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Background: Olfactory dysfunction significantly impacts daily life, affecting safety, appetite, and sensory enjoyment. Olfactory receptor neurons (ORNs) are essential for odor detection, but environmental exposure can lead to dysfunction. Regeneration of these neurons is crucial for maintaining olfactory function, and elevated calcium levels in nasal mucus are linked to this dysfunction., Objective: The study evaluated chitosan nasal gel for persistent olfactory dysfunction lasting over 6 months, focusing on ORNs regeneration and reduced calcium levels in nasal mucus., Methods: A randomized, double-blind trial included 215 participants with persistent olfactory dysfunction lasting over 6 months. Participants were divided into two groups: 116 received nasal chitosan gel, and 99 received a control sodium chloride gel. Over 3 months, 11 participants in the chitosan group and 9 in the control group were lost to follow-up. Olfactory function was assessed with the Sniffin' Sticks test, and calcium levels were measured before and after treatment., Results: Patients treated with chitosan nasal gel showed an increased composite threshold, discrimination, identification (TDI) score, indicating improved olfactory function. Discrimination and identification scores improved, while threshold scores showed no significant change. Notably, while the total TDI score improved by 4.55 points, it did not reach the threshold for clinical significance (5.5 points). Furthermore, chitosan nasal gel significantly reduced calcium levels in nasal secretions compared to the control group. No improvement was observed in the placebo group, likely due to the strict inclusion criteria targeting individuals with treatment-resistant olfactory dysfunction persisting over 6 months., Conclusion: This small-scale pilot study highlights the potential of chitosan nasal gel to improve specific domains of olfactory dysfunction and reduce nasal calcium levels. However, further studies with larger sample sizes, diverse populations, and longer follow-up periods are required to confirm these preliminary findings., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The environmental impact of chemicals used in aquaculture, particularly nitrofurantoin, has raised global concern. Nitrofurantoin, a broad-spectrum antimicrobial, is commonly used in aquaculture despite safety risks. Determination of nitrofurantoin in water samples of fish ponds is necessary to ensure the safety and quality of seafood. Herein, a new spectrofluorometric method was created for the determination of nitrofurantoin in water samples from fish ponds. Carbon quantum dots were functionalized with nitrofurantoin tetra phenyl borate modifying their surface to be selective for nitrofurantoin quantification. When nitrofurantoin is present, the functionalized carbon quantum dots show concentration-dependent fluorescence quenching, allowing estimation of the drug. The method was validated and demonstrated accepted linearity in the range of 5-150 ng/mL, with a limit of detection at 1.251 ng/mL. The method offers a broader and more sensitive detection range compared with a previous UHPLC method. Additionally, the environmental friendliness of the described method was conducted and compared with the reported UHPLC method using the analytical eco-scale and the analytical greenness metric. The results demonstrate that the current method exhibits higher levels of sustainability compared with the previously reported method., (© 2025 John Wiley & Sons Ltd.)

Ascorbic acid (Vitamin C) is crucial for bodily functions, including collagen synthesis, immune system support and antioxidant defense. Despite autism spectrum disorder's multifactorial nature involving genetic, environmental and neurological factors, robust evidence exploring the association between ascorbic acid and this disorder is notably lacking. This study introduces an innovative spectrofluorometric method to quantify ascorbic acid in the plasma of healthy children and those with autism spectrum disorder. The method relies on the interaction of ascorbic acid with the fluorescent dye propidium iodide. In acidic conditions, propidium iodide undergoes protonation and selectively binds to the negatively charged ascorbic acid forming an ion-pair complex. This complex alters the molecular structure of propidium iodide inducing chemical fluorescence quenching, that can be utilized for ascorbic acid quantification. The developed method undergoes rigorous validation following ICH guidelines, demonstrating a linear relationship within a concentration range of 4-40 μg/mL, with high precision and accuracy metrics. Analysis of real plasma samples from autistic and healthy children reveals clinically and statistically elevated levels of ascorbic acid in those with autism spectrum disorder., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relations that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Futibatinib is a powerful inhibitor of fibroblast growth factor receptors that impedes its phosphorylation and subsequently leading to a reduction in in cell viability across various cell lines. Futibatinib was approved for initial use as an effective treatment for several diseases, including non-small cell lung cancer and breast cancer. Herein, a novel selective fluorescence probe was created for futibatinib quantification in various matrices, including pharmaceutical formulation and human plasma. The technique primarily depends on futibatinib's chemical conversion into a fluorescent product through a reaction with trimethylamine and bromoacetyl bromide. The created fluorescent probe exhibits maximum emission peak at 338 nm upon excitation at 248 nm. The method provided a low detection limit of 0.120 ng/mL and maintained a linear concentration-dependent relationship across the range of 1-200 ng/mL. High sensitivity, accuracy and precision were demonstrated for futibatinib quantification in pharmaceutical formulation and spiked plasma matrix by the method, which was validated in accordance with ICH requirements., 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.)

Nasal ions environment plays a crucial role in maintaining nasal physiology and supports olfactory transmission. Addressing the limited research on nasal ion levels and their association with olfactory function, paper-based sensors were developed for determination of sodium, potassium, calcium and chloride in the nasal mucus of healthy volunteers and patients with olfactory dysfunction. Multi-walled carbon nanotubes and carbon quantum dots from beetroot were incorporated into paper substrate where sensors were designed with ion association complexes for sodium, potassium, calcium and chloride enhancing the recognition sensing capabilities. The sensors composition was optimized, including ion-exchange materials and plasticizers, to enhance sensitivity and selectivity. The performance of the sensors is evaluated based on Nernstian slope, dynamic range, detection limit and response time. Selectivity of the sensors was tested and the results demonstrated high selectivity for the target ions. The sensors were successfully determined sodium, potassium, calcium and chloride levels in nasal mucus of healthy volunteers and patients with olfactory dysfunction. The results revealed elevated calcium levels in patients with olfactory dysfunction, highlighting associated diagnostic implications. This suggests that the proposed sensors could serve as a diagnostic tool for olfactory evaluation, particularly in resource-constrained settings where access to advanced diagnostic tools is limited., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relations that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Olfactory dysfunction is increasingly common among COVID-19 patients, impacting their well-being. Reports have demonstrated decreased levels of cyclic adenosine monophosphate and cyclic guanosine monophosphate among patients with chronic olfactory dysfunction. A prospective randomized clinical trial was developed to demonstrate the efficacy of an oral forskolin regimen treatment, an adenylyl cyclase activator that raises intracellular levels of cyclic adenosine monophosphate, for the treatment of olfactory dysfunction following COVID-19, compared to placebo regimen., Methods: The study enrolled 285 participants with persistent olfactory dysfunction post COVID-19 infection, randomly assigning them to receive either placebo capsules (n = 120) or oral forskolin capsules (n = 165). Follow-up was conducted to track progress, with 18 participants from the placebo group and 12 from the forskolin group lost during this period. Olfactory function was assessed using the "Sniffin' Sticks" test, measuring threshold, discrimination and identification scores before and after treatment., Results: Subjects administered forskolin capsules demonstrated a significant enhancement in their composite TDI (threshold, discrimination and identification) score, suggesting a notable amelioration in olfactory functionality. Moreover, the discrimination and identification scores notably improved within the forskolin group. Conversely, no significant alterations were observed in the threshold scores., Conclusion: This study suggests that forskolin can contribute potentially to improve chronic olfactory dysfunction post COVID-19., Trial Registration: DFM-IRB00012367-23-10-001., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ionic microenvironment of the nasal secretions especially calcium ions play essential role in the olfactory transmission. However, there is a critical need to determine the free calcium levels in healthy people's nasal secretions in contrast to those of patients with olfactory impairment. A selective spectrofluorometric method was created to quantify nasal calcium levels utilizing its quenching ability to the fluorescence of the functionalized carbon quantum dots. The surface of carbon quantum dots was functionalized with calcium ionophore A23187 and ion association complex, calcium phosphotungstate, to improve the selectively to quantify calcium ions. The functionalized carbon quantum dots exhibited a concentration-dependent fluorescence quenching upon interaction with calcium ions. Different factors influencing the quenching process were done to provide efficient analytical process. The new method, demonstrated accurate calcium determination over the concentration range of 200-4000 ng/mL. The suggested technique was used to measure the calcium in the nasal secretions of both healthy people and patients with olfactory impairment. The findings revealed significantly higher calcium levels in the patient with olfactory dysfunction (healthy vs. patient; 735 ± 20 ng/mL vs. 2987 ± 37 ng/mL, p < 0.05)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relations that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

