A Selective Gas Chromatography-Tandem Mass Spectrometry Method for Quantitation of Ethylene and Diethylene Glycol in Paediatric Syrups.

Ethylene Glycol (EG) and diethylene Glycol (DEG) are two contaminants known to cause various human health problems. These glycols might be present in drug syrups that are based on glycerol, sorbitol, or polyethylene glycol. In late 2022, several batches of cough, antipyretics, and antihistamine syrups were reported to contain toxic levels of EG and DEG in multiple countries; this incident concerned the World Health Organization (WHO). From an analytical perspective, several methods of glycols analysis in pharmaceuticals have been reported in the literature, with the majority being dedicated to raw material analysis. This study aims to develop a selective method capable of evaluating a wide range of paediatric syrups in order to assess the safety of commercially available paediatric syrups currently distributed in the local market. This research introduces a method for determining glycols utilizing gas chromatography-tandem mass spectrometry (GC-MS/MS), which offers significantly higher selectivity than conventional single quadrupole gas chromatography-mass spectrometry (GC-MS). The developed method meets the current International Council for Harmonisation (ICH) guidelines for validation. The absence of any interfering peaks in both the unspiked sample of promethazine syrup and the reference standard solutions proved the method's selectivity. Furthermore, 2,2,2-trichloroethanol was used as an internal standard, and a new GC-MS/MS method was developed to analyze it. The calibration curves for EG and DEG were linear within the selected concentration range of 1-10 µg/mL. The detection limit for both EG and DEG was 400 ng/mL, while the quantification limit was 1 µg/mL. Recovery values for both EG and DEG met the accuracy acceptance criterion. Thus, the developed method proved to be efficient and accurate for determining EG and DEG levels in suspected contaminated syrups.

Spinal Cord Termination and Lumbar Puncture Safety in Spinal Deformities.

Background Lumbar puncture, a common diagnostic and therapeutic procedure, is performed regardless of individual spinal alignment variations. However, the impact of kyphosis, scoliosis, and kyphoscoliosis on spinal cord termination level and lumbar puncture safety remains unclear. Objectives This study aimed to determine if the termination level of the spinal cord is different in individuals with spinal deformities and to assess the necessity of routine neuroimaging for safe lumbar puncture localization. Study design and settings This single-center retrospective study was conducted at a university hospital using patients' electronic medical records. The study was focused on patients diagnosed with kyphosis, scoliosis, or kyphoscoliosis using spinal magnetic resonance imaging from January 2010 to December 2022. Participants We evaluated 240 patients: 120 with diagnosed spinal deformities (kyphosis, scoliosis, or kyphoscoliosis) and 120 without deformities, categorized by sex (deformed: 92 females, 28 males; non-deformed: 72 females, 48 males). Patients with spinal trauma, bleeding, or tumors were excluded. Results No statistically significant correlation was found between spinal deformities and spinal cord termination, with L1 remaining the most common endpoint in all groups. Conclusion Routine neuroimaging prior to lumbar puncture in patients with spinal deformities was not associated with a safer procedure due to no observed impact on the termination level of the spinal cord.

Frequency and characteristics of chronic fatigue syndrome in multiple sclerosis patients at a university hospital in Eastern Saudi Arabia.

