Association between Chronic Misophonia-Induced Stress and Gastrointestinal Pathology in Children-A Hypothesis.

Misophonia is a neurophysiological disorder with behavioral implications, is complex and multifactorial in origin, and is characterized by an atypical and disproportionate emotional response to specific sounds or associated visual stimuli. Triggers include human-generated sounds, mainly sounds related to feeding and breathing processes, and repetitive mechanical sounds. In response to the triggering stimulus, the patient experiences immediate, high-intensity, disproportionate physical and emotional reactions that affect their quality of life and social functioning. The symptoms of misophonia can occur at any age, but onset in childhood or adolescence is most common. Affected children live in a constant state of anxiety, suffer continuous physical and emotional discomfort, and are thus exposed to significant chronic stress. Chronic stress, especially during childhood, has consequences on the main biological systems through the dysregulation of the hypothalamic-pituitary-adrenal axis, including the gastrointestinal tract. Here, we provide arguments for a positive correlation between misophonic pathology and gastrointestinal symptoms, and this hypothesis may be the starting point for further longitudinal studies that could investigate the correlations between these childhood vulnerabilities caused by misophonia and their effect on the gastrointestinal system. Further research to study this hypothesis is essential to ensure correct and timely diagnosis and optimal psychological and pharmacological support.

Qualitative Study on the Factors Influencing the Utilisation of Products Labelled "Food for Special Medicinal Use" (FSMP).

This study aimed to investigate Romanian physicians' awareness, recommendation practices, and opinions regarding the use of Foods for Special Medical Purposes (FSMPs) products. A total of ten physicians were interviewed using a structured questionnaire, and their responses were analysed using thematic content analysis. The study found that physicians were aware of FSMPs and recommended them to their patients based on nutritional deficits, weight loss, or deglutition impairments. In addition, disease stage, treatment scheme, taste, affordability, and availability were identified as factors influencing the recommendation and use of FSMPs. While physicians generally did not consult clinical trials, clinical experience was deemed essential for recommending FSMPs to patients. Patients' feedback regarding the usage and sourcing of FSMPs was generally positive, with some expressing concerns about the availability of different flavours and the costs of purchasing the products. This study concluded that physicians play a vital role in recommending FSMPs to patients and ensuring they have the necessary nutritional support during treatment. However, it may be imperative to consider the provision of additional patient education materials and fostering collaborative efforts with nutritionists in order to optimise the prospects of positive outcomes in oncology treatment, while simultaneously alleviating the financial burdens faced by patients.

Development and Evaluation of Cannabidiol Orodispersible Tablets Using a 23-Factorial Design.

Orodispersible tablets (ODTs) are pharmaceutical formulations used to obtain fast therapeutic effects, usually recommended for geriatric and pediatric patients due to their improved compliance, bioavailability, ease of administration, and good palatability. This study aimed to develop ODTs with cannabidiol (CBD) phytocannabinoid extracted from Cannabis sativa used in the treatment of Lennox-Gastaut and Dravet syndromes. The tablets were obtained using an eccentric tableting machine and 9 mm punches. To develop CBD ODTs, the following parameters were varied: the Poloxamer 407 concentration (0 and 10%), the type of co-processed excipient (Prosolv® ODT G2-PODTG2 and Prosolv® EasyTab sp-PETsp), and the type of superdisintegrant (Croscarmellose-CCS, and Soy Polysaccharides-Emcosoy®-EMCS), resulting in eleven formulations (O1-O11). The following dependent parameters were evaluated: friability, disintegration time, crushing strength, and the CBD dissolution at 1, 3, 5, 10, 15, and 30 min. The dependent parameters were verified according to European Pharmacopoeia (Ph. Eur.) requirements. All the tablets obtained were in accordance with quality requirements in terms of friability (less than 1%), and disintegration time (less than 180 s). The crushing strength was between 19 N and 80 N. Regarding the dissolution test, only four formulations exhibited an amount of CBD released higher than 80% at 30 min. Taking into consideration the results obtained and using the Modde 13.1 software, an optimal formulation was developed (O12), which respected the quality criteria chosen (friability 0.23%, crushing strength of 37 N, a disintegration time of 27 s, and the target amount of CBD released in 30 min of 99.3 ± 6%).