HIV treatment has greatly improved over the years, with the introduction of antiretroviral drugs that target the virus and suppress its replication. Dolutegravir and lamivudine are two such antiretroviral drugs that are commonly used in HIV treatment regimens. Herein, three spectrophotometric methods manipulating ratio spectra were developed for the simultaneous analysis of dolutegravir and lamivudine in their binary mixtures. These methods include mathematical processing stages like ratio difference method or signal processing approaches such as the first derivative of the ratio spectra, and continuous wavelet transform. The developed spectrophotometric methods exploit the characteristic spectral differences between dolutegravir and lamivudine in order to quantify them simultaneously. These methods have shown promising results in terms of sensitivity and selectivity as validated per the ICH guidelines. Moreover, these methods offer a straightforward and economical alternative to more intricate analytical methodologies like high-performance liquid chromatography. By incorporating the analytical eco-scale and AGREE for greenness evaluation of the proposed methods, we can further ensure that these techniques are effective and environmentally friendly, aligning with the principles of green chemistry. This evaluation will provide a comprehensive understanding of the environmental friendliness of these spectrophotometric methods in pharmaceutical analysis., (© 2024. The Author(s).)

Attention deficit hyperactivity disorder (ADHD) is a neurological condition frequently identified in early childhood and frequently co-occurs with other neuropsychological disorders, particularly autism. Viloxazine hydrochloride, a non-stimulant medication, has recently gained approval for treating attention-deficit hyperactivity disorder. This paper describes the first spectrofluorimetric method for precisely measuring the content of viloxazine in pharmaceutical capsules and rat plasma. This method employed NBD-Cl (4-chloro-7-nitrobenzo-2-oxa-1,3-diazole) as a fluorescent probe, which transformed viloxazine in an alkaline environment into a remarkably sensitive fluorescent adduct. Upon excitation at 476 nm, this adduct becomes detectable at a wavelength of 536 nm. The method was validated using ICH criteria, revealing acceptable linearity across a concentration range of 200-2000 ng/ml and high sensitivity with LOD and LOQ values of 46.774 ng/ml and 141.741 ng/ml, respectively. This method was adeptly applied in a pharmacokinetic study of viloxazine in rat plasma following a single oral dose (10 mg/kg), yielding a mean peak plasma concentration (C max ) of 1721 ng/ml, achieved within 1.5 h. Furthermore, the environmental impact of the technique was assessed using two greenness assessment tools, revealing a notable level of eco-friendliness and sustainability., (© 2024 John Wiley & Sons, Ltd.)

Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has gained recent approval for treating cardiovascular and kidney-related conditions. Herein, an innovative fluorescence chemo sensor was developed for the determination of finerenone in the pharmaceutical dosage form and the plasma matrix. The method is basically based on chemical transformation of finerenone into a fluorescent product through sequential reactions. This transformation occurs through a sequence of steps involving the interaction of finerenone with trimethylamine, resulting in the formation of a nucleophilic intermediate that subsequently reacts with bromoacetyl bromide to form fluorescent product, (S)-N-(2-bromoacetyl)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide. The formed fluorescent product exhibits defined emission peak at 338 nm when excited at 248 nm. Significant concentration-dependent fluorescence enhancement was obtained enabling precise finerenone determination in the pharmaceutical formulation and plasma matrix. The method was optimized and validated providing sensitive determination over linearity range of 1-200 ng/mL with a lower limit of detection at 0.280 ng/mL. This strategy provides an efficient, economical substitute and straightforward, more sensitive analytical method for finerenone assessment in various matrices, in contrast to the previously published method, high-performance liquid chromatography-tandem mass spectrometry, which is expensive and time-consuming., 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.)

Augmented least squares models such as concentration residual augmented classical least squares (CRACLS) and spectral residual augmented classical least squares (SRACLS) are powerful chemometric approaches that can be applied for spectroscopic analysis of many pharmaceutical compounds. Herein, both CRACLS and SRACL have been employed for UV spectral analysis of three antiretroviral therapy namely abacavir (ACV), lamivudine (LMV) and dolutegravir (DTG) in their ternary mixture. A partial factorial design has been utilized for calibration set construction then both CRACLS and SRACLS models have been optimized regarding the number of iterations and principal components, respectively, using a leave-one-out cross-validation procedure. It was found that a higher number of iterations and principal components were required for modelling the minor component DTG indicating more augmentation procedures to improve the models' accuracy. Validation of the proposed models was performed using external validation set of 13 mixtures and different validation parameters have been evaluated regarding models' predictive abilities. Both models showed excellent performance for analyzing ACV and LMV with relative root mean square error of prediction (RRMSEP) below 2 %. However, higher RRMSEP values around 5 % were observed for the minor component DTG suggesting that these models should be utilized with caution when analyzing minor components in mixtures. Furthermore, the suggested models have been applied for analyzing ACV, LMV and DTG in their pharmaceutical formulation and excellent agreement was observed between the suggested models and the reported chromatographic method posing these models as powerful chemometric approaches for quality control analysis of many pharmaceutical compounds., 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 Elsevier B.V. All rights reserved.)

Histamine is crucial for controlling a variety of physiological processes and its dysregulation is linked to various pathological conditions, including allergic disorders, autoimmune diseases and inflammatory conditions. Herein, a novel fluorescence chemo sensor was produced to measure histamine in the pure form and spiked human plasma matrix. The proposed method is based on chemical transformation of histamine into a fluorescent product, N-(2-(1H-imidazol-4-yl) ethyl)-2-bromoacetamide, exhibiting unique fluorescence properties compared to non-fluorescent histamine molecule. This transformation occurs through a sequence of chemical reactions involving the interaction of histamine with trimethylamine, resulting in the formation of a nucleophilic intermediate that subsequently reacts with electrophilic bromoacetyl bromide. The transformed fluorescent product demonstrates an emission at 340 nm after being excited at 250 nm. Significant concentration-dependent fluorescence enhancement was obtained enabling histamine determination. The procedures were examined for accuracy, precision, selectivity, and robustness in line with the ICH M10 recommendations. The method exhibits a lower limit of quantification at 0.25 ng/mL and dynamic detection throughout a linearity range of 1-200 ng/mL, providing accurate assessment of histamine in the plasma matrix., 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 Elsevier B.V. All rights reserved.)

