Densitometry and indirect normal‐phase HPTLC–ESI–MS for separation and quantitation of drugs and their glucuronide metabolites from plasma

The present work describes novel methods using densitometry and indirect or off‐line high performance thin‐layer chromatography–mass spectrometry (HPTLC–MS) for the simultaneous detection and quantification of asenapine, propranolol and telmisartan and their phase II glucuronide metabolites. After chromatographic separation of the drugs and their metabolites the analytes were scraped, extracted in methanol and concentrated prior to mass spectrometric analysis. Different combinations of toluene and methanol–ethanol–n‐butanol–iso‐propanol were tested for analyte separation and the best results were obtained using toluene–methanol–ammonia (6.9:3.0:0.1, v/v/v) as the elution solvent. All of the drug–metabolite pairs were separated with a homologous retardation factor difference of ≥22. The conventional densitometric approach was also studied and the method performances were compared. Both of the approaches were validated following the International Conference on Harmonization guidelines, and applied to spiked human plasma samples. The major advantage of the TLC–MS approach is that it can provide much lower limits of detection (1.98–5.83 pg/band) and limit of quantitation (5.97–17.63 pg/band) with good precision (?3.0% coefficient of variation) compared with TLC–densitometry. The proposed indirect HPTLC–MS method is simple yet effective and has tremendous potential in the separation and quantitation of drugs and their metabolites from biological samples, especially for clinical studies.     

Preparation of dummy template‐imprinted polymers for the rapid extraction of nonsteroidal anti‐inflammatory drugs residues in aquatic environmental samples

A molecularly imprinted polymer was synthesized and applied as a sorbent in the solid‐phase extraction device. The imprinted polymer was characterized by fourier‐transform infrared spectroscopy and scanning electron microscope. The results revealed that imprinted polymer possess sensitive selectivity and reliable adsorption properties for five NSAIDs. The imprinted polymer was successfully applied to the pre‐concentration for five NSAIDs in different water samples prior to UPLC‐MS/MS. In the early studies, several factors were investigated, including pH adjustment, the kind of elution solvent and the volume of elution solvent. Finally, we found that the pH 5 and an aliquot of 2 mL methanol were suitable for the water samples. The limits of detection and limits of quantitation of five nonsteroidal anti‐inflammatory drugs varied from 0.007 to 0.480 μg L⁻¹ and 0.03 to 1.58 μg L⁻¹, respectively. The spiking recoveries of the target analytes were 50.33‐127.64% at the levels of 0.2 μg L⁻¹, 2 μg L⁻¹ and 5 μg L⁻¹. The precision and accuracy of this method showed a great increase compared with traditional solid‐phase extraction. The developed method was successfully applied to extraction and analysis of NSAIDs in different water samples with satisfactory results which could help us better understand their environmental fate and risk to ecological health.     

Synthesis,spectroscopic characterization,thermal behaviour,in vitro antimicrobial and anticancer activities of novel ruthenium tricarbonyl complexes containing monodentate V‐shaped Schiff bases

The interaction of Ru₃(CO)₁₂ with a novel family of monodentate V‐shaped Schiff base ligands (L^1–4; L¹: (E)‐1‐(4‐((4‐bromobenzylidene)amino)phenyl)ethanone, L²: (E)‐1‐(3‐(4‐(dimethylamino)benzylideneamino)phenyl)ethanone, L³: (E)‐1‐(4‐(4‐(dimethylamino)benzylideneamino)phenyl)ethanone, L⁴: (E)‐1‐(3‐(3,4‐dimethoxybenzylideneamino)phenyl)ethanone) in air under atmospheric pressure afforded the novel complexes [Ru(CO)₃(L^1–4)₂]. The parent ligands and their complexes were characterized using elemental analyses and spectroscopic techniques. In addition, the structure of the representative ligand L¹ was determined using single‐crystal X‐ray analysis. The stereochemistry and theoretical optimization of the three‐dimensional geometry of the ligands and their complexes were justified. In vitro antimicrobial screening against bacterial stains Escherichia coli and Staphylococcus aureus and fungus Candida albicans was conducted. Cytotoxicity of the compounds as anti‐tumour agents was evaluated against liver carcinoma (HepG2), breast carcinoma (MCF7) and colon carcinoma (HCT‐116) cell lines relative to cisplatin and doxorubicin. The complexes showed variable in vitro cytotoxic activities against the three studied cell lines, with IC₅₀ values less than those of cis‐platin, and thus appear to be building blocks for promising anti‐tumour agents.     

Stability of Antimicrobial Drug Molecules in Different Gravitational and Radiation Conditions in View of Applications during Outer Space Missions

The evolution of different antimicrobial drugs in terrestrial, microgravity and hypergravity conditions is presented within this review, in connection with their implementation during human space exploration. Drug stability is of utmost importance for applications in outer space. Instabilities may be radiation-induced or micro-/hypergravity produced. The antimicrobial agents used in space may have diminished effects not only due to the microgravity-induced weakened immune response of astronauts, but also due to the gravity and radiation-altered pathogens. In this context, the paper provides schemes and procedures to find reliable ways of fighting multiple drug resistance acquired by microorganisms. It shows that the role of multipurpose medicines modified at the molecular scale by optical methods in long-term space missions should be considered in more detail. Solutions to maintain drug stability, even in extreme environmental conditions, are also discussed, such as those that would be encountered during long-duration space exploratory missions. While the microgravity conditions may not be avoided in space, the suggested approaches deal with the radiation-induced modifications in humans, bacteria and medicines onboard, which may be fought by novel pharmaceutical formulation strategies along with radioprotective packaging and storage.     

