Phonatory function and characteristics of voice in recovering COVID-19 survivors.

INTRODUCTION: This study aimed to evaluate the phonatory function of recovered COVID-19 survivors. The universal outbreak of COVID-19 led to the occurrence of otolaryngological manifestations that raised concerns about the assessment of the phonatory function in recovering patients. METHODS: This is a prospective, cross-sectional, case-controlled study carried out on 364 laboratory-confirmed non-critical COVID-19 survivors and 100 as healthy controls. The study participants were classified into two groups according to the disease severity. Group1 comprised 212 survivors who recovered from pneumonia and group 2 was made up of 152 survivors of severe pneumonia. All patients were subjected to an auditory perceptual assessment of the voice (APA) and Maximum Phonation Time (MPT) measurements. RESULTS: Phonasthenic manifestations were significantly more frequent in COVID-19 survivors than in controls (P < 0.000) with a higher percentage recorded among severe pneumonia survivors (87.5%) than among pneumonia survivors (60.8%) with a P value of < 0.01. Dysphonia and excessively soft loudness were significantly more common among survivors than among controls (P < 0.002 and P < 0.000, respectively) with no significant difference between the patient groups. The MPT was significantly shorter among survivors than among controls (P < 0.000). The mean MPT was 15.97 s in the control group, 10.72 s in the pneumonia group, and 8.88 s in the severe pneumonia group, with the differences between the groups being statistically significant (P < 0.000), suggesting a higher impairment of lung volume and phonatory function in severe cases. CONCLUSIONS: Phonasthenia, dysphonia, and decreased MPT could be otolaryngological manifestations of COVID-19. Laryngeal function assessment should be considered in COVID-19 survivors.

Spectroscopic and computational investigation of the interaction between the new anticancer agent enasidenib and human serum albumin.

Enasidenib (EDB) is a new therapeutic agent for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation. This research aimed at utilizing experimental and theoretical approaches to characterize the binding mechanism between EDB and human serum albumin (HSA). Formation of an EDB-HSA static complex was demonstrated by quenching of the HSA intrinsic fluorescence by EDB. Using well known mathematical relations (e.g. Stern-Volmer and Lineweaver-Burk equations), the recorded EDB-HSA fluorescence data were interpreted and revealed binding constants in the magnitude order of 104 M-1 for the different investigated temperatures. These determined results were taken into further mathematical calculations to reveal the thermodynamic properties of EDB-HSA binding. Results demonstrated that spontaneous EDB and HSA binding takes place led by electrostatic forces. Computational docking studies have further confirmed the latter finding showing that EDB fits into the HSA Sudlow site I. Molecular dynamic simulation was performed to calculate the root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg) and hydrogen bond parameters for the EDB-HSA complex.

Simple and efficient spectroscopic-based univariate sequential methods for simultaneous quantitative analysis of vandetanib, dasatinib, and sorafenib in pharmaceutical preparations and biological fluids.

Six sequential spectrophotometric-based univariate methods were developed and validated for the simultaneous estimation of three novel anticancer drugs vandetanib (VAN), dasatinib (DAS), and sorafenib (SOR) in a mixture, without the requirement for separation. These methods are novel, simple, precise, and accurate. Different steps including zero crossing, ratio-based, and/or derivative spectra were utilized to develop these analytical methods, namely, ratio difference spectrophotometric method, constant center method, successive derivative ratio method, isoabsorptive method, mean centering of the ratio spectra method, and derivative ratio spectrum-zero crossing method. The calibration curve linearity was ranged from 2 to 9, 2-9, and 3-9 µgmL-1 for VAN, DAS, and SOR, respectively. These established methods were applied for the quantification of the three selected drugs in different biological fluids (spiked human plasma and urine) and pharmaceutical preparations. The aforementioned methods were established for the concurrent estimation of ternary and binary mixtures to enhance the signal-to-noise ratio. The results did not statistically differ from the other reported methods, indicating no significant difference in accuracy and precision at p = 0.05.

Validated spectral manipulations for determination of an anti-neoplastic drug and its related impurities including its hazardous degradation product.