BACKGROUND: Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease that affects various parts of the central nervous system. Fatigue, a common symptom, transient, prolonged, or chronic experienced by individuals with MS, can significantly impact daily functioning. It can be associated with underlying pathological processes or can have an idiopathic cause, such as chronic fatigue syndrome (CFS). The study aimed to assess the presence and etiology of fatigue in MS patients and its relationship with CFS. MATERIALS AND METHODS: This cross-sectional study was conducted in the Eastern Province of Saudi Arabia. Data were collected using a questionnaire from a sample of 225 MS patients receiving care at our university hospital. The questionnaire included the Centers for Disease Control and Prevention (CDC) criteria for diagnosing CFS and the Expanded Disability Status Scale to evaluate fatigue in MS patients. RESULTS: Of the total of 225 MS patients who participated in this study, 87.1% were diagnosed with relapsing-remitting MS, 6.7% with primary progressive MS, 3.6% with clinically isolated syndrome, and 2.7% with secondary progressive MS. About 53% had experienced fatigue that persisted for over 6 months. Analysis of CFS diagnosis revealed that 7.3% of patients met both CDC criteria and self-reported answers while 17.5% reported having CFS despite not meeting the CDC criteria. These findings highlight a significant lack of agreement between patient-reported diagnoses and established criteria, indicating poor agreement (P = 0.028). CONCLUSION: The study found an association between CFS and MS, and a significant impact on daily functioning. The study revealed lack of agreement between patient-reported diagnoses and established criteria for CFS. This emphasizes the need for a standardized approach to diagnosis and evaluation of fatigue in MS patients.

Spinal cord compression secondary to intraspinal extramedullary hematopoiesis.

Extramedullary hematopoiesis (EMH) is a rare cause of spinal cord compression (SCC) occurring in various hematological illnesses such as myeloproliferative disorders, thalassemias, and various types of anemia. EMH represents the growth of blood cells outside the bone marrow. Common EMH locations include the spleen, liver, lymph nodes, and paravertebral regions. When this occurs in the spinal cord, the mass effect can compress the spinal cord and cause different neurological symptoms depending on the area of the spinal cord affected. This report describes a 27-year-old female with a known case of beta-thalassemia major, who presented with mid-thoracic back pain, weakness, and paresthesia at the T10 level. In addition, this report illustrates the importance of considering EMH in the differential diagnosis of SCC in patients with thalassemia.

Development and validation of a simple method for the determination of triamcinolone acetonide in nasal spray.

A rapid, convenient, and sensitive analytical technique for quantitative analysis of triamcinolone acetonide (TAC) in pharmaceutical nasal spray dosage form using the blue tetrazolium colorimetric reaction and UV spectrophotometric method was developed and validated. Beer's law of the developed method was proven in the concentration range of 10-40 µg/mL and showed a specific linear relationship with coefficient value R2 = 0.998. The LOQ level was 9.99 µg/mL, with (RSD = 0.26%). From precision assay, RSD values have been obtained for the repeatability and intermediate precision, which were found to be (RSD = 1.65%) and (RSD = 2.01%), respectively, indicating that the method is reproducible. Recovery studies showed mean recoveries in the range of (100.08-103.65 %), meeting the acceptance criteria for accuracy. In addition, we compared the results of the developed method UV-Vis spectrophotometric procedure with those of a well-established official USP analytical procedure (HPLC), and the results showed good agreement. The proposed UV method represents a potential alternative to the official USP analytical assay procedure (HPLC) for estimating TAC in nasal spray forms. Furthermore, it has the potential to be implemented in routine use for rapid qualitative and quantitative determinations for TAC.

Correction: Evaluation of the Level of Dural Sac Tip in Saudi Population: A Magnetic Resonance Imaging Study.

[This corrects the article DOI: 10.7759/cureus.32533.].

Estimated prevalence study of attention-deficit/hyperactivity disorder among eastern province children in the Kingdom of Saudi Arabia.