Background: The defects of the upper third of the auricle are considered significant reconstructive challenges, as they require frequent operations with a high risk of morbidity at the donor site and result in unacceptable cosmetic abnormalities., Objective: Is to perform the reconstruction of a full-thickness auricular defect located in the upper third of the ear using a conchal cartilage graft with postauricular flap coverage, aiming to minimize both donor and recipient morbidity., Patients and Methods: The current study included 20 patients with unilateral upper-third auricular defects. The repair involved 2 components: a cartilage graft from the concha to provide structural support and a flap for coverage. Follow-up was conducted for 6 months after the operation., Results: Successful outcomes were achieved in both subjective and doctors' assessments. Regarding subjective outcomes, 85% of the patients reported high satisfaction ( P  < .001). In terms of doctors' subjective assessment, 90% of the patients had excellent results ( P  < .001). Mild early and postoperative complications, if encountered, resolved spontaneously., Conclusion: The use of a combined conchal cartilage graft and postauricular flap in treating a full-thickness upper third auricular defect is safe and effective, with no major complications. The technique preserves the cosmetic and functional outcomes of the auricle, providing an excellent color match and minimal donor-site morbidity., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This study presents the development of an eco-friendly and highly selective mitrogen-doped carbon quantum dot based sensor (N-CQDs) for the detection of gabapentin - a commonly misused drug. A detailed characterization of N-CQDs spectral features and their interaction with gabapentin is provided. The optimal conditions for sensing, including pH value, buffer volume, N-CQDs concentration, and incubation time, were established. The results showed excellent fluorescence quenching at 475 nm ( λ ex = 380 nm) due to the dynamic quenching mechanism, and the sensor demonstrated excellent linearity in the 0.5-8.0 μg mL -1 concentration range with correlation coefficients of more than 0.999, a limit of detection (LOD) of 0.160 and limit of quantification (LOQ) of 0.480 μg mL -1 . The accuracy of the proposed sensor was acceptable with a mean accuracy of 99.91 for gabapentin detection. In addition, precision values were within the acceptable range, with RSD% below 2% indicating good repeatability and reproducibility of the sensor. Selectivity was validated using common excipients and pooled plasma samples. The proposed sensor accurately estimated gabapentin concentration in commercial pharmaceutical formulations and spiked plasma samples, exhibiting excellent comparability with previously published methods. The 'greenness' of the sensing system was evaluated using the Analytical GREEnness calculator, revealing low environmental impact and strong alignment with green chemistry principles with a greenness score of 0.76. Thus, the developed N-CQDs-based sensor offers a promising, eco-friendly, and effective tool for gabapentin detection in various situations, ranging from clinical therapeutics to forensic science., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Chronic otitis media is a common condition characterized by fluid accumulation in the middle ear, leading to a perforated eardrum and persistent middle ear drainage. Despite its impact on global health, the role of heavy metals, particularly copper and zinc, in its development and progression remains understudied. Herein, a spectrofluorometric method was developed for the precise determination of copper and zinc in human plasma samples and investigate their association with chronic otitis media. The method involves the use of the fluorescent probe 6,7-dihydroxy-4-phenylcoumarin to selectively quantify copper through fluorescence quenching and zinc through fluorescence enhancement with a remarked bathochromic shift. The method was validated and exhibited good linearity over a concentration range of 100-3000 ng/mL for copper and 200-5000 ng/mL for zinc. Application of the method to healthy volunteers and patients with chronic otitis media revealed significantly decreased copper and zinc levels in patients with chronic otitis media compared to the healthy individuals. These findings shed light on the involvement of copper and zinc in the pathogenesis of chronic otitis media and open avenues for additional treatment approaches., 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 Elsevier B.V. All rights reserved.)

Histamine plays a crucial role in regulating various physiological functions and is significantly involved in the development of allergic rhinitis. Accurately measuring histamine levels in nasal secretions can serve as a specific indicator for studying mast cell activation and diagnosing allergic reactions. However, the controversy surrounding histamine levels in nasal secretions during allergenic stimulation suggests potential inaccuracies and imprecision in the analytical methods used, as well as the presence of substances that may interfere with the determination of histamine. In this study, a sensitive and selective spectrofluorometric method was developed using carbon quantum dots (CQDs) derived from beetroot slices, which are non-toxic and eco-friendly materials. These CQDs were functionalized with histamine tetra phenyl borate to determine histamine levels in nasal secretions. Various characterization techniques were employed to confirm the successful synthesis and functionalization of the CQDs. The functionalized CQDs demonstrated enhanced fluorescence and selective interaction with histamine, leading to concentration-dependent fluorescence quenching. The developed method was successfully utilized to compare histamine levels in nasal secretions of healthy individuals and patients with allergic rhinitis. The results showed that the histamine level was significantly higher in patients with allergic rhinitis than in healthy individuals, suggesting a potential association between allergic rhinitis and histamine, (normal vs. patient: 350 ± 20 ng/mL vs. 2520 ± 37 ng/mL, p < 0.05). Furthermore, the proposed spectrofluorometric method exhibited improved linearity range, dynamic range, and detection limit compared to a previously reported spectrophotometric 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 © 2023 Elsevier B.V. All rights reserved.)

The relationship between zinc levels and olfactory function is an area of active research due to the role of zinc-dependent metalloenzyme, carbonic anhydrase, in maintaining olfactory function. In this study a spectrofluorometric method was developed for determining zinc levels in the human plasma of healthy participants and patients with olfactory dysfunction. The method relies on the fluorescence property changes of 4-Methylesculetin, which interacts with zinc. In this interaction, the oxygen atom of hydroxyl groups serves as a ligand, coordinating with zinc as a Lewis acid. As a result, the formed complex exhibits significant fluorescence enhancement attributed to the rigid chelate structure, thereby enhancing quantum yield. The resulting complex displays emission peak at 520 nm, which is distinct from the emission peak of 4-Methylesculetin at 460 nm. This bathochromic shift indicates heightened excited-state energy, attributed to zinc coordination and complex formation. The reaction conditions were carefully optimized to ensure selective zinc determination in plasma samples. The developed method demonstrates linearity over a concentration range of 200-4000 ng/mL, with a lower limit of quantification of 115 ng/mL. When applied to quantify plasma zinc levels, the method revealed significantly decreased zinc levels in patients with olfactory dysfunction compared to healthy individuals. These results suggest a potential link between olfactory dysfunction and zinc levels (normal vs. patient; 1150 ± 19 ng/mL vs. 940 ± 14 ng/mL, p < 0.05). The developed method was validated following the ICH M10 guidelines and provided a feasible investigative link between zinc and olfactory function., 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 Elsevier B.V. All rights reserved.)

Harmaline and harmine are naturally occurring closely related β-carboline alkaloids found in Peganum and Banisteriopsis plants. They have historical significance in traditional practices due to their potential psychoactive and therapeutic properties. Herein, a highly sensitive spectrofluorometric method was developed for the quantifying of harmaline and harmine in diverse matrices, including pure forms, seed samples, and spiked plasma. The procedures lie in addressing the challenge of overlapping fluorescence spectra exhibited by harmaline and harmine through the incorporation of hydroxypropyl-β-cyclodextrin, altering their chemical properties and fluorescence characteristics. Synchronous fluorescence measurements coupled with first derivative mathematical technique make it possible to distinguish between the harmaline and harmine at 419 and 456 nm, respectively. The method effectiveness is demonstrated through spectral analysis, optimization of the measurement conditions, adopting validation parameters and application to the pure form, seed samples and spiked human plasma. This methodology facilitates accurate determination of these alkaloids over the concentration range of 10─200 ng/mL. Thus, the developed approach provides a robust mean for the precise determination of harmaline and harmine, contributing to analytical chemistry's ongoing efforts to address complex challenges in quantification across diverse matrices., (© 2023. The Author(s).)

Background: COVID-19 has been associated with olfactory dysfunction in many infected patients. The rise of calcium levels in the nasal secretions plays an essential role in the olfaction process with a desensitization effect on the olfactory receptor neurons and a negative impact on the olfaction transmission. Ethylene diamine tetra acetic acid (EDTA) is a chelating agent that can bind free calcium in the nasal secretions, thereby reducing the adverse effects of calcium on olfactory function., Objectives: The objective of this work is to demonstrate the effect of intranasal EDTA on improving olfactory dysfunction following COVID-19., Methods: Fifty patients with a history of COVID-19 and olfactory dysfunction that persisted for more than 6 months were enrolled in the current prospective randomized clinical trial. Participants were randomized into 2 equal groups. Twenty-five patients were treated with olfactory training only, while the remaining 25 patients received treatment with olfactory training and a topical nasal spray of ethylene diamine tetra acetic acid. The olfactory function was assessed before treatment and 3 months later using the Sniffin' Sticks test. Additionally, the determination of calcium level in the nasal secretions was performed using an ion-selective electrode before treatment and 3 months later., Results: Eighty-eight percent of the patients treated with olfactory training in addition to EDTA exhibited clinical improvement, while 60% showed improvement in patients treated with olfactory training only. Furthermore, a significant decrease in the measured calcium level in the nasal secretions was demonstrated after the use of ethylene diamine tetra compared to patients treated with olfactory training only., Conclusion: Ethylene diamine tetra acetic acid may be associated with an improvement of the olfactory function post-COVID-19., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Favipiravir and aspirin are co-administered during COVID-19 treatment to prevent venous thromboembolism. For the first time, a spectrofluorometric method has been developed for the simultaneous analysis of favipiravir and aspirin in plasma matrix at nano-gram detection limits. The native fluorescence spectra of favipiravir and aspirin in ethanol showed overlapping emission spectra at 423 nm and 403 nm, respectively, after excitation at 368 nm and 298 nm, respectively. Direct simultaneous determination with normal fluorescence spectroscopy was difficult. The use of synchronous fluorescence spectroscopy for analyzing the studied drugs in ethanol at Δλ = 80 nm improved spectral resolution and enabled the determination of favipiravir and aspirin in the plasma matrix at 437 nm and 384 nm, respectively. The method described allowed sensitive determination of favipiravir and aspirin over a concentration range of 10-500 ng/mL and 35-1600 ng/mL, respectively. The described method was validated with respect to the ICH M10 guidelines and successfully applied for the simultaneous determination of the mentioned drugs in pure form and in the spiked plasma matrix. Moreover, the compliance of the method with the concepts of environmentally friendly analytical chemistry was evaluated using two metrics, the Green Analytical Procedure Index and the AGREE tool. The results showed that the described method was consistent with the accepted metrics for green analytical chemistry., 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 Elsevier B.V. All rights reserved.)

