Electrochemical reconstruction of a 1D Cu(PyDC)(H2O) MOF into in situ formed Cu-Cu2O heterostructures on carbon cloth as an efficient electrocatalyst for CO2 conversion.

Electrochemical carbon dioxide (CO2) conversion has enormous potential for reducing high atmospheric CO2 levels and producing valuable products simultaneously; however the development of inexpensive catalysts remains a great challenge. In this work, we successfully synthesised a 1D Cu-based metal-organic framework [Cu(PyDC)(H2O)], which crystallizes in an orthorhombic system with the Pccn space group, by the hydrothermal method. Among the different catalysts utilized, the heterostructures of cathodized Cu-Cu2O@CC demonstrate increased efficiency in producing CH3OH and C2H4, achieving maximum FE values of 37.4% and 40.53%, respectively. Also, the product formation rates of CH3OH and C2H4 reach up to 667 and 1921 µmol h-1 cm-2. On the other side, Cu-Cu2O/NC-700 carbon composites simultaneously produced C1-C3 products with a total FE of 23.27%. Furthermore, a comprehensive study involving detailed DFT simulations is used to calculate the energetic stability and catalytic activity towards the CO2 reduction of Cu(111), Cu2O(111), and Cu@Cu2O(111) surfaces. During the early phase of electrochemical treatment, Cu(II) carboxylate nodes (Cu-O) in the Cu(PyDC)(H2O) MOF were reduced to Cu and Cu2O, with a possible synergistic enhancement from the PyDC ligands. Thus, the improved activity and product enhancement are closely associated with the cathodized reconstruction of Cu-Cu2O@CC heterostructures on carbon cloth. Hence, this study provides efficient derivatives of Cu-based MOFs for notable electrocatalytic activity in CO2 reduction and gives valuable insights towards the advancement of practical CO2 conversion technology.

Hydrogen spillover inspired bifunctional Platinum/Rhodium Oxide-Nitrogen-Doped carbon composite for enhanced hydrogen evolution and oxidation reactions in base.

The poor activity of Pt-based-catalysts for alkaline hydrogen oxidation/evolution reaction (HOR/HER) encourages scientific society to design an effective electrocatalyst to develop alkaline fuel cells/electrolyzers. Herein, platinum/rhodium oxide-nitrogen-doped carbon (Pt/Rh2O3-CNx) composite is prepared for alkaline HER and HOR inspired by hydrogen spillover. The HER performance of Pt/Rh2O3-CNx is âˆ¼ 6 times higher than Pt/C. In HOR, Pt/Rh2O3-CNx possesses an exchange current density of 657.60 mA/mgmetal, which is âˆ¼ 3.4 times higher than Pt/C. Hydrogen and hydroxyl binding energy (HBE and OHBE) contribute equally to alkaline HOR/HER. The experimental and theoretical evidence suggests that the enhanced HER and HOR activity of Pt/Rh2O3-CNx may be due to hydrogen spillover from Pt to Rh2O3. Small work function difference [0.08 eV] of the system suggested hydrogen-spillover is feasible, which has been justified by reaction-free energy calculations. We proposed that the dissociation of hydrogen (H2) and water (H2O) occurs at Pt to form Pt-adsorbed hydrogen species (Pt-Had). Then, some Had moves to Rh2O3 through hydrogen spillover and reacts with neighboring Had or adsorbed hydroxyl species (OHad) to form H2 or H2O, which enhances the HER and HOR activity, respectively. The role of water-metal-hydroxyl species in the electrical double layer was also demonstrated on alkaline HOR/HER. This work may help to design the hydrogen-spillover-based catalysts for several renewable energy technologies.

Identification of potential chemical biomarkers of hexaconazole using in vitro metabolite profiling in rat and human liver microsomes and in vivo confirmation through urinary excretion study in rats.