Optimization of Microwave Assisted Extraction Conditions to Improve Phenolic Content and In Vitro Antioxidant and Anti-Microbial Activity in Quercus cerris Bark Extracts.

The species of the Quercus genus, including Quercus cerris L., are widely used and their wood represents a valuable material utilized for various purposes. The intense industrial processing of wood results in a considerable amount of poorly-used natural by-products, such as bark, and a loss of potentially useful raw materials. Thus, the aim of our study was to evaluate the phytochemical characteristics and potential biological activities of Quercus cerris bark extracts obtained by optimizing the parameters of microwave assisted extraction (MAE). The optimum conditions for MAE were determined using a design of experiments (DoE) model, which set the experimental variables (irradiation time and microwave power) and their values. Aqueous and hydroalcoholic extractions were performed and the optimum parameters of extraction were determined for both solvents. The total polyphenolic and tannin contents were determined. The biological activities representative of antioxidant capacity were determined using two free radical scavenging methods, the DPPH and ABTS methods, and the antibacterial activity was assessed with the microdilution method. The results showed different optimal extraction conditions for aqueous (30 min at 850 W) and hydroalcoholic (18 min at 650 W) extracts. A higher yield of total polyphenols was observed in the hydroalcoholic bark extract (403.73 ± 7.35 mg gallic acid equivalents/g dried weight); however a lower level of tannins was registered in comparison to the aqueous extract. In addition, both extracts exerted high antioxidant activities, with the aqueous extracts having a stronger inhibitory effect against the DPPH radical. Moreover, the extracts exhibited antibacterial activity against the tested bacterial strains, especially against the Gram-positive strains and Klebsiella pneumoniae, with the hydroalcoholic extracts being more efficient overall. To conclude, the optimized MAE was an efficient method to extract phytochemical compounds with potential biological effects from Quercus cerris bark.

Pharmacotechnical and analytical preformulation studies for cannabidiol orodispersible tablets.

Obtaining orodispersible tablets (ODT) containing substances from the second Biopharmaceutical Class has raised concerns as the dissolution test is challenging. This study aimed to select suitable excipients for developing orodispersible tablets containing cannabidiol (CBD) by direct compression method. No similar studies were found in the literature. Excipients from different classes were characterized using the SeDeM-ODT tool: fillers - lactose (LCT) and microcrystalline cellulose (CelMC), sweeteners - sorbitol (SRB) and mannitol (MNT), disintegrants - sodium starch glycolate (SSG), sodium croscarmellose (CCS), soy polysaccharides (Emcosoy® - EMCS) and two co-processed excipients (Prosolv®-ODT G2 - PODTG2 and Prosolv® EasyTab sp - PETsp). Drug compatibility with excipients in binary mixtures (1:1) was verified by Differential Scanning Calorimetry (DSC) and Fourier Transform-Infrared (FTIR) spectroscopy. Using the SeDeM-ODT expert system, the fillers and the co-processed excipients showed good properties regarding compressibility and disintegration behavior. Also, the DSC and FTIR results showed that small or no interactions between the CBD and the excipients took place.

Biochemical and Histo-Anatomical Responses of Lavandula angustifolia Mill. to Spruce and Beech Bark Extracts Application.

