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We present a scalable mixed-species Coulomb crystal clock based on the ^{1}S_{0}↔^{3}P_{0} transition in ^{115}In^{+}. ^{172}Yb^{+} ions are cotrapped and used for sympathetic cooling. Reproducible interrogation conditions for mixed-species Coulomb crystals are ensured by a conditional preparation sequence with permutation control. We demonstrate clock operation with a 1In^{+}-3Yb^{+} crystal, achieving a relative systematic uncertainty of 2.5×10^{-18} and a relative frequency instability of 1.6×10^{-15}/sqrt[τ/1  s]. We report on absolute frequency measurements with an uncertainty of 1.3×10^{-16} and optical frequency comparisons with clocks based on ^{171}Yb^{+} (E3) and ^{87}Sr. With a fractional uncertainty of 4.4×10^{-18}, the former is-to our knowledge-the most accurate frequency ratio value reported to date. For the ^{115}In^{+}/^{87}Sr ratio, we improve upon the best previous measurement by more than an order of magnitude. We also demonstrate operation with four ^{115}In^{+} clock ions, which reduces the instability to 9.2×10^{-16}/sqrt[τ/1  s].

Einstein's general theory of relativity from 1915 1 remains the most successful description of gravitation. From the 1919 solar eclipse 2 to the observation of gravitational waves 3 , the theory has passed many crucial experimental tests. However, the evolving concepts of dark matter and dark energy illustrate that there is much to be learned about the gravitating content of the universe. Singularities in the general theory of relativity and the lack of a quantum theory of gravity suggest that our picture is incomplete. It is thus prudent to explore gravity in exotic physical systems. Antimatter was unknown to Einstein in 1915. Dirac's theory 4 appeared in 1928; the positron was observed 5 in 1932. There has since been much speculation about gravity and antimatter. The theoretical consensus is that any laboratory mass must be attracted 6 by the Earth, although some authors have considered the cosmological consequences if antimatter should be repelled by matter 7-10 . In the general theory of relativity, the weak equivalence principle (WEP) requires that all masses react identically to gravity, independent of their internal structure. Here we show that antihydrogen atoms, released from magnetic confinement in the ALPHA-g apparatus, behave in a way consistent with gravitational attraction to the Earth. Repulsive 'antigravity' is ruled out in this case. This experiment paves the way for precision studies of the magnitude of the gravitational acceleration between anti-atoms and the Earth to test the WEP., (© 2023. The Author(s).)

A simple, reliable and efficient fluorescent probe has been developed for the detection and quantitation of betahistine using inner filter effect (IFE) of silver nanoparticles (AgNPs) on zinc sulphide (ZnS) quantum dots. The synthesized ZnS exhibited blue emission at 403 nm which was quenched upon mixing with AgNPs due to intensive localized surface plasmon resonance (LSPR) absorption at 401 nm. The presence of IFE was confirmed by UV-Visible and fluorescence spectroscopy, dynamic light scattering and transmission electron microscopy. Addition of betahistine caused aggregation of AgNPs as visualized by the change in colour of nano-suspension. The reduced absorption at LSPR resulted in inhibition of IFE leading to higher fluorescence intensities in the presence of betahistine. Parameters such as pH, incubation time and concentration of AgNPs were suitably optimized. The fluorescence signal (I - I 0 /I 0 ) responded linearly for betahistine in the concentration range from 0.1 to 10 μM under the optimized experimental conditions. Due to the aggregation of AgNPs, a simple colorimetric approach was also studied for quantitation of betahistine in the range 1.0-20 μM. The limit of detection for fluorescence measurement and colorimetric approach was 0.02 μM and 0.23 μM, respectively. Further, the proposed method exhibited excellent selectivity towards betahistine in presence of several cations, biomolecules such as glucose, uric acid, creatinine, amino acids and several anti-vertigo medications. The method was applied to quantify betahistine from pharmaceutical products and results obtained were in good agreement with the claimed values. The proposed sensor can serve a low cost, selective, sensitive and a precise tool for routine quantitation of betahistine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The present work describes a dual-readout assay for the determination of an antipsychotic drug olanzapine using Rhodamine B modified silver nanoparticles (AgNPs). AgNPs, when mixed with Rhodamine B, quenched its fluorescence emission with high quenching efficiency as evident from the Stern Volmer plot. Transmission electron microscopy image and Dynamic Light Scattering histogram of Rhodamine B bound AgNPs showed a stable monodispersed nanosuspension. Addition of olanzapine to Rhodamine B-bound AgNPs resulted in reappearance of fluorescence, which was dependent on the amount of olanzapine added to the system. Besides displacing the surface bound Rhodamine B molecules, it caused aggregation of AgNPs which formed the basis of dual-readout sensor. Several parameters such as pH, reaction time and order of addition of the three components which may influence the analytical signal were studied and optimized. The method was validated for linearity, sensitivity, selectivity, accuracy, precision and recovery. Based on this dual-readout system, linear concentration range was established from 0.05 to 10 µM (fluorescence measurement) and 5.0 to 50 µM (colorimetric response) for olanzapine. The limit of detection (LOD) using fluorescence and colorimetric approach was 0.013 µM and 1.25 µM, respectively. The proposed method showed excellent selectivity for olanzapine in presence of several antipsychotic drugs, cations, sugars and amino acids. Finally, the method was successfully applied to a pharmacokinetic study of olanzapine in rats and also for analyzing pharmaceutical formulations.

