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Mohamed W Attwa, 1, 2 Adnan A Kadi, 1 Hany W Darwish 1, 3 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Students’ University Hospital, Mansoura University, Mansoura 35516, Egypt; 3Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptCorrespondence: Hany W Darwish Tel +966 1146 77343Fax +966 1146 76 220Email hdarwish@ksu.edu.saIntroduction: Larotrectinib (VITRAKVI) is an orally potent tropomyosin receptor kinase (Trk) inhibitor that acts by competitive inhibition of all corresponding receptor kinases. It demonstrated a marked response rate (75%) and robust anticancer activity in Trk fusion-positive patients. This response is independent of cancer type, age and gender.Methods: In this study, an efficient and accurate LC-MS/MS analytical method was developed for Larotrectinib (LRB) quantification in addition to evaluation of its metabolic stability. LRB and lapatinib (LTP) (which is chosen as an internal standard; IS) were eluted utilizing an isocratic mobile phase with a reversed phase elution system (C 18 column).Results and Discussion: The linearity range of the established method was 5– 500 ng/mL (r 2 ≥ 0.9999) in the human liver microsomes (HLMs) matrix. Various parameters were calculated to validate the method sensitivity (limit of quantification was 5 ng/mL) and reproducibility (inter and intra-day accuracy and precision were below 3% in all samples) of our methodology. For evaluation of LRB metabolic stability in HLMs matrix, in vitro half-life (48.8 min) and intrinsic clearance (14.19 μL/min/mg) were computed.Conclusion: Accordingly, we can conclude that LRB is a moderate extraction ratio drug when compared with other tyrosine kinase inhibitors (TKIs). According to our knowledge, the discussed procedure in this study is the first LC-MS/MS analytical method for evaluating LRB metabolic stability.Keywords: larotrectinib, human liver microsomes, metabolic stability evaluation, tandem mass spectrometry

Due to their susceptibility to degradation, vitamin levels in food formulations may differ from those found in the finished product. Vitamin levels can be impacted by processing and storage. In this work, the ingredients of Strong B50 ® film-coated tablets were estimated simultaneously using simple efficient stability indicating HPLC method. Strong B50 ® film-coated tablets contain thiamine (VB1), riboflavin (VB2), calcium pantothenate (VB5), pyridoxine (VB6), vitamin C (VC), folic acid (FA), biotin (BT), inositol (IS), niacin (NC), para-aminobenzoic acid (PB), cyanocobalamine (B12), choline bitartarate, and iron gluconate. Hypersil BDS C18 column was used for achieving reasonable separation. Mobile phases (A) and (B) were utilized, the mobile phase (A) consisted of 0.015 M Hexane sulfonic acid sodium salt + 0.1 % Triethylamine and orthophosphoric acid was used to adjust the pH to (2.9) while (B) system consisted of acetonitrile. Validation of the method was assessed using International Conference of Harmonization (ICH) parameters, where linearity, accuracy, selectivity, and robustness of the method were investigated. Correlations were above 0.99, accuracy results ranged from 97.6 to 102.8 % and limits for detection and quantitation (LOD and LOQ) values were determined for each vitamin in μg/mL except for FA and BT in ng/mL. LOD values were between 0.006 and 15.08 μg/mL while LOQ values ranged from 0.031 to 49.77 μg/mL. Stability studies were conducted under stressed conditions and degradation percentages were computed. Where, VB5, VB6, FA and PB, VC, and NC were the most degradable vitamins. Whiteness evaluation using the modern RGB 12 algorithm compared our method and the old reported one by Sasaki et al., 2020. The comparison favored our newly developed method in terms of analytical performance, practical applicability and greenness. Besides, AGREE and GAPI soft wares were used to assess the greenness of the method. It was clear that the results of colored pictograms confirm low hazardous impact and that the new method is greener with AGREE score of 0.66. Furthermore, the functionality and applicability of the novel HPLC approach were concluded via the Blue Applicability Grade Index (BAGI) tool with a final score of 82.5., 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 © 2024 Elsevier B.V. All rights reserved.)

Aim: The present study describes benzothiazole derived thiazolidinone based thiadiazole derivatives ( 1-16 ) as anti-Alzheimer agents. Materials & methods: Synthesis of benzothiazole derived thiazolidinone based thiadiazole derivatives was achieved using the benzothiazole bearing 2-amine moiety. These synthesized compounds were confirmed via spectroscopic techniques ( 1 H NMR, 13 C NMR and HREI-MS). These compounds were biologically evaluated for their anti-Alzheimer potential. Binding interactions with proteins and drug likeness of the analogs were explored through molecular docking and ADMET analysis, respectively. In the novel series, compound- 3 emerged as the most potent inhibitor when compared with other derivatives of the series. Conclusion: The present study provides potent anti-Alzheimer's agents that can be further optimized to discover novel anti-Alzheimer's drugs.

A stable and efficient hole-transport material (HTM) is crucial for high-performance perovskite solar cells (PSCs). A 2,2',7,7'-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9'-spirobifluorene (Spiro-MeOTAD) being used widely to prepare highly efficient PSCs. However, Spiro-MeOTAD has some limitations due to its complex synthesis, which increases its cost, and it also requires dopants to improve its performance. Therefore, we designed thirteen unique small-molecule-based HTMs (MK1-MK13), which are easy to synthesize, highly cost-effective, and don't require dopants to prepare efficient PSCs. Their electrical and optical properties are then investigated theoretically using advanced quantum chemical approaches. The designed molecules showed lower energy gaps and improved optical and optoelectronic characteristics because of the improved phase inversion geometry. The detailed photo-physical and optoelectronic characteristics have been studied using density functional theory (DFT) and time-dependent (TD-DFT) calculations. Moreover, we investigated the impact of holes and electrons and the density of states, open-circuit voltage, frontier molecular orbital, transition density matrix, and other structural and photovoltaic characteristics of these materials. Among these, the MK3 molecule possesses the much narrower optical band gap of 1.04 eV and absorbance (λ max ) of 684 nm, respectively. In addition, a profound investigation of the MK3/PC 61 BM blend shows excellent charge transfer at the acceptor-donor interface. Therefore, our proposed technique is necessary for generating appropriate photovoltaic materials for efficient optoelectronic devices and is helpful in further advancing the field., 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 © 2024 Elsevier B.V. All rights reserved.)

Background: The formation of charge transfer complexes (CTCs) of iodine with five chemotherapeutic drugs used for the treatment of different types of cancer has not been investigated. These drugs were olaparib, seliciclib, vandetanib, dasatinib, and tozasertib. Additionally, these drugs need an appropriate general spectrophotometric assay for their analysis in the dosage forms regardless of the differences in their chemical structures., Objective: The aim of this study was the development of a novel microwell spectrophotometric assay (MW-SPA) for one-step determination of these drugs via their intereactions with iodine resulted in instantaneous producing a bright lemon yellow-colored CTCs., Methods: The spectrophotometric study of the CTCs were conducted, and all CTCs were characterized. Site(s) of interaction on each drug were assigned, and the MW-SPA was developed and applied to the analysis of dosage forms., Results: The findings confirmed that the reactions proceeded via CTCs formation. Beer's law was obeyed over a general concentration range of 1-6 µg/mL. The limits of detection and quantitation were in the ranges of 0.5-2.1 and 1.5-6.4 µg/mL, respectively. The proposed MW-SPA demonstrated excellent precisions as the relative standard deviations were < 2.24 and 2.23% for the intra- and inter-assay precision, respectively. Recovery studies demonstrated the accuracy of MW-SPA. Successful determination of all drugs in bulk and tablet forms was achieved using the MW-SPA. The environmental sustainability of the proposed methodology was determined, providing evidence of the assay's alignment with the basis of green analytical chemistry. The high throughput of the assay was documented., Conclusions: In contrast to other existing methods, the MW-SPA described herein valid for analyzing all drugs at the same wavelength., Highlights: The assay is useful for routine analysis of drugs in their formulations in quality control laboratories., (© The Author(s) 2024. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Nonfullerene acceptors (NFAs) have emerged as tremendous materials, efficiently advancing bulk-heterojunction organic solar cells (OSCs) technology. Unlike their fullerene counterparts, NFAs offer the unique advantage of finely tunable electronic energy levels and optical characteristics, which correspond to substantial enhancement in power conversion efficiency of OSCs. Herein, we have introduced a new series of near-infrared NFAs (AY1-AY8) to advance this technology further. Our research deeply investigates the structure-property relationship and thoroughly explores the optical, optoelectronics, photophysical, and photovoltaic characteristics of a synthetic reference molecule (R) and the modeled AY1-AY8 NFAs series. We performed advanced quantum chemical simulations using density functional theory (DFT) and time-dependent DFT methods. Additionally, we also estimated key geometric characteristics such as frontier molecular orbitals, hole-electron overlap, density of states, molecular electrostatic potential, molecular excitation and binding energies, transition density matrix, and reorganizational energy of electrons and holes and compared them with those of a synthetic reference molecule (R). Our findings show that all designed materials (AY1-AY8) exhibit red-shift absorption, improved electronic charge mobility, and low binding and excitation energies compared to R. Notably, these designed materials (AY1-AY8) display significantly narrower electronic energy gaps ( E g 1.89-1.71 eV), indicating enhanced charge shifting from the highest occupied molecular orbital to lowest unoccupied molecular orbital and broadening of the absorption spectrum. Moreover, we also revealed a comprehensive study of the donor/acceptor complex of PTB7-Th/AY8 to understand charge shifting between donor and acceptor molecules. Therefore, we strongly recommend this designed (AY1-AY8) series to the experimentalists for the future development of highly efficient OSC devices., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pirzada, Khan, Alam, Darwish, Elhenawy, Kuznetsov and Daglia.)

