Poly(D,L-lactide-co-glycolide)/hydroxyapatite core-shell nanosphere. Part 2: Simultaneous release of a drug and a prodrug (clindamycin and clindamycin phosphate)

The novel concept of a simultaneous, controlled release of a drug and a prodrug with different physico-chemical properties was applied in order to prolong the release period of antibiotics and estimate their high local concentrations, which are the necessary preconditions for the treatment of some chronic infection diseases. For this purpose poly(D,L-lactide-co-glycolide)/hydroxyapatite (PLGA/HAp) core-shell nanostructures were used as the carrier of clindamycin-base, as a drug, and clindamycin-2-phosphate, as a prodrug model. As a result, a two-step release was observed: the controlled release of the more soluble phosphate form and the sustained release of the less-soluble base form of clindamycin, resulting in a high overall concentration of the released drug during the period of 30 days in vitro. The HAp phase within the PLGA core-shells, applied as a drug carrier, delayed the process of the degradation of the polymer; however, the presence of the drug affected the process of degradation and this influence was the dominant factor in the control over the degradation of the polymer phase of PLGA/HAp and the consequent kinetics of the drug release.     

Direct detection of nanoparticles and components in smoke by time-of-flight mass spectrometry with soft plasma ionization

A new system combining a soft plasma ionization (SPI) source with a time-of-flight mass spectrometer (TOFMS) has been successfully developed and applied to direct and on-line analysis of nanoparticles in smoke generated during combustion of mosquito coils with no sample preparation. The mass spectra of nanoparticles in smoke were examined in conjunction with the effects of species, pressure and current of the SPI discharge on fragmentation. The results indicated that a maximum mass of m/z 1576 was detectable when the following optima SPI conditions were satisfied: a He gas pressure of 1000 Pa with an air pressure of 1600 Pa and a discharge current of 110 mA. Furthermore, considering the results for emission spectra we suppose an ionization mechanism of SPI in which excitation and ionization of nitrogen molecule is promoted by the presence of He gas, leading to promote the smoke sample ionization. The mass spectrum of nanoparticles showed specific patterns of a peak interval of 74 which were assigned to triacetylene (1,3,5-hexatriyne). The most abundant peak in the mass spectrum, at m/z 452, was assigned to triacontanoic acid.     

Time-resolved fluorescence study on the photomerocyanine form of spiropyran and its derivative with azobenzene

The excited state dynamics of the photomerocyanine (PMC) form originating from spirobenzopyran and the bi-functional photochromic compound spirobenzopyran–azobenzene (SpAz), containing typical photochromic molecules of spirobenzopyran (Sp) and azobenzene (Az), were investigated using picosecond time-resolved fluorescence measurements in solution at 200 and 285 K and in a PMMA polymer film at 298 K. While the fluorescence lifetimes of PMC were about twice as long as those of SpAz under all experimental conditions, both lifetimes showed similar strong dependence on viscosity rather than temperature. These results suggest that non-radiative decay to an intermediate state could be accompanied by a significant conformational change. The effect of the Az moiety in this relaxation process is also discussed. It is unlikely that an energy transfer from the PMC moiety to the Az moiety occurs. It was concluded that the PMC moiety in the bi-functional SpAz is independent from the Az moiety.     

Rapid determination of fumagillin residues in honey by liquid chromatography-tandem mass spectrometry using the QuEChERS method

A new, rapid, and efficient method for determining the fumagillin residues in honey was developed. The samples extracted were analyzed using LC/MS/MS. Chromatographic separation of fumagillin was performed in gradient mode on a C8 column (100 x 2.0 mm, 5 microm) at 40 degrees C. The mobile phase consisted of a mixture of 2 mM ammonium formate-0.01% formic acid solution and methanol; the flow rate was set to 0.2 mL/min. Under these conditions, it was possible to measure fumagillin and its isomers as a single peak. The sample preparation procedure used is based on the QuEChERS (quick, easy, cheap, effective, rugged, and safe) method, which is fast (approximately 30 min) and uses less organic solvent. The fumagillin was extracted with acetonitrile containing 0.1% formic acid, then purified using a solid-phase extraction method with an Oasis mixed-mode weak anion-exchange cartridge. The overall recovery of fumagillin ranged from 88.1 to 99.4%; the intra- and interassay CVs were <4.5% and <4.9%, respectively. The LOQ was 0.1 microg/kg. LC/MS/MS coupled with the QuEChERS method showed strong potential as a method for determining fumagillin residues in honey.     

"Click-made" biaryl-linker improving efficiency in protein labelling for the membrane target protein of a bioactive compound

We report on the design, synthesis and assessment of a novel biaryl-linked (BArL) molecular probe for the exploration of low-abundant target proteins for bioactive compounds based on the activity based protein profiling (ABPP) approach. Surprisingly, the performance of the BArL probe was better than that of the stepwise tagging approach that is considered to be the most effective method used in ABPP study.     

