Enhanced spectrofluorimetric determination of the multitargeted tyrosine kinase inhibitor, crizotinib, in human plasma via micelle-mediated approach

Purpose: To quantify the multi-targeted tyrosine kinase inhibitor, crizotinib, in human plasma and bulk powder by highly sensitive micellar enhanced spectrofluorimetric procedure.Method: The developed procedure was based on measuring the fluorescence intensity of crizotinib (CRZ) in sodium dodecyl sulphate (SDS) micellar system at 404 nm after excitation at 271 nm. Validation of the developed procedure was carried out following ICH (International Council for Harmonization) guidelines.Results: Maximum fluorescence intensity (FI) was attained by addition of 0.2 mL SDS and 0.2 mL HCl (1N) to CRZ aliquots and then dilution with distilled water. There was a linear relationship between the FI of CRZ and its concentration over the range, 5 – 400 ng/mL, with limit of detection and of quantification of 1.857 and 5.628 ng/mL respectively. The developed procedure was successfully applied to assay CRZ in pure powder form and spiked human plasma with mean recovery of 100.68 ± 0.37 and 99.98 ± 0.20 %, respectively.Conclusion: The developed procedure is simple and sensitive, and can be applied to routine analysis of CRZ in pure powder form as well as in clinical laboratories for the determination of CRZ in plasma.Keywords: Crizotinib, Spectrofluorimetry, Micelle, Human plasma, Sodium dodecyl sulphat

A new spectrofluorimetric assay method for vandetanib in tablets, plasma and urine

Purpose: To develop a simple and sensitive spectrofluorimetric method for the determination of vandetanib (VDB) in tablets (containing 100 mg of the drug) and biological fluids (spiked human plasma and urine).Methods: The proposed method is based on examining the intrinsic fluorescence intensity of VDB in acetonitrile at 480 nm after excitation at 330 nm. Factors affecting fluorescence intensity of the cited drug (VDB), including the influence of pH, diluting solvent and time, were studied and optimized by one factor at a time approach. A calibration curve was constructed by plotting VDB fluorescence intensity at 480 nm versus VDB concentrations in ng mL-1. The method was validated according to the recommendations of International Conference on Harmonisation (ICH) for validation of the analytical proceduresResults: The linearity range of the method was 20 – 600 ng mL-1, with limits of quantification (LOQ) and of detection (LOD) of 30.45 and 10.05 ng mL-1, respectively. The adopted method was applied successfully to the quantitation of VDB in pure powder form (100.90 ± 0.91 %), laboratory prepared tablets (97.86 ± 1.42 %), spiked human plasma (97.97 ± 2.36 %) and urine (97.59 ± 0.87 %). Comparison of the proposed method with that of liquid chromatography-tandem mass spectrometry showed that there was no significant difference (p < 0.05) between the two methods in terms of accuracy and precision.Conclusion: The proposed method is simple and highly sensitive and, consequently, can be applied to assay VDB in biological samples as well as in dosage form.Keywords: Vandetanib, Spectrofluorimetry, Assay, Validation, Human plasma, Human urine, Dosage form

Rapid validated liquid chromatographic method coupled with Tandem mass spectrometry for quantification of nintedanib in human plasma

Purpose: To develop and validate a fast, sensitive, and simple liquid chromatographic method coupled with tandem mass spectrometry for the determination of the potent tyrosine kinase inhibitor, ninetedanib (NTB) in plasma, utilizing cyclobenzaprine (CBP) as internal standard (IS).Methods: Separation of the two components (NTB and CBP) was performed on a pentafluorophenyl (PFP) reversed phase column (50 × 2 mm, 3μm) at ambient temperature using isocratic elution with acetonitrile-water (60:40, v/v) containing 0.01 M ammonium formate buffer (pH 4.2) at a flow rate of 0.4 mL/min. NTB and CBP were monitored by a triple quadrupole tandem mass spectrometer with electrospray ionization source in the positive ion mode. The current method was validated following the European Medicines Agency (EMA) guidelinesResults: The proposed method allowed rapid and specific quantification of NTB in the calibration range of 2 - 150 ng/mL and determination coefficient of ≥ 0.999. Intra- and inter-day accuracy and precision were < 4 % in all cases.Conclusion: The developed procedure is rapid, specific, reliable, and validated for quantification of NTB in human plasma, and thus can be applied efficiently for the analysis of clinical samples containing NTB.Keywords: Nintedanib assay, Cyclobenzaprine, LC-MS/MS, Validatio

Simultaneous quantitative analysis of olmesartan, amlodipine and hydrochlorothiazide in their combined dosage form utilizing classical and alternating least squares based chemometric methods

