molecule. Changes of the exciton couplet measured in different solvents and the near-UV CD profile upon binding to human serum albumin (HSA) refer to the structural adaptability of EVD.

Cationic permethylated 6-monoamino-6-monodeoxy-β-cyclodextrin as chiral selector of dansylated amino acids in capillary electrophoresis.

The resolution power of permethylated 6-monoamino-6-monodeoxy-βCD (PMMABCD) - a single isomer, cationic CD derivative - developed previously for chiral analyses in capillary electrophoresis was further studied here. Dansylated amino acids (Dns-AA) were chosen as amphoteric chiral model compounds. Changes in the resolutions of Dns-AAs by varying pH and selector concentrations were investigated and correlated with their structures and chemical properties (isoelectric point and lipophilicity).

Intercalation of bovine serum albumin coated gold clusters between phospholipid bilayers: temperature-dependent behavior of lipid-AuQC@BSA assemblies with red emission and superlattice structure.

A method has been developed to encapsulate bovine serum albumin (BSA)-coated gold quantum clusters (AuQC@BSA) in a multilamellar system of dipalmitoylphosphatidylcholine (DPPC). Results have shown that intercalation of AuQC@BSA particles into lipid bilayers occurs in the presence of CaCl2. Intense red photoluminescence emission was observed after encapsulation of the clusters.

Influence of acid-induced conformational variability on protein separation in reversed phase high performance liquid chromatography.

Influence of acid concentration in the mobile phase on protein separation was studied in a wide concentration range using trifluoroacetic acid (TFA) and formic acid (FA). At low, 0.001-0.

Development of novel chiral capillary electrophoresis methods for the serotonin receptor (5-HT2A) antagonist MDL 100,907 (volinanserin) and for its key intermediate compound.

Enantioselective capillary electrophoretic methods were elaborated for the determination of the enantiomeric purity of (R)-MDL 100,907 and its preparatively resolved key intermediate compound during the synthesis route. The pKa values of the intermediate compound and the end product determined by CE were 10.5±0.

Fatty acid modulated human serum albumin binding of the β-carboline alkaloids norharmane and harmane.

Harmane and norharmane are representative members of the large group of natural β-carboline alkaloids featured with diverse pharmacological activities. In blood, these agents are transported by human serum albumin (HSA) which has a profound impact on the pharmacokinetic and pharmacodynamic properties of many therapeutic drugs and xenobiotics. By combination of various spectroscopic methods, the present contribution is aimed to elucidate how nonesterified fatty acids (FAs), the primary endogenous ligands of HSA, affect the binding properties of harmane and norharmane.

Synthesis and pharmacological investigation of new N-hydroxyalkyl-2-aminophenothiazines exhibiting marked MDR inhibitory effect.

Novel N-hydroxyalkyl-2-aminophenothiazines implying a tetrazole moiety at the alkyl chain have been synthesized by hydroboration-oxidation of dienes followed by Buchwald-Hartwig cross-coupling reaction. Also, some sulfoxide and sulfone derivatives have been prepared by selective oxidations. MDR inhibition studies on rat hepatocyte cell culture revealed that some derivatives exhibit marked biological efficacy exceeding that of the standard verapamil (e.

Polyamidoamine dendrimer impairs mitochondrial oxidation in brain tissue.

Background: The potential nanocarrier polyamidoamine (PAMAM) generation 5 (G5-NH(2)) dendrimer has been shown to evoke lasting neuronal depolarization and cell death in a concentration-dependent manner. In this study we explored the early progression of G5-NH(2) action in brain tissue on neuronal and astroglial cells.

Results: In order to describe early mechanisms of G5-NH(2) dendrimer action in brain tissue we assessed G5-NH(2) trafficking, free intracellular Ca(2+) and mitochondrial membrane potential (Ψ(MITO)) changes in the rat hippocampal slice by microfluorimetry.

Cryptocapsinepoxide-type carotenoids from red mamey, Pouteria sapota.

New carotenoids, cryptocapsin-5,6-epoxide, 3'-deoxycapsanthin-5,6-epoxide, and cryptocapsin-5,8-epoxides, have been isolated from the ripe fruits of red mamey (Pouteria sapota). Cryptocapsin-5,6-epoxide was prepared by partial synthesis via epoxidation of cryptocapsin, and the (5R,6S)- and (5S,6R)-stereoisomers were identified by HPLC-ECD analysis. Spectroscopic data of the natural (anti) and semisynthetic (syn) derivatives obtained by acid-catalyzed rearrangement of cryptocapsin-5,8-epoxide stereoisomers were compared for structural elucidation.

Structure and stability of warfarin-sodium inclusion complexes formed with permethylated monoamino-β-cyclodextrin.

Inclusion complexes of warfarin enantiomers with permethylated monoamino-β-cyclodextrin (PMMABCD) were characterized using CE and (1)H NMR spectroscopy in aqueous solution. These techniques gave complementary information on the stability and the structure of the diastereomeric host-guest inclusion complexes. The stability constants were determined from CE experiments in a wide pH range.

Comparison of separation performances of novel β-cyclodextrin-based chiral stationary phases in high-performance liquid chromatographic enantioseparation.

Three β-cyclodextrin-based chiral stationary phases were developed applying novel bonding chemistry. The separation performances of β-cyclodextrin, (R,S)-2-hydroxypropyl-β-cyclodextrin, and permethyl-β-cyclodextrin-based CSPs were compared in the resolution of structurally divergent analytes, such as coumarins, dansyl amino acids, and propionic acid derivatives. Separations were carried out in reversed phase mode applying 0.

Stereoselective analysis of endomorphin diastereomers: resolution of biologically active analogues by capillary electrophoresis applying cyclodextrins as mobile phase additives.