Knowledge of the acid-base dissociation constants of drugs is the key to understanding their biopharmaceutical characteristics. In the present work, the effect of pH and organic modifiers (acetonitrile and methanol) was investigated in the determination of dissociation constants (pK a ) of nine representative drugs (atenolol, betahistine, clarithromycin, deferiprone, diclofenac, ibuprofen, metoprolol, naproxen and propranolol) using reversed-phase thin-layer chromatography. Mobile phase consisting of various buffers and methanol-acetonitrile (10, 20, 30, 40, 50 and 60%, v/v) was used to evaluate the retention pattern on reversed-phase plates. Compared with methanol, acetonitrile gave better results for the experimentally determined pK a values by extrapolation to zero organic modifier volume fractions. To assess the effectiveness of the developed method the results were correlated using principal component analysis and hierarchical cluster analysis. The calculated values of the aqueous dissociation constant were compared with those reported previously using potentiometry and capillary electrophoresis and also with different computational platforms like ACD/Lab, ChemAxon and Jchem calculator. The results obtained by the RPTLC method were in good agreement with potentiometric methods for pK a determination., (© 2019 John Wiley & Sons, Ltd.)

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., (© 2019 John Wiley & Sons, Ltd.)

Lipophilicity constitutes one of the most important physicochemical properties in the design and development of drug molecules. In the present work thin layer chromatography (TLC) has been utilized to evaluate lipophilicity of 11 representative drugs, which included six proton pump inhibitors (omeprazole, pantoprazole, rabeprazole, lansoprazole, ilaprazole, and tenatoprazole), an anti-vertigo drug, betahistine, nonsteroidal anti-inflammatory drug, ibuprofen, anti-malarial drug, atovaquone, an anti-HIV agent, atazanavir and a hormonal drug, calcitriol. Normal as well as reversed-phase separation modes were evaluated to study the effect of different organic modifiers for the estimation of lipophilicity. The quantitative descriptor of lipophilicity, the partition coefficient (logP) was estimated by suitably optimizing the solvent systems for both the modes. The best mobile phase pairs for NPTLC and RPTLC were toluene-acetonitrile and water-methanol respectively. Principal component analysis, hierarchical cluster analysis, as well as non-parametric methods like sum of ranking differences and generalized pair wise correlation revealed the dominant pattern in the data. The results obtained from both the separation modes were comparable and were in good agreement with the computational data for all the drugs., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Biological sex is thought to influence mitochondrial bioenergetic function. Previous respiration measurements examining brain mitochondrial sex differences were made at atmospheric oxygen using isolated brain mitochondria. Oxygen is 160 mm Hg (21%) in the atmosphere, while the oxygen tension in the brain generally ranges from ∼5 to 45 mm Hg (∼1-6% O 2 ). This study tested the hypothesis that sex and/or brain physiological oxygen tension influence the mitochondrial bioenergetic properties of primary rat cortical astrocytes and microglia. Oxygen consumption was measured with a Seahorse XF24 cell respirometer in an oxygen-controlled environmental chamber. Strikingly, male astrocytes had a higher maximal respiration than female astrocytes when cultured and assayed at 3% O 2 . Three percent O 2 yielded a low physiological dissolved O 2 level of ∼1.2% (9.1 mm Hg) at the cell monolayer during culture and 1.2-3.0% O 2 during assays. No differences in bioenergetic parameters were observed between male and female astrocytes at 21% O 2 (dissolved O 2 of ∼19.7%, 150 mm Hg during culture) or between either of these cell populations and female astrocytes at 3% O 2 . In contrast to astrocytes, microglia showed no sex differences in mitochondrial bioenergetic parameters at either oxygen level, regardless of whether they were non-stimulated or activated to a proinflammatory state. There were also no O 2 - or sex-dependent differences in proinflammatory TNF-α or IL-1β cytokine secretion measured at 18 h activation. Overall, results reveal an intriguing sex variance in astrocytic maximal respiration that requires additional investigation. Findings also demonstrate that sex differences can be masked by conducting experiments at non-physiological O 2 ., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A simple and efficient high-performance thin-layer chromatographic method was developed for chiral separation of rac-bupropion (BUP) and its active metabolite rac-hydroxybupropion (HBUP). Design of experiment (DoE)-based optimization was adopted instead of a conventional trial-and-error approach. The Box-Behnken design surface response model was used and the operating variables were optimized based on 17 trials design. The optimized method involved impregnation of chiral reagent, L(+)-tartaric acid, in the stationary phase with simultaneous addition in the mobile phase, which consisted of acetonitrile : methanol : dichloromethane : 0.50% L-tartaric acid (6.75:1.0:1.0:0.25, v/v/v/v). Under the optimized conditions, the resolution factor between the enantiomers of BUP and HBUP was 6.30 and 9.26, respectively. The limit of detection and limit of quantitation for (R)-BUP, (S)-BUP, (R,R)-HBUP, and (S,S)-HBUP were 9.23 and 30.78 ng spot -1 , 10.32 and 34.40 ng spot -1 , 12.19 and 40.65 ng spot -1 , and 14.26 and 47.53 ng spot -1 , respectively. The interaction of L-tartaric acid with analytes and their retention behavior was thermodynamically investigated using van't Hoff's plots. The developed method was validated as per the International Conference on Harmonization guidelines. Finally, the method was successfully applied to resolve and quantify the enantiomeric content from marketed tablets as well as spiked plasma samples., (© 2016 Wiley Periodicals, Inc.)