Background: Ritonavir was recently combined with nirmatrelvir in a new approved co-packaged medication form for the treatment of COVID-19. Quantitative analysis based on fluorescence spectroscopy measurement was extensively used for sensitive determination of compounds exhibited unique fluorescence features., Objective: The main objective of this work was to develop higher sensitive cost effective spectrofluorometric method for selective determination of ritonavir in the presence of nirmatrelvir in pure form, pharmaceutical tablet as well as in spiked human plasma., Methods: Ritonavir was found to exhibit unique native emission fluorescence at 404 nm when excited at 326 nm. On the other hand, nirmatrelvir had no emission bands when excited at 326 nm. This feature allowed selective determination of ritonavir without any interference from nirmatrelvir. The variables affecting fluorescence intensity of ritonavir were optimized in terms of sensitivity parameters and principles of green analytical chemistry. Ethanol was used a green solvent which provided efficient fluorescence intensity of the cited drug., Results: The method was validated in accordance with the ICH Q2 (R1) standards in terms of linearity, limit of detection (LOD), limit of quantification (LOQ), accuracy, precision and specificity. The described method was successfully applied for ritonavir assay over the concentration range of 2.0-20.0 ng/mL., Conclusion: Ritonavir determination in the spiked human plasma was successfully done with satisfactory accepted results., (© 2023. Springer Nature Switzerland AG.)

The environmentally friendly design of analytical methods is gaining interest in pharmaceutical analysis to reduce hazardous environmental impacts and improve safety and health conditions for analysts. The adaptation and integration of chemometrics in the development of environmentally friendly analytical methods is strongly recommended in the hope of promising benefits. Favipiravir and remdesivir have been included in the COVID-19 treatment guidelines panel of several countries. The main objective of this work is to develop green, tuned spectrophotometric methods based on chemometric based models for the determination of favipiravir and remdesivir in spiked human plasma. The UV absorption spectra of favipiravir and remdesivir has shown overlap to some extent, making simultaneous determination difficult. Three advanced chemometric models, classical least squares, principal component regression, and partial least squares, have been developed to provide resolution and spectrophotometric determination of the drugs under study. A five-level, two-factor experimental design has been used to create the described models. The spectrally recorded data of favipiravir and remdesivir has been reviewed. The noise region has been neglected as it has a negative impact on the significant data. On the other hand, the other spectral data provided relevant information about the investigated drugs. A comprehensive evaluation and interpretation of the results of the described models and a statistical comparison with accepted values have been considered. The proposed models have been successfully applied to the spectrophotometric determination of favipiravir and remdesivir in pharmaceutical form spiked human plasma. In addition, the environmental friendliness of the described models was evaluated using the analytical eco-scale, the green analytical procedure index and the AGREE evaluation method. The results showed the compliance of the described models with the environmental characteristics., (© 2023. The Author(s).)

Background: COVID-19 has been frequently demonstrated to be associated with anosmia. Calcium cations are a mainstay in the transmission of odor. One of their documented effects is feedback inhibition. Thus, it has been advocated that reducing the free intranasal calcium cations using topical chelators such as pentasodium diethylenetriamine pentaacetate (DTPA) could lead to restoration of the olfactory function in patients with post-COVID-19 anosmia., Methodology: This is a randomized controlled trial that investigated the effect of DTPA on post-COVID-19 anosmia. A total of 66 adult patients who had confirmed COVID-19 with associated anosmia that continued beyond three months of being negative for SARS-CoV-2 infection. The included patients were randomly allocated to the control group that received 0.9 % sodium chloride-containing nasal spray or the interventional group that received 2 % DTPA-containing nasal spray at a 1:1 ratio. Before treatment and 30 days post-treatment, the patients' olfactory function was evaluated using Sniffin' Sticks, and quantitative estimation of the calcium cations in the nasal mucus was done using a carbon paste ion-selective electrode test., Results: Patients in the DTPA-treated group significantly improved compared to the control group in recovery from functional anosmia to hyposmia. Additionally, they showed a significant post-treatment reduction in the calcium concentration compared to the control group., Conclusion: This study confirmed the efficacy of DTPA in treating post-COVID-19 anosmia., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A computationally-assisted and green spectrophotometric method has been developed for the determination of fostemsavir, a recently FDA-approved drug used in combination with antiretroviral drugs to treat multidrug-resistant HIV-1 infection. The method was developed using computational studies and solvent selection based on green chemistry principles. The density functional theory method was employed to identify bromophenol blue as the preferred acid dye for efficient extraction of fostemsavir. The solvent selection process involved a careful evaluation of the green ranking of solvents, which led to the use of water as the solvent. The method involved the extraction of fostemsavir with bromophenol blue to form a yellow ion-pair complex, which exhibited maximally sharp peaks at 418 nm, enabling sensitive visible spectrophotometric determination of fostemsavir in bulk and pharmaceutical preparations. The extraction procedures were optimized, and the method was demonstrated to be sensitive over the concentration range of 2-12 μg/mL fostemsavir. Furthermore, the method was evaluated with respect to green chemistry principles using the analytical eco-scale, the green analytical method index, and analytical greenness metric approach, all of which confirmed that the data obtained by the proposed method were environmentally acceptable., (© 2023. The Author(s).)

Favipiravir and remdesivir have been included in the COVID-19 treatment guidelines panel of several countries. The main objective of the current work is to develop the first validated green spectrophotometric methods for the determination of favipiravir and remdesivir in spiked human plasma. The UV absorption spectra of favipiravir and remdesivir have shown some overlap, making simultaneous determination difficult. Due to the considerable overlap, two ratio spectra manipulating spectrophotometric methods, namely, ratio difference and the first derivative of ratio spectra, enabled the determination of favipiravir and remdesivir in their pure forms and spiked plasma. The ratio spectra of favipiravir and remdesivir were derived by dividing the spectra of each drug by the suitable spectrum of another drug as a divisor to get the ratio spectra. Favipiravir was determined by calculating the difference between 222 and 256 nm of the derived ratio spectra, while calculating the difference between 247 and 271 nm of the derived ratio spectra enabled the determination of remdesivir. Moreover, the ratio spectra of every drug were transformed to the first order derivative using ∆λ = 4 and a scaling factor of 100. The first-order derivative amplitude values at 228 and 251.20 nm enabled the determination of favipiravir and remdesivir, respectively. Regarding the pharmacokinetic profile of favipiravir (C max 4.43 µg/mL) and remdesivir (C max 3027 ng/mL), the proposed methods have been successfully applied to the spectrophotometric determination of favipiravir and remdesivir in plasma matrix. Additionally, the greenness of the described methods was evaluated using three metrics systems: the national environmental method index, the analytical eco-scale, and the analytical greenness metric. The results demonstrated that the described models were in accordance with the environmental characteristics., (© 2023. The Author(s).)

