Development and validation of an HPLC method for the determination of benzodiazepines and tricyclic antidepressants in biological fluids after sequential SPE

A novel method for the simultaneous determination of six benzodiazepines (BZDs) and four tricyclic antidepressants (TCAs) in biological fluids by HPLC with UV detection at 240 nm has been developed. After a deproteinization step biological fluids were analyzed by direct injection. SPE on Nexus cartridges was also applied. Since two compounds, namely imipramine and diazepam, were coeluting, a sequential SPE protocol has been developed. BZDs were eluted by a mixture of methanol/ACN(1:1), followed by the elution of TCAs with methanol. Separation was performed on a Kromasil C8 column (250 x 64 mm(2) id, 5 microm) using a mobile phase of 0.05 MCH3COONH4/ACN/methanol (initial composition 55:15:30 v/v/v) at a flow rate of 1.0 mL/min delivered by a gradient program within 15 min. Colchicine was used as the internal standard (4 ng/microL). The method was linear for all analytes up to 20 ng/lL, with coefficients of regression between 0.996 and 0.99996. LODs and LOQs were 0.08-1.17 and 0.28-3.91 ng/lL, respectively. Recovery was in the range of 92.8-108.7% for within-day and 91.9-109.9% for between-day assays, with RSD values lower than 10.0% for all matrices.     

Supported Liquid Membrane Work-Up of Blood Plasma Samples Coupled On-Line to Liquid Chromatographic Determination of Basic Antidepressant Drugs

An automated sample pretreatment of human blood plasma for liquid chromatographic determination of three antidepressant drugs, dibenzepine; a tricyclic antidepressant (TCA), reboxetine; a selective noradrenaline reuptake inhibitor (SNRI) and fluvoxamine; a selective serotonin reuptake inhibitor (SSRI), based on supported liquid membrane (SLM) for unsurpassed sample clean-up and analyte enrichment, has been developed. The chromatograms after enrichment of plasma blank and aqueous blank are virtually indistinguishable. The entire analytical procedure revealed good linearity and low detection limits of 5, 15 and 20 ng mL^–1 for dibenzepine, reboxetine and fluvoxamine, respectively. No carry-over effects were noted. The repeatability of extraction at three concentrations in the range 40–150 ng mL^–1 for the three drugs was between ca. 3% and 7% as relative standard deviation. The reproducibility relative standard deviation during three different days (replacing the membrane each day) was not significantly higher.     

Palladium-catalyzed cyclization of 1,6-enyne with 2-bromoarylaldehyde: domino sequence to [5-7-6] tricyclic ring systems

A domino sequence of cyclization of 1,6-enyne with 2-bromoarylaldehyde followed by the intramolecular Aldol-condensation has been realized in the presence of 5 mol % of palladium catalyst. This sequence provides a convenient protocol to access polycyclic ring systems with readily available starting materials under simple Pd(0)-catalyzed conditions. The intramolecular Aldol-condensation has been proposed as the key step for the catalytic cycle.     

Simultaneous Determination of 1,4‐Benzodiazepines and Tricyclic Antidepressants in Saliva after Sequential SPE Elution by the Same HPLC Conditions

A new method has been described to determine both benzodiazepines (six) and tricyclic antidepressants (four) simultaneously in saliva by HPLC with a UV detector set at 240 nm using cholchicine as the internal standard. A careful specific sequential solid‐phase elution was optimized and performed to elute benzodiazepines using a mixture of methanol‐acetonitrile (1:1 v/v) followed by the elution of tricyclic antidepressants with methanol. Separation of the compounds was performed on a Kromasil column (250 × 4 mm, 5 μm) by a gradient eluents consisting of 0.05 M CH₃COONH₄‐acetonitrile‐methanol (55:15:30 v/v/v). The results were linear for both benzodiazepines and tricyclic antidepressants up to 20 ng μL^‐1 with the correlation coefficients greater than 0.998. The sensitivity limits, LOD and LOQ were 0.08‐0.34 ng μL^‐1 and 0.28‐1.13 ng μL^‐1, respectively. The method is simple, fast and reliable with good specificity and sensitivity, will be suitable for use in a clinical setting, where there is a concomitant use of 1,4‐benzodiazepines and tricyclic antidepressants.     

Direct UVC photodegradation of imipramine in aqueous solutions: a mechanistic study

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Synthesis, complexation studies and biological activity of some novel mono and tricyclic cyclophane amides and cyclophane sulfonamides

A series of mono, tricyclic cyclophane tetraamides and cyclophane sulfonamides have been synthesized and characterized from spectral and XRD studies. All the cyclophane amides form charge transfer (CT) complex with TCNQ. The cyclophane amides show moderate to good anti-inflammatory activity. Some of them were active against Gram positive (Klebsiella pneumonia) and Gram negative (Escherichia coli and Staphylococcus aureus) human pathogens.     

Synthetic study of yonarolide: stereoselective construction of the tricyclic core

Stereoselective construction of the tricyclic core of yonarolide (1), a marine norditerpenoid, was achieved. This synthetic route includes a Diels-Alder reaction and an intramolecular aldol condensation. It also involves efficient epimerization through a retro-Michael reaction-Michael addition and will be applicable to the total synthesis of 1.     

Simultaneous Differential Pulse Adsorptive Stripping Determination of Imipramine and Its Metabolite Desipramine by the PLS‐1 Multivariate Method

A method, using stripping differential pulse voltammetry, for the simultaneous determination of Imipramine and its metabolite Desipramine is reported. Both compounds produce, at glassy carbon electrode, an electrochemical signal due to an adsorptive‐oxidative process. The voltammograms show a very high overlap degree between IM and DE peaks. The multivariate calibration method PLS‐1 was employed for the simultaneous determination of both compounds. An experimental design together with the response surface methodology has been used to find the optimum experimental conditions. The developed procedure has been utilized in the analysis of fortified human serum samples with good recovery values for each analyte.     

Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors

Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.     

Extraction of antidepressant drugs in biological samples using alkanol‐based nano structured supramolecular solvent microextraction followed by gas chromatography with mass spectrometric analysis

In the present study, a supramolecular solvent was formed from reverse micelle aggregates of octanol. The proposed supramolecular solvent was used for rapid extraction of some antidepressants drugs including amitriptyline, imipramine, desipramine, maprotiline, sertraline, and doxepin from biological samples. Alkanol‐based supramolecular solvents have a unique array of physicochemical properties, making them a very attractive alternative to replace organic solvents in analytical extractions. The parameters affecting the extraction of target analytes (i.e., the volume of tetrahydrofuran and octanol as the major components comprising the supramolecular solvent, chain length of alkanols, sample solution pH, salt addition, and ultrasonic time) were investigated and optimized by factor by factor optimization method. Under the optimum conditions, preconcentration factors of 470, 490, 460, 385, 370, and 430 were obtained for amitriptyline, doxepin, imipramine, desipramine, maprotiline, and sertraline, respectively. The linear ranges and coefficients of determination (R²) were obtained in the range of 0.01–100 μg/L and 0.9974–0.9991, respectively. Also the limits of detection (S/N = 3) of 0.003–0.03 μg/L, and precisions (n = 5) of 4.9–8.9% were calculated. Finally, the method was successfully applied for the extraction of antidepressant drugs in biological samples, and relative recoveries in the range of 91–102% were obtained.