Innovative and specific double dual wavelength, dual ratio subtraction spectrophotometric methods were carried out along with a successive ratio subtraction spectrophotometric method for determination of dacarbazine and its related impurities including toxic and hazardous ones. For determination of dacarbazine by the double dual wavelength method, the absorbance differences between 323 and 350 nm of the zero order absorption spectra of dacarbazine were used. The values of absorbance difference between 267.2 and 286.2 nm of the zero order spectra of 5-amino-imidazole-4 carboxamide were used for its determination by the dual ratio subtraction method. The zero order absorption spectrum of 2-azahypoxanthine at 235 nm was used for its determination after applying the successive ratio subtraction method. ICH guidelines were followed for validation of the developed methods, where linear relationships were obtained in the range of 4-20, 1-16, and 2-20 µg mL-1 for dacarbazine, 5-amino imidazole-4-carboxamide and 2-azahypoxanthine, respectively. Accurate, precise, and specific results were obtained upon applying the proposed methods according to ICH guidelines. Furthermore, the developed methods were successfully applied for determination of dacarbazine in its pharmaceutical formulation. Comparing the results of the developed methods with those of the official USP spectrophotometric method statistically showed no significant difference. The developed methods don't need any sophisticated techniques so they are considered cost effective methods. Moreover, the introduced methods have the advantages of being green where water was used as a solvent. The methods proved to be more economic, fast and simple than other reported HPLC methods.

Probing the chemoprevention potential of the antidepressant fluoxetine combined with epigallocatechin gallate or kaempferol in rats with induced early stage colon carcinogenesis.

The enhanced chemopreventive action against 1,2 Dimethylhydrazine (DMH)-induced preneoplastic lesion in rats could be achieved via simultaneous administration of the antidepressant fluoxetine (FLX) with two natural polyphenolic compounds viz., kaempferol (KMP) and/or epigallocatechin-gallate (EGCG). The obtained results revealed that single FLX pre-treatment possess a significant apoptotic effect by increasing the activity of serum and colon tissue caspase 3. It also attenuated the DMH driven increase in, colon tissue MDA, NO, PCNA and COX-2 expression as well as serum and colon tissue ß-catenin, with a decrease in the multiplicity of ACF and number of MPLs. The combination of FLX with either KMP or EGCG improved the antioxidant, anti-inflammatory and antiproliferating activities but with higher apoptotic activity in case of KMP. Eventually, histopathological assessment of colon tissues exposed that while sole pre-treatment can improve DMH-induced hyperplasia with only moderate inflammatory infiltration, tissues from the combined pre-treatment regimens groups exhibited almost a normal colonic architecture with slight submucosal edema. The study proved that single FLX administration prior to DMH exerts a chemopreventive effect and that the investigated combined pre-treatment regimens demonstrated more potent chemopreventive and antiproliferative actions.

Development and Validation of RP-HPLC and an Ecofriendly HPTLC Method for Simultaneous Determination of Felodipine and Metoprolol Succinate, and their Major Metabolites in Human Spiked Plasma.

BACKGROUND: Felodipine is a calcium channel blocker used together with metoprolol succinate for treatment of hypertension. OBJECTIVE: Two chromatographic methods were developed for simultaneous determination of felodipine (FEL) and metoprolol succinate (MET), and their major metabolites, dehydrofelodipine and metoprolol acid, respectively. METHODS: The first method was RP-HPLC which comprised separation of the studied components by gradient elution using a Phenomenex C8 column and a mobile phase composed of water (adjusted to pH 3.5 with o-phosphoric acid)-acetonitrile - methanol (45:40:15, by volume) for the first 6 min and (30:60:10, by volume) for the next 4 min at a flow rate of 1 mL/min followed by UV detection of the eluted peaks at 225 nm. The second method was an HPTLC method where separation was achieved using a mobile phase consisting of toluene-ethyl acetate-methanol-ammonia-formic acid (10:5:2.5:0.3:0.1, by volume) and scanning of the separated bands at 225 nm. RESULTS: Validation of the developed methods was done according to ICH guidelines. Successful application of the developed methods was carried out for determination of the studied drugs in human spiked plasma and in Logimax® tablets. CONCLUSIONS: The developed RP-HPLC and HPTLC methods can be further applied for quality control testing of the studied drugs. HIGHLIGHTS: RP-HPLC and HPTLC methods for determination of FEL, MET and their major metabolites. The developed methods were successfully applied for determination of FEL and MET in Logimax® tablets.