This paper aims to assess the biological responses of Lavandula angustifolia Mill. to beech and spruce bark crude extract application. Thus, the biological activity of bark extracts was assessed by determining the germination capacity, biomass production, histo-anatomical aspects and photo-assimilatory pigment accumulation, and by quantitative and qualitative volatile compounds analysis. The application of spruce bark extract (500 mg dry bark/100 mL solvent) resulted in a better development of the leaf tissue and an increase in foliar biomass. We observed the stimulating effect of photo-assimilating pigments accumulation, for all experimental variants, compared to the control. Also, the amount of volatile oil was significantly higher in the treated plants with spruce bark extract (500 mg dry bark/100 mL solvent). Some volatile compounds (cyclen, borneol, cryptone, santalen, and caryophyllene oxide ß-farnesene) were identified only in the experimental variants. Also, in the experimental variants, an increase in the quantity of limonene, linalyl acetate and lavandulol was observed. These preliminary results showed that the beech and spruce bark extracts can have biological activities and influence the production of volatile oil in Lavandula angustifolia, causing significant changes in the phytochemical profile of the essential oil. Thus, forest waste bark extracts could be recommended as natural bioregulators in lavender crops.

Enantioseparation of citalopram enantiomers by capillary electrophoresis: Method development through experimental design and computational modeling.

Citalopram (CIT) is a frequently used modern antidepressant that inhibits selectively serotonin reuptake in the brain. It has a chiral center in its structure and is used in therapy as both racemic mixture and pure enantiomer as its pharmacological effect is almost entirely associated with S-CIT. The aim of this study was the development of a simple and rapid capillary electrophoresis (CE) method for the separation and quantification of CIT enantiomers. To establish the optimum chiral selector, several native and derivatized, neutral, and ionized cyclodextrins (CDs) were examined at different pH levels. An experimental design strategy was adopted for method optimization; a fractional factorial design was applied for screening purposes to identify significant experimental factors followed by a face-centered central composite design used for optimization purposes. Computational modeling was used to obtain information on the interaction energy and the geometry of the complexes to aid in the understanding of chiral separation mechanism. The best results were obtained when using a 25-mM phosphate buffer at pH 7.0, 3-mM CM-ß-CD as chiral selector, 17.5°C temperature, 15-kV voltage, and 50 mbar/s hydrodynamic injection. The separation time was fast, below 3 min, and the migration order was S-CIT followed by R-CIT. The analytical performance of the method was verified in terms of precision, linearity, accuracy, sensibility, and robustness, and the method was applied for the determination of CIT enantiomers from pharmaceutical preparations.

Analytical methodologies for the enantiodetermination of citalopram and its metabolites.

Citalopram (CIT) is a highly selective serotonin reuptake inhibitor (SSRI) frequently used in the treatment of major depressive disorders. It has a chiral centre in its structure and is used in therapy both as a racemic mixture (R,S-CIT) and a pure enantiomer (S-CIT). The differences between the pharmacokinetic and pharmacological profiles of the two enantiomers are well established. Consequently, the development of new efficient chiral analysis methods for their enantiomeric separation is a topic of great actuality. CIT metabolism is stereoselective as it is metabolized in chiral active metabolites, which retain considerable SSRI activity and contribute to the pharmacological effect. Chiral analytical methods are employed for the determination of enantiomeric ratio in pharmaceutical preparations and for monitoring the enantiomer levels in biological samples for therapeutic and toxicologic purposes. The current study reviews the published literature for the chiral analysis of CIT and its metabolites based on chromatographic and electrophoretic methods coupled with UV, fluorescence and mass spectrometry detectors.

Biological and Chemical Insights of Beech (Fagus sylvatica L.) Bark: A Source of Bioactive Compounds with Functional Properties.