In this article we report a novel method for colorimetric sensing and selective determination of a non-chromophoric drug-azithromycin, which lacks native absorbance in the UV-Visible region using unmodified silver nanoparticles (AgNPs). The citrate-capped AgNps dispersed in water afforded a bright yellow colour owing to the electrostatic repulsion between the particles due to the presence of negatively charged surface and showed surface plasmon resonance (SPR) band at 394nm. Addition of positively charged azithromycin at a concentration as low as 0.2μM induced rapid aggregation of AgNPs by neutralizing the negative charge on the particle surface. This phenomenon resulted in the colour change from bright yellow to purple which could be easily observed by the naked eye. This provided a simple platform for rapid determination of azithromycin based on colorimetric measurements. The factors affecting the colorimetric response like pH, volume of AgNPs suspension and incubation time were suitably optimized. The validated method was found to work efficiently in the established concentration range of 0.2-100.0μM using two different calibration models. The selectivity of the method was also evaluated by analysis of nanoparticles-aggregation response upon addition of several anions, cations and some commonly prescribed antibiotics. The method was successfully applied for the analysis of azithromycin in pharmaceuticals and spiked human plasma samples with good accuracy and precision. The simplicity, efficiency and cost-effectiveness of the method hold tremendous potential for the analysis of such non-chromophoric pharmaceuticals., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A simple, accurate and precise high-performance thin-layer chromatographic method has been developed and validated for the analysis of proton pump inhibitors (PPIs) and their co-formulated drugs, available as binary combination. Planar chromatographic separation was achieved using a single mobile phase comprising of toluene: iso-propranol: acetone: ammonia 5.0:2.3:2.5:0.2 (v/v/v/v) for the analysis of 14 analytes on aluminium-backed layer of silica gel 60 FG 254 . Densitometric determination of the separated spots was done at 290nm. The method was validated according to ICH guidelines for linearity, precision and accuracy, sensitivity, specificity and robustness. The method showed good linear response for the selected drugs as indicated by the high values of correlation coefficients (≥0.9993). The limit of detection and limit of quantiation were in the range of 6.9-159.2ng/band and 20.8-478.1ng/band respectively for all the analytes. The optimized conditions afforded adequate resolution of each PPI from their co-formulated drugs and provided unambiguous identification of the co-formulated drugs from their homologous retardation factors (hR f ). The only limitation of the method was the inability to separate two PPIs, rabeprazole and lansoprazole from each other. Nevertheless, it is proposed that peak spectra recording and comparison with standard drug spot can be a viable option for assignment of TLC spots. The method performance was assessed by analyzing different laboratory simulated mixtures and some marketed formulations of the selected drugs. The developed method was successfully used to investigate potential counterfeit of PPIs through a series of simulated formulations with good accuracy and precision., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Context Oxidative stress induces apoptosis within Islets of Langerhans in diabetes mellitus (DM). Enicostemma littorale blume, herb of the Gentianaceae family is used as an anti-diabetic agent across rural India. Objective This report demonstrates potent anti-apoptotic and cyto-protective activity of Enicostemma littorale MeOH extract (EL MeOH ext.) against 50 μM H2O2 in isolated rat Islets. Materials and methods In this study, the whole plant methanolic extract of EL with doses 0.25-4 mg/mL each for the preincubation duration of 0.5-4 h against 50 μM H2O2 were tested for optimum protective dose and time by Trypan blue dye exclusion assay. Islet intracellular reactive oxygen species (ROS) was quantified by DCFDA staining and cell death using PS/PI & FDA/PI staining. Further, comet assay, biochemical assessment of caspase-3 and antioxidant enzyme activities along with immunoblotting of PARP-1, caspase-3, TNF-α activation and p-P38 MapK (stress kinase) induction was performed. Results The optimized dose of EL MeOH ext. 2 mg/mL for 2 h was used throughout the study, which significantly decreased total Intracellular ROS and cell death. Further, caspase-3 activity, PARP-1 cleavage, p-P38 MapK (stress kinase) activation and TNF-α levels, which had been significantly elevated, were normalized. Antioxidant enzymes like catalase, superoxide dismutase, reduced glutathione and glutathione peroxidase, along with Comet assay, demonstrated that pretreatment with EL MeOH ext. can augment antioxidant enzyme activities and protect from DNA damage. Discussion and conclusions Significant anti-apoptotic and cyto-protective effects were mediated by EL with Islets of Langerhans subjected to oxidative stress-induced cell death.