Pholcodine, an anti-tussive medication widely used as an over-the-counter, OTC drug, has recently faced restrictions in several countries. This paper presents a sensitive electrochemical approach for pholcodine detection. The electrochemical method involved fabricating a graphene nanoplatelets electrode, incorporating polythiophene nanospheres polymer to promote electron transfer and increase the activated surface area. Characterization of the fabricated electrode was performed using transmission electron microscopy, ATR-Fourier-transform infrared spectroscopy, X-ray crystallography, X-ray photoelectron spectroscopy, and electrochemical impedance spectroscopy. The electrochemical behavior of pholcodine with the fabricated electrode was investigated using cyclic voltammetry, chronoamperometry, square wave voltammetry (SWV), and differential pulse voltammetry (DPV). The developed electrode led to a linear response for pholcodine ranging from 10 to 45 mg/L with detection limits of 1.41 and 1.51 mg/mL for SWV and DPV, respectively and quantification limits of 4.27 and 4.57 mg/L for SWV and DPV, respectively. The proposed method has accurately recovered pholcodine in spiked serum samples with a recovery percentage ranging from 1.2 to 2.9%. The optimized method is found to be accurate, precise, and robust by applying validation parameters provided by International Council for Harmonization. Two green metrics were computed to assess the method's greenness, the findings showed that the developed method is environmentally friendly with minimum sample preparation steps., (© 2024. The Author(s).)

This study addressed the cytotoxic potential of four compounds: monocarbonyl curcuminoid, ethyl (2E)-2-benzylidene-3-oxobutanoate 1 , 1,2-dimethoxy-12-methyl-13H- [1,3] benzodioxolo[5,6- c ] phenanthridine 2 , 3,5-dibenzyloxybenzyl bromide 3 , and (E)-4-(4-chlorobenzylidene)-1-(4-nitrophenyl)hexan-3-one 4 . In vitro cytotoxic assays were carried out in HL-60 and BJ cells using the MTT assay along with analysis of apoptosis with the annexin V detection kit. Additional network pharmacology and docking analyses were carried out. In the in vitro assays , compounds 2 and 4 displayed significant antiproliferative effects in HL-60 cells, exhibiting IC 50 values of 5.02 and 9.50 μM, respectively. Compound 1 showed no activity, and compound 3 displayed toxicity in BJ cells. In addition, both compounds 2 and 4 induced apoptosis in HL-60 cells. Network pharmacology and docking analyses indicated that compounds 2 and 4 had synergistic effects targeting the CASP3 and PARP1 proteins. Notably, these proteins play pivotal roles in cancer-related pathways. Thus, by modulating these proteins, monocarbonyl curcuminoid has the potential to influence various cancer-related pathways. In summary, our novel findings provide valuable insights into the potential of these compounds to serve as novel anticancer therapeutic agents, warranting further mechanistic studies and clinical exploration., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

In this paper, we present a comprehensive analysis of HCl-HCl interactions, including QZVPP calculations, energy fitting, conformation validation, and the determination of the second virial coefficient B using improved Lennard-Jones (ILJ) potential parameters. To acquire accurate interaction energies, initial QZVPP calculations are performed on approximately 1851 randomly generated HCl-HCl conformations. Then, these energies are used to fit an improved Lennard-Jones potential energy surface, allowing for a robust description of HCl-HCl interactions. The ILJ potential parameters are then used to validate particular HCl dimer conformations, ensuring their stability and consistency with experimental observations. The correlation between calculated and experimental conformations strengthens the validity of the ILJ potential parameters. In addition, the second viral coefficient B is calculated at various temperatures using the ILJ potential. The obtained B values are compared to experimental data, demonstrating close agreement, and validating the ILJ potential's ability to accurately capture the intermolecular interactions and gas-phase behavior of the HCl-HCl system. The results of this study demonstrate the effective implementation of QZVPP calculations, energy fitting, and ILJ potential parameters in validating HCl-HCl conformations and accurately determining the second virial coefficient B . The high degree of concordance between calculated B values and experimental data demonstrates the validity of the ILJ potential and its suitability for modeling HCl-HCl interactions. This research contributes to a greater comprehension of HCl-HCl interactions and their implications for numerous chemical and atmospheric processes. The validated conformations, energy fitting method, and calculated second virial coefficients provide valuable instruments for future research and pave the way for more accurate modeling and simulations of HCl-HCl systems., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Duvelisib (DUV) is chemically named as (S)-3-(1-((9H-Purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one. It is a novel drug with a small molecular weight and characterized by dual phosphoinositide-3-kinase (PI3K)- and PI3K-inhibitory activity. The Food and Drug Administration (FDA) recently approved DUV for the management of small lymphocytic lymphoma (SLL) and relapsed or refractory chronic lymphocytic leukemia (CLL) in adult patients. DUV is marketed under the brand name of Copiktra® (Verastem, Inc., Needham, MA, USA). This chapter provides a critical extensive review of the literature, the description of DUV in terms of its names, formulae, elemental composition, appearance, and use in the treatment of CLL, SLL, and follicular lymphoma. The chapter also describes the methods for preparation of DUV, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information., (Copyright © 2024. Published by Elsevier Inc.)

Exposure to air pollutants has been associated with various adverse health outcomes, including chronic obstructive pulmonary disease (COPD). However, the precise underlying mechanism by which air pollution impacts COPD through remains insufficiently understood. To elucidated the molecular mechanism by which air pollutant exposure contributes to alterations in the gut microbiome and metabolism in AECOPD patients, we employed metagenomics and untargeted metabolomics to analyse the gut microbial, faecal, and serum metabolites. The correlations among air pollutants, gut microbes, serum metabolites, and blood biochemical markers were assessed using generalised additive mixed models and Spearman correlation analysis. The findings revealed that for every 10 μg/m 3 increase in PM 2.5 concentration, the α-diversity of the gut flora decreased by 2.16% (95% CI: 1.80%-2.53%). We found seven microorganisms that were significantly associated with air pollutants, of which Enterococcus faecium, Bacteroides fragilis, Ruthenibacterium lactatiformans, and Subdoligranulum sp.4&#95;3&#95;54A2FAA were primarily associated with glycolysis. We identified 13 serum metabolites and 17 faecal metabolites significantly linked to air pollutants. Seven of these metabolites, which were strongly associated with air pollutants and blood biochemical indices, were found in both serum and faecal samples. Some of these metabolites, such as 2,5-furandicarboxylic acid, C-8C1P and melatonin, were closely associated with disturbances in lipid and fatty acid metabolism in AECOPD patients. These findings underscore the impact of air pollutants on overall metabolism based on influencing gut microbes and metabolites in AECOPD patients. Moreover, these altered biomarkers establish the biologic connection between air pollutant exposure and AECOPD outcomes.The identification of pertinent biomarkers provides valuable insights for the development of precision COPD prevention strategies., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Exposure to metal mixtures is recognized as a real-life scenario, needing novel studies that can assess their complex effects on brain development. There is still a significant public health concern associated with chronic low levels of metal exposure. In contrast to other metals, these three metals (As, Pb, and Mn) are commonly found in various environmental and industrial contexts. In addition to additive or synergistic interactions, concurrent exposure to this metal mixture may also have neurotoxic effects that differ from those caused by exposure to single components. The NMDA receptor and several important signaling proteins are involved in learning, memory, and synaptic plasticity in the hippocampus, including CaMKII, postsynaptic density protein-95 (PSD-95), synaptic Ras GTPase activating protein (SynGAP), a negative regulator of Ras-MAPK activity, and CREB. We hypothesized that alterations in the above molecular players may contribute to metal mixture developmental neurotoxicity. Thus, the aim of this study was to investigate the effect of these metals and their mixture at low doses (As 4 mg, Pb 4 mg, and Mn 10 mg/kg bw/p.o) on NMDA receptors and their postsynaptic signaling proteins during developing periods (GD6 to PD59) of the rat brain. Rats exposed to As, Pb, and Mn individually or at the same doses in a triple-metal mixture (MM) showed impairments in learning and memory functions in comparison to the control group rats. Declined protein expressions of NR2A, PSD-95, p- CaMKII, and pCREB were observed in the metal mix-exposed rats, while the expression of SynGAP was found to be enhanced in the hippocampus as compared to the controls on PD60. Thereby, our data suggest that alterations in the NMDA receptor complex and postsynaptic signaling proteins could explain the cognitive dysfunctions caused by metal-mixture-induced developmental neurotoxicity in rats. These outcomes indicate that incessant metal mixture exposure may have detrimental consequences on brain development.