Hexaconazole (HEX) is an azole fungicide widely used in agricultural practices across various countries and numerous studies have reported the toxic effects of HEX, such as endocrine disruption, immunotoxicity, neurotoxicity and carcinogenicity. Despite its widespread agricultural use and toxic effects, the metabolism of HEX is not completely understood, and information on urinary elimination of HEX or its metabolites is limited. Therefore, in the present study, we aimed to identify HEX metabolites in rat and human liver microsomes followed by their in vivo confirmation using a urinary excretion study in rats to identify potential candidate for exposure biomarkers for human biomonitoring studies. From the in vitro assay, a total of 12 metabolites were observed, where the single oxidation metabolites (M5 and M6) were the most abundant metabolites in both rat and human liver microsomes. The triple oxidation followed by dehydration metabolite, M8 (which could also be hexaconazole acid or hydroxy keto-hexaconazole), and the double oxidation metabolite (M9) were the major metabolites found in rat urine and were detectable in rat urine longer than the parent. These metabolites increased with decreasing concentrations of HEX in the rat urine samples. Therefore, metabolites M8, M9 and M5 could be pursued further as potential biomarkers for assessing and monitoring human exposure to HEX.

Catechol Sensing Performance of Pd-Functionalized Two-Dimensional Polyaramid: A DFT Investigation.

Catechol (Cc) molecule adsorption on a pristine and transition metal (TMs = Sc, Pd, and Cu)-functionalized two-dimensional polyaramid (2DPA) monolayer is systematically studied by the first-principles density functional theory method. The weak physisorption (-0.29 eV) and charge transfer of the Cc molecule with p-2DPA result in a very quick recovery time (150 µs), hindering the Cc sensing capability of p-2DPA. Although TM functionalization greatly improved the adsorption ability, the Pd-functionalized 2DPA was shown to be the best choice for Cc adsorption due to the reasonable adsorption energy of -1.39 eV and expedited charge transfer between the Cc and Pd atom. The change of band gap and, hence, the conductivity of the Pd-2DPA system in response to the adsorption of the Cc molecule demonstrate its higher sensitivity than that of p-2DPA. The work function sensitivity of Pd-2DPA upon the Cc adsorption is also investigated. In addition to the change in the electronic properties, the change in the optical properties of Pd-2DPA after Cc adsorption is also analyzed. The structural stability of Pd-2DPA is validated by performing ab initio molecular dynamics simulations at 300 K. The complete desorption of the Cc molecule from Pd-2DPA is attained by annealing the material at 550 K under visible light (τ = 5.4 s) and at 450 K under UV light (τ = 3.7 s). Moreover, the higher diffusion energy barrier of +1.35 eV confirmed that the functionalized Pd atoms did not diffuse through the crystal to form clusters. This study could lay a theoretical foundation for developing possibly new-generation sensors for detecting Cc molecules.

Hydrogen spillover enhances alkaline hydrogen electrocatalysis on interface-rich metallic Pt-supported MoO3.

Efficient and cost-effective electrocatalysts for the hydrogen oxidation/evolution reaction (HOR/HER) are essential for commercializing alkaline fuel cells and electrolyzers. The sluggish HER/HOR reaction kinetics in base is the key issue that requires resolution so that commercialization may proceed. It is also quite challenging to decrease the noble metal loading without sacrificing performance. Herein, we report improved HER/HOR activity as a result of hydrogen spillover on platinum-supported MoO3 (Pt/MoO3-CNx-400) with a Pt loading of 20%. The catalyst exhibited a decreased over-potential of 66.8 mV to reach 10 mA cm-2 current density with a Tafel slope of 41.2 mV dec-1 for the HER in base. The Pt/MoO3-CNx-400 also exhibited satisfactory HOR activity in base. The mass-specific exchange current density of Pt/MoO3-CNx-400 and commercial Pt/C are 505.7 and 245 mA mgPt-1, respectively. The experimental results suggest that the hydrogen binding energy (HBE) is the key descriptor for the HER/HOR. We also demonstrated that the enhanced HER/HOR performance was due to the hydrogen spillover from Pt to MoO3 sites that enhanced the Volmer/Heyrovsky process, which led to high HER/HOR activity and was supported by the experimental and theoretical investigations. The work function value of Pt [Φ = 5.39 eV) is less than that of ß-MoO3 (011) [Φ = 7.09 eV], which revealed the charge transfer from Pt to the ß-MoO3 (011) surface. This suggested the feasibility of hydrogen spillover, and was further confirmed by the relative hydrogen adsorption energy [ΔGH] at different sites. Based on these findings, we propose that the H2O or H2 dissociation takes place on Pt and interfaces to form Pt-Had or (Pt/MoO3)-Had, and some of the Had shifted to MoO3 sites through hydrogen spillover. Then, Had at the Pt and interface, and MoO3 sites reacted with H2O and HO- to form H2 or H2O molecules, thereby boosting the HER/HOR activity. This work may provide valuable information for the development of hydrogen-spillover-based electrocatalysts for use in various renewable energy devices.