Background: Studying mental disorders in children is significantly important due to the huge suffering of educational and psychosocial impairments in adult life. Attention-deficit/hyperactivity disorder (ADHD) is considered the most common mental disorder in children, especially in early school-aged children. It manifests in about 8%-12% of children in the world. In Saudi Arabia, it affects 4%-12% of children. Objective: The study aimed to count the number of undiagnosed ADHD cases and the associated risk factors in Eastern Province in Kingdom of Saudi Arabia (KSA). Methods: A cross-sectional study was performed among girls' and boys' children aged 6-10 years old in Eastern Province in KSA with a random selection of parents. Sample size is equal to 1658. The assessment was done by an online questionnaire filled it by parents using Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnostic criteria and Connor's scale of ADHD excluding any developmental or mental disorder at the beginning of the questionnaire. Results: After excluding the participants who were diagnosed with behavioral and growth developmental disorder, the remaining 1430 have been screened for ADHD based on Connor's scale. 185 of a child out of 1430 were suggested to have ADHD, of which 10 out of them show the signs of ADHD, 76 of them have moderately severe ADHD, and 99 out of them have atypical or severe ADHD based on Connor's scale of ADHD. The study shows that there is a significant relationship between the positive screening of ADHD and gender males (71.35%), females (28.64%), family history (20.5%), nervous system diseases (4.32%), brain damage from trauma (9.72%), smoking habit of the mother (8.64%), smoking during pregnancy (3.78%), mother exposure to second-hand smoking (42.16%), child exposure to a toxic substance like lead during the early life (1.62%), and the preterm labor (15.13%). However, the study shows there is no significant relationship between the positive screening of ADHD with age, drinking alcohol, and central nervous system infection. Conclusion: The prevalence of undiagnosed ADHD is slightly high. Also, it has many causes of ADHD including gender, smoking, parental psychiatric disorders, and obstetric and pregnancy problems.

Résumé Background: L'étude des troubles mentaux chez les enfants est d'une importance considérable en raison des souffrances liées aux difficultés scolaires et psychosociales qui perdurent à l'âge adulte. Le trouble du déficit de l'attention avec hyperactivité (TDAH) est considéré comme le trouble mental le plus courant chez les enfants, notamment chez les enfants d'âge scolaire précoce. Il se manifeste chez environ 8% à 12% des enfants dans le monde. En Arabie saoudite, il touche entre 4% et 12% des enfants. Objective: L'étude visait à dénombrer le nombre de cas de TDAH non diagnostiqués et les facteurs de risque associés dans la province orientale du Royaume d'Arabie saoudite (KSA). Methods: Une étude transversale a été réalisée auprès d'enfants de filles et de garçons âgés de 6 à 10 ans dans la province orientale de l'Arabie saoudite, en utilisant une sélection aléatoire des parents. La taille de l'échantillon est égale à 1658. L'évaluation a été réalisée à l'aide d'un questionnaire en ligne rempli par les parents, en utilisant les critères diagnostiques du Manuel diagnostique et statistique des troubles mentaux, cinquième édition, ainsi que l'échelle de Connor pour le TDAH, en excluant tout trouble du développement ou trouble mental au début du questionnaire. Résultats: Après exclusion des participants ayant été diagnostiqués avec un trouble du comportement et du développement, les 1430 restants ont été dépistés pour le TDAH à l'aide de l'échelle de Connor. Parmi ces enfants, 185 ont été suggérés d'avoir un TDAH, dont 10 présentent des signes de TDAH, 76 présentent un TDAH modérément sévère et 99 présentent un TDAH atypique ou sévère selon l'échelle de Connor. L'étude révèle qu'il existe une relation significative entre le dépistage positif du TDAH et le genre masculin (71,35 %), féminin (28,64 %), les antécédents familiaux (20,5 %), les maladies du système nerveux (4,32 %), les lésions cérébrales suite à un traumatisme (9,72 %), la consommation de tabac par la mère (8,64 %), la consommation de tabac pendant la grossesse (3,78 %), l'exposition de la mère à la fumée secondaire (42,16 %), l'exposition de l'enfant à une substance toxique comme le plomb pendant la petite enfance (1,62 %) et le travail prématuré (15,13 %). Cependant, l'étude montre qu'il n'existe aucune relation significative entre le dépistage positif du TDAH et l'âge, la consommation d'alcool et les infections du système nerveux central. Conclusion: La prévalence du TDAH non diagnostiqué est légèrement élevée. De plus, il existe de nombreuses causes du TDAH, dont le genre, le tabagisme, les troubles psychiatriques des parents, ainsi que les problèmes obstétriques et durant la grossesse. Mots-clés: Attention, trouble du déficit de l'attention/hyperactivité, Province orientale, hyperactivité, Royaume d'Arabie saoudite.