Luminescent PtII and PtIV Platinacycles with Anticancer Activity Against Multiplatinum-Resistant Metastatic CRC and CRPC Cell Models

Platinum-based chemotherapy persists to be the only effective therapeutic option against a wide variety of tumours. Nevertheless, the acquisition of platinum resistance is utterly common, ultimately cornering conventional platinum drugs to only palliative in many patients. Thus, encountering alternatives that are both effective and non-cross-resistant is urgent. In this work, we report the synthesis, reduction studies, and luminescent properties of a series of cyclometallated (C,N,N′)Pt^IV compounds derived from amine–imine ligands, and their remarkable efficacy at the high nanomolar range and complete lack of cross-resistance, as an intrinsic property of the platinacycle, against multiplatinum-resistant colorectal cancer (CRC) and castration-resistant prostate cancer (CRPC) metastatic cell lines generated for this work. We have also determined that the compounds are effective and selective for a broader cancer panel, including breast and lung cancer. Additionally, selected compounds have been further evaluated, finding a shift in their antiproliferative mechanism towards more cytotoxic and less cytostatic than cisplatin against cancer cells, being also able to oxidize cysteine residues and inhibit topoisomerase II, thereby holding great promise as future improved alternatives to conventional platinum drugs.     

Determination of mazindol in human oral fluid by high performance liquid chromatography–electrospray ionization mass spectrometry

Brazil is one of the countries most affected by abuse of stimulant medications by professional drivers, especially fenproporex, amfepramone and mazindol. Even though their sale is banned, they can be found in illegal markets, such as those located on the country's borders. The use of oral fluid to monitor drug levels has many advantages over plasma and urine because it is noninvasive, easier to collect and more difficult to adulterate. The aim of this study was to develop and validate a sensitive and specific method to quantify mazindol in human oral fluid by liquid chromatography–mass spectrometry (LC‐MS). The LC system consisted of an LC‐MS system operated in selected ion monitoring mode. The mobile phase was composed of water at pH 4.0, acetonitrile and methanol (60:15:25 v/v/v) at a flow rate of 1.0 mL/min and propranolol was used as internal standard. Total running time was 10 min. The lower limit of quantification was 0.2 ng/mL and the method exhibited good linearity within the 0.2–20 ng/mL range (r = 0.9987). A rapid, specific, sensitive, linear, precise and accurate method was developed for determination of mazindol in human oral fluid according to European Medicines Agency guidelines, and is suitable for monitoring mazindol levels in oral fluid of professional drivers. Copyright © 2014 John Wiley & Sons, Ltd.     

A highly sensitive LC–MS/MS method for simultaneous determination of glycyrrhizin and its active metabolite glycyrrhetinic acid: Application to a human pharmacokinetic study after oral administration

A highly sensitive liquid chromatography tandem mass spectrometry (LC–MS/MS) method for simultaneous determination of glycyrrhizin (GL) and its active metabolite, glycyrrhetinic acid (GA), from human plasma was validated and applied to a human pharmacokinetic study. The analytes were extracted from human plasma using an Oasis MAX cartridge and chromatographic separation was performed on an Inertsil ODS‐3 column. The detection was performed using an API 4000 mass spectrometer operating in the positive electrospray ionization mode. Selected ion monitoring transitions of m /z 823 → 453 for GL and m /z 471 → 149 for GA were obtained. The response was a linear function of concentration over the ranges of 0.5–200 ng/mL for GL and 2–800 ng/mL for GA (both R ² > 0.998). Using this method, the pharmacokinetics of GL after single oral administration of a clinical dose (75 mg) to six healthy male Japanese volunteers were evaluated. GL was detected in the plasma of all subjects and the average peak concentration was 24.8 ± 12.0 ng/mL. In contrast, peak concentration of GA was 200.3 ± 60.3 ng/mL, i.e. ~8‐fold higher than that of GL. This is the first report clarifying pharmacokinetic profiles of GL and GA simultaneously at a therapeutic oral dose of a GL preparation.     

Anti‐cancer potential of selenium‐ and tellurium‐containing species: opportunities abound!

An overview highlighting the anti‐cancer potential of (bio‐essential) selenium‐ and tellurium‐containing species, with an emphasis on biological targets and mechanisms of action, is presented. Studies thus far have focused on selenium(II) compounds (along with – to a lesser extent – inorganic selenium and selenium nanoparticles) which often successfully exploit the inherent anti‐oxidizing ability of selenium. Significantly less work has been conducted in developing anti‐cancer tellurium compounds, yet two tellurium(IV) species are proven, clinically, as anti‐cancer agents. Given the prevalence of the disease and the accumulated insights into mechanisms of action, the continued development of selenium‐ and tellurium‐containing molecules is an area deserving greater attention. Copyright © 2012 John Wiley & Sons, Ltd.