Effect of iron deficiency anemia on language development in preschool Egyptian children.

BACKGROUND: Iron deficiency anemia (IDA) is the most common nutritional deficiency primarily in developing countries. OBJECTIVE: This study evaluates the effect of IDA on language development in preschool children. METHODOLOGY: The study is a multicenter, comparative cross-sectional study included 226 children between ages 4-6 years. The children were classified into two groups' anemic (patients) and non anemic (controls) according to the hemoglobin level. All anemic children subjected to complete iron study including; Serum iron, total iron binding capacity (TIBC), Serum ferritin level, to confirm the diagnosis of iron deficiency anemia. Cognitive assessment was done using the Arabic translation Stanford Binet intelligence scale, version four which comprised of four cognitive area scores; visual reasoning, verbal reasoning, quantitative reasoning and short-term memory. Measurement of IQ and mental age were calculated for each child. Language evaluation was done using the Arabic Language test. Receptive language quotient, expressive language quotient and total language quotient were calculated for each child. RESULTS: 122 children were anemic and 90 were non-anemic with hemoglobin level 10.65 and 11.96 g/dL, respectively (P < 0.000). Anemic children had significantly lower serum ferritin (p < 0.0001), and serum iron (p < 0.0001) compared to the controls. Both groups were matched as regards age, sex, socioeconomic levels and parental educational level. No significant differences observed regarding IQ, mental age, receptive, expressive and total language quotients between anemic and non-anemic children. CONCLUSIONS: IDA does not seem to have an effect on language development in preschool Egyptian Children. Future large controlled studies with long follow-up time for the younger age group are needed to determine whether there are existent associations between IDA with language development.

Partial least squares and linear support vector regression chemometric models for analysis of Norfloxacin and Tinidazole with Tinidazole impurity.

The aim of the presented work is to compare two popular chemometric methods which are partial least squares regression (PLSR) and support vector regression (SVR). The comparison shows their characteristics via application of the suggested methods to analysis of Norfloxacin (NF) and Tinidazole (TZ) with the presence of a potential impurity of Tinidazole; 2-Methyl-5-nitro-1H-imidazole (MNZ). For appropriate analysis, a 3 factor 4 level experimental design was constructed, which results in a training set composed of 16 mixtures which contains different concentrations of the three components; achieving symmetry, rotatability and orthogonality in mixture space. In order to validate the prediction ability of the suggested models, an independent test set consisting of 8 in-space and 8 out-of-space mixtures was used. The presented results show high specificity and accuracy of the mentioned multivariate calibration models for analysis of in-space samples of NF and TZ in presence of (MNZ) using UV spectral data. Statistical comparisons of predictive abilities of proposed models against classical least squares CLS model and against each other was performed; whether for analysis of test set mixtures or dosage form. CLS model showed lower predictive ability compared to other models. Results obtained by SVR model are as accurate as PLSR model, however, optimization and implementation of PLSR is faster and easier, hence PLSR could be of choice for this given case study. The developed chemometric models were validated as directed by ICH strategies. The validated methods were efficiently used for estimation of NF and TZ in pure powders and pharmaceuticals which indicates their suitability for application in quality control examination of both of the drugs.

Spectroscopic and molecular docking studies reveal binding characteristics of nazartinib (EGF816) to human serum albumin.