Seven diastereomer pairs of tetrapeptide analogues (TP) of endomorphin-1 and -2 were synthesized. A stereoselective capillary electrophoretic method was developed for controlling stereoisomeric ratio or purity. The isoelectric points of the tetrapeptides were between 8.

Characterization of binding mode of imatinib to human α1-acid glycoprotein.

Imatinib (IMT) is a selective tyrosine kinase inhibitor, used in the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Its strong plasma protein binding was found to belong to the F1*S genetic variant of α(1)-acid glycoprotein (AGP). In this work, comparative AGP binding studies were performed with IMT fragment molecules to reveal which parts of the molecule are important in the high-affinity interaction provoking specific spectral changes.

Assessing toxicity of polyamidoamine dendrimers by neuronal signaling functions.

We report for the first time on neuronal signaling for the evaluation of interactions between native plasmamembrane and polyamidoamine (PAMAM) dendrimers. Generation 5 polycationic (G5-NH(2)), novel β-D-glucopyranose-conjugated G5-NH(2) and generation 4.5 polyanionic (G4.

Enantiomeric separation of antimalarial drugs by capillary electrophoresis using neutral and negatively charged cyclodextrins.

Capillary electrophoresis (CE) methods for chiral resolution of five antimalarial drugs (primaquine, tafenoquine, mefloquine, chloroquine and quinacrine) were developed by using a wide selection of neutral and anionic cyclodextrin (CD) derivatives. The use of sulfobutyl-β-CD and carboxymethyl-β-CD (CMBCD) resulted in good resolution of quinacrine and tafenoquine, respectively. New results are presented for resolutions of chloroquine and mefloquine.

Separation of cis-beta-lactam enantiomers by capillary electrophoresis using cyclodextrin derivatives.

Chiral separation of 19 pairs of cis-beta-lactam (BL) stereoisomers of pharmacological importance was examined by capillary electrophoresis using cyclodextrin (CD) derivatives. In order to select the most effective conditions separating the highest number of stereoisomers of BLs, single carboxymethyl alpha-, beta- and gamma-, as well as sulfobutyl beta-CD derivatives were applied. Additionally, carboxymethyl and sulfobutyl beta-CD derivatives complemented with neutral beta-CD derivatives as dual CD systems were tested.

Chiral separation by a monofunctionalized cyclodextrin derivative: from selector to permethyl-beta-cyclodextrin bonded stationary phase.

Preparation of (6-monoureido-6-monodeoxy) permethylated beta-cyclodextrin bonded chiral stationary phase from permethylated 6-monoamino-6-monodeoxy-beta-cyclodextrin is described. The optimized chiral stationary phase was evaluated by using HPLC separation of racemates of coumarin derivatives. Column characterization was performed by solid-state (13)C, (15)N, (29)Si NMR using cross-polarization at the magic angle spinning.

Selective binding interactions of deramciclane to the genetic variants of human alpha(1)-acid glycoprotein.

Background: alpha(1)-Acid glycoprotein (AGP) plays a decisive role in the serum protein binding of several drugs.Genetic variants of AGP have different ligand binding properties. The binding of deramciclane (DER), a chiral anxiolytic agent, has been studied on A and F1/S genetic variants of AGP.

Validation of high-affinity binding sites for succinic acid through distinguishable binding of gamma-hydroxybutyric acid receptor-specific NCS 382 antipodes.

Gamma-hydroxybutyric acid (GHB) binding to multiple sites for the tricarboxylic acid cycle intermediate succinic acid (SUC) has been disclosed recently. In order to better characterize these targets, distinguishable binding of GHB receptor-specific NCS 382 antipodes to [(3)H]-SUC or [(3)H]-GHB labelled sites in rat brain synaptic membranes was explored. Eutomer binding parameters suggest identity of the high-affinity target for SUC with a synaptic GHB receptor subtype.

Cyclothiazide binding to the GABAA receptor.

In order to explore the molecular interaction between cyclothiazide (CTZ) and gamma-aminobutyric acidA (GABAA) receptors, possibly underlying inhibition of GABAA receptor currents, [3H]-CTZ was synthesized. Binding of [3H]-CTZ to rat brain synaptic membranes could be observed only in the presence of the GABAA receptor antagonist (-)[1S,9R]-bicuculline methiodide (BMI) (EC(50,BMI)=500+/-80microM). GABA decreased [(3)H]-CTZ binding induced by the presence 300microM and 3mM BMI with IC(50,GABA) values of 300+/-50microM and 5.

Selective plasma protein binding of antimalarial drugs to alpha1-acid glycoprotein.

Human plasma protein binding of six antimalarial agents of quinoline and acridine types was investigated by using spectroscopic techniques, affinity chromatography, ultrafiltration and HPLC methods. Induced circular dichroism (ICD) spectra showed binding of amodiaquine (AMQ), primaquine (PRQ), tafenoquine (TFQ), and quinacrine (QR) to alpha(1)-acid glycoprotein (AAG), the serum level of which greatly increases in Plasmodium infections. Association constant (K(a)) values of about 10(5)-10(6) M(-1) could be determined.

Conformation selectivity in the binding of diazepam and analogues to alpha1-acid glycoprotein.

Diazepam, a 1,4-benzodiazepine lacking chiral centre, exists in an equimolar mixture of two chiral conformers. Induced circular dichroism spectra for the binding of diazepam and its 3,3-dimethyl substituted analogues to alpha1-acid glycoprotein (AGP) revealed that opposite to human serum albumin, AGP preferably binds the P-conformers. Accordingly, slightly favoured binding of (R)-enantiomers of 3-alkyl derivatives having P-conformation was found.