Quantitative analysis of pharmaceutical compounds up to Nano gram levels is highly recommended to introduce feasible and sensitive tool for determination of the compounds in the pharmaceutical and biological samples. Nirmatrelvir plus ritonavir was recently approved in the US, the UK and Europe as a new co-packaged dosage form for the treatment of COVID-19. The objective of this work was to develop a more sensitive TLC method based on using β-cyclodextrin as a chiral selector additive in the mobile phase for simultaneous determination of nirmatrelvir and ritonavir in pure form, pharmaceutical formulation and spiked human plasma. The analysis procedures were developed using TLC aluminum silica gel plates and methanol-water- 2% urea solution of β-cyclodextrin (40:10:.5, by volume) as a mobile phase with UV detection at 215 nm. The developed method was successfully applied over a linearity range of 10-50 ng/band for both nirmatrelvir and ritonavir. The method was validated for limits of detection and quantitation, accuracy, precision, specificity, system suitability, and robustness. Furthermore, the eco-friendliness of the proposed method was assessed using the analytical eco-scale and the green analytical procedure index. The described method exhibited compliance with green analytical chemistry principles based on common green metric values., (© 2023. The Author(s).)

Remdesivir and apixaban have been included in the treatment guidelines of several countries for severe COVID-19 infections. To date, no analytical method has been developed for the determination of remdesivir and apixaban in plasma matrix. The main objective of this work was to develop a highly sensitive, green-adapted spectrofluorometric method for the determination of remdesivir and apixaban at the Nanoscale. Remdesivir and apixaban showed overlapping fluorescence emission spectra at 403 nm and 456 nm when excited at 246 nm and 285 nm, respectively. This overlap was resolved in two steps. The first step was synchronous fluorescence scanning of remdesivir and apixaban, and the second step was manipulation of the second-order derivative for the obtained spectra. These steps allowed complete resolution of the overlapping fluorescence spectra and selective determination of remdesivir and apixaban at 410 and 469 nm, respectively. The variables affecting the synchronous scanning of the aforementioned drugs were optimized in terms of sensitivity parameters and principles of green analytical chemistry. The described method allowed sensitive determination of remdesivir and apixaban over the concentration range of 5-200 ng/mL and 50-3000 ng/mL, respectively. The described method was validated and successfully applied for the simultaneous determination of the mentioned drugs in pure form and in spiked human plasma., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: Low-dose aspirin (ASP) is prescribed to millions of people around the world as a secondary preventative strategy for the majority of significant cardiovascular events; however, it carries a substantial risk of gastric ulcer and bleeding. Cabpirin® tablets, which include low-dose ASP and vonoprazan fumarate (VON), are approved in Japan for the treatment of acid-related diseases in patients who require a low dose of ASP but are at risk of ASP-associated gastric ulcers., Objective: This paper describes the first published quantitative analytical approaches for the determination of ASP and VON., Method: The normal ultraviolet absorption spectra of ASP and vonoprazan overlap significantly. The ratio spectra of the studied drugs were created and manipulated by ratio difference (RD) and first derivative of ratio spectra approaches. In the RD approach, the differences in the amplitude values between 229 and 283 nm enabled the quantitative analysis of ASP, and the differences in the amplitude values between 255 and 212 nm enabled the quantitative analysis of vonoprazan. In the first derivative of the ratio spectra approach, the created ratio spectra of each drug were transformed to the first-order derivative. ASP could be determined selectively at 237.40 nm without interference from vonoprazan. Moreover, vonoprazan could be determined selectively at 244 nm without interference from ASP., Results: The applied approaches were validated according to the ICH guideline, with good results. Linear correlations were obtained for ASP and vonoprazan over concentration ranges of 2-25 and 1-10 µg/mL, respectively., Conclusions: The described methods were optimized, validated, and applied for determination of the studied drugs in the synthetic mixtures and in pharmaceutical tablets without interferences., Highlights: Two spectrophotometric ratio spectra manipulating approaches were developed for the determination of the ASP and vonoprazan in their pharmaceutical combination tablets., (© The Author(s) 2022. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lesinurad and allopurinol have been formulated in a combined dosage form providing a new challenge for the treatment of gout attacks. Two mathematical based spectrophotometric methods, area under the curve, and artificial neural networks have been developed for simultaneous determination of lesinurad and allopurinol in pure form and in combined pharmaceutical dosage form. Area under the curve has been utilized to resolve the spectral overlap between lesinurad and allopurinol. Values of area under the curve and area absorptivity were measured at two selected wavelength ranges of 242-250 nm and 255-265 nm. Two mathematically constructed equations have been used to determine the concentrations of the drugs under the study. Advanced chemometry based model, artificial neural network, has been developed utilizing the UV spectral data of lesinurad and allopurinol through various defined steps. A five-level, two-factor experimental design was used to construct 25 mixtures. Thirteen mixtures were used to set up the calibration model and 12 mixtures were used to construct a validation set. The artificial neural network model was optimized to enable precise spectrophotometric determination of the drugs under the study. The described mathematically bases spectrophotometric methods have been successfully applied to the determination of lesinurad and allopurinol in the new combined, Duzallo® tablets. Furthermore, the greenness of the described methods was assessed using four different tools namely, the national environmental method index, the analytical eco-scale, the green analytical procedure index and the AGREE evaluation method. The proposed methods showed more adherence to the greenness characters in comparison to the previously reported HPLC 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 © 2022 Elsevier B.V. All rights reserved.)

Molnupiravir is an oral antiviral drug developed to provide significant benefit in reducing hospitalizations or deaths in mild COVID-19. Integrated green computational spectrophotometric method was developed for the determination of molnupiravir. Theoretical calculations were performed to predict the best coupling agent for efficient diazo coupling of molnupiravir. The binding energy between molnupiravir and various phenolic coupling agents, α-naphthol, β-naphthol, 8-hydroxyquinoline, resorcinol, and phloroglucinol, was measured using Gaussian 03 software based on the density functional theory method and the basis set B3LYP/6-31G(d). The results showed that the interaction between molnupiravir and 8-hydroxyquinoline was higher than that of other phenolic coupling agents. The method described was based on the formation of a red colored chromogen by the diazo coupling of molnupiravir with sodium nitrite in acidic medium to form a diazonium ion coupled with 8-hydroxyquinoline. The absorption spectra showed maximum sharp peaks at 515 nm. The reaction conditions were optimized. Beer's law was followed over the concentration range of 1-12 μg/ml molnupiravir. Job's continuous variation method was developed and the stoichiometric ratio of molnupiravir to 8-hydroxyquinoline was determined to be 1:1. The described method was successfully applied to the determination of molnupiravir in pure form and in pharmaceutical dosage form. The results showed that the proposed method has minimal environmental impact compared to previous HPLC 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 © 2022 Elsevier B.V. All rights reserved.)

The greening of analytical methods has gained interest in the quantitative analysis field to reduce environmental impact and improve safety health conditions for analysts. Nirmatrelvir plus ritonavir is a new FDA approved co-packaged medication developed for the treatment of COVID-19. The aim of this research was to develop green fitted HPLC method using pre experimental computational testing of different stationary phases as well as selecting mobile phase regarding to green analytical chemistry principles. Computational study was designed to test the physical interaction between nirmatrelvir and ritonavir and different columns (C8, C18, Cyano column). The study showed that the C18 column was better for simultaneous HPLC analysis of the cited drugs. Regarding to green point of view, mobile phase consisted of ethanol: water (80:20, v/v) provided an efficient chromatographic separation of nirmatrelvir and ritonavir within a short analytical run time, reasonable resolution and excellent sensitivity. Isocratic elution was performed on a selected C18 column and a green adjusted mobile phase at flow rate of 1 mL/min and UV detection at 215 nm. The chromatographic system allowed complete baseline separation with retention times of 4.9 min for nirmatrelvir and 6.8 min for ritonavir. The method succeeded to determine nirmatrelvir and ritonavir over the concentration range of 1.0-20.0 μg/mL in the pure form and in pharmaceutical dosage form. Greenness profiles of the applied HPLC method was assessed using analytical eco-scale, the green analytical procedure index and the AGREE evaluation method. The results revealed adherence of the described method to the green analytical chemistry principles. The authors hope to provide a promising challenge for achieving green goals through integrating computational tools and applying them with green assessment metrics., (© 2023. The Author(s).)