A hybrid library of compounds based on indazole-based thiadiazole containing thiazolidinone moieties ( 1 - 17 ) was synthesized. The synthesized compounds were screened in vitro for their inhibition profile against targetedacetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities. All the derivatives demonstrated a varied range of inhibitory activities having IC 50 values ranging from 0.86 ± 0.33 μM to 26.73 ± 0.84 μM (AChE) and 0.89 ± 0.12 μM to 27.08 ± 0.19 μM (BuChE), respectively. The results obtained were compared with standard Donepezil drugs (IC 50 = 1.26 ± 0.18 μM for AChE) and (1.35 ± 0.37 μM for BuChE), respectively. Specifically, the derivatives 1 - 17 , 1 , 9 , and 14 were found to be significantly active, with IC 50 values of 0.86 ± 0.30, 0.92 ± 0.10, and 1.10 ± 0.37 μM (against AChE) and 0.89 ± 0.12, 0.98 ± 0.48 and 1.19 ± 0.42 μM (against BuChE), respectively.The structure-activity relationship (SAR) studies revealed that derivatives bearing para -CF 3 , ortho -OH, and para -F substitutions on the phenyl ring attached to the thiadiazole skeleton, as well as meta -Cl, -NO 2 , and para -chloro substitutions on the phenyl ring, having a significant effect on inhibitory potential. The synthesized scaffolds have been further characterized by using 1 H-NMR, 13 C-NMR, and (HR-MS) to confirm the precise structures of the synthesized compounds. Additionally, the molecular docking approach was carried out for most active compounds to explore the binding interactions established by most active compounds, with the active sites of targeted enzymes and obtained results supporting the experimental data.

In the present work, a concise library of benzothiazole-derived pyrazoline-based thiazole ( 1 - 17 ) was designed and synthesized by employing a multistep reaction strategy. The newly synthesized compounds were screened for their α-glucosidase and urease inhibitory activities. The scaffolds ( 1 - 17 ) were characterized using a combination of several spectroscopic techniques, including FT-IR, 1 H-NMR, 13 C-NMR, and EI-MS. The majority of the synthesized compounds demonstrated a notable potency against α -glucosidase and urease enzymes. These analogues disclosed varying degrees of α -glucosidase and urease inhibitory activities, with their IC 50 values ranging from 2.50 to 17.50 μM ( α -glucosidase) and 14.30 to 41.50 (urease). Compounds 6 , 7 , 14 , and 12 , with IC 50 values of 2.50, 3.20, 3.40, and 3.50 μM as compared to standard acarbose (IC 50 = 5.30 µM), while the same compounds showed 14.30, 19.20, 21.80, and 22.30 comparable with thiourea (IC 50 = 31.40 μM), respectively, showed excellent inhibitory activity. The structure-activity relationship revealed that the size and electron-donating or electron-withdrawing effects of substituents influenced the enzymatic activities such as α-glucosidase and urease. Compound 6 was a dual potent inhibitor against α -glucosidase and urease due to the presence of -CF 3 electron-withdrawing functionality on the phenyl ring. To the best of our knowledge, these synthetic compounds were found to be the most potent dual inhibitors of α-glucosidase and urease with minimum IC 50 values. Moreover, in silico studies on most active compounds, i.e., 6 , 7 , 14 , and 12 , were also performed to understand the binding interaction of most active compounds with active sites of α-glucosidase and urease enzymes.

Cognitive decline and Alzheimer-like neuropathology are common manifestations of cadmium toxicity. Thanks to its antioxidant/anti-apoptotic features, dapagliflozin has demonstrated promising neuroprotective actions. However, its effect on cadmium-induced neurotoxicity is lacking. The present work aimed to examine whether dapagliflozin could protect rats from cadmium-evoked cognitive decline. In this study, the behavioral disturbances and hippocampal biomolecular alterations were studied after receiving dapagliflozin. Herein, cadmium-induced memory/learning decline was rescued in the Morris water maze, novel object recognition task, and Y-shaped maze by dapagliflozin. Meanwhile, the hippocampal histopathological abnormalities were mitigated. The molecular mechanisms revealed that dapagliflozin lowered hippocampal expression of p-tau and Aβ42 neurotoxic proteins while augmenting acetylcholine. The cognitive enhancement was triggered by hippocampal autophagy stimulation, as indicated by decreased SQSTM-1/p62 and Beclin 1 upregulation. Meanwhile, a decrease in p-mTOR/total mTOR and an increase in p-AMPK/total AMPK ratio were observed in response to dapagliflozin, reflecting AMPK/mTOR cascade stimulation. Dapagliflozin, on the other hand, dampened the pro-apoptotic processes in the hippocampus by downregulating Bax, upregulating Bcl-2, and inactivating GSK-3β. The hippocampal oxidative insult was mitigated by dapagliflozin as seen by lipid peroxide lowering, antioxidants augmentation, and SIRT1/Nrf2/HO-1 pathway activation. In conclusion, dapagliflozin's promising neuroprotection was triggered by its pro-autophagic, anti-apoptotic, and antioxidant properties.

Infigratinib, a protein kinase inhibitor employed in the therapeutic management of cholangiocarcinoma, was subjected to various stress conditions, including hydrolytic (acidic and alkaline), oxidative, photolytic, and thermal stress, in accordance with the rules established by the International Council for Harmonization. A cumulative count of five degradation products was observed. The application of the Quality by Design principle was utilized in the development of a rapid and specific separation method for Infigratinib and its degradation products. The methodology employed in this study was derived from an experimental design approach, which was utilized to examine the critical process parameters associated with chromatographic systems. The reversed-phase high-performance liquid chromatography technique, employing a C18 column and a mobile phase composed of a gradient mixture of 25 mM ammonium acetate buffer at pH 6.0 and acetonitrile, successfully facilitated the chromatographic separation. The methodology was expanded to include the utilization of UPLC-quadrupole tandem mass spectrometry in order to conduct a comprehensive analysis of the structural properties and characterize the degradation products. Overall, five degradation products were found in different stress conditions. The method was verified at certain working points, wherein a linearity range (5.0-200.0 µg/mL) was developed and other parameters such as accuracy, repeatability, selectivity, and system suitability were evaluated. Finally, the toxicity and mutagenicity of Infigratinib and its degradation products were predicted using in silico software, namely DEREK Nexus ® (version 6.2.1) and SARAH Nexus ® (version 3.2.1). Various toxicity endpoints, including chromosomal damage, were predicted. Additionally, two degradation products were also predicted to be mutagenic.

The classical least squares (CLS) model and three augmented CLS models are adopted and validated for the analysis of pyridoxine HCl (PYR), cyclizine HCl (CYC), and meclizine HCl (MEC) in a quinary mixture with two related impurities: the CYC main impurity, Benzhydrol (BEH), which has carcinogenic and hepatotoxic effects, and the MEC official impurity, 4-Chlorobenzophenone (BEP). The proposed augmented CLS models are orthogonal signal correction CLS (OSC-CLS), direct orthogonal signal correction CLS (DOSC-CLS), and net analyte processing CLS (NAP-CLS). These models were applied to quantify the three active constituents in their raw materials and their corresponding dosage forms using their UV spectra. To evaluate the CLS-based models sensibly, we design a comparative study involving two sets: the training set to construct models and the validation set to assess the prediction abilities of these models. A five-level, five-factor calibration design was established to produce 25 mixtures for the calibration set. In addition, 16 experiments were performed for a test set distributed equally between the in-space and out-space samples. The primary criterion for comparing the models' performance was the validation set's root mean square error of prediction (RMSEP) value. Finally, augmented CLS models showed acceptable results for assaying the three analytes. The results were compared statistically with the reported HPLC methods; however, the DOSC-CLS model proved the best for assaying the dosage forms.