Electric-Field Emission Mechanism in Q-Carbon Field Emitters.

In this paper, we report the excellent field emission properties of Q-carbon and analyze its field emission characteristics through structural, morphological, and electronic property correlations, supported by density functional theory (DFT) simulation studies. The Q-carbon field emitters show impressive and stable field emission properties, such as a low turn-on electric field of ∼2.38 V/µm, a high emission current density of ∼33 µA/cm2, and a critical field of ∼2.44 V/µm for the transition from a linear region to the saturation region in the F-N plot. The outstanding field emission properties of Q-carbon are attributed to (i) a unique sp2/sp3 mixture in Q-carbon, (ii) sp2-bonded highly conductive amorphous carbon-rich channels inside the Q-carbon cluster, (iii) a large local field enhancement due to the local geometry and microstructure of Q-carbon, and (iv) the presence of sp2-bonded amorphous carbon regions in the composite film. The temperature-dependent field emission properties, such as extreme sensitivity and an enhancement in the emission current density with temperature, can be explained by the local density of states near the Fermi level and the excellent thermal stability of the Q-carbon field emitters. From DFT simulation studies, the computed work function and the field-enhancement factor were determined to be 3.62 eV and ∼2300, respectively, which explains the excellent field emission characteristics of Q-carbon. The obtained field emission properties, in most cases, were superior to those from other carbon/diamond-based field emitters, which will open new frontiers in field emission-based electronic applications.

Metal-decorated γ-graphyne as a drug transporting agent for the mercaptopurine chemotherapy drug: a DFT study.

In recent years, carbon-based two-dimensional (2D) materials have gained popularity as the carriers of various anticancer therapy drugs, which could reduce the crucial side effects by directly applying the drugs to the intended tumor cells. In this study, through first-principles density functional theory simulations, we have investigated the adsorption properties of a famous cancer chemotherapy drug called mercaptopurine (MC) on a 2D γ-graphyne (GYN) monolayer. Analyzing the geometric and electronic properties, we can summarize that the MC interaction with the pristine GYN is weak, with a small adsorption energy of -0.15 eV, which is too low for potential applications. Therefore, we have decorated the GYN monolayer with biocompatible metals such as Al, Ag, and Cu to trigger the adsorption capacity. The Al- and Cu-decorated GYN offered improved adsorption towards MC compared to the pristine case. The drug release from these metal-decorated systems was examined by creating an acidic environment. In addition, the desorption temperature of the drug from the system was also evaluated using ab initio molecular dynamics simulations. The calculations demonstrated that the Al-decorated GYN is a potential vehicle for MC drug delivery because of the favourable adsorption energy of -0.63 eV, charge transfer of 0.17e and desorption temperature above 270 K. The current research will stimulate the investigation of other low-dimensional carbon materials for drug-delivery applications.

Highly Stable Electrochemical Supercapacitor Performance of Self-Assembled Ferromagnetic Q-Carbon.