The present study aimed, on the one hand, to improve the yield of microwave assisted extraction (MAE) of polyphenols from beech bark by using a design of experiments (DoE) approach. On the other hand, beech bark extracts (BBE) were characterized in terms of their phytochemical profile and evaluated for biological potential (antioxidant, antibacterial, antifungal, antimutagen, anti-α-glucosidase, and anti-tyrosinase). The extraction time varies with the amount of extracted total phenolic content (TPC). The microwave power favors TPC extraction but in different proportions. The optimum conditions which gave the highest TPC (76.57 mg GAE/g dry plant material) were reached when the microwave power was 300 W, extraction time was 4 min, and the solvent was an ethanol-water (50:50) mixture. The practical value of TPC after a controlled experiment was 76.49 mg GAE/g plant material. The identified compounds were vanillic acid, gallic acid, epicatechin, catechin, protocatechuic acid, chlorogenic acid, ferulic acid, and isoquercitrin. The antioxidant potential of BBEs was demonstrated by in vitro experiments. The BBEs were active against Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, and Candida species. All extracts were antimutagenic and expressed an inhibition on α-glucosidase and tyrosinase activity. Regarding antimutagen activity, the assayed extracts may be considered to have low or no antimutagen effects.

Determination of iohexol by capillary blood microsampling and UHPLC-MS/MS.

One of the most important tools used to evaluate kidney function in the context of chronic kidney disease or other renal function related pathologies is the exploration of glomerular filtration rate (GFR). Iohexol is up to this moment a good candidate molecule for the GFR assessment since it exhibits minimum protein binding rates and minimum extra-renal clearance, being neither secreted nor reabsorbed at the tubular level. This study proposes and evaluates a new LC-MS/MS method for the iohexol determination from capillary blood, prelevated using volumetric absorbative microsampling (VAMS) systems. As an alternative to VAMS, a brand new HemaPEN® device for micro-prelevation was also tested. A new high throughput sample preparation protocol adapted for iohexol quantification from whole blood VAMS samples was developed. The medium term stability study of iohexol in dried whole blood VAMS samples that was conducted showed a good stability of this molecule for up to 12 days. By collecting only 10 µL of blood, iohexol can be analyzed from dried whole blood VAMS samples for concentration ranges between 1 and 250 µg/mL. Due to the analyte stability in VAMS for up to 12 days, this approach might be successfully applied for GFR assessment for clinical cases allowing minimum invasiveness and even delayed analysis.

A Critical Review of Phenolic Compounds Extracted from the Bark of Woody Vascular Plants and Their Potential Biological Activity.

Polyphenols are one of the largest and most widespread groups of secondary metabolites in the plants world. These compounds are of particular interest due to their occurrence and the properties they possess. The main sources of phenolic compounds are fruits and vegetables, but lately, more and more studies refer to woody vascular plants, especially to bark, as an important source of phenolic compounds with a potential biological effect. This study aims to bring together information on the phenolic compounds present in the bark of woody vascular plants by discussing extraction methods, the chemical composition of the extracts and potential biological effects. The literature data used in this paper were collected via PubMed (2004⁻2019). Search terms were: bark, rhytidome, woody vascular plant, polyphenols, phenolic compounds, biologic activity, antioxidant, immunostimulatory, antimutagenic, antibacterial, anti-inflammatory, and antitumoral. This paper intends to highlight the fact that the polyphenolic extracts obtained from the bark of woody vascular plants represent sources of bioactive compounds with antioxidant, immunostimulatory, antimutagenic, antibacterial properties, etc. Future research directions should be directed towards identification and isolation of bioactive compounds. Consequently, biologically active compounds obtained from the bark of woody plants could be exploited on an industrial scale.

Ultra-high-performance liquid chromatography-mass spectrometry method for neutrophil gelatinase-associated lipocalin as a predictive biomarker in acute kidney injury.

Neutrophil gelatinase associated lipocalin (NGAL) is a protein that was found to be overexpressed in acute kidney injury (AKI). The rise in NGAL concentration, both in urine or plasma, appears earlier than for other classical renal function markers such as serum creatinine, thus making it a suitable marker for early pathology detection. The aim of this study was to develop a method involving tryptic digestion, solid phase extraction and LC-MS/MS analysis to analyze NGAL in plasma medium using an isotope labeled surrogate protein, containing NGAL signature tags, as internal standard (QPrEST). The method was validated for the analysis of NGAL in an analytical range from 50 to 1250 ng/mL using two different proteotypic peptides. The method was further used to quantify the NGAL in human plasma samples for whom elevated NGAL values were expected. NGAL values were between 190.8 and 242.6 ng/mL for control group and between 228.1 and 3526.2 ng/mL for patient group. This study proved that the selection of the right internal standard is of utmost importance in targeted proteomics studies as the digestion steps might cause high variability. This study also confirmed that, although NGAL is highly resistant to proteases such as trypsin, the method could be fully validated according to FDA guidelines and subsequently used to assess NGAL levels in patient plasma with high analytical confidence.