The interactions of novel anti-cancer therapeutic agents with the different plasma and tissue components, specifically serum albumins, have lately gained considerable attention due to the significant influence of such interactions on the pharmacokinetics and/or -dynamics of this important class of therapeutics. Nazartinib (EGF 816; NAZ) is a new anti-cancer candidate proposed as a third-generation epidermal growth factor receptor tyrosine kinase inhibitor that is being developed and clinically tested for the management of non-small cell lung cancer. The current study aimed to characterize the interaction between NAZ and human serum albumin (HSA) using experimental and theoretical approaches. Experimental results of fluorescence quenching of HSA induced by NAZ revealed the development of a statically formed complex between NAZ and HSA. Interpretation of the observed fluorescence data using Stern-Volmer, Lineweaver-Burk and double-log formulae resulted in binding constants for HSA-NAZ complex in the range of (2.34-2.81) × 104 M-1 over the studied temperatures. These computed values were further used to elucidate thermodynamic attributes of the interaction, which showed that NAZ spontaneously binds to HSA with a postulated electrostatic force-driven interaction. This was further verified by theoretical examination of the NAZ docking on the HSA surface that revealed an HSA-NAZ complex where NAZ is bound to HSA Sudlow site I driven by hydrogen bonding in addition to electrostatic forces in the form of pi-H bond. The HSA binding pocket for NAZ was shown to encompass ARG 257, ARG 222, LYS 199 and GLU 292 with a total binding energy of -25.59 kJ mol-1.

Comparative study of eco-friendly spectrophotometric methods for accurate quantification of Mebendazole and Quinfamide combination; Content uniformity evaluation.

Development and validation of accurate and selective spectrophotometric methods were carried out for determination of a new combination of Mebendazole and Quinfamide in bulk powder and pharmaceutical formulation. Extended ratio subtraction coupled with isoabsorptive point methods were used for determination of the binary mixture. A comparative study was carried out between the newly developed methods; simultaneous ratio subtraction, absorbance subtraction, and dual wavelength spectrophotometric methods were applied as well. The developed methods were validated in accordance with the ICH guidelines. The developed methods were successfully carried out for determination of Quinfamide and Mebendazole in Vermox Plus® tablets. Upon statistical comparison of the results obtained by the developed methods with those obtained by the reported simultaneous equation spectrophotometric method, no significant difference was shown among them. Moreover, the introduced methods have the advantages of being more sensitive and have wider linearity ranges than other reported spectrophotometric methods.

Development and Validation of HPTLC and Green HPLC Methods for Determination of a New Combination of Quinfamide and Mebendazole.

Two selective and sensitive chromatographic methods were developed for simultaneous determination of new combination of quinfamide and mebendazole in bulk powder and in pharmaceutical formulation. The first method is HPTLC by which separation was obtained using silica gel HPTLC F254 plates and a simple mobile phase consisting of methanol:toluene (2:6, v/v) and the separated bands were scanned at 254 nm. The second method RP-HPLC that comprised isocratic separation of both drugs on a Phenomenex C18 column using a green mobile phase consisting of double distilled water:methanol (30:70, v/v) at a flow rate of 0.8 mL/min and UV detection at 254 nm. The developed methods were validated and proved to meet ICH guidelines. Successful application of the developed methods was carried out for determination of quinfamide and mebendazole in Vermox Plus® tablets. Statistical comparison between the developed chromatographic methods and the reported simultaneous equation spectrophotometric method showed that there was no significant difference between them, proving the ability of applying the proposed methods in quality control testing of the studied drugs. The developed methods are considered the first chromatographic methods for simultaneous determination of quinfamide and mebendazole; moreover, they offered sensitive and selective eco-friendly methods for analysis of the studied drugs.

Antiproliferative activity and possible mechanism of action of certain 5-methoxyindole tethered C-5 functionalized isatins.