Research targeting natural cosmeceuticals is now increasing due to the safety and/or limited side effects of natural products that are highly valued in cosmetology. Within a research program exploring botanical sources for valuable skincare antioxidant components, the current study investigated the phytochemical content and the biological potential of Faucaria tuberculosa . Phytochemical investigation of F. tuberculosa extract resulted in purification and characterization of six phytoconstituents, including a new one. The structure of the new constituent was elucidated as (-) catechin-(2→1',4→2')-phloroglucinol ( 4 ). The structural identity of all isolated compounds were confirmed on the basis of extensive physical and spectral (1D, 2D-NMR and HRESIMS) investigations. The ethanolic extract exhibits a rich content of total phenolics (TPC) and total flavonoids (TFC), estimated as 32 ± 0.034 mg GAE/g and 43 ± 0.004 mg RE/g, respectively. In addition, the antioxidant (ABTS and FRAP), antihyaluronidase and antityrosinase activities of all purified phytoconstituents were evaluated. The results noted (-) catechin-(2→1',4→2') phloroglucinol ( 4 ) and phloroglucinol ( 1 ) for their remarkable antioxidant activity, while isorhamnetin 3- O -rutinoside ( 3 ) and 3,5-dihydroxyphenyl β -D-glucopyranoside ( 2 ) achieved the most potent inhibitory activity against tyrosinase (IC 50 22.09 ± 0.7 µM and 29.96 ± 0.44 µM, respectively) and hyaluronidase enzymes (IC 50 49.30 ± 1.57 µM and 62.58 ± 0.92, respectively) that remarkably exceeds the activity of the standard drugs kojic acid (IC 50 = 65.21 ± 0.47 µM) and luteolin, (IC 50 = 116.16 ± 1.69 µM), respectively. A molecular docking study of the two active compounds ( 3 and 2 ) highlighted their high potential to bind to the active sites of the two enzymes involved in the study.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorders worldwide. Its pathologic features include massive neuroinflammation with abnormal deposition of β-amyloid peptide in the cerebral tissues leading to degeneration of the brain neurons. Adverse effects associated with the traditional drugs used for the treatment of this pathological condition have directed the research efforts towards searching for alternative effective agents with minimal adverse effects. The aim of this study was to elucidate the potential ameliorative effects of dapagliflozin and/or hesperidin on Alzheimer's disease (AD) induced by lipopolysaccharide (LPS) injection in rats. In a rodent model of AD, the effect of dapagliflozin with or without hesperidin on the biochemical parameters and the behavioral tests as well as the histopathological parameters was determined. Each of dapagliflozin and hesperidin restored the behavioral tests to the reference values, augmented the antioxidant defense mechanisms, ameliorated the neuronal inflammatory responses, combatted the changes in Toll-like receptor-4 (TLR-4)/High-mobility group box 1 (HMGB1) protein signaling and receptors of advanced glycation end products (RAGE) levels, and restored the balance between the apoptotic signals and autophagy in the hippocampal tissues. Additionally, both agents exhibited an outstanding ability to combat LPS-induced perturbations in the histopathological and electron microscopic image of the brain tissues. These favorable effects were significantly encountered in the group treated with dapagliflozin/hesperidin combination when compared versus animals treated with either dapagliflozin or hesperidin. In conclusion, inhibition of the hippocampal HMGB1/TLR4/RAGE signaling, the pro-inflammatory axis, and apoptosis alongside augmentation of the antioxidant defenses and autophagy can be regarded as beneficial effects by which dapagliflozin/hesperidin combination may combat LPS-triggered AD.

Lorlatinib (LOR) is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor drug. The Food and Drug Administration (FDA) has granted an approval for the use of LOR as a first therapeutic intervention for individuals diagnosed with ALK-positive metastatic and advanced non-small-cell lung cancer (NSCLC). The present study outlines, for the first time, the development and validation of an innovative microwell-based spectrofluorimetric (MW-SFL) method for the quantification of LOR. The proposed method involved the enhancement of the weak native fluorescence of LOR by its micellization into the sodium lauryl sulfate (SLS) micelles. The procedures of the method were conducted in white opaque plates with 96 microwells, and the enhanced fluorescence signals were measured by a fluorescence plate reader at 405 nm after excitation at 310 nm. The measured relative fluorescence intensity (RFI) had a linear relationship with LOR concentrations in the range of 60-1600 ng mL -1 . The limit of detection (LOD) and the limit of quantification (LOQ) were found to be 19 and 56 ng mL -1 , respectively. The method's accuracy and precision were assessed using a recovery study; the recovery values ranged from 99.98% to 101.40%, accompanied by relative standard deviation (RSD) values of 0.42% to 1.59%. The proposed MW-SFL method combined the advantages of the intrinsically high sensitivity of the spectrofluorimetric measurement and the excellent throughput of the microwell-based approach. The results proved the method is effective in the determination of LOR in its pharmaceutical tablets, tablet dissolution testing, as well as in spiked urine with a high degree of precision and accuracy. The MW-SFL method is notable for its simple procedures and utilization of water as a solvent, as well as minimal quantities of sample solutions. These features align with its ecofriendly approach to green chemistry principles. These advantages gave the proposed MW-SFL method a high potential value for the determination of LOR in clinical and quality control laboratories.

Cadmium is an environmental toxicant that instigates cognitive deficits with excessive glutamate excitatory neuroactivity in the brain. Topiramate, a glutamate receptor antagonist, has displayed favorable neuroprotection against epilepsy, cerebral ischemia, and Huntington's disease; however, its effect on cadmium neurotoxicity remains to be investigated. In this study, topiramate was tested for its potential to combat the cognitive deficits induced by cadmium in rats with an emphasis on hippocampal oxidative insult, apoptosis, and autophagy. After topiramate intake (50 mg/kg/day; p.o.) for 8 weeks, behavioral disturbances and molecular changes in the hippocampal area were explored. Herein, Morris water maze, Y-maze, and novel object recognition test revealed that topiramate rescued cadmium-induced memory/learning deficits. Moreover, topiramate significantly lowered hippocampal histopathological damage scores. Mechanistically, topiramate significantly replenished hippocampal GLP-1 and dampened Aβ42 and p-tau neurotoxic cues. Notably, it significantly diminished hippocampal glutamate content and enhanced acetylcholine and GABA neurotransmitters. The behavioral recovery was prompted by hippocampal suppression of the pro-oxidant events with notable activation of SIRT1/Nrf2/HO-1 axis. Moreover, topiramate inactivated GSK-3β and dampened the hippocampal apoptotic changes. In tandem, stimulation of hippocampal pro-autophagy events, including Beclin 1 upregulation, was triggered by topiramate that also activated AMPK/mTOR pathway. Together, the pro-autophagic, antioxidant, and anti-apoptotic features of topiramate contributed to its neuroprotective properties in rats intoxicated with cadmium. Therefore, it may be useful to mitigate cadmium-induced cognitive deficits.

Cadmium is an environmental contaminant associated with marked neurotoxicity and cognitive impairment. Linagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, has demonstrated promising neuroprotection against cerebral ischemia and diabetic dementia. However, there has been no study of its effect on cadmium-induced cognitive deficits. In the present work, linagliptin's prospective neuroprotective effects against cadmium-evoked cognitive decline were examined in vivo in rats. The molecular pathways related to oxidative stress, apoptosis, and autophagy were investigated. Histology, immunohistochemistry, ELISA, and biochemical assays were performed on brain hippocampi after receiving linagliptin (5 mg/kg/day). The current findings revealed that cadmium-induced learning and memory impairment were improved by linagliptin as seen in the Morris water maze, Y-maze, and novel object recognition test. Moreover, linagliptin lowered hippocampal neurodegeneration as seen in histopathology. At the molecular level, linagliptin curtailed hippocampal DPP-4 and augmented GLP-1 levels, triggering dampening of the hippocampal neurotoxic signals Aβ42 and p-tau in rats. Meanwhile, it enhanced hippocampal acetylcholine and GABA and diminished the glutamate spike. The behavioral recovery was associated with dampening of the hippocampal pro-oxidant response alongside SIRT1/Nrf2/HO-1 axis stimulation. Meanwhile, linagliptin counteracted hippocampal apoptosis markers and inhibited the pro-apoptotic kinase GSK-3β. In tandem, linagliptin activated hippocampal autophagy by lowering SQSTM-1/p62 accumulation, upregulating Beclin 1, and stimulating AMPK/mTOR pathway. In conclusion, linagliptin's antioxidant, antiapoptotic, and pro-autophagic properties advocated its promising neuroprotective impact. Thus, linagliptin may serve as a management approach against cadmium-induced cognitive deficits.