Novel phase Q-carbon thin films exhibit some intriguing features and have been explored for various potential applications. Herein, we report the growth of different Q-carbon structures (i.e., filaments, clusters, and microdots) by varying the laser energy density from 0.5 to 1.0 J/cm2 during pulsed laser annealing of amorphous diamond-like carbon films with different sp3-sp2 carbon compositions. These unique nano- and microstructures of Q-carbon demonstrate exceptionally stable electrochemical performance by cyclic voltammetry, galvanostatic charging-discharging, and electrochemical impedance spectroscopy for energy applications. The temperature-dependent magnetic studies (magnetization vs magnetic field and temperature) reveal the ferromagnetic nature of the Q-carbon microdots. The saturation magnetization and coercive field values decrease from 132 to 14 emu/cc and 155 to 92 Oe by increasing the temperature from 2 to 300 K, respectively. The electrochemical performances of Q-carbon filament, cluster, and microdot thin-film supercapacitors were investigated by two-electrode configurations, and the highest areal specific capacitance of ∼156 mF/cm2 was observed at a current density of 0.15 mA/cm2 in the Q-carbon microdot thin film. The Q-carbon microdot electrodes demonstrate an exceptional capacitance retention performance of ∼97.2% and Coulombic efficiency of ∼96.5% after 3000 cycles due to their expectational reversibility in the charging-discharging process. The kinetic feature of the ion diffusion associated with the charge storage property is also investigated, and small changes in equivalent series resistance of ∼9.5% and contact resistance of ∼9.1% confirm outstanding stability with active charge kinetics during the stability test. A high areal power density of ∼5.84 W/cm2 was obtained at an areal energy density of ∼0.058 W h/cm2 for the Q-carbon microdot structure. The theoretical quantum capacitance was obtained at ∼400 mF/cm2 by density functional theory calculation, which gives an idea about the overall capacitance value. The obtained areal specific capacitance, power density, and impressive long-term cyclic stability of Q-carbon thin-film microdot electrodes endorse substantial promise in high-performance supercapacitor applications.

DFT and MD investigations of the biomolecules of phenothiazine derivatives: interactions with gold and water molecules and investigations in search of effective drug for SARS-CoV-2.

Theoretical analyses of two phenothiazine derivatives, 10-[3-(dimethylamino)-2-methylpropyl]phenothiazine-2-carbonitrile (CYM) and 2-[4-[3-(2-chlorophenothiazin-10-yl)propyl]piperazin-1-yl]ethanol (PAZ) are reported using density functional theory (DFT) and molecular dynamics (MD) simulations. Spectroscopic studies, different electronic and chemical parameters are predicted. Red and yellow in electrostatic potential plot is in rings and oxygen atom in PAZ and C≡N and rings in CYM are sensitive to nucleophilic attacks. The blue in hydrogen atoms refer to electrophilic attack in both PAZ and CYM. Stability of the protein-ligand complex formed with these derivatives and angiotensin-converting enzyme 2 (ACE2) was investigated using MD simulation. Radius of gyration of C-alpha atom of 6VW1 displayed the conformational convergence toward a compact structure leading to stable 6VW1-ligand complex which are also in agreement with root mean square fluctuation (RMSF) values. Localized area predicts reactive sites for Au and H2O molecules interaction with these compounds for further practical applications. Charge density is localized on both molecules and also tries to move toward Au-Au dimer and water molecule and such they are expected to contribute to the sensing performance.Communicated by Ramaswamy H. Sarma.

Site-Specific Labeling Reveals Cas9 Induces Partial Unwinding Without RNA/DNA Pairing in Sequences Distal to the PAM.

CRISPR-Cas9 is an RNA-guided nuclease that has been widely adapted for genome engineering. A key determinant in Cas9 target selection is DNA duplex unwinding to form an R-loop, in which the single-stranded RNA guide hybridizes with one of the DNA strands. To advance understanding on DNA unwinding by Cas9, we combined two types of spectroscopic label, 2-aminopurine and nitroxide spin-label, to investigate unwinding at a specific DNA base pair induced by Streptococcus pyogenes Cas9. Data obtained with RNA guide lengths varying from 13 to 20 nucleotide revealed that the DNA segment distal to the protospacer adjacent motif can adopt a "partial unwinding" state, in which a mixture of DNA-paired and DNA-unwound populations exist in equilibrium. Significant unwinding can occur at positions not supported by RNA/DNA pairing, and the degree of unwinding depends on RNA guide length and modulates DNA cleavage activity. The results shed light on Cas9 target selection and may inform developments of genome-engineering strategies.