Unilateral Hypertrophy of Tensor Fascia Lata: A Case Report.

Hypertrophy of the tensor fascia lata muscle is a rare entity that may be observed in patients presenting with a palpable mass in the antero-lateral aspect of the proximal thigh area. Imaging confirms the diagnosis of such a rare entity. This case report highlights a case of isolated hypertrophy of the tensor fascia lata muscle with no identifiable etiology. Biopsy and surgical intervention were not needed due to the interval stability throughout a three-year period. The orthopedic oncology team reassured the patient and followed up the patient annually.

Evaluation of the Level of Dural Sac Tip in Saudi Population: A Magnetic Resonance Imaging Study.

Background For the success of procedures such as caudal block, craniospinal irradiation (CSI), and management of lower back pain and to minimize the risk of dural puncture the exact level of dural sac (DS) termination should be known. Objective The evaluation of DS tip location in the Saudi population and exploring possible significant factors that could be used as predictors in clinical prognosis. Methods A total of 200 patients' lumbar sagittal Weighted T2 Magnetic Resonance Imaging (MRI) study were randomly selected from a single-center hospital in-between 2020 and 2021. The DS tip location was determined by generating a perpendicular line from the longitudinal axis of its termination to the corresponding level. Then naming it after an intervertebral disk or a corresponding vertebrate that is divided into three thirds (upper, middle, and lower). Results In most cases, the level of DS termination is at the middle part of S2 (26.5%), followed by the upper part of S2 (25.1%), and the lower part of S2 (20%). In Saudi nationals, the DS tip was in the middle S2 level at 21.5%, upper S2 level at 19.1%, and lower S2 level at 17%. Factors such as age, sex, cause of referral, and nationality had no statistical significance in relation to DS tip location. Conclusion The DS termination level in the Saudi population ranges from disk between L5-S1 to the lower third of S3. Moreover, nationality, age, and cause of referral were not significant in determining the DS termination level. Therefore, it is still important to individualize patients' treatment by using MRI for each case that requires it.

Assessment of disinfectant efficacy in reducing microbial growth.

The incidence of hospital- and community-acquired infections has been dramatically increased worldwide. Accordingly, hands hygiene and the use of disinfectants have been increased leading to the expansion in hand sanitizers production to meet public demand. This study was conducted to assess the efficiency of common disinfectants in the market of Riyadh, Saudi Arabia in inhibiting the microbial growth during the time of Coronavirus disease 2019 (COVID-19) pandemic. Five bacterial strains of commonly hospital-acquired infections (Pseudomonas aeruginosa, Escherichia coli, Salmonella enteritidis, Staphylococcus aureus, and Enterococcus faecalis) (ATCC reference strains and clinical isolates) were examined for their susceptibility against 18 disinfectants collected from the Saudi market. The tested 18 disinfectants were broadly clustered into different groups based on their active chemical composition as following: 12 products contained alcohol, 2 products had chlorhexidine, 3 products contained mixed concentration of alcohol/chlorhexidine and 1 product had a mixture of chlorhexidine/Hexamidine/Chlorocresol. By measuring the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC), our results revealed that all the 18 disinfectants have reduced the microbial growth of all the tested strains. Generally, the MICs and the MBCs for the clinical strains are higher than those of the reference strains. Taken together, our findings showed that all tested products have high disinfectants' killing rate against microbes of different origins, which suggest the high quality of these disinfectants and the good surveillance practice by the local authorities in Saudi Arabia.

The occurrence and dietary intake related to the presence of microplastics in drinking water in Saudi Arabia.