Cadmium (Cd) is a widespread environmental pollutant that triggers testicular dysfunction. Dapagliflozin is a selective sodium-glucose co-transporter-2 inhibitor with notable antioxidant and anti-apoptotic features. It has shown marked cardio-, reno-, hepato-, and neuroprotective effects. Yet, its effect on Cd-evoked testicular impairment has not been examined. Hence, the goal of the current study was to investigate the potential positive effect of dapagliflozin against Cd-induced testicular dysfunction in rats, with an emphasis on autophagy, apoptosis, and oxidative insult. Dapagliflozin (1 mg/kg/day) was given by oral gavage, and testicular dysfunction, impaired spermatogenesis, and biomolecular events were studied via immunohistochemistry, histopathology, and ELISA. The current findings demonstrated that dapagliflozin improved relative testicular weight, serum testosterone, and sperm count/motility and reduced sperm abnormalities, signifying mitigation of testicular impairment and spermatogenesis disruption. Moreover, dapagliflozin attenuated Cd-induced histological abnormalities and preserved testicular structure. The testicular function recovery was prompted by stimulating the cytoprotective SIRT1/Nrf2/HO-1 axis, lowering the testicular oxidative changes, and augmenting cellular antioxidants. As regards apoptosis, dapagliflozin counteracted the apoptotic machinery by downregulating the pro-apoptotic signals together with Bcl-2 upregulation. Meanwhile, dapagliflozin reactivated the impaired autophagy, as seen by a lowered accumulation of SQSTM-1/p62 and Beclin 1 upregulation. In the same context, the testicular AMPK/mTOR pathway was stimulated as evidenced by the increased p-AMPK (Ser487)/total AMPK ratio alongside the lowered p-mTOR (Ser2448)/total mTOR ratio. Together, the favorable mitigation of Cd-induced testicular impairment/disrupted spermatogenesis was driven by the antioxidant, anti-apoptotic, and pro-autophagic actions of dapagliflozin. Thus, it could serve as a tool for the management of Cd-evoked testicular dysfunction.

The metabolic activation of small-molecule drugs into electrophilic reactive metabolites is widely recognized as an indicator of idiosyncratic adverse drug reactions (IADRs). Three novel anti-breast cancer drugs containing piperazine rings, ribociclib (Kisqali®, RCB), abemaciclib (Verzenio®, ABC), and olaparib (Lynparza®, OLP), were selected to study the effect of different chemical environment on the piperazine ring activation using in silico and in vitro metabolic experiments. ABC and RCB were previously studied and we noticed the piperazine ring in ABC could be strongly bioactivated generating more reactive intermediates than piperazine ring in RCB. OLP was further used as a case study to show the power of in silico software to predict the piperazine ring activation that was approved using in vitro experiments. Initially, predictions of susceptible sites in the metabolism and reactivity pathways were performed using the StarDrop P450 model and XenoSite reactivity tool, respectively. Later, in vitro OLP metabolites were characterized based on rat liver microsomes (RLMs) using KCN (trapping agent) using LC-MS/MS. The main goal of the current study was to answer the question of whether the presence of a piperazine ring in the chemical structure should be always considered a structural alert. Piperazine ring in RBC and ABC was bioactivated through a metabolic sequence that involves the hydroxylation of α-carbon to the tertiary nitrogen atoms of the piperazine ring. In the case of OLP, no cyano adduct was formed due to the presence of two carbonyl groups attached to the two nitrogen atoms of the piperazine ring (neutral amide groups). From the results, piperazine ring in certain cases should not be considered as a structural alert as in the case of OLP due to the presence of two electron withdrawing group that stops the proposed toxicity. Also blocking the bioactive center (α-carbon) using steric hindrances such as methyl group, also the isosteric replacement of α-carbon hydrogen with fluoro atom can aid in reducing the toxic side effects of ABC and RCB. These experiments were done in vitro through incubation with RLMs in the presence of KCN. Also, the results are supported by data generated from in silico software. In the future, drug discovery studies using this concept could be undertaken, allowing for the development of new drugs with reasonable safety profiles. Overall, in vitro RLMs incubations and in silico experiments were able to predict successfully that the piperazine ring should not always be considered a structural alert., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Quetiapine (QP) is a second-generation short-acting antipsychotic drug extensively metabolized in the liver, producing pharmacologically inactive metabolites and leading to diminished bioavailability. Therefore, this study aimed to develop an intravenous QP albumin nanoparticles (NPs) system for improving QP antipsychotic activity and brain targeting. QP-loaded albumin NPs were prepared by the desolvation method. The fabricated NPs were characterized in terms of particle size, zeta potential, entrapment efficiency (EE%), and in vitro drug release. In vivo pharmacokinetics and biodistribution in rats were studied. In addition, the antipsychotic activity of the optimized platform was also investigated. Human serum albumin (HSA) concentration, pH, and stirring time were modulated to optimize QP albumin NPs with a particle size of 103.54 ± 2.36 nm and a QP EE% of 96.32 ± 3.98%. In addition, the intravenous administration of QP albumin NPs facilitated QP brain targeting with a 4.9-fold increase in targeting efficiency compared to the oral QP solution. The QP albumin NPs improved the QP antipsychotic activity, indicated by suppressing rats' hypermobility and reducing the QP's extrapyramidal side effects. The obtained results proposed that intravenous QP- NPs could improve QP brain targeting and its antipsychotic efficiency.

The feasibility of using lipid-polymer hybrid (LPH) nanocarriers as a potential platform for the intranasal delivery of ziprasidone (ZP), a second-generation antipsychotic, was explored. Different ZP-loaded LPH composed of a PLGA core and cholesterol-lecithin lipid coat were prepared using a single step nano-precipitation self-assembly technique. Modulation of polymer, lipid and drug amounts, as well as stirring-speed-optimized LPH with a particle size of 97.56 ± 4.55 nm and a ZP entrapment efficiency (EE%) of 97.98 ± 1.22%. The brain deposition and pharmacokinetics studies proved the efficiency of LPH to traverse the blood-brain barrier (BBB) following intranasal delivery with a 3.9-fold increase in targeting efficiency compared to the intravenous (IV) ZP solution with a direct nose-to-brain transport percentage (DTP) of 74.68%. The ZP-LPH showed enhanced antipsychotic activity in terms of animals' hypermobility over an IV drug solution in schizophrenic rats. The obtained results showed that the fabricated LPH was able to improve ZP brain uptake and proved its antipsychotic efficiency.

Durvalumab (DUR) is a human monoclonal antibody used for the immunotherapy of lung cancer. It is a novel immune-checkpoint inhibitor, which blocks the programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) proteins and works to promote the normal immune responses that attack the tumour cells. To support the pharmacokinetic (PK) studies, therapeutic drug monitoring (TDM) and refining the safety profile of DUR, an efficient assay is required, preferably immunoassay. This study describes, for the first time, the development of a highly sensitive chemiluminescence immunoassay (CLIA) for the quantitation of DUR in plasma samples with enhanced chemiluminescence detection system. The CLIA protocol was conducted in 96-microwell plates and involved the non-competitive binding reaction of DUR to its specific antigen (PD-L1 protein). The immune complex of DUR with PD-L1 formed onto the inner surface of the assay plate wells was quantified by a chemiluminescence (CL)-producing horseradish peroxidase (HRP) reaction. The reaction employed 4-(1,2,4-triazol-1-yl)phenol (TRP) as an efficient enhancer of the HRP-luminol-hydrogen peroxide (H 2 O 2 ) CL reaction. The optimum protocol of the proposed CLIA was established, and its validation parameters were assessed as per the guidelines for the validation of immunoassays for bioanalysis. The working dynamic range of the assay was 10-800 pg mL -1 with a limit of detection (LOD) of 10.3 pg mL -1 . The assay enables the accurate and precise quantitation of DUR in human plasma at a concentration as low as 30.8 pg mL -1 . The CLIA protocol is simple and convenient; an analyst can analyse several hundreds of samples per working day. This high throughput property enables the processing of many samples in clinical settings. The proposed CLIA has a significant benefit in the quantitation of DUR in clinical settings for assessment of its PK, TDM and refining the safety profile., Competing Interests: 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, (© 2023 Published by Elsevier Ltd.)

Meloxicam has shown significant neuroprotection in experimental models of stroke, Alzheimer's disease, and Parkinson's disease. However, the potential of meloxicam to treat depression-like neuropathology in a chronic restraint stress (CRS) model and the associated molecular changes has been insufficiently explored. The current work aimed to explore the potential neuroprotective actions of meloxicam against CRS-evoked depression in rats. In the current experiments, animals received meloxicam (10 mg/kg/day; i.p.) for 21 days, and CRS was instigated by restraining the animals for 6 h/day during the same period. The sucrose preference test and the forced swimming test were used to explore the depression-linked anhedonia/despair, whereas the open-field test examined the animals' locomotor activity. The current findings revealed that CRS elicited typical depression behavioral anomalies in the animals, including anhedonia, despair, and diminished locomotor activity; these findings were reinforced with Z-normalization scores. These observations were corroborated by brain histopathological changes and increased damage scores. In CRS-exposed animals, serum corticosterone spiked, and the hippocampi revealed decreased monoamine neurotransmitter levels (norepinephrine, serotonin, and dopamine). Mechanistically, neuroinflammation was evident in stressed animals, as shown by elevated hippocampal TNF-α and IL-1β cytokines. Moreover, the hippocampal COX-2/PGE 2 axis was activated in the rats, confirming the escalation of neuroinflammatory events. In tandem, the pro-oxidant milieu was augmented, as seen by increased hippocampal 8-hydroxy-2'-deoxyguanosine alongside increased protein expression of the pro-oxidants NOX1 and NOX4 in the hippocampi of stressed animals. In addition, the antioxidant/cytoprotective Nrf2/HO-1 cascade was dampened, as evidenced by the lowered hippocampal protein expression of Nrf2 and HO-1 signals. Interestingly, meloxicam administration mitigated depression manifestations and brain histopathological anomalies in the rats. These beneficial effects were elicited by meloxicam's ability to counteract the corticosterone spike and hippocampal neurotransmitter decrease while also inhibiting COX-2/NOX1/NOX4 axis and stimulating Nrf2/HO-1 antioxidant pathway. Together, the present findings prove the neuroprotective/antidepressant actions of meloxicam in CRS-induced depression by ameliorating hippocampal neuroinflammation and pro-oxidant changes, likely by modulating COX-2/NOX1/NOX4/Nrf2 axis.