With or Without Internal Standard in HPLC Bioanalysis. A Case Study.

The mandatory strategy of using internal standard in HPLC is still controversial. Despite that the introduction of internal standard methodology in the early stage of development of HPLC technology was used to improve method accuracy and precision, there are still practical situations in which a simple external standard quantification is adequate. The aim of the study is to compare the determination of meloxicam (MXC) in human plasma by HPLC with or without using an internal standard according to some key points related to the reason of introducing the internal standardization such as the reducing of sample preparation errors or variability for low injection volumes. The HPLC analysis was performed on reversed phase with UV detection after protein precipitation. Piroxicam (PXC) was used as an internal standard. The two methods are compared in terms of accuracy and precision over the same concentration range. The stability of the analyte has been proved. According to the results, the quantitative determination of MXC in human plasma after simple protein precipitation by using PXC as an internal standard does not bring any significant improvement of accuracy and precision of the experimental measurements.

Lung injury patterns in newborns, infants and young children - morphological and immunohistochemical approaches.

Lower respiratory infections are an important cause of morbidity and mortality in children, especially in newborns, infants and young children. We conducted a retrospective study and we analyzed the causes of death in newborns, infants and young children, in the necropsy protocols from two Departments of Pathology (Mures County Hospital and Emergency County Hospital of Târgu Mures, Romania), between 2016-2018. We performed descriptive statistics: number of necropsies per year, distribution by gender (male∕female), by place of origin (rural∕urban), by age and leading causes of death in our study. To establish the pattern of lung injuries, we performed a morphological, histopathological and immunohistochemical study [cluster of differentiation (CD) 3, CD14, CD20, CD31, CD34, CD68]. Our study is showing the most frequent and typical aspects of pulmonary pathologies in fetuses, newborns, infants and young children. In this way, we are highlighting the microscopic aspects of the immature lung, amniotic fluid and meconium aspiration, pulmonary distress syndrome in children, pneumonia, bronchopneumonia and vascular pulmonary disease developed in patients with congenital cardiac defects. Most deaths were recorded in the first 30 days or in the first year of life. Primary respiratory diseases were the leading causes of death in these patients. Secondary respiratory diseases were associated with the major causes of death in these patients as an aggravating or precipitating factor.

Determination of iohexol by capillary blood microsampling and UHPLC-MS/MS / 药物分析学报

One of the most important tools used to evaluate kidney function in the context of chronic kidney disease or other renal function related pathologies is the exploration of glomerular filtration rate (GFR). Iohexol is up to this moment a good candidate molecule for the GFR assessment since it exhibits minimum protein binding rates and minimum extra-renal clearance, being neither secreted nor reabsorbed at the tubular level. This study proposes and evaluates a new LC-MS/MS method for the iohexol determination from capillary blood, prelevated using volumetric absorbative microsampling (VAMS) systems. As an alter-native to VAMS, a brand new HemaPEN? device for micro-prelevation was also tested. A new high throughput sample preparation protocol adapted for iohexol quantification from whole blood VAMS samples was developed. The medium term stability study of iohexol in dried whole blood VAMS samples that was conducted showed a good stability of this molecule for up to 12 days. By collecting only 10 mL of blood, iohexol can be analyzed from dried whole blood VAMS samples for concentration ranges between 1 and 250 mg/mL. Due to the analyte stability in VAMS for up to 12 days, this approach might be suc-cessfully applied for GFR assessment for clinical cases allowing minimum invasiveness and even delayed analysis.