A randomized, double-blind, parallel-group, single-dose comparative pharmacokinetic study of DRL_TZ, a candidate biosimilar of trastuzumab, with Herceptin® (EU) in healthy adult males.

BACKGROUND & OBJECTIVES: Trastuzumab (TZ) is a recombinant DNA-derived humanized monoclonal antibody approved for human epidermal growth factor receptor 2 positive early breast cancer, metastatic breast and gastric cancers. For the development of TZ biosimilars, establishing pharmacokinetic equivalence is required. The primary objective of this study was to compare the pharmacokinetics (PK) of Dr Reddy's Laboratories TZ (DRL_TZ) with that of EU-approved Reference Medicinal Product (RMP), Herceptin® in healthy adult male subjects. METHODS: In this double-blind, parallel-group, phase I study (TZ-01-003), healthy male subjects aged 18-55 yr were randomized 1:1 to receive a single intravenous infusion of 6 mg/kg of TZ as DRL_TZ or RMP. Similarity for primary PK parameters was defined as the 90 per cent confidence intervals (CIs) for the geometric mean ratios (GMRs) falling within 75-133 per cent limits. Primary endpoints included area under the concentration-time curve - from time zero (pre-dose) to the last quantifiable concentration [AUC(0-t)] and from time zero (pre-dose) extrapolated to infinity [AUC(0-∞)], and maximum observed serum concentration (Cmax). Secondary objectives were to compare the safety and immunogenicity of DRL_TZ with that of the RMP. RESULTS: Thirty two subjects were dosed (DRL_TZ, 16; RMP, 16). Primary PK parameters were found to be comparable with their 90 per cent CIs for the GMR falling within the usual more stringent limits of 80-125 per cent. The number of subjects reporting at least one TEAE in both the arms was similar. No serious adverse events were reported. Fifteen subjects, eight in DRL_TZ arm and seven in Herceptin® arm, tested positive for anti-drug antibodies (ADAs), none of the ADAs were neutralizing in nature. INTERPRETATION & CONCLUSIONS: In this study, DRL_TZ demonstrated PK equivalence with the RMP and had comparable safety and immunogenicity profiles in healthy adult male subjects.

A concise review of bioanalytical methods of small molecule immuno-oncology drugs in cancer therapy.

Immuno-oncology (IO) is an emerging option to treat cancer malignancies. In the last two years, IO has accounted for more than 90% of the new active drugs in various therapeutic indications of oncology drug development. Bioanalytical methods used for the quantitation of various IO small molecule drugs have been summarized in this review. The most commonly used are HPLC and LC-MS/MS methods. Determination of IO drugs from biological matrices involves drug extraction from the biological matrix, which is mostly achieved by simple protein precipitation, liquid-liquid extraction and solid-phase extraction. Subsequently, quantitation is usually achieved by LC-MS/MS, but HPLC-UV has also been employed. The bioanalytical methods reported for each drug are briefly discussed and tabulated for easy access. Our review indicates that LC-MS/MS is a versatile and reliable tool for the sensitive, rapid and robust quantitation of IO drugs.

Validated HPLC-UV method for simultaneous quantification of phosphatidylinositol 3-kinase inhibitors, copanlisib, duvelisib and idelalisib, in rat plasma: Application to a pharmacokinetic study in rats.

Phosphatidylinositol 3-kinase (PI3K) inhibitors are a novel class of anticancer drugs that are approved to treat various malignancies. We report the development and validation of a HPLC method for the simultaneous quantitation of three PI3K inhibitors, namely copanlisib, duvelisib and idelalisib, in rat plasma as per the regulatory guidelines of the United States Food and Drug Administration. The method involves extraction of copanlisib, duvelisib and idelalisib along with an internal standard (IS; filgotinib) from rat plasma (100 µL) using a liquid-liquid extraction process. The chromatographic separation of the analytes was achieved using step-wise gradient elution on a Hypersil Gold C18 column. The UV detection wavelength was set at λmax = 280 nm. Copanlisib, duvelisib, idelalisib and the IS eluted at 7.16, 12.6, 11.9 and 9.86 min, respectively, with a total run time of 15 min. The calibration curve ranged from 50 to 5000 ng/mL for all the analytes. Inter- and intra-day precision and accuracy, stability studies, dilution integrity and incurred sample reanalysis were investigated for all three analytes, and the results met the acceptance criteria. The validated HPLC method was successfully applied to a pharmacokinetic study in rats.

Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.

Simultaneous determination of colchicine and febuxostat in rat plasma: Application in a rat pharmacokinetic study.

A selective, sensitive and rapid LC-MS/MS method has been developed and validated as per US Food and Drug Administration regulatory guidelines for the simultaneous quantitation of colchicine and febuxostat in rat plasma. Colchicine and febuxostat were extracted from the rat plasma using 10% tert-butyl methyl ether in ethyl acetate using colchicine-d6 as an internal standard (IS). The chromatographic separation of colchicine, febuxostat and the IS was achieved using a mobile phase comprising 5 mm ammonium formate and 0.025% formic acid in acetonitrile (20:80, v/v) in isocratic mode on an Eclipse XDB-C18 column. The injection volume and flow rate were 5.0 µl and 0.9 ml/min, respectively. Colchicine and febuxostat were detected by positive electrospray ionization in multiple reaction monitoring mode using transition pairs (Q1 → Q3) of m/z 400.10 → 358.10 and 317.05 → 261.00, respectively. The assay was linear in the ranges of 0.25-254 and 2.60-622 ng/ml for colchicine and febuxostat, respectively. The inter- and intra-day precision values were 0.58-13.0 and 1.03-4.88% for colchicine and febuxostat, respectively. No matrix or carryover effects were observed during the validation. Both analytes were stable on the bench-top, in the autosampler and in storage (freeze-thaw cycles and long-term storage at -80°C). A pharmacokinetic study in rats was performed to show the applicability of the validated method.

Development and Validation of an HPLC Method for Quantification of Filgotinib, a Novel JAK-1 Inhibitor in Mice Plasma: Application to a Pharmacokinetic Study.

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, filed in Japan for the treatment of rheumatoid arthritis. In this paper, we present the data of development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of filgotinib in mice plasma as per the FDA regulatory guideline. The method involves the extraction of filgotinib along with internal standard (IS, tofacitinib) from mice plasma (100 µL) using ethyl acetate as an extraction solvent. The chromatographic analysis was performed using an isocratic mobile phase comprising 10 mM ammonium acetate (pH 4.5) and acetonitrile (70:30, v/v) at a flow-rate of 0.8 mL/min on a Hypersil Gold C18 column. The UV detection wavelength was set at λmax 300 nm. Filgotinib and the IS eluted at 5.56 and 4.28 min, respectively with a total run time of 10 min. The calibration curve was linear over a concentration range of 0.05 to 5.00 µg/mL (r 2+=≥0.992). The intra- and inter-day precision and accuracy results were within the acceptable limits. Results of stability studies indicated that filgotinib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycles and long-term storage at -80°C. The validated HPLC method was successfully applied to a pharmacokinetic study in mice.

Validated LC-MS/MS method for quantitation of a selective JAK1 inhibitor, filgotinib in rat plasma, and its application to a pharmacokinetic study in rats.

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, filed in Japan for the treatment of rheumatoid arthritis. In this paper, we report a validated liquid chromatography coupled with tandem mass spectrometry for the quantification of filgotinib in rat plasma using tofacitinib as an internal standard (IS) as per the Food and Drug Administration regulatory guidelines. Filgotinib and the IS were extracted from rat plasma using ethyl acetate as an extraction solvent and chromatographed using an isocratic mobile phase (0.2% formic acid:acetonitrile; 20:80, v/v) at a flow rate of 0.9 mL/min on a Gemini C18 column. Filgotinib and the IS were eluted at ~1.31 and 0.89 min, respectively. The MS/MS ion transitions monitored were m/z 426.3 → 291.3 and m/z 313.2 → 149.2 for filgotinib and the IS, respectively. The calibration range was 0.78-1924 ng/mL. No matrix effect and carryover were observed. Intra- and inter-day accuracies and precisions were within the acceptance range. Filgotinib was stable for three freeze-thaw cycles: on bench-top up to 6 h, in an autosampler up to 21 h, and at -80°C for 1 month. This novel method has been applied to a pharmacokinetic study in rats.

