Development and validation of stability indicating method for determination of sertraline following ICH guidlines and its determination in pharmaceuticals and biological fluids

<p>Abstract</p> <p>Background</p> <p>Sertraline is a well known antidepressant drug which belongs to a class called selective serotonin reuptake inhibitor. Most published methods do not enable studying the stability of this drug in different stress conditions.</p> <p>Results</p> <p>Two new methods were developed for the determination of sertraline (SER). Both methods are based on coupling with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD-Cl) in borate buffer of pH 7.8 and measuring the reaction product spectrophotometrically at 395 nm (Method I) or spectrofluorimetrically at 530 nm upon excitation at 480 nm (Method II). The response-concentration plots were rectilinear over the range 2-24 μg/mL and 0.25-5 μg/mL for methods I and II respectively with LOD of 0.18 μg/mL and 0.07 μg/mL, and LOQ of 0.56 μg/mL and 0.21 μg/mL for methods I and II, respectively.</p> <p>Conclusion</p> <p>Both methods were applied to the analysis of commercial tablets and the results were in good agreement with those obtained using a reference method. The fluorimetric method was further applied to the in vivo determination of SER in human plasma. A proposal of the reaction pathway was presented. The spectrophotometric method was extended to stability study of SER. The drug was exposed to alkaline, acidic, oxidative and photolytic degradation according to ICH guidelines. Moreover, the method was utilized to investigate the kinetics of oxidative degradation of the drug. The apparent first order rate constant and t_1/2of the degradation reaction were determined.</p

Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Different Classes of Antidepressants

Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects

Climate controls on rainfall isotopes and their effects on cave drip water and speleothem growth: the case of Molinos cave (Teruel, NE Spain)

The interpretation of stable isotopes in speleothems in terms of past temperature variability or precipitation rates requires a comprehensive understanding of the climatic factors and processes that influence the δ18O signal in the way through the atmosphere to the cave, where carbonate precipitates acquiring its final isotopic composition. This study presents for the first time in the Iberia Peninsula an integrated analysis of the isotopic composition of rainfall (δ18Op) during 2010–2012 years and, through a detailed monitoring survey, the transference of the primary isotopic signal throughout the soil and epikarst into the Molinos cave (Teruel, NE Spain). Both air temperature and amount of precipitation have an important effect on δ18Op values, clearly imprinting a seasonal variability modulated by an amount effect when rainfall events are more frequent or intense. Air mass history and atmospheric circulation influences are considered through the study of weather types, synoptic-scale climate patterns and large-scale atmospheric circulation indexes (North Atlantic Oscillation and Western Mediterranean Oscillation) revealing a dominant source effect on δ18Op values in this region where tropical North Atlantic and Western Mediterranean are the two moisture source regions. A delay of 2–3 months occurs between the dripwater oxygen isotopic composition (δ18Od) respect to δ18Op values as a consequence of large residence time in the epikarst. Limited calcite precipitates are found from winter to spring when δ18Od values are less negative and dripwater rates are constant. This study suggests that NE Iberian δ18Ocalcite proxy records are best interpreted as reflecting a combination of parameters, not just paleotemperature or paleorainfall and, if extending present-day situation towards the recent past, a biased signal towards winter values should be expected in Molinos speleothem records

Synchronous precipitation reduction in the American Tropics associated with Heinrich 2

Abstract During the last ice age temperature in the North Atlantic oscillated in cycles known as Dansgaard-Oeschger (D-O) events. The magnitude of Caribbean hydroclimate change associated with D-O variability and particularly with stadial intervals, remains poorly constrained by paleoclimate records. We present a 3.3 thousand-year long stalagmite δ18O record from the Yucatan Peninsula (YP) that spans the interval between 26.5 and 23.2 thousand years before present. We estimate quantitative precipitation variability and the high resolution and dating accuracy of this record allow us to investigate how rainfall in the region responds to D-O events. Quantitative precipitation estimates are based on observed regional amount effect variability, last glacial paleotemperature records, and estimates of the last glacial oxygen isotopic composition of precipitation based on global circulation models (GCMs). The new precipitation record suggests significant low latitude hydrological responses to internal modes of climate variability and supports a role of Caribbean hydroclimate in helping Atlantic Meridional Overturning Circulation recovery during D-O events. Significant in-phase precipitation reduction across the equator in the tropical Americas associated with Heinrich event 2 is suggested by available speleothem oxygen isotope records