The implications and health effects of microplastics (MPs) ingestion are still unclear, yet researchers and organizations around the world are increasingly examining the levels of microplastics and nanoplastics in the environment. This study investigated the presence and the quantity of microplastics in bottled and tap water from five regions in Saudi Arabia and estimated the dietary intake of microplastics. Thirty samples of drinking water were collected from the retail markets in Saudi Arabia. The samples included plastic bottled drinking water, 2 glass bottles, and 2 samples of tap water to represent ground water and desalinated seawater. Sample preparation in the laboratory involved a vacuum-assisted filtration with an inorganic filter membrane (0.2-µm pore size). Identification and classification of microplastics particles using Fourier-transform infrared microspectroscopy (FTIR microspectroscopy). The particle size range screened for in this study was 25-500 µm. Microplastics were identified in 17 out of 30 samples. The average of the detected microplastic particles was 1.9 pcs/L (lower bound estimate, LB) and 4.7 pcs/L (upper bound estimate, UB), respectively. The most frequently identified plastic type was polyethylene (PE), followed by polystyrene (PS), and polyethylene terephthalate (PET). Given an average recommended water intake of 3.7 and 2.7 L per day for men and women, respectively, the corresponding daily exposure to microplastics would result in 0.1-0.2 pcs/kg bw. The estimate for high water consumers increases to a daily exposure of 1.7-1.9 pcs/kg bw based on the recommended intake for water in hot weather by the WHO. From these results, we conclude that the level of dietary intake of microplastics from drinking water in Saudi Arabia is low, and according to current state of knowledge, microplastics from drinking water do not pose any concern to the consumers in Saudi Arabia.

N-nitrosodimethylamine (NDMA) contamination of ranitidine products: A review of recent findings.

Ranitidine is a medication that has been used to alleviate heartburn and other disorders for over 40 years. Following reports of N-nitrosodimethylamine (NDMA) contamination in ranitidine products, there have been many recalls and registration suspensions. Here, we revise the literature information confirming ranitidine association with NDMA. Then, we highlight the documented mechanisms for NDMA release from ranitidine. In addition, the stability issue for this medicine is discussed. After that, we review and discuss the results of the United States Food and Drug Administration and the Australian Therapeutic Goods Administration laboratory testing of ranitidine products and the detected NDMA levels. Finally, the case of NDMA generation in Angiotensin II Receptor Blockers (ARBs) and ranitidine were compared in an attempt to address the circumstances leading to the current contamination.

HS-SPME-GC-MS as an alternative method for NDMA analysis in ranitidine products.

N-nitrosodimethylamine (NDMA) is a carcinogenic contaminant that was accidentally discovered in drugs, such as valsartan and ranitidine, and more recently in metformin. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is the method typically used for the analysis of NDMA in ranitidine. It seems that using gas chromatography (GC) for NDMA analysis is problematic as ranitidine is sensitive to high temperatures. In the present study, we assessed the usefulness of solid-phase microextraction (SPME) as a method of extraction and introduction into the GC. When using headspace (HS) and liquid injection modes in GC for NDMA analysis in ranitidine, higher NDMA levels were detected compared to using LC-MS/MS. Interestingly, using HS-SPME-GC-MS was advantageous because we could avoid the high temperature utilized in the liquid injection and HS modes. Moreover, the results obtained using HS-SPME-GC-MS provided a good match with those achieved using LC-MS/MS. The feasibility of using HS-SPME-GC-MS to successfully analyze NDMA in ranitidine opens new opportunities for the analysis of this contaminant in pharmaceuticals, specifically those that are heat-labile.

Resveratrol and Resveratrol-Aspirin Hybrid Compounds as Potent Intestinal Anti-Inflammatory and Anti-Tumor Drugs.