Lorlatinib (LRL) is the first drug of the third generation of anaplastic lymphoma kinase (ALK) inhibitors used a first-line treatment of non-small cell lung cancer (NSCLC). This study describes, for the first time, the investigations for the formation of a charge transfer complex (CTC) between LRL, as electron donor, with chloranilic acid (CLA), as a π-electron acceptor. The CTC was characterized by ultraviolet (UV)-visible spectrophotometry and computational calculations. The UV-visible spectrophotometry ascertained the formation of the CTC in methanol via formation of a new broad absorption band with maximum absorption peak (λmax) at 530 nm. The molar absorptivity (ε) of the complex was 0.55 × 10 3 L mol -1 cm -1 and its band gap energy was 2.3465 eV. The stoichiometric ratio of LRL/CLA was found to be 1:2. The association constant of the complex was 0.40 × 10 3 L mol -1 , and its standard free energy was -0.15 × 10 2 J mole -1 . The computational calculation for the atomic charges of an energy minimized LRL molecule was conducted, the sites of interaction on the LRL molecule were assigned, and the mechanism of the reaction was postulated. The reaction was adopted as a basis for developing a novel 96-microwell spectrophotometric method (MW-SPA) for LRL. The assay limits of detection and quantitation were 2.1 and 6.5 µg/well, respectively. The assay was validated, and all validation parameters were acceptable. The assay was implemented successfully with great precision and accuracy to the determination of LRL in its bulk form and pharmaceutical formulation (tablets). This assay is simple, economic, and more importantly has a high-throughput property. Therefore, the assay can be valuable for routine in quality control laboratories for analysis of LRL's bulk form and pharmaceutical tablets.

Background and Objective : Tyrosine kinase inhibitors (TKIs) are used for the treatment of different types of cancers. The current study describes, for the first time, the ultraviolet-visible spectrophotometric investigation of charge transfer complexes (CTCs) of seven TKIs, as electron donors, and iodine, as σ-electron. Materials and Methods : The formation of CTCs was promoted in dichloromethane, among the other solvents used in the investigation. The molar absorptivity values, association constants, and free energy changes of the CTCs were determined. Stoichiometric ratio of TKI: iodine as well as TKIs site(s) of interaction were addressed. Reaction was the basis for constructing a novel simple and accurate 96-microwell spectrophotometric assay (MW-SPA) with high-throughput property for the quantitative determination of TKIs in their pharmaceutical formulations. Results : Beer's law, which relates CTC absorbances to TKI concentrations, was followed within the optimal range of 2 to 100 µg/well (r ranged from 0.9991 to 0.9998). Detection and quantification limits ranged from 0.91 to 3.60 and 2.76 to 10.92 g µmL -1 , respectively. Relative standard deviations values for the intra- and inter-assay precisions of the proposed MW-SPA did not exceed 2.13 and 2.34%, respectively. Studies of recovery demonstrated MW-SPA accuracy, with results ranging from 98.9% to 102.4%. All TKIs, both in bulk form and in pharmaceutical formulations (tablets), were effectively determined using the suggested MW-SPA. Conclusions : The current MW-SPA involved a simple procedure and it was convenient as it could analyse all proposed TKIs utilizing a single assay system at once measuring wavelengths for all TKIs. In addition, the proposed MW-SPA has high throughput which enables the processing of a batch of huge samples' number in very short reasonable time period. In conclusion, TKIs can be routinely analysed in their dosage forms in quality control laboratories, and the assay can be highly valuable and helpful in this regard.

Background and Objectives: Lorlatinib (LOR) belongs to the third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors. People who are diagnosed with ALK-positive metastatic and advanced non-small cell lung cancer (NSCLC) are eligible to get it as a first-line treatment option after it was given the approval by "the Food and Drug Administration (FDA)". However, no study has described constructing high-throughput analytical methodology for LOR quantitation in dosage form. For the first time, this work details the construction of a high-throughput, innovative microwell spectrophotometric assay (MW-SPA) for single-step assessment of LOR in its tablet form, for use in pharmaceutical quality control. Materials and Methods: Assay depended on charge transfer complex (CTC) formation between LOR, as electron donor, with 2,3-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ), as π-electron acceptor. Reaction conditions were adjusted, the CTC was characterized by ultraviolet (UV)-visible spectrophotometry and computational molecular modeling, and its electronic constants were determined. Site of interaction on LOR molecule was allocated and reaction mechanism was suggested. Under refined optimum reaction conditions, the procedures of MW-SPA were performed in 96-well assay plates, and the responses were recorded by an absorbance plate reader. Validation of the current methodology was performed in accordance with guidelines of "the International Council on Harmonization (ICH)", and all validation parameters were acceptable. Results: Limits of detection and quantitation of MW-SPA were 1.8 and 5.5 µg/well, respectively. The assay was applied with great success for determining LOR in its tablets. Conclusions: This The assay is straightforward, economic and has high-throughput characteristics. Consequently, the assay is recommended as a valuable analytical approach in quality control laboratories for LOR's tablets' analysis.

This study describes the development of a one-step microwell spectrofluorimetric assay (MW-SFA) with high sensitivity and throughput for the determination of four statins in their pharmaceutical and formulations (tablets). These statins were pitavastatin (PIT), fluvastatin (FLU), rosuvastatin (ROS) and atorvastatin (ATO). The MW-SFA involves the measurement of the native fluorescence of the statin aqueous solutions. The assay was conducted in white opaque 96-microwell plates, and the fluorescence intensities of the solutions were measured by using a fluorescence microplate reader. The optimum conditions of the assay were established; under which, linear relationships with good correlation coefficients (0.9991-0.9996) were found between the fluorescence intensity and the concentration of the statin drug in a range of 0.2-200 µg mL -1 with limits of detection in a range of 0.1-4.1 µg mL -1 . The proposed MW-SFA showed high precision, as the values of the relative standard deviations did not exceed 2.5%. The accuracy of the assay was proven by recovery studies, as the recovery values were 99.5-101.4% (±1.4-2.1%). The assay was applied to the determination of the investigated statins in their tablets. The results were statistically compared with those obtained by a reference method and the results proved to have comparable accuracy and precision of both methods, as evidenced by the t- and F-tests, respectively. The green and eco-friendly feature of the proposed assay was assessed by four different metric tools, and all the results proved that the assay meets the requirements of green and eco-friendly analytical approaches. In addition, ever-increasing miniaturization as handling of large numbers of micro-volume samples simultaneously in the proposed assay gave it a high-throughput feature. Therefore, the assay is a valuable tool for the rapid routine application in the pharmaceutical quality control units for the determination of statins.

Duvelisib (DUV) is a new oral phosphoinositide-3-kinase (PI3K)-δ and PI3K-γ inhibitor. It is used for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). This study describes the development and validation of a new highly sensitive and efficient UPLC-ESI-MS/MS method for quantitation of DUV in plasma samples and its application to the pharmacokinetic study of DUV in rats. The method employed a very simple step for plasma sample pretreatment via precipitation of protein using methanol. DUV and ceritinib (CRB) as an internal standard (IS) were separated on a porous Hypersil BDS-C18 column (125 mm × 2 mm, 3 μm) using a mobile phase consisting of ammonium formate (10 mM, pH 4.2):acetonitrile (42 : 58, v/v), pumped isocratically at a flow rate of 0.3 mL min -1 . DUV and CRB were eluted at 0.58 and 1.10 min, respectively. The mass spectrometric analysis was performed using an ESI in positive mode with multiple reaction monitoring (MRM). The technique was validated in accordance with the standards for validating bioanalytical methods established by the International Conference on Harmonization (ICH). The method's linear range was 5-500 ng mL -1 , and its correlation coefficient was satisfactory as it is almost unity (0.9999). The limit of quantitation (LOQ) was 5 ng mL -1 , while the limit of detection (LOD) was 1.7 ng mL -1 . The recovery of the spiking DUV was between 94.95 and 102.21%, and the relative standard deviation (RSD) was less than 2.70%, confirming the method's accuracy and precision. The specificity/carryover of the method was proved. The robustness and ruggedness of the method was proved as the recovery values were 97.6-101.96% (±01.17-2.20%) and 98.74-102.00 (±1.18-4.02%) for robustness and ruggedness, respectively. The stability of DUV under the different analytical conditions were documented as the recovery values were in the range of 95.89-103.28% and the RSD values did not exceed 7.36%. The method was efficiently used to analyze DUV in human plasma samples that had been spiked with DUV and to conduct pharmacokinetic investigations of DUV in rats after giving them a single oral dosage of 25 mg kg -1 of the drug. The methodology is distinguished by excellent sensitivity, accuracy, and ease of sample pretreatment. Furthermore, it is efficient and has a short run time, which makes it high throughput and accordingly enables faster processing of many samples in clinical laboratories., Competing Interests: The authors report no conflicts of interest for this work., (This journal is © The Royal Society of Chemistry.)