BACKGROUND: Cancer is one of the most dreaded human diseases, that has become an ever-increasing health problem and is a prime cause of death globally. The potential antiproliferative activity of certain indole-isatin molecular hybrids 5a-w was evaluated in vitro against three human cancer cell lines. METHODS: Standard protocols were adopted to examine the antiproliferative potential and mechanisms of compounds 5a-w. Western blot analysis was carried out on compound 5o. RESULTS: Compounds 5a-w demonstrated in vitro antiproliferative activity in the range of 22.6-97.8%, with compounds 5o and 5w being the most active antiproliferative compounds   with IC50 values of 1.69 and 1.91 µM, which is fivefold and fourfold more potent than sunitinib (IC50=8.11 µM), respectively. Compound 5o was selected for in-depth pharmacological testing to understand its possible mechanism of antiproliferative activity. It caused a lengthening of the G1 phase and a reduction in the S and G2/M phases of the cell cycle and had an IC50 value of 10.4 µM with the resistant NCI-H69AR cancer cell line. Moreover, compound 5o significantly decreased the amount of phosphorylated Rb protein in a dose-dependent fashion, which was confirmed via Western blot analysis. CONCLUSION: The current investigation highlighted the potential antiproliferative activity of compounds 5a-w as well as the antiproliferative profile of compound 5o. These compounds can be harnessed as new lead antiproliferatives in the preclinical studies of cancer chemotherapy.

Novel BTK inhibitor acalabrutinib (ACP-196) tightly binds to site I of the human serum albumin as observed by spectroscopic and computational studies.

Spectrofluorometric, UV-vis spectroscopic and theoretical tools were recruited to comprehend the interaction of acalabrutinib (ACP-196; ACLB) with human serum albumin (HSA). Fluorescence intensity determinations revealed that ACLB statically quenched the HSA-native fluorescence. Analysis of the observed fluorescence data resulting from the ACLB-HSA interaction presented binding constants in the range of 6.65-7.54 × 104 M-1 with the studied temperatures. Those constants showed steady decline with the rising temperatures that further signifies static interaction of the HSA and ACLB. Binding energetics were also interpreted using the fluorescence-recorded results that exhibited a spontaneous exothermic binding reaction with a negative change in Gibbs free energy as well as negative enthalpy and positive entropy changes. Those results suggested the involvement of electrostatic forces as discovered by further computational investigation. Those docking results verified that ACLB binds to domain IIA (site I) of the HSA as demonstrated experimentally by site markers displacement binding studies. Circular dichroism studies along with the synchronous and 3D fluorescence observations showed that ACL binding does not alter the HSA conformation.

HPTLC method for Simultaneous Determination of Norfloxacin and Tinidazole in presence of Tinidazole Impurity.

Sensitive, selective and accurate high-performance thin layer chromatographic HPTLC method for quantitative determination of Norfloxacin (NF), Tinidazole (TZ) and 2-Methyl-5-nitroimidazole (MNZ) as potential impurity of Tinidazole is developed and validated in the presented work. Calibration curves were linear over the concentration ranges of 0.4-2.4, 0.4-1.6, 0.2-1.2 µg/band for NF, TZ and MNZ, respectively. The method depends on separation and quantitation of NF, TZ and MNZ on aluminium plates pre-coated with silica gel HPTLC 60F254 as stationary-phase using chloroform: methanol: formic acid (7.5:1: 0.3, by volume) as developing system followed by densitometric measurement of bands at 298 nm. The developed method was validated and proved to meet the requirements delineated by ICH guidelines with respect to linearity, accuracy, precision, specificity and robustness. The validated method was successfully applied for determination of studied drugs in bulk powders and in their pharmaceutical formulation indicating the ability of proposed method to be used for routine quality control analysis of these drugs.

Chemopreventive effect of sulindac in combination with epigallocatechin gallate or kaempferol against 1,2-dimethyl hydrazine-induced preneoplastic lesions in rats: A Comparative Study.

A systematic investigation of the chemopreventive effect of sulindac (SL) in combination with either epigallocatechin gallate (EGCG) or kaempferol similar (KMP) has been carried out 1,2-dimethyl hydrazine-treated rats (DMH). Those SL combinations with KMP and EGCG have enhanced the SL activity producing greater antioxidant, anti-inflammatory, antiproliferating, and apoptotic activities in both combinations than SL alone. The chemopreventive effects of SL with both EGCG and KMP were demonstrated by a decrease in thiobaribituric acid reactive substances level, tissue nitric oxide (NO), serum, and tissue ß-catenin as well as a reduction in the multiplicity of aberrant crypt foci (ACF) with alleviation in the dysplastic changes that resulted from DMH administration. Down-regulation of proliferating cell nuclear antigen (PCNA) and cyclooxygenase-2 (COX-2) were also confirmed by immunohistochemical staining. The current study paves the way for the use of sulindac combination with kaempferol or EGCG as potential chemopreventive agents against colon cancer with more effect in combination with EGCG.