A simple, rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous determination of cilostazol and its pharmacologically active metabolite 3,4-dehydro cilostazol in human plasma using deuterated analogs as internal standards (ISs). Plasma samples were prepared using solid phase extraction and chromatographic separation was performed on UPLC BEH C 18 (50 mm×2.1 mm, 1.7 µm) column. The method was established over a concentration range of 0.5-1000 ng/mL for cilostazol and 0.5-500 ng/mL for 3,4-dehydro cilostazol. Intra- and inter-batch precision (% CV) and accuracy for the analytes were found within 0.93-1.88 and 98.8-101.7% for cilostazol and 0.91-2.79 and 98.0-102.7% for the metabolite respectively. The assay recovery was within 95-97% for both the analytes and internal standards. The method was successfully applied to support a bioequivalence study of 100 mg cilostazol in 30 healthy subjects.

Objective: Three sensitive, selective, and precise spectrophotometric methods based on manipulation of ratio spectra, have been developed and validated for the determination of diclofenac sodium and pantoprazole sodium., Materials and Methods: The first method is based on ratio spectra peak to peak measurement using the amplitudes at 251 and 318 nm; the second method involves the first derivative of the ratio spectra (Δλ = 4 nm) using the peak amplitudes at 326.0 nm for diclofenac sodium and 337.0 nm for pantoprazole sodium. The third is the method of mean centering of ratio spectra using the values at 318.0 nm for both the analytes., Results: All the three methods were linear over the concentration range of 2.0-24.0  μ g/mL for diclofenac sodium and 2.0-20.0 μg/mL for pantoprazole sodium. The methods were validated according to the ICH guidelines and accuracy, precision, repeatability, and robustness are found to be within the acceptable limit. The results of single factor ANOVA analysis indicated that there is no significant difference among the developed methods., Conclusions: The developed methods provided simple resolution of this binary combination from laboratory mixtures and pharmaceutical preparations and can be conveniently adopted for routine quality control analysis.

We investigated the protective effects of Enicostemma littorale Blume (EL) extract on hypertension and insulin resistance along with its associated cardiovascular complications in high fructose (HF) fed rats. For this, rats were divided among 4 groups: (i) control, fed laboratory chow; (ii) fed with a high level of fructose; (iii) fed with a high level of fructose plus E. littorale extract; and (iv) fed with a high level of fructose plus rosiglitazone (Rg). EL and Rg treatments were given simultaneously with HF diet. The results show that untreated HF-fed rats showed altered oral glucose tolerance, increased fasting insulin, and increased fasting glucose. These rats also exhibited hypertriglyceridemia, moderate hypertension, platelet hyperaggregability, decreased prothrombin time, activated partial thromboplastin time, altered vascular reactivity, and increased serum levels of enzymes (creatine kinase, type muscle-brain (CK-MB), aspartate aminotransferase (SGOT), lactate dehydrogenase (LDH), and alanine aminotransferase (SGPT). This is the first demonstration of platelet hyperaggregation and prothrombotic alteration in HF-fed rats. HF-fed rats treated with EL showed improved insulin resistance, along with reduced hypertriglyceridemia, hypertension, platelet aggregability, blood coagulation, serum enzymes (CK-MB, SGOT, LDH and SGPT), and vascular reactivity. These effects of EL in HF-induced hypertensive rats might be associated with the suppression of hyperinsulinemia and hypertriglyceridemia, along with its antiatherogenic and antithrombogenic potential. These data indicate that the aqueous extract of EL has great therapeutic potential for the prevention and (or) management of insulin resistance and the associated hypertension.