Background and Objectives: This study presents the development and validation of the 96-microwell-based spectrofluorimetric (MW-SFL) and high performance liquid chromatography (HPLC) with fluorescence detection (HPLC-FD) methods for the quantitation of alectinib (ALC) in its bulk powder form and in urine samples. Materials and Methods: The MW-SFL was based on the enhancement of the native fluorescence of ALC by the formation of micelles with the surfactant cremophor RH 40 (Cr RH 40) in aqueous media. The MW-SFL was executed in a 96-microwell plate and the relative fluorescence intensity (RFI) was recorded by utilizing a fluorescence plate reader at 450 nm after excitation at 280 nm. The HPLC-FD involved the chromatographic separation of ALC and ponatinib (PTB), as an internal standard (IS), on a C 18 column and a mobile phase composed of methanol:potassium dihydrogen phosphate pH 7 (80:20, v / v ) at a flow rate of 2 mL min -1 . The eluted ALC and PTB were detected by utilizing a fluorescence detector set at 365 nm for excitation and 450 nm for emission. Results: Validation of the MW-SFL and HPLC-FD analytical methods was carried out in accordance with the recommendations issued by the International Council for Harmonization (ICH) for the process of validating analytical procedures. Both methods were efficaciously applied for ALC quantitation in its bulk form as well as in spiked urine; the mean recovery values were ≥86.90 and 95.45% for the MW-SFL and HPLC-FD methods, respectively. Conclusions: Both methodologies are valuable for routine use in quality control (QC) laboratories for determination of ALC in pure powder form and in human urine samples.

Remdesivir (REM) is an adenosine triphosphate analog antiviral drug that has received authorization from European Commission and approval from the U.S. Food and Drug Administration for treatment of coronavirus disease 2019 (Covid-19). This study, describes, for the first time, the synthesis of a novel charge transfer complex (CTC) between REM, as electron donor, with chloranilic acid (CLA), as π electron acceptor. The CTC was characterized using different spectroscopic and thermogravimetric techniques. UV-visible spectroscopy ascertained the formation of the CTC in methanol via formation of a new broad absorption band with maximum absorption peak (λ max ) at 530 nm. The molar absorptivity (ε) of the complex was 3.33 × 10 3  L mol -1 cm -1 and its band gap energy was 1.91 eV. The stoichiometric ratio of REM:CLA was found to be 1:1. The association constant of the complex was 1.11 × 10 9  L mol -1 , and its standard free energy was 5.16 × 10 4  J mole -1 . Computational calculation for atomic charges of energy minimized REM was conducted, the site of interaction on REM molecule was assigned and the mechanism of the reaction was postulated. The solid-state CTC was further characterized by FT-IR and 1 H NMR spectroscopic techniques. Both FT-IR and 1 H NMR confirmed the formation of the CTC and its structure. The reaction was adopted as a basis for developing a novel 96-microwell spectrophotometric method (MW-SPA) for REM. The assay limits of detection and quantitation were 3.57 and 10.83 µg/well, respectively. The assay was validated, and all validation parameters were acceptable. The assay was implemented successfully with great precision and accuracy to the determination of REM in its bulk form and pharmaceutical formulation (injection). This assay is simple, economic, and more importantly, has high throughput property. Therefore, the assay can be valuable for routine in quality control laboratories for analysis of REM's bulk form and pharmaceutical injection., Competing Interests: The authors state that they have no recognized competing financial interests or personal connections that could have influenced the research presented in this study., (© 2022 Elsevier B.V. All rights reserved.)

Duvelisib (DUV) is a is a small-molecule with inhibitory action for phosphoinositide 3-kinase (PI3K). It has been recently approved for the effective treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). Novel charge transfer complex (CTC) between DUV, as electron donor, with chloranilic acid (CLA), as π electron acceptor has been synthesized and characterized using different spectroscopic and thermogravimetric techniques. UV-visible spectroscopy ascertained the formation of the CTC in different solvents of varying polarity indexes and dielectric constants via formation of new broad absorption band with maximum absorption peak (λ max ) in the range of 488-532 nm. The molar absorptivity of the CTC was dependent on the polarity index and dielectric constant of the solvent; the correlation coefficients were 0.9955 and 0.9749, respectively. The stoichiometric ratio of DUV:CLA was 1:1. Electronic spectral analysis was conducted for characterization of the complex in terms of its electronic constants. Computational calculation for atomic charges of energy minimized DUV was conducted and the site of interaction on DUV molecule was assigned. The solid-state CTC of DUV:CLA (1:1) was synthesized, and its structure was characterized by UV-visible, mass, FT-IR, and 1 H NMR spectroscopic techniques. Both FT-IR and 1 H NMR confirmed that both CT and hydrogen bonding contributed to the molecular composition of the complex. The reaction was adopted as a basis for developing a novel 96-microwell spectrophotometric assay (MW-SPA) for DUV. The assay limits of detection and quantitation were 0.57 and 1.72 µg/well, respectively. The assay was validated and all validation parameters were acceptable. The method was implemented successfully with great precision and accuracy to the analysis of the DUV in its bulk and capsules., 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 © 2021 Elsevier B.V. All rights reserved.)

Crizotinib (CZT) is a potent and selective tyrosine kinase inhibitor used for treatment of non-small cell lung cancer (NSCLC). The development of high-throughput assays for its quality control (QC) is very essential to assure its therapeutic benefits. CZT molecule has multiple electron-donating atoms that can contribute to the formation of colored charge-transfer (CT) complex with iodine as σ-electron acceptor and with 2,5-dichloro-3,6-dihydroxy-1,4-benzoquinone (CHBQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π-electron acceptors. These reactions were prospective basis for development of three innovative 96-microwell-based spectrophotometric assays for CZT. The reactions of CZT with iodine, CHBQ and TCNQ were performed in 96-microwell assay plates and absorbances of the CT complexes were measured by microwell absorbance reader at their corresponding maximum absorption peaks. The measured absorbances were correlated with the CZT concentrations in its sample solutions. Beer's law was obeyed with excellent correlation coefficients in the range of 0.5-30, 2-500, and 5-500 µg mL -1 for assays using iodine, CHBQ and TCNQ, respectively. The limits of detection were 2.17, 0.85 and 6.23 µg mL -1 for assays using iodine, CHBQ and TCNQ, respectively. The validation studies confirmed the accuracy and precision of all the proposed assays. The assays were successfully applied in the determination of CZT in Xalkori capsules. The proposed assays have very simple procedures to run in QC laboratories. Also, both assays enable analyst to process large number of samples and use of very small volumes of the organic solvent (ecofriendly and inexpensive)., 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 © 2021 Elsevier B.V. All rights reserved.)

This work investigates a sensitive and precise enhanced spectrofluorimetric assay for assay of foretinib (FTB); a tyrosine kinase inhibitor drug used for treatment of breast cancer, in tablets and urine through response surface optimization by micelle mediated protocol. The basis of the described method is the enhancement of the fluorescence behavior of FTB in Cremophor RH 40 (Cr RH 40) micellar medium and measuring the fluorescence of FTB at 344 nm after excitation at 245 nm. Optimization was performed through evaluation of diluting solvent, types of organized media, buffer type and its relevant pH. Response surface methodology was applied to obtain the optimized values of variables that mostly affect interaction of Cr RH 40 with FTB using Box-Behnken design. ICH guidelines were adhered for the validation of merit figures. Acceptable linear relationship was obtained between relative fluorescence intensity (RFI) and FTB concentrations in the range of 50 - 1000 µg L -1 , with correlation coefficient of 0.998. Accuracy was ≥ 99.82% and calculated limit of detection (LOD) was 10.60 µg L -1 . Method applications included FTB assaying in pure bulk powder. Furthermore, applications on urine samples were performed with accuracy of 100.59 ± 3.40%. The method represents echo-friendly approach and effective alternating methodology to the relevant analytical ones for FTB assaying., 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 © 2021 Elsevier B.V. All rights reserved.)