HPTLC and RP-HPLC methods for simultaneous determination of Paracetamol and Pamabrom in presence of their potential impurities.

Two chromatgraphic methods were developed for determination of Paracetamol (PCM) and Pamabrom (PAM) in presence of P-aminophenol (PAP) and Theophylline (THEO) as potential impurities of both drugs respectively. First method is HPTLC which depends on separation and quantitation of the studied drugs on aluminum plates pre-coated with silica gel 60 F254 as a stationary phase using chloroform:methanol:ethyl acetate:glacial acetic acid (8:0.8:0.6:0.2, v/v/v/v) as mobile phase followed by densitometric measurement of the bands at 254 nm. Second method is RP-HPLC which comprises separation of the studied drugs on a Phenomenex C8 column by gradient elution using mobile phase consisting of sodium dihydrogen phosphate buffer (0.05 M): methanol:acetonitrile (85:10:5, v/v/v) at a flow rate of 1 mL/min for first 7.5 min and (70:20:10, v/v/v) at a flow rate of 1.5 mL/min for the next 5 min. The proposed methods were successfully applied for determination of the potential impurities of PCM and PAM after resolving them from the pure drugs. The developed methods have been validated and proved to meet the requirements delineated by ICH guidelines with respect to linearity, accuracy, precision, specificity and robustness. The validated methods were successfully applied for determination of the studied drugs in their pharmaceutical formulation. The results were statistically compared to those obtained by the reported RP-HPLC method where no significant difference was found; indicating the ability of proposed methods to be used for routine quality control analysis of these drugs.

Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials.

CONTEXT: With few exceptions, the umbilical cord of every newborn is clamped and cut at birth, yet the optimal timing for this intervention remains controversial. OBJECTIVE: To compare the potential benefits and harms of late vs early cord clamping in term infants. DATA SOURCES: Search of 6 electronic databases (on November 15, 2006, starting from the beginning of each): the Cochrane Pregnancy and Childbirth Group trials register, the Cochrane Neonatal Group trials register, the Cochrane library, MEDLINE, EMBASE, and CINHAL; hand search of secondary references in relevant studies; and contact of investigators about relevant published research. STUDY SELECTION: Controlled trials comparing late vs early cord clamping following birth in infants born at 37 or more weeks' gestation. DATA EXTRACTION: Two reviewers independently assessed eligibility and quality of trials and extracted data for outcomes of interest: infant hematologic status; iron status; and risk of adverse events such as jaundice, polycythemia, and respiratory distress. DATA SYNTHESIS: The meta-analysis included 15 controlled trials (1912 newborns). Late cord clamping was delayed for at least 2 minutes (n = 1001 newborns), while early clamping in most trials (n = 911 newborns) was performed immediately after birth. Benefits over ages 2 to 6 months associated with late cord clamping include improved hematologic status measured as hematocrit (weighted mean difference [WMD], 3.70%; 95% confidence interval [CI], 2.00%-5.40%); iron status as measured by ferritin concentration (WMD, 17.89; 95% CI, 16.58-19.21) and stored iron (WMD, 19.90; 95% CI, 7.67-32.13); and a clinically important reduction in the risk of anemia (relative risk (RR), 0.53; 95% CI, 0.40-0.70). Neonates with late clamping were at increased risk of experiencing asymptomatic polycythemia (7 studies [403 neonates]: RR, 3.82; 95% CI, 1.11-13.21; 2 high-quality studies only [281 infants]: RR, 3.91; 95% CI, 1.00-15.36). CONCLUSIONS: Delaying clamping of the umbilical cord in full-term neonates for a minimum of 2 minutes following birth is beneficial to the newborn, extending into infancy. Although there was an increase in polycythemia among infants in whom cord clamping was delayed, this condition appeared to be benign.