Chitosan-Based In Situ Gels for Ocular Delivery of Therapeutics: A State-of-the-Art Review.

Ocular in situ gels are a promising alternative to overcome drawbacks of conventional eye drops because they associate the advantages of solutions such as accuracy and reproducibility of dosing, or ease of administration with prolonged contact time of ointments. Chitosan is a natural polymer suitable for use in ophthalmic formulations due to its biocompatibility, biodegradability, mucoadhesive character, antibacterial and antifungal properties, permeation enhancement and corneal wound healing effects. The combination of chitosan, pH-sensitive polymer, with other stimuli-responsive polymers leads to increased mechanical strength of formulations and an improved therapeutic effect due to prolonged ocular contact time. This review describes in situ gelling systems resulting from the association of chitosan with various stimuli-responsive polymers with emphasis on the mechanism of gel formation and application in ophthalmology. It also comprises the main techniques for evaluation of chitosan in situ gels, along with requirements of safety and ocular tolerability.

Erratum to: Chirality of Modern Antidepressants: An Overview.

[This corrects the article DOI: 10.15171/apb.2017.061.].

Capillary electrophoresis in the enantioseparation of modern antidepressants: An overview.

Chirality is a key subject in modern drug research as well as in the pharmaceutical industry and drug development. Almost all second-generation modern antidepressants are chiral substances; however in therapy some are used as racemic mixtures while others are used as pure enantiomers. The development of enantioseparation methods of chiral antidepressants and their metabolites is one of the keys in understanding their enantioselective drug action. For this purpose, efficient and reliable analytical methods are needed, and capillary electrophoresis has proved to be an interesting and advantageous alternative to the more frequently used chromatographic techniques. In this review electrodriven methods available for the chiral discrimination of selective serotonin reuptake inhibitors (fluoxetine, citalopram, sertraline) and selective serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine) are presented and discussed.

Validated capillary electrophoretic method for the enantiomeric quality control of R-praziquantel.

The enantiomers of praziquantel, the drug of choice in schistosomiasis, were separated by electrokinetic chromatography with cyclodextrins. Nine anionic cyclodextrins were screened for their ability to discriminate between the uncharged enantiomers. Seven investigated selectors presented chiral interactions with the enantiomers, these cases being interpreted in terms of stability constants and complex mobilities. The best results were delivered by sulfated-ß-cyclodextrin, where quasi-equal stability constants were accompanied by extreme selectivity values and was explained on the basis of highly different mobilities of the transient diastereomeric complexes. Since the enantiomer migration order was unfavorable, a simple polarity switch was employed (detection end at anode), which apart from migration order reversal, also resulted in extreme resolution values (Rs > 35) and increased migration times. After optimization (50 mM phosphate buffer pH 2.0, supplied with 15 mM sulfated-ß-cyclodextrin, 15 kV, capillary temperature 25°C, short-end injection with 50 mbar × 2 s), analysis time under 10 min were obtained, while still maintaining high resolution (Rs > 10). The method was validated according to the ICH guidelines and application of the method was tested on in-house synthetized R-praziquantel batches and on commercial, combination tablets containing racemic mixture of the drug.

Chirality of Modern Antidepressants: An Overview.

The majority of modern antidepressants (selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors) have one or two centers of asymmetry in their structure; resulting in the formation of enantiomers which may exhibit different pharmacodynamic and pharmacokinetic properties. Recent developments in drug stereochemistry has led to understanding the role of chirality in modern therapy correlated with increased knowledge regarding the molecular structure of specific drug targets and towards the possible advantages of using pure enantiomers instead of racemic mixtures. The current review deals with chiral antidepressant drugs; presenting examples of stereoselectivity in the pharmacological actions of certain antidepressants and their metabolites and emphasizing the differences between pharmacological actions of the racemates and pure enantiomers.