Favipiravir, remdesivir and hydroxychloroquine have been suggested in COVID-19 Treatment Guidelines Panel of many countries. Synchronous spectrofluorometric measurement provides sensitive tool for resolving the overlapped spectra of multicomponent drugs through converting the wider spectra to narrower sharp spectra. This work introduces the first fluorescence spectroscopic method for quantitative analysis of favipiravir, remdesivir and hydroxychloroquine in spiked human plasma. Testing the fluorescence spectra of favipiravir, remdesivir and hydroxychloroquine shows severe overlap, which hinders the direct quantification of the cited drugs. To overcome the overlapping issue, the drugs under the study have been measured in the synchronous mode at Δλ = 60 nm. Favipiravir could be measured directly at 423 nm without interference of remdesivir or hydroxychloroquine. Synchronous measuring the cited drugs at Δλ = 130 nm with mathematical transforming to the first order derivative spectra allowing remdesivir and hydroxychloroquine at 384 nm and 394 nm, respectively without interference from favipiravir. Different factors affecting the spectrofluorometric measurement process have been verified. The drugs under the study have been successfully quantitatively analyzed in the spiked plasma using the proposed method., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: COVID-19 has been associated with temporary olfactory dysfunction in many infected patients. Calcium plays a great role in the olfaction process with negative feedback for the olfaction transmission. Many reports demonstrated calcium elevation in the nasal secretions with a negative effect on olfaction. Sodium gluconate is a water-soluble salt with a chemical structure that lends to act as a highly efficient chelating agent. It can bind the elevated calcium in the nasal secretions reducing the adverse effects on olfactory function., Objective: To evaluate the impact of intranasal sodium gluconate on decreasing the rise of nasal calcium and improving the sense of smell in patients with olfactory dysfunction post-COVID-19 infection., Methods: Fifty patients with a history of confirmed COVID-19 suffering from olfactory dysfunction persisted more than 90 days after severe acute respiratory syndrome-coronavirus-2 negative testing were included in a prospective randomized blinded controlled clinical trial. Patients were divided into 2 equal groups, receiving either 0.9% sodium chloride or 1% sodium gluconate. Olfactory function was assessed before treatment and 1 month later using the Sniffin' Sticks test. Quantitative analysis of the nasal calcium concentration was performed before treatment and 1 month later using a laboratory-designed screen-printed ion-selective electrode., Results: After using sodium gluconate, the measured olfactory scores indicated a clinical improvement from anosmia to hyposmia compared to the nonimprovement sodium chloride receiving group. Also, a remarked decrease in the calcium nasal concentration was observed after using sodium gluconate compared to sodium chloride., Conclusion: Based on the proposed results, sodium gluconate may associate with an improvement of the olfactory dysfunction post-COVID-19 infection.

Background: Pain is a global, complex health problem that includes physical, emotional, and social components. The pain management process has many goals, including patient satisfaction, reducing clinical complications, and lowering costs. The physician describes pain medications in terms of the proven cause and classification of the severity of the pain. The combination of celecoxib and tramadol was recently approved by the Food and Drug Administration (FDA) in October 2021 for the treatment of acute pain in adults., Objective: This paper presents the first published quantitative analytical methods for celecoxib and tramadol., Methods: The UV absorption spectra of celecoxib and tramadol showed strong overlap. Mathematical simultaneous equation and ratio difference methods were developed to resolve the spectral overlap and quantify the drugs in the combination mixture. In the simultaneous equation method, the absorbance and absorptivity values at 252 and 217 nm were used to construct two mathematical equations that were used for the simultaneous mathematical quantification of the above drugs. The mathematical manipulation of the ratio difference based on the calculation of the differences in the amplitude values between 250 and 280 nm enabled the quantitative analysis of celecoxib, and the differences in the amplitude values between 221 and 272 nm enabled the quantitative analysis of tramadol., Results: The proposed methods were successfully applied to the selective quantitative analysis of celecoxib and tramadol in the synthetic mixtures and in the pharmaceutical tablets without interference from the tablet additives., Conclusions: The applied methods demonstrated good linearity in the concentration range of 1-20 µg/mL and 3-45 µg/mL for celecoxib and tramadol, respectively, with acceptable accuracy and precision. The methods were found to be sensitive with LOD values of 0.183 µg/mL and 0.626 µg/mL for celecoxib and tramadol, respectively, in simultaneous equation method and of 0.275 µg/mL and 0.772 µg/mL for celecoxib and tramadol, respectively, in ratio difference method., Highlights: The first established simple and validated UV spectrophotometric methods were described for concurrent quantification of the celecoxib and tramadol in their recently approved pharmaceutical formulation., (© The Author(s) 2022. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Acotiamide and esomeprazole are co-administrated and prescribed for gastrointestinal disorder diseases., Objective: Development of the first UV spectrophotometric methods for the quantitative analysis of acotiamide and esomeprazole in their mixture., Methods: The UV absorption spectra of acotiamide and esomeprazole showed severe overlapping. To solve the spectral overlapping and quantify the studied drugs in their mixture, simultaneous equation and ratio difference methods were developed. For simultaneous equation method, the absorbance and absorptivity values at 279 and 302 nm were used to construct two mathematical equations applied for the spectrophotometric assay of the cited drugs. Ratio difference spectra manipulated method was developed and enabled successful quantitative determination of acotiamide and esomeprazole. The differences in the amplitude values between 280 and 260 nm enabled estimation of acotiamide, and the differences in the amplitude values between 303 and 282 nm enabled estimation of esomeprazole., Results: The proposed methods succeeded to quantify acotiamide and esomeprazole in the synthetic mixtures and in their pharmaceutical tablets without any interference from each other or from tablet additives., Conclusions: The applied methods demonstrated good linearity in the concentration range of 2-30 µg/mL and 2-20 µg/mL for acotiamide and esomeprazole, respectively, with acceptable accuracy and precision. The methods were found to be sensitive with LOD values of 0.336 µg/mL and 0.332 µg/mL for acotiamide and esomeprazole, respectively, in simultaneous equation method and of 0.410 µg/mL and 0.333 µg/mL for acotiamide and esomeprazole, respectively, in ratio difference method., Highlights: Simple and validated UV spectrophotometric methods were described for selective quantification of the acotiamide and esomeprazole in their mixture., (© The Author(s) 2022. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Computational studies introduce an integral approach for finding greener methods through testing solvents for reactions and extractions. Lesinurad is a novel selective uric acid reabsorption inhibitor prescribed for the treatment of chronic gout. Computational calculations were achieved to choose the best acid dye used for sensitive visible spectrophotometric determination of lesinurad. The calculations were performed using Gaussian 03 software based on density functional theory method with B3LYP/6-31G(d) basis set. The obtained results revealed that bromophenol blue was preferred for lesinurad than other acid dyes based on the higher calculated interaction energy. The described method was based on the reaction of lesinurad with the theoretically selected acid dye bromophenol blue to form a yellow ion-pair complex. The absorption spectra showed maximum sharp peaks at 418 nm. Different factors affecting the reaction were optimized. Beer's law was demonstrated over the concentration range of 2-12 μg/mL lesinurad. The described reaction was utilized for the spectrophotometric determination of lesinurad in pure form and in the pharmaceutical preparation. The greenness of the described method was assessed using four different tools namely, the national environmental method index, the analytical eco-scale, the green analytical procedure index and the novel analytical greenness metric. The proposed method seemed to be superior to the reported HPLC method with respect to the metrics of the greenness characters., 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 © 2022. Published by Elsevier B.V.)

Purpose: An association between COVID-19 and olfactory dysfunction has been noted in many patients worldwide. The olfactory adaptation process leads to an increase in intracellular calcium cation levels. Nitrilotriacetic acid trisodium salt has high selective chelation for calcium cations from olfactory mucus. The aim of this work is to test the effect of an intranasal nitrilotriacetic acid trisodium salt to lower the elevated calcium cations in COVID-19 patients with relevant symptoms of olfactory dysfunction., Methods: Fifty-eight COVID-19 adult patients with relevant symptoms of olfactory dysfunction were enrolled in a prospective randomized controlled trial. They received a nasal spray containing either 0.9% sodium chloride or 2% nitrilotriacetic acid trisodium salt. Olfactory function was assessed before and after treatment using the Sniffin' Sticks test. Quantitative analysis of calcium cation concentration in nasal secretions was performed using a carbon paste ion-selective electrode., Results: After the application of nitrilotriacetic acid trisodium salt compared to sodium chloride, a significant improvement from functional anosmia to healthy normosmia with significant decrease in calcium cation concentration was observed., Conclusions: Further collaborative research is needed to fully investigate the effect of an intranasal nitrilotriacetic acid trisodium salt in the treatment of olfactory disorders., (© 2022. The Author(s).)