Simultaneous spectrophotometric analysis of a multi-component dosage form of olmesartan, amlodipine and hydrochlorothiazide used for the treatment of hypertension has been carried out using various chemometric methods. Multivariate calibration methods include classical least squares (CLS) executed by net analyte processing (NAP-CLS), orthogonal signal correction (OSC-CLS) and direct orthogonal signal correction (DOSC-CLS) in addition to multivariate curve resolution-alternating least squares (MCR-ALS). Results demonstrated the efficiency of the proposed methods as quantitative tools of analysis as well as their qualitative capability. The three analytes were determined precisely using the aforementioned methods in an external data set and in a dosage form after optimization of experimental conditions. Finally, the efficiency of the models was validated via comparison with the partial least squares (PLS) method in terms of accuracy and precision

A novel method to determine new potent angiotensin inhibitor, azilsartan, in human plasma via micelle-enhanced spectrofluorimetry using cremophor RH 40

Purpose: To develop a micelle-enhanced spectrofluorimetric method for the assay of azilsartan (AZL) in bulk form and spiked human plasma without the need for derivatization procedure.Method: The proposed method was based on studying the fluorescence behavior of AZL in Cremophor RH 40 (Cr RH 40) micellar system. The fluorescence intensity was measured at 371 nm after excitation at 264 nm. The proposed procedure was validated according to International Council on Harmonization (ICH) guidelines.Results: In aqueous solution, the fluorescence intensity of AZL was greatly enhanced by more than 3- fold in the presence of Cr RH 40. The fluorescence –concentration plot was linear over the range of 10 – 500 ng.mL-1, with a limit of detection of 3.287 ngmL-1. The proposed method was successfully applied to the determination of AZL in pure powder form and spiked human plasma. The mean recovery of AZL in spiked human plasma using the proposed method was 90.54 ± 1.17 %.Conclusion: The suggested method is highly sensitive and simple, and can easily be applied for the quantification of AZL in pure powder form as well as in biological fluids such as plasmaKeywords: Azilsartan, Spectrofluorimetry, Spiked human plasma, Micellar syste

Liquid chromatographic-tandem mass spectrometric assay for simultaneous quantitation of tofacitinib, cabozantinib and afatinib in human plasma and urine

Purpose: To develop a simple, adequately sensitive, and practical liquid chromatographic-mass spectrometric method to simultaneously quantify three tyrosine kinase inhibitors, viz, tofacitinib (TOF), cabozantinib (CBZ) and afatinib (AFB) after their extraction from both human plasma and urine.Methods: Blood and urine samples were obtained from healthy volunteers who admitted to not being on any medications. The investigated analytes were chromatographically separated on a C18 column (Luna®-PFP 100Å column, 50 mm × 2.0 mm i.d., 3.0 μm) with the aid of a mobile phase containing A; acetonitrile (ACN) and B; 0.01 M ammonium formate buffer (pH 4.1) pumped at a rate of 0.3 mL.min-1 in the ratio A:B, 50:50 v/v. Analyte monitoring was achieved by tandem mass spectrometry interfaced with an electrospray ionization source with the aid of multiple reaction monitoring (MRM) mode for analytes quantification.Results: The proposed method permitted a specific and sensitive determination of the investigated TKIs in the linear range of 1.0 - 100 ng mL-1 with correlation coefficient (r2) of 0.9991, 0.9997, and 0.9998 for TOF, CBZ and AFB, respectively. The method was validated with regard to its limits of quantification (ranging from 0.91 to 1.24 ng mL-1 for the 3 analytes), intra- and inter assay accuracy (in the range -1.85 to 1.22 %) and precision (0.71 - 5.12 %). The method was also validated in terms of recovery from both studied matrices, robustness and matrix effect.Conclusion: The results obtained reveal that the developed method is simple, specific and highly efficient for routine determination of the studied analytes in human plasma and urine. It can be reliably applied for high throughput analysis of clinical samples containing the investigated analytes.Keywords: Tyrosine kinase inhibitors, Tofacitinib, Cabozantinib, Afatinib, LC-MS/MS, human plasm

Physicochemical properties, pharmacokinetic studies, DFT approach, and antioxidant activity of nitro and chloro indolinone derivatives