Structure, solution chemistry, antiproliferative actions and protein binding properties of non-conventional platinum(II) compounds with sulfur and phosphorus donors

Twelve Pt(II) complexes with cis-PtP(2)S(2) pharmacophores (where P(2) refers to two monodentate or one bidentate phosphane ligand and S(2) is a dithiolato ligand) were prepared, characterized and evaluated as potential antiproliferative agents. The various compounds were first studied from the structural point of view; afterward, their solubility properties as well as their solution behaviour were analyzed in detail. Antiproliferative properties were specifically evaluated against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin. For comparison purposes similar studies were carried out on four parent cis-dichloro bisphosphane Pt(II)complexes. On the whole, the cis-PtP(2)S(2) compounds displayed significant antiproliferative properties while the cis-PtP(2)Cl(2) (cis-dichloro bisphosphane Pt(II)) compounds revealed quite poor biological performances. To gain further insight into the molecular mechanisms of these bisphosphane Pt(II) compounds, the reactions of selected complexes against the model protein cytochrome c were investigated by ESI-MS and their adduct formation explored. A relevant reactivity with cyt c was obtained only for cis-PtP(2)Cl(2) compounds, whereas cis-PtP(2)S(2) compounds turned out to be nearly unreactive. The obtained results are interpreted and discussed in the frame of the current knowledge of anticancer platinum compounds and their structure-activity-relationships. The observation of appreciable antiproliferative effects for the relatively inert cis-PtP(2)S(2) compounds strongly suggests that these compounds will undergo specific activation within the cellular environment.     

Anti-allergic effect of the flavonoid myricitrin from Myrica rubra leaf extracts in vitro and in vivo

Flavonoids are ingested by the general population as anti-oxidant and anti-inflammatory agents. In this study, we investigated the effects of myricitrin, a flavonoid rich in Myrica rubra leaf, upon anti-inflammatory action. Myrica rubra leaf extracts inhibited pro-inflammatory TNFα production in a macrophage cell line, Raw264.7 cells. We observed that the serum IgE levels in the leaf extract-treated DO11.10, a mouse allergy model, were down-regulated. HPLC was performed to demonstrate that M. rubra leaf extracts contain a large amount of myricitrin. We observed an inhibitory effect of HPLC-purified myricitrin on TNFα production in Raw264.7 cells. Thus, myricitrin may be of potential interest in the management of inflammatory conditions.     

High-throughput and simultaneous analysis of eight central-acting muscle relaxants in human plasma by ultra-performance liquid chromatography–tandem mass spectrometry in the positive and negative ionization modes

In this report, a high-throughput and sensitive method for analysis of eight central-acting muscle relaxants in human plasma by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) in the positive and negative ionization modes using tolbutamide as internal standard is presented. After pretreatment of a plasma sample by solid-phase extraction with an Oasis HLB cartridge, muscle relaxants were analyzed by UPLC with Acquity UPLC BEH C₁₈ column and Acquity TQD tandem quadrupole mass spectrometer equipped with an electrospray ionization interface. The calibration curves for muscle relaxants spiked into human plasma equally showed good linearities in the nanogram per milliliter order range. The detection limits (signal-to-noise ratio = 3) was as low as 0.1–2 ng/mL. The method gave satisfactory recovery rates, accuracy, and precision for quality control samples spiked with muscle relaxants. To further validate the present method, 250 mg of chlorphenesin carbamate was orally administered to a healthy male volunteer, and the concentrations of chlorphenesin carbamate in plasma were measured 0.5, 1, 2, 4, 6, and 8 h after dosing; their concentrations in human plasma were between 0.62 and 2.44 μg/mL. To our knowledge, this is the first report describing simultaneous analysis of over more than two central-acting muscle relaxants by liquid chromatography–tandem mass spectrometry. This has been realized by the capability of our instrument for simultaneous multiple reaction monitoring of the target compounds in both positive and negative ionization modes. Therefore, the present method seems very useful in forensic and clinical toxicology and pharmacokinetic studies.     

Enantiocontrolled total syntheses of breviones A, B, and C

Enantiocontrolled total syntheses of the breviones A, B, and C have been accomplished using a highly diastereoselective oxidative coupling of an α-pyrone with a tricyclic diene prepared from an optically pure Wieland-Miescher ketone derivative through the 7-endo-trig mode of acyl radical cyclization.     

Tigloylshikonin, a new minor Shikonin derivative, from the roots and the commercial root extract of lithospermum erythrorhizon

Tigloylshikonin, a new shikonin derivative esterified with tiglic acid ((E)-2-methylbut-2-enoic acid), was isolated as a minor pigment from a food colorant "Shikon color," a commercial root extract from Lithospermum erythrorhizon SIEBOLD et ZUCCARINI. The structure of tigloylshikonin was elucidated using (1)H, (13)C, the difference nuclear Overhauser effect (NOE), and 2D NMR techniques. Its stereochemistry was determined by chiral-phase HPLC analysis. Tigloylshikonin was also found in the roots of L. erythrorhizon, which indicated that this new shikonin derivative is a typical component of naphthoquinone pigments in the roots of L. erythrorhizon.