Fexofenadine hydrochloride and pseudoephedrine hydrochloride are prescribed in a combined dosage form for the treatment of allergic rhinitis. In the present work, a sensitive synchronous fluorescence spectroscopic method was applied in conjunction with first derivative for quantitative estimation of fexofenadine hydrochloride and pseudoephedrine hydrochloride in pure form, pharmaceutical tablets and spiked human plasma. Fexofenadine hydrochloride showed its conventional emission spectrum at 294 nm when excited at 267 nm. On the other hand, pseudoephedrine hydrochloride showed its conventional emission spectra at 286 nm when excited at 261 nm. The fluorescence intensities were greatly enhanced by the use of sodium dodecyl sulphate as a micellar surfactant. Application of the synchronous mode to measure the fluorescence spectra of the above drugs provided sharp narrowing bands, but the overlap was not completely resolved. Derivatization of the synchronous spectra to the first order completely resolved the overlap of the fluorescence spectra and allowed simultaneous quantitative determination of the drugs under study. Fexofenadine hydrochloride and pseudoephedrine hydrochloride could be determined from their first-order synchronous spectra at 286 and 294 nm, respectively, without interfering with each other. The method showed linearity with an excellent correlation coefficient in the concentration range of 100-1500 ng/mL for Fexofenadine hydrochloride and 50-1000 ng/mL for pseudoephedrine hydrochloride. The method was successfully applied for the simultaneous determination of the studied drugs in pharmaceutical formulation, with mean percent recoveries for Fexofenadine hydrochloride and pseudoephedrine hydrochloride of 99.49 ± 0.931 and 98.67 ± 0.634, respectively, and in spiked human plasma, with mean percent recoveries for Fexofenadine hydrochloride and pseudoephedrine hydrochloride of 95.21 ± 1.938 and 94.89 ± 1.763, respectively. Furthermore, the greenness of the described method was assessed using four different tools namely, the national environmental method index, the analytical eco-scale, the green analytical procedure index and the AGREE evaluation method. The proposed method seemed to be superior to the reported HPLC method with respect to the metrics of the greenness characters., (© 2022. The Author(s).)

Several quantitative analytical methods were used to estimate aspirin and omeprazole in recently FDA-approved tablets. The first derivative of the ratio spectra was used to resolve the recorded overlapping spectra between aspirin and omeprazole. The first derivative of the ratio spectra of the studied drug mixtures was divided by a spectrum of a standard solution of omeprazole for the estimation of aspirin. Also, the first derivative of the ratio spectra of the studied drug mixtures was divided by a spectrum of the standard solution of aspirin for the estimation of omeprazole. For the simultaneous quantitative analysis of aspirin and omeprazole, the TLC densitometry technique was applied using TLC aluminum silica gel plates, toluene-acetonitrile-methanol (7:2:0.5, by volume) as the mobile phase, and UV detection at 272 nm. The advantages and disadvantages of the proposed techniques were discussed in the context of the results and the sensitivity limits of the methods. The proposed techniques were validated and successfully applied to the analysis of drugs in pure and pharmaceutical forms. A statistical comparison of the data obtained by the described methods with other data obtained by a previously published HPLC method was performed. The results agreed well with respect to the recommended statistical tests. Furthermore, the greenness of the described methods was assessed using different tools, the analytical eco-scale, the green analytical procedure index and the AGREE evaluation method. The proposed methods showed more adherence to the greenness characters in comparison to the previously reported HPLC method., (© 2022. The Author(s).)

Remdesivir was approved by the Food and Drug Administration for the treatment of COVID -19 in hospitalized adult and pediatric patients. Application of computational calculations for choosing the sensitive reagent in spectrophotometric quantitative analysis is very limited. Computational and theoretical studies were used for choosing the best acid dye for selective visible spectrophotometric quantitative analysis of remdesivir. The calculations were performed using Gaussian 03 software with the density functional theory method using B3LYP/6-31G(d) basis set. The theoretical studies revealed that bromophenol blue is a better match for remdesivir than other acid dyes due to the higher calculated interaction energy. The proposed method was based on the reaction of remdesivir with the computationally selected acid dye bromophenol blue to form a yellow ion-pair complex. The spectra showed absorption peaks at 418 nm. Various factors affecting the reaction were optimized. The method was successfully applied for the determination of remdesivir in the pharmaceutical preparation with good accuracy and precision. Beer's law was observed in the concentration range of 2-12 μg/mL of remdesivir. The proposed reaction was used as a basis for the spectrophotometric determination of remdesivir in pure form and in the pharmaceutical preparation., 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 © 2022 Elsevier B.V. All rights reserved.)

Background: Olfactory dysfunction is recognized as a symptom of COVID-19. Reports revealed the nasal calcium increase has adverse effects on olfactory function. Tetra sodium pyrophosphate, a chelating agent, can bind calcium and help improve olfaction., Methods: Sixty-four patients with olfactory dysfunction persisting for more than 90 days after COVID-19 were recruited. Participants were divided into 2 groups that received either 0.9% sodium chloride or 1% tetra sodium pyrophosphate for topical application. Olfactory function was tested with the Sniffin' Sticks test before treatment and 1 month later. In addition, nasal calcium was determined with an ion-selective electrode., Results: After topical application of tetra sodium pyrophosphate compared to sodium chloride, improvement from anosmia to hyposmia with decrease in calcium level was demonstrated. As for the results of tetra-sodium pyrophosphate, 81% showed improved olfactory function and 19% did not exhibit olfaction improvement., Conclusions: Intranasal application of tetra sodium pyrophosphate may be associated with improvement in olfactory function after COVID -19 infection. Trial registration Ethical Committee of Damietta Faculty of Medicine approved this study on January 2021 (approval number, IRB 00012367-21-03-010)., (© 2022. The Author(s).)

Entadfi™ is a recently FDA approved pharmaceutical combination capsule of finasteride and tadalafil. It was prescribed for the treatment of urinary tract disorders caused by benign prostatic hyperplasia in men. This paper introduced the first spectrophotometric methods for simultaneous determination of finasteride and tadalafil in the pure form and in the pharmaceutical capsules. UV absorption spectra of finasteride and tadalafil exhibited overlap hindered the direct simultaneous determination of the cited drugs. The UV absorption spectra of finasteride and tadalafil were transformed to the second order derivative. Finasteride could be determined selectively at 230.80 nm without interference from tadalafil. Moreover, tadalafil could be determined selectively at 292 nm without interference from finasteride. The ratio spectra of the studied drugs were derived and the derived ratio spectra of each drug were transformed to the first order derivative. Finasteride could be determined selectively at 218.80 nm without interference from tadalafil. Moreover, tadalafil could be determined selectively at 289.60 nm without interference from finasteride. The methods showed linearity with an excellent correlation coefficient in the concentration range of 10-140 µg/mL for finasteride and 3-40 µg/mL for tadalafil. The methods were validated following ICH guidelines for accuracy, precision, robustness, limit of detection, limit of quantification, and selectivity. The methods were found to be sensitive with LOD values for finasteride and tadalafil of 2.406 µg/mL and 0.876 µg/mL using the second derivative with zero crossing method and 2.229 µg/mL and 0.815 µg/mL using the first derivative of ratio spectra method. The methods were successfully applied for the determination of the studied drugs in their laboratory prepared mixtures, with mean percent recovery for finasteride and tadalafil of 99.37% and 99.17% using the second derivative with zero crossing method and 99.74% and 99.56% using the first derivative of ratio spectra method. Furthermore, the described methods were successfully applied for determination of the studied drugs in Entadfi™ capsules without interference from excipients. Based on the proposed results, the described methods could be utilized as simple method for the quality control of the studied drugs., (© 2022. The Author(s).)