The process of developing of new drugs is greatly hampered by their inadequate physicochemical, pharmacokinetic, and intrinsic characteristics. In this regard, the selected chloro indolinone, (Z)-6-chloro-3-(2-chlorobenzylidene)indolin-2-one (C1), and nitro indolinone, (Z)-6-chloro-3-(2-nitrobenzylidene)indolin-2-one (C2), were subjected to SwissADME and density function theory (DFT) analysis. For compounds C1 and C2, the BOILED-Egg pharmacokinetic model predicted intestinal absorption, blood–brain barrier (BBB) penetration, and p-glycoprotein interaction. According to the physicochemical analysis, C1 has exceptional drug-like characteristics suitable for oral absorption. Despite only being substrates for some of the major CYP 450 isoforms, compounds C1 and C2 were anticipated to have strong plasma protein binding and efficient distribution and block these isoforms. The DFT study using the B3LYP/6-311G(d,p) approach with implicit water effects was performed to assess the structural features, electronic properties, and global reactivity parameters (GRP) of C1 and C2. The DFT results provided further support for other studies, implying that C2 is more water-soluble than C1 and that both compounds can form hydrogen bonds and (weak) dispersion interactions with other molecules, such as solvents and biomolecules. Furthermore, the GRP study suggested that C1 should be more stable and less reactive than C2. A concentration-dependent 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity was shown by both C1 and C2. In brief, this finding has provided a strong foundation to explore further the therapeutic potential of these molecules against a variety of human disorders

DNA binding Test, x-ray crystal structure, spectral studies, TG-DTA, and electrochemistry of [CoX2 (dmdphphen)] (dmdphphen is 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline,x = Cl, and NCS) complexes

Two new neutral mixed-ligand cobalt(II) complexes, CoCl2(dmdphphen) 1 and Co(NCS)dmdphphen) 2, where dmdphphen is 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline, were synthesized and characterized by an elemental analysis, UV-Vis, IR, TG/DTA, cyclic voltammetry CV, and single X-ray diffraction. Complex 2 crystallized as monoclinic with a space group P21/c. Co(II) ions are located in a distorted tetrahedral environment. TG/DTA result shows that these complexes are very stable and decomposed through one-step reaction. The two complexes exhibit a quasireversible one-electron response at -550 and 580 mV versus Cp2Fe/Cp2Fe+, which has been assigned to Co(I)/Co(II) and Co(II)/Co(III) couples. Absorption spectral studies reveal that such complexes exhibit hypochromicity during their interaction with CT-DNA. © 2014 Mousa Al-Noaimi et al

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Mapping geographical inequalities in access to drinking water and sanitation facilities in low-income and middle-income countries, 2000-17

Background: Universal access to safe drinking water and sanitation facilities is an essential human right, recognised in the Sustainable Development Goals as crucial for preventing disease and improving human wellbeing. Comprehensive, high-resolution estimates are important to inform progress towards achieving this goal. We aimed to produce high-resolution geospatial estimates of access to drinking water and sanitation facilities. Methods: We used a Bayesian geostatistical model and data from 600 sources across more than 88 low-income and middle-income countries (LMICs) to estimate access to drinking water and sanitation facilities on continuous continent-wide surfaces from 2000 to 2017, and aggregated results to policy-relevant administrative units. We estimated mutually exclusive and collectively exhaustive subcategories of facilities for drinking water (piped water on or off premises, other improved facilities, unimproved, and surface water) and sanitation facilities (septic or sewer sanitation, other improved, unimproved, and open defecation) with use of ordinal regression. We also estimated the number of diarrhoeal deaths in children younger than 5 years attributed to unsafe facilities and estimated deaths that were averted by increased access to safe facilities in 2017, and analysed geographical inequality in access within LMICs. Findings: Across LMICs, access to both piped water and improved water overall increased between 2000 and 2017, with progress varying spatially. For piped water, the safest water facility type, access increased from 40·0% (95% uncertainty interval [UI] 39·4–40·7) to 50·3% (50·0–50·5), but was lowest in sub-Saharan Africa, where access to piped water was mostly concentrated in urban centres. Access to both sewer or septic sanitation and improved sanitation overall also increased across all LMICs during the study period. For sewer or septic sanitation, access was 46·3% (95% UI 46·1–46·5) in 2017, compared with 28·7% (28·5–29·0) in 2000. Although some units improved access to the safest drinking water or sanitation facilities since 2000, a large absolute number of people continued to not have access in several units with high access to such facilities (>80%) in 2017. More than 253 000 people did not have access to sewer or septic sanitation facilities in the city of Harare, Zimbabwe, despite 88·6% (95% UI 87·2–89·7) access overall. Many units were able to transition from the least safe facilities in 2000 to safe facilities by 2017; for units in which populations primarily practised open defecation in 2000, 686 (95% UI 664–711) of the 1830 (1797–1863) units transitioned to the use of improved sanitation. Geographical disparities in access to improved water across units decreased in 76·1% (95% UI 71·6–80·7) of countries from 2000 to 2017, and in 53·9% (50·6–59·6) of countries for access to improved sanitation, but remained evident subnationally in most countries in 2017. Interpretation: Our estimates, combined with geospatial trends in diarrhoeal burden, identify where efforts to increase access to safe drinking water and sanitation facilities are most needed. By highlighting areas with successful approaches or in need of targeted interventions, our estimates can enable precision public health to effectively progress towards universal access to safe water and sanitation