Resveratrol (3,4,5-Trihydroxy-trans-stilbene) is a naturally occurring polyphenol that exhibits beneficial pleiotropic health effects. It is one of the most promising natural molecules in the prevention and treatment of chronic diseases and autoimmune disorders. One of the key limitations in the clinical use of resveratrol is its extensive metabolic processing to its glucuronides and sulfates. It has been estimated that around 75% of this polyphenol is excreted via feces and urine. To possibly alleviate the extensive metabolic processing and improve bioavailability, we have added segments of acetylsalicylic acid to resveratrol in an attempt to maintain the functional properties of both. We initially characterized resveratrol-aspirin derivatives as products that can inhibit cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) activity, DNA methyltransferase (DNMT) activity, and cyclooxygenase (COX) activity. In this study, we provide a detailed analysis of how resveratrol and its aspirin derivatives can inhibit nuclear factor kappa B (NFκB) activation, cytokine production, the growth rate of cancer cells, and in vivo alleviate intestinal inflammation and tumor growth. We identified resveratrol derivatives C3 and C11 as closely preserving resveratrol bioactivities of growth inhibition of cancer cells, inhibition of NFκB activation, activation of sirtuin, and 5' adenosine monophosphate-activated protein kinase (AMPK) activity. We speculate that the aspirin derivatives of resveratrol would be more metabolically stable, resulting in increased efficacy for treating immune disorders and as an anti-cancer agent.

Probiotics and Their Quality-Related Concerns: Highlights From the Saudi Arabian Market.

BACKGROUND: Probiotics are pharmaceutical products that contain living bacteria and are used to manage certain disorders, as well as to enhance general health. There are some reports criticizing the quality of these products, highlighting findings such as pathogen contamination and misleading labeling. Regulation and control of probiotics vary between international regulatory authorities, creating a gap between probiotic manufacturers and regulatory bodies. METHODS: In this article, the probiotics available in Saudi Arabia were analyzed in regard to their presented method of identification and labeling information. RESULTS: Only 1 of 22 products had confirmed the bacterial strain using a genotypic method; the rest presented various phenotypic methods. More than half of the reviewed products did not contain the strain designation on the outside labeling of the probiotic. CONCLUSION: The Saudi Food and Drug Authority should act by adopting a new guideline to control and regulate probiotics in Saudi Arabia, which could then be expanded to cover gulf countries (GCC).

Synthesis and Biological Evaluation of New Tyrosol-Salicylate Derivatives as Potential Anti-Inflammatory Agents.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly used medications in inflammatory illnesses. However, the gastrointestinal bleeding and toxicity associated with NSAIDs long term use prompted the quest towards investigations for new anti-inflammatory agents. Natural and natural-derived molecules proved its anti-inflammatory efficacy in vitro as well as in vivo. Given this background, the scope of this research involves structural changes of the natural polyphenol (tyrosol) generating two new salicylate derivatives and testing their biological properties, focusing on anti-inflammatory effects assessed in vitro and in vivo assays. The first molecular modification was the introduction of a carboxylic acid group adjacent to the phenol group present in this compound, which creates a new salicylate-like tyrosol. In addition, the acetylation of phenol group in this molecule produced an acetylsalicylate derivative, which may be regarded as aspirin-like natural polyphenol. Interestingly, tyrosol and its novel derivatives attenuated the edema in acute inflammatory response on carrageenan- induced local inflammation in mice. In addition, our results demonstrated that tyrosol and its novel derivatives were able to reduce the chemotaxis of neutrophil assessed in vitro model by chemo attractant (fMLP). Furthermore, only derivative 2 was able to reduce this effect in the acute inflammatory model. In (DPPH)- scavenging activity, tyrosol derivatives demonstrated a minor antioxidant activity, which may suggest that radical scavenging is not a major pathway involved in the anti-inflammatory effects of these derivatives. Salicylate-like tyrosol derivatives are of particular interest for future studies.

Anti-inflammatory and antioxidant properties of a novel resveratrol-salicylate hybrid analog.