Background: Two fixed-dose combination tablets of amlodipine (AML) with bisoprolol (BIS) and amlodipine with candesartan (CAN) were recently approved for the treatment of hypertension., Objective: Three UV spectrophotometric analytical methods were developed for the estimation of the above drugs in their combination mixtures., Methods: For the AML and BIS mixture, AML was quantified directly by a zero-order spectrophotometric method at 360 nm without interference from BIS, whereas BIS was quantified by the ratio difference (RD) spectrophotometric method by calculating the difference between the amplitude values of the ratio spectra at 226 and 215 nm. For the AML and CAN mixture, AML was quantified directly by a zero-order spectrophotometric method at 360 nm without interference from CAN, whereas CAN was quantified by the first derivative of ratio spectra method by measuring the amplitude values of the derived spectra at 259 nm.BIS)., Results: The proposed methods were successfully applied for quantitative analysis of AML with BIS and AML with CAN in their synthetic laboratory-prepared mixtures and pharmaceutical tablets with acceptable results in terms of accuracy and precision., Conclusion and Highlights: Simple, accurate, and environmentally friendly spectrophotometric methods were described for selective determination of the investigated drugs in their fixed-dose combinations., (© The Author(s) 2022. Published by Oxford University Press on behalf of AOAC INTERNATIONAL. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Simeprevir and sofosbuvir are direct-acting antiviral drugs approved for the treatment of chronic HCV infection. Reports demonstrate the similarities between HCV and SARS-CoV-2 in terms of structure and replication mechanism. Therefore, it is suggested that a combination of simeprevir and sofosbuvir may be considered for COVID-19 patients. To date, no spectrophotometric methods have been published for quantitative analysis of simeprevir and sofosbuvir in combination. In this work, two simple spectrophotometric methods allowed quantitative analysis of the studied drugs in the mixed form. The zero-order direct method allowed quantitative analysis of simeprevir at 333 nm, with sofosbuvir showing zero absorbance values. The dual wavelength method allowed quantitative analysis of sofosbuvir by measuring the difference in absorbance values at 259.40 and 276 nm, where the difference in absorbance values of simeprevir was zero. With the applied methods, the investigated drugs in the mixtures and tablets prepared in the laboratory were successfully analyzed quantitatively with acceptable results., 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 © 2022. Published by Elsevier B.V.)

Velpatasvir and sofosbuvir are new drugs prescribed in a combined pharmaceutical dosage form that pose a new challenge for the treatment of chronic hepatitis C. In this work, a comparative evaluation of the classical mathematical model, simultaneous equations, and the advanced mathematical model, partial least squares, for the spectrophotometric quantitative analysis of velpatasvir and sofosbuvir in bulk powder and in the new combined pharmaceutical dosage form was presented. The mathematical simultaneous equation method was used to resolve the overlap between velpatasvir and sofosbuvir. The absorbance and absorbativity values at 255 and 244.8 were used to construct two mathematical equations required for spectrophotometric quantitative analysis of the drugs under study. Partial least squares, an advanced mathematical tool dealing with the full spectral data of velpatasvir and sofosbuvir, was also introduced. An experimental design for the calibration sets and validation sets for the binary mixture of the drugs under study were created. The model was optimized based on a five-level, two-factor experimental design. Pre-processing of the spectral data was applied and resulted in the exclusion of the spectral region from 200 to 230 nm due to noise. The described methods were successfully applied to the spectrophotometric quantitative analysis of velpatasvir and sofosbuvir in Epclusa® tablets., 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. Published by Elsevier B.V.)

Acetylsalicylic acid and omeprazole were recently formulated by the new FDA-approved drug Yosprala ® Tablets. This novel combination was prescribed to reduce the risk of myocardial infarction in patients who were at risk for developing peptic ulcer while taking acetylsalicylic acid. In the current work, two different high precision sensitive fluorescence spectroscopic methods were developed for quantitative analysis of the above drugs in pharmaceutical dosage form and spiked human plasma. Acetylsalicylic acid was quantitatively analyzed due to its unique native fluorescence nature. The fluorescence emission of acetylsalicylic acid was quantitatively determined at 404 nm after excitation at 296 nm without any interference from omeprazole. Omeprazole, which has a free terminal secondary amino group, reacted with 4-chloro-7-nitrobenzo-2-oxa-1, 3-diazole (NBD-Cl) by a nucleophilic substitution mechanism to form a highly fluorescent dark yellow fluorophore. Omeprazole was quantitatively analyzed by measuring the emission fluorescence intensity of the dark yellow fluorophore at 535 nm after excitation at 465 nm. Various parameters affecting the described methods were carefully checked and optimized. The calibration curves were found to be linear over the concentration range of 50-1600 ng/ml for acetylsalicylic and 30-2000 ng/ml for omeprazole. The proposed methods were successfully applied to the quantitative analysis of the two drugs in the pharmaceutical dosage form Yosprala ® and in spiked human plasma., 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. Published by Elsevier B.V.)

Artificial neural networks and genetic algorithm artificial neural networks, chemometric assisted spectrophotometric models, were developed for the quantitative analysis of elbasvir and grazoprevir in their newly FDA approved pharmaceutical dosage form. The UV absorption spectra of elbasvir and grazoprevir show severe degree of overlap which caused difficulty for selecting certain spectrophotometric method with advantage of simultaneous quantitative analysis of the cited drugs. After extensive study and many experimental trials, artificial neural networks and genetic algorithm artificial neural networks were the suitable models for the quantitative analysis of studied drugs in their binary mixture. Experimental design and constructing the calibration and validation sets of the binary mixture were achieved to implement the proposed models. The models were optimized with the aid of five-levels, two factors experimental design. The designed models were successfully applied to the quantitative analysis of Zepatier® tablets. The results were statistically compared with another reported HPLC quantitative analytical method with no significant difference by applying Student t-test and variance ratio F-test., 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. Published by Elsevier B.V.)

Four chemometric assisted spectrophotometric models were developed for the quantitative analysis of velpatasvir and sofosbuvir, in their newly FDA approved pharmaceutical dosage form. Due to the existed overlap of the scanned absorption spectra between velpatasvir and sofosbuvir, this resulted in degree of difficulty of the possibility of the conventional spectrophotometric methods to quantify and analyze the cited drugs simultaneously. Classical least squares, principal component regression, partial least squares and genetic algorithm partial least squares were designed and compared for the quantitative analysis of velpatasvir and sofosbuvir in their binary mixture. Experimental design for different concentrations of the studied drugs was done based on the spectral sensitivity of velpatasvir and sofosbuvir and the confirmed ratio of the two drugs in the commercial pharmaceutical dosage form. Optimization of the described models was adopted with the aid of five-levels, two factors experimental design. Successfully quantitative assay of the drugs in Epclusa® tablets was done by the proposed models. Statistically comparative analysis for the obtained models results with another published capillary electrophoresis quantitative analytical method was performed. It is noteworthy mentioning that there was no significant difference between the proposed models and the published method with respect to the accepted statistical parameters., 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. Published by Elsevier B.V.)

Two chemometric assisted spectrophotometric models were applied for the quantitative analysis of velpatasvir and sofosbuvir in their newly FDA approved pharmaceutical dosage form. The UV absorption spectra of velpatasvir and sofosbuvir showed certain degree of overlap which exhibited degree of difficulty for the choice of certain method provides simultaneous quantitative analysis of the cited drugs. Artificial neural networks and genetic algorithm artificial neural networks were the suitable model for the quantitative analysis of velpatasvir and sofosbuvir in their binary mixture. Experimental design and building the calibration set for the binary mixture were achieved to implement the described models. The proposed models were optimized with the aid of five-levels, two factors experimental design. Spectral region of 380-400 nm was rejected which resulted in 181 variables. GA reduced absorbance matrix to 72 and 36 variables for velpatasvir and sofosbuvir respectively. The models succeeded to estimate the studied drugs with acceptable values of root mean square error of calibration and root mean square error of prediction. The developed models were successfully applied to the quantitative analysis of the two drugs in Epclusa® tablets. The results were statistically compared with another published quantitative analytical method with no significant difference by applying Student t-test and variance ratio F-test., 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. Published by Elsevier B.V.)