Validated LC–MS/MS method for quantification of agomelatine in human plasma and its application in a pharmacokinetic study

An analytical method based on liquid–liquid extraction has been developed and validated for analysis of agomelatine in human plasma. Fluoxetine was used as an internal standard for agomelatine. A Betasil C18 (4.0 × 100 mm, 5 µm) column provided chromatographic separation of analytes followed by detection with mass spectrometry. The method involves simple isocratic chromatographic conditions and mass spectrometric detection in the positive ionization mode using an API‐4000 system. The proposed method has been validated with linear range of 0.050–8.000 ng/ml for agomelatine. The intra‐run and inter‐run precision values are within 12.12% and 9.01%, respectively, for agomelatine at the lower limit of quantification level. The overall recovery for agomelatine and fluoxetine was 67.10% and 72.96%, respectively. This validated method was used successfully for analysis of plasma samples from a pharmacokinetic study. Copyright © 2012 John Wiley & Sons, Ltd.     

Simultaneous quantitative resolution of atorvastatin calcium and fenofibrate in pharmaceutical preparation by using derivative ratio spectrophotometry and chemometric calibrations.

In the present work, five different spectrophotometric techniques for simultaneous determination of formulations containing atorvastatin calcium (ATOR) and fenofibrate (FENO) in various combinations are described. In ratio spectra derivative spectrophotometry, analytical signals were measured at wavelengths corresponding to either maximums or minimums for both drugs in first derivative spectra of ratio spectra obtained by using either spectrum as divisor. For the remaining four methods using chemometric techniques, namely, classical least squares (CLS), inverse least squares (ILS), principal component regression (PCR) and partial least squares (PLS), the calibrations were constructed by using the absorption data matrix corresponding to the concentration data matrix, with measurements in the range of 231 - 310 nm (Deltalambda = 1 nm) in their zero-order spectra. The linearity range was found to be 4 - 22 and 2 - 20 microg/ml for ATOR and FENO, respectively. The validity of the proposed methods was successfully assessed for analyses of both drugs in laboratory-prepared mixtures and in commercial tablet formulations.     

Total synthesis of natural cis-3-hydroxy-l-proline from d-glucose

Synthesis of cis-3-hydroxy-l-proline from d-glucose is reported. The methodology involves conversion of d-glucose into N-benzyloxycarbonyl-γ-alkenyl amine which on 5-endo-trig-aminomercuration gave the pyrrolidine ring skeleton with sugar appendage in 25% yield. Alternatively, N-benzyloxycarbonyl-γ-alkenyl amine on hydroboration-oxidation, mesylation and intramolecular S_N2 cyclisation afforded pyrrolidine ring compound in high yield. Hydrolysis of 1,2-acetonide functionality, NaIO₄ cleavage followed by oxidation of an aldehyde into acid and hydrogenolysis afforded cis-3-hydroxy-l-proline in overall 29% yield from d-glucose.     

ON AVOIDANCE ACTIVITIES IN FISHERY ENFORCEMENT MODELS

Compliance and enforcement in fisheries are important issues from an economic point of view since management measures are useless without a certain level of enforcement. These conclusions come from the well‐established theoretical literature on compliance and enforcement problems within fisheries and a common result is that, it is efficient to set fines as high as possible and monitoring as low as possible, when fines are costless and offenders are risk neutral. However, this result is sensitive to the assumption that fishermen cannot engage in avoidance activities, e.g., activities to reduce the likelihood of being detected when noncomplying. The paper presents a model of fisheries that allows the fishermen to engage in avoidance activities. The conclusions from the model are that, under certain circumstances, fines are costly transfers to society since they not only have a direct positive effect on the level of deterrence, but also an indirect negative effect in the form of increased avoidance activities to reduce the probability of detection. The paper contributes to the literature on avoidance activities by introducing the externality from the illegal behavior as an endogenous effect on other offenders. For an externality, that has an exogenous effect on other actors, Malik shows that fines are only costly transfers for conditional deterrence (when one actor is deterred while another actor is not). For fisheries, we show that fines are also costly transfers under no deterrence (when no agents are deterred).     

Chiron approach to the synthesis of (2S,3R)-3-hydroxypipecolic acid and (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine from D-glucose

The first chiron approach from d-glucose for the total synthesis of (2 S,3 R)-3-hydroxypipecolic acid (-)-1a and (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine (-)-2a is reported. The synthetic pathway involves conversion of d-glucose into 3-azidopentodialdose (5) followed by the Wittig olefination and reduction to give the piperidine ring skeleton (8) with a sugar appendage that on cleavage of an anomeric carbon followed by oxidation gives (-)-1a which on reduction affords (-)-2a.     

Validated LC-MS/MS method for quantification of agomelatine in human plasma and its application in a pharmacokinetic study

An analytical method based on liquid-liquid extraction has been developed and validated for analysis of agomelatine in human plasma. Fluoxetine was used as an internal standard for agomelatine. A Betasil C18 (4.0?×?100?mm, 5?μm) column provided chromatographic separation of analytes followed by detection with mass spectrometry. The method involves simple isocratic chromatographic conditions and mass spectrometric detection in the positive ionization mode using an API-4000 system. The proposed method has been validated with linear range of 0.050-8.000?ng/ml for agomelatine. The intra-run and inter-run precision values are within 12.12% and 9.01%, respectively, for agomelatine at the lower limit of quantification level. The overall recovery for agomelatine and fluoxetine was 67.10% and 72.96%, respectively. This validated method was used successfully for analysis of plasma samples from a pharmacokinetic study.     

Concise and practical route to tri- and tetra-hydroxy seven-membered iminocyclitols as glycosidase inhibitors from d-(+)-glucurono-γ-lactone

An efficient and short total synthesis of tetrahydroxy-1c and trihydroxy-azepane 1d is reported in 72% and 57% overall yields, respectively, from d-(+)-glucurono-γ-lactone. Thus, d-glucuronolactone 2 on acetonide protection, DIBAL-H reduction and one-pot intermolecular reductive amination followed by -NCbz protection afforded 6-(N-benzyl-N-benzyloxycarbonyl) amino-6-deoxy-1,2-O-isopropylidene-α-d-gluco-1,4-furanose 5a. 1,2-Acetonide hydrolysis in 5a and Pd-mediated intramolecular reductive aminocyclization afforded tetrahydroxyazepane 1c. An analogous pathway with 5-deoxy-1,2-O-isopropylidene-α-d-glucurono-6,3-lactone 3b gave trihydroxy-azepane 1d. Glycosidase inhibitory activity of 1c/1d was studied and 1d was found to be potent inhibitor of α-mannosidase and β-galactosidase.