Resveratrol is a natural compound with a plethora of activities as well as limitations. We recently reported a series of resveratrol-salicylate analogs with potential chemopreventive activity. Herein, we report the anti-inflammatory and antioxidant properties of these resveratrol derivatives. Using an in vitro COX inhibition assay, and two in vivo protocols (carrageenan-induced peritonitis and paw edema), we identified a novel compound (C10) as a potent anti-inflammatory agent. The enhanced potency of C10 was associated with the ability of C10 to decrease the activity of myeloperoxidase (MPO) enzyme at 10mg/kg, whereas resveratrol and it's natural analog (TMS) did not exert the same effect. Additionally, C10 significantly reduced the concentration of intracellular reactive oxygen species. Because of the proven association between cancer, inflammation, and oxidative stress, we believe that C10 is a promising chemopreventive molecule.

Synthesis, Molecular Structure Optimization, and Cytotoxicity Assay of a Novel 2-Acetyl-3-amino-5-[(2-oxopropyl)sulfanyl]-4-cyanothiophene.

A novel thiophene-containing compound, 2-acetyl-3-amino-5-[(2-oxopropyl)sulfanyl]-4-cyanothiophene (4) was synthesized by reaction of malononitrile with CS2 in the presence of K2CO3 under reflux in DMF and the subsequent reaction with chloroacetone followed by cyclization. This compound has been characterized by means of FT-IR, ¹H-NMR, (13)C-NMR, and mass spectrometry as well as elemental analysis. In addition, the molecular structures of compound 4 was determined by X-ray crystallography. The geometry of the molecule is stabilized by an intramolecular interaction between N1-H1···O1 to form S6 graf set ring motif. In the crystal, molecules are linked via N1-H2···O1 and C7-H7A···N2 interactions to form a three-dimensional network. Molecular structure and other spectroscopic properties of compound 4 were calculated using DFT B3LYP/6-31G (d,p) method. Results revealed a good agreement between the optimized geometric parameters and the observed X-ray structure. Furthermore, and by employing the natural bond orbital (NBO) method, the intramolecular charge transfer (ICT) interactions along with natural atomic charges at different sites, were calculated; results indicated strong n→π* ICT from LP(1)N5→BD*(2)C15-C16 (63.23 kcal/mol). In addition, the stabilization energy E(2) of the LP(2)O3→ BD*(1)N5-H6 ICT (6.63 kcal/mol) indicated the presence of intramolecular N-H···OH bonding. Similarly, calculations of the electronic spectra of compound 4 using, TD-DFT revealed a good agreement with the experimental data. Finally, compound 4 was evaluated for its in vitro cytotoxic effect against PC-3 and HeLa cell lines, as an anticancer agent, and found to be nontoxic.

Resveratrol-salicylate derivatives as selective DNMT3 inhibitors and anticancer agents.

Resveratrol is a natural polyphenol with plethora of biological activities. Resveratrol has previously shown to decrease DNA-methyltransferase (DNMT) enzymes expression and to reactivate silenced tumor suppressor genes. Currently, it seems that no resveratrol analogs have been developed as DNMT inhibitors. Recently, we reported the synthesis of resveratrol-salicylate derivatives and by examining the chemical structure of these analogs, we proposed that these compounds could exhibit DNMT inhibition especially that they resembled NSC 14778, a compound we previously identified as a DNMT inhibitor by virtual screening. Indeed, using in vitro DNMT inhibition assay, some of the resveratrol-salicylate analogs we screened in this work that showed selective inhibition against DNMT3 enzymes which were greater than resveratrol. A molecular docking study revealed key binding interactions with DNMT3A and DNMT3B enzymes. In addition, the most active analog, 10 showed considerable cytotoxicity against three human cancer cells; HT-29, HepG2 and SK-BR-3, which was greater than resveratrol. Further studies are needed to understand the anticancer mechanisms of these derivatives.

NSAIDs do not require the presence of a carboxylic acid to exert their anti-inflammatory effect - why do we keep using it?

The carboxylic acid group (-COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.