Validated HPLC method for quantification of copanlisib in mice plasma: application to a pharmacokinetic study.

Copanlisib is a pan phosphatidylinositol 3-kinase (PI3K) inhibitor approved for follicular lymphoma. In this paper, we present the data of development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of copanlisib in mice plasma as per the FDA regulatory guideline. The method involves the extraction of copanlisib along with internal standard (IS, enasidenib) from mice plasma (100 µL) using ethyl acetate as an extraction solvent. The chromatographic resolution of copanlisib and the IS was achieved on a Hypersil Gold C18 column maintained at 40 °C using a binary gradient mobile phase [10 mM ammonium formate (pH 4.0) and acetonitrile]. The flow-rate was 0.8 mL/min. For the detection of copanlisib and the IS, the photo-diode array detector was set at λmax 310 nm. Copanlisib and the IS eluted at 6.60 and 7.80 min, respectively with a total run time of 10 min. The calibration curve was linear over a concentration range of 50 to 5000 ng/mL for copanlisib (r2≥ 0.998). The results of intra- and inter-day accuracy and precision studies were within the acceptable limits. Copanlisib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycle and long-term storage at -80 °C. The application of the validated method was shown in a mice pharmacokinetic study.

A review of bioanalytical methods for chronic lymphocytic leukemia drugs and metabolites in biological matrices.

Quantitation of drugs used for the treatment of chronic lymphocytic leukemia in various biological matrices during both pre-clinical and clinical developments is very important, often in routine therapeutic drug monitoring. The first developed methods for quantitation were traditionally done on LC in combination with either UV or fluorescence detection. However, the emergence of LC with mass spectrometry in tandem in early 1990s has revolutionized the quantitation as it has provided better sensitivity and selectivity within a shorter run time; therefore it has become the choice of method for the analysis of various drugs. In this article, an overview of various bioanalytical methods (HPLC or LC-MS/MS) for the quantification of drugs for the treatment of chronic lymphocytic leukemia, along with applicability of these methods, is given.

Bacillus Calmette-Guérin vaccine induces a selective serotonin reuptake inhibitor (SSRI)-resistant depression like phenotype in mice.

Preclinical studies have shown that administration of Bacillus Calmette-Guérin (BCG) vaccine induces depression-like behaviors in mice; however, the effect of antidepressant drug treatment has not been reported earlier. In the present study, we induced depression-like behavior by administering BCG vaccine to BALB/c mice. BCG treatment produced robust serum sickness as shown by a decrease in body weight, reduced spontaneous locomotor activity and reduced voluntary wheel running activity. BCG treatment also elevated plasma IL6 and IFNγ levels and produced a marked activation of lung IDO activity. At a time point when serum sickness-related behaviors had fully recovered (i.e., day 14) BCG-treated mice showed a significant increase in immobility in the forced swim test (FST) and tail suspension test (TST) indicative of a pro-depressant phenotype. We observed significant increase in [(3)H]PK11195 binding in cortex and hippocampus regions of BGC-treated mice in comparison to saline-treated mice indicating prominent neuroinflammation. Pharmacological evaluation of FST behavior in BCG-treated mice demonstrated selective resistance to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and escitalopram. In contrast the tricyclic antidepressant imipramine, the dual serotonin/norepinephrine reuptake inhibitor (SNRI) duloxetine, and the dual dopamine/norepinephrine reuptake inhibitor (DNRI) nomifensine retained antidepressant efficacy in these mice. The lack of efficacy with acute treatment with SSRIs could not be explained either by differences in drug exposure or serotonin transporter (SERT) occupancy. Our results demonstrate that BCG-vaccine induced depression like behavior is selectively resistant to SSRIs and could potentially be employed to evaluate novel therapeutic agents being developed to treat SSRI-resistance in humans.