Tyramine (TYR) is a vasoactive biogenic amine found in food products due to improper storage and poor hygiene. High TYR intake results in a wide range of life-threatening physiological reactions. The work optimizes a solid-state potentiometric sensor in the absence of a reported potentiometric method for rapid and direct TYR assay. The optimization study included thirteen membrane cocktails of different compositions. The optimized sensor proved a near-Nernstian slope of 57.30 mV/decade, a quantification limit of 10.6 ppm, and a detection limit of 7.9 ppm. Validation results confirmed the sensor ability for the direct assay of TYR in blue cheese, aged cheese, Egyptian pickled cottage cheese, and pickled herring. A comparison with the reported chromatographic method expresses the merits and potentials of the developed sensor for the rapid testing of food edibility, quality, and safety based on its TYR content. Chemical compounds studied in this article: Tyramine (PubChem CID: 5610); Tyramine hydrochloride (PubChem CID: 66449); Poly(vinyl chloride) (PubChem SID: 24864273); Tricresyl phosphate (PubChem CID: 6529); sodium phosphotungstate tribasic hydrate (PubChem SID: 329753864)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The tyrosine kinase inhibitors (TKIs) are chemotherapeutic drugs used for targeted therapy of various types of cancer. In literature, there is no existing universal chromogenic reagent used for development of spectrophotometric assay for all TKIs regardless the diversity of their chemical structures. This work discusses, for the first time, the experimental and computational evaluation of chloranilic acid (CLA) as a universal chromogenic reagent for developing a novel 96-microwell spectrophotometric assay (MW-SPA) for TKIs. The reaction of CLA with seven TKIs was examined in different organic solvents of various dielectric constants and polarity indexes. The reaction resulted in an instantaneous formation of intensely purple coloured products with all the investigated TKIs. Spectrophotometric investigations confirmed that the reactions proceeded via the formation of charge-transfer complexes (CTC). The physical parameters (molar absorptivity, molar ratio, association constant and standard free energy) were determined for the CTC of all TKIs. Computational calculations for the relative electron densities on each atom of the TKI molecule and molecular modelling for the CTC were conducted, and the site(s) of interaction on each TKI molecule were determined. Under the optimized conditions, Beer's law correlating the absorbances of the CTC with the concentrations of TKIs were obeyed in the range of 5-500 µg/well with good correlation coefficients (0.9991-0.9998). The limits of detection and quantitation were in the ranges of 1.89-5.09 and 5.74-15.42 µg/well, respectively. The proposed MW-SPA showed high precisions as the values of the relative standard deviations did not exceed 2.01 and 2.45% for the intra- and inter-assay precision, respectively. The accuracy of MW-SPA was proved by recovery studies as the recovery values were in the range of 98.8-103.7%. The proposed MW-SPA was successfully applied for the determination of all TKIs in their bulk forms and pharmaceutical formulations (tablets) with good accuracy and precisions. The proposed MW-SPA is the first assay that can analyse all the TKIs on a single assay system without modifications in the detection wavelength. Additional advantages of the proposed MW-SPA are simple, economic, and more importantly have high throughput. Therefore, the assay can be helpful and beneficial for routine analysis of TKIs in their pharmaceutical formulations in quality control laboratories., 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 © 2021 Elsevier B.V. All rights reserved.)

The concurrent use of oral encorafenib (Braftovi, ENF) and binimetinib (Mektovi, BNB) is a combination anticancer therapy approved by the United States Food and Drug Administration (USFDA) for patients with BRAFV600E/V600K mutations suffering from metastatic or unresectable melanoma. Metabolism is considered one of the main pathways of drug elimination from the body (responsible for elimination of about 75% of known drugs), it is important to understand and study drug metabolic stability. Metabolically unstable compounds are not good as they required repetitive dosages during therapy, while very stable drugs may result in increasing the risk of adverse drug reactions. Metabolic stability of compounds could be examined using in vitro or in silico experiments. First, in silico metabolic vulnerability for ENF and BNB was investigated using the StarDrop WhichP450 module to confirm the lability of the drugs under study to liver metabolism. Second, we established an LC-MS/MS method for the simultaneous quantification of ENF and BNB applied to metabolic stability assessment. Third, in silico toxicity assessment of ENF and BNB was performed using the StarDrop DEREK module. Chromatographic separation of ENF, BNB, and avitinib (an internal standard) was achieved using an isocratic mobile phase on a Hypersil BDS C 18 column. The linear range for ENF and BNB in the human liver microsome (HLM) matrix was 5-500 ng/mL ( R 2 ≥ 0.999). The metabolic stabilities were calculated using intrinsic clearance and in vitro half-life. Furthermore, ENF and BNB did not significantly influence each other's metabolic stability or metabolic disposition when used concurrently. These results indicate that ENF and BNB will slowly bioaccumulate after multiple doses.

The developed spectrofluorimetric method was successfully applied to the analysis of brigatinib (BRG) in its bulk powder form, and human urine sample. It is based on the investigation of the fluorescence spectrum behavior of the BRG-eosin Y complex. The relative fluorescence intensity (RFI) was recorded at 560 nm after excitation at 480 nm. The principle of the proposed method was thoroughly explained. All experimental parameters affecting method development were optimized. Moreover, the obtained results were fully discussed and statistically analyzed. The molar ratio method was applied to study the stoichiometric relationship between BRG and eosin Y complex. The method revealed a ratio of 1:3 for BRG-eosin Y afforded the highest RFI. The developed method was validated over the concentration range of 62.5-4000 ng mL -1 . The results were compared positively with the reported method., 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.)

A reliable, selective and sensitive stability-indicating RP-HPLC assay was established for the quantitation of bromazepam (BMZ) and one of the degradant and stated potential impurities; 2-(2-amino-5-bromobenzoyl) pyridine (ABP). The assay was accomplished on a C18 column (250 mm × 4.6 mm i.d., 5 μm particle size), and utilizing methanol-water (70: 30, v/v) as the mobile phase, at a flow rate of 1.0 ml min-1. HPLC detection of elute was obtained by a photodiode array detector (DAD) which was set at 230 nm. ICH guidelines were adhered for validation of proposed method regarding specificity, sensitivity, precision, linearity, accuracy, system suitability and robustness. Calibration curves of BMZ and ABP were created in the range of 1-16 μg mL-1 with mean recovery percentage of 100.02 ± 1.245 and 99.74 ± 1.124, and detection limit of 0.20 μg mL-1 and 0.24 μg mL-1 respectively. BMZ stability was inspected under various ICH forced degradation conditions and it was found to be easily degraded in acidic and alkaline conditions. The results revealed the suitability of the described methodology for the quantitation of the impurity (ABP) in a BMZ pure sample. The determination of BMZ in pharmaceutical dosage forms was conducted with the described method and showed mean percentage recovery of 99.39 ± 1.401 and 98.72 ± 1.795 (n = 6), respectively. When comparing the described procedure to a reference HPLC method statistically, no significant differences between the two methods in regard to both accuracy and precision were found., Competing Interests: The authors have declared that no competing interests exist.

The tyrosine kinase inhibitors (TKIs) are chemotherapeutic drugs used for the targeted therapy of various types of cancer. This work discusses the experimental and computational evaluation of chloranilic acid (CLA) as a universal chromogenic reagent for developing a novel 96-microwell spectrophotometric assay (MW-SPA) for TKIs. The reaction resulted in an instantaneous formation of intensely purple colored products with TKIs. Spectrophotometric results confirmed that the reactions proceeded via the formation of charge-transfer complexes (CTCs). The physical parameters were determined for the CTCs of all TKIs. Computational calculations and molecular modelling for the CTCs were conducted, and the site(s) of interaction on each TKI molecule were determined. Under the optimized conditions, Beer's law correlating the absorbances of the CTCs with the concentrations of TKIs were obeyed in the range of 10-500 µg/well with good correlation coefficients (0.9993-0.9998). The proposed MW-SPA fully validated and successfully applied for the determination of all TKIs in their bulk forms and pharmaceutical formulations (tablets). The proposed MW-SPA is the first assay that can analyze all the TKIs on a single assay system without modifications in the detection wavelength. The advantages of the proposed MW-SPA are simple, economic and, more importantly, have high throughput.

Irbesartan, (2-butyl-3-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one), is a member of non-peptide angiotensin II receptor antagonists used worldwide in the treatment of hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. Irbesartan can be used alone or in combination with other antihypertensive agents (e.g., hydrochlorothiazide). These combination products are indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy. Irbesartan is also indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension, an elevated serum creatinine, and proteinuria. Irbesartan exerts its action mainly via a selective blockade action on AT1 receptors and the consequent reduced pressor effect of angiotensin II. This article discusses, by a critical comprehensive review of the literature on irbesartan in terms of its description, names, formulae, elemental composition, appearance, and therapeutic uses. The article also discusses the methods for preparation of irbesartan, its physical-chemical properties, analytical methods for its determination, pharmacological-toxicological properties, and dosing information., (© 2021 Elsevier Inc. All rights reserved.)