Microbiological monitoring of COVID-19 patients in the ICU: a prospective observational study.

Objective. To study spectrum of pathogens and the time to colonization of respiratory samples in patients with severe and critical COVID-19 as well as to analyze incidence of nosocomial infections and structure of prescribed antibacterial drugs. Materials and methods. The prospective observational study included patients aged 18 years and older with confirmed severe and critical COVID-19 from December 2021 to February 2022. During the first 48 hours and then every 2-3 days of hospitalization, a respiratory sample was collected: sputum, tracheal aspirate (if intubated), bronchoalveolar lavage (if bronchoscopy was performed) for microscopy and microbiological examination. Some patients were screened for invasive aspergillosis. Clinical and demographic data, comorbidities, pathogenetic therapy for COVID-19, antibiotic therapy, cases of probable/documented bacterial nosocomial infections, antibiotic-associated diarrhea, and hospital treatment outcomes were recorded. Results. A total of 82 patients were included in this study. Patients with lung parenchyma involvement of more than 50% by computer tomography predominated;most of them (77%) required intubation and mechanical ventilation due to progression of respiratory failure, and 76% of patients had a lethal outcome. During the first 48 hours, a respiratory sample was obtained from 47 patients;the rest of the patients presented with non-productive cough. No growth of microorganisms was detected in 31 (36.8%) cases;clinically significant pathogens were detected in 16 (19.5%) patients. A subsequent analysis included data from 63 patients with a sufficient number of samples for dynamic observation were used. During the first 3 days of ICU stay, the most common bacterial pathogens were Klebsiella pneumoniae without acquired antibiotic resistance and methicillin-susceptible Staphylococcus aureus. From 3rd day and afterwards, an increase in the proportion of Acinetobacter baumannii, other non-fermenting bacteria, and carbapenem-resistant Enterobacterales was noted. Among the pathogens causing lower respiratory tract infections, A. baumannii and carbapenem-resistant K. pneumoniae were predominant pathogens and accounted for 76% of cases. Positive galactomannan test results were obtained in 4 cases. Conclusions. The study confirmed importance of bacterial nosocomial infections in patients with severe and critical COVID-19. In the case of the development of nosocomial lower respiratory tract infections, empirical antimicrobial therapy should take into account the predominance of carbapenem-resistant Enterobacteria and A. baumannii, as well as the possibility of invasive aspergillosis.Copyright © 2022, Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy. All rights reserved.

Medicinal bismuth: Bismuth-organic frameworks as pharmaceutically privileged compounds

Historically organometallic compounds have been used to cure certain diseases with limited applications. Although bismuth belongs to the category of heavy metals, many of its derivatives have found applications in modern drug discovery research, mainly because of its low toxicity and higher bioavailability. Being an eco-friendly mild Lewis acid, compounds having bismuth as a central atom are capable of binding several proteins in humans and other species. Bismuth complexes demonstrated antibacterial potential in syphilis, diarrhea, gastritis, and colitis. Apart from antibacterial activities, bismuth compounds exhibited anticancer, antileishmanial, and some extent of antifungal and other medicinal properties. This article discusses major synthetic methods and pharmacological potentials of bismuth complexes exhibiting in vitro activity to significant clinical performance in a systematic and timely manner.Copyright © 2022 Elsevier Ltd

A new short synthesis route for favipiravir and its analogue: Their tautomerization behaviour

The study of tautomerism in biologically relevant heterocycles is essential, as it directly affects their chemical properties and biological function. Lactam-lactim tautomerization in pyridine/pyrazine derivatives is such a phenomenon. Favipiravir, a pyrazine derivative, is an essential antiviral drug molecule having notable performance against SARS-CoV-2. Along with a better yielding synthetic method for favipiravir, we have also investigated the lactam-lactim tautomerization of favipiravir and its analogous molecules. Most of these molecules were crystalized and studied for various interactions in their lattice. Many interesting supramolecular interactions such as hydrogen bonding, pi-pi stacking and halogen bonding were revealed during the analysis. Some of these structures show interesting F-F halogen bonding and water channels in their solid state.Copyright © 2022 The Royal Society of Chemistry.

Impact Analysis of Aspirin over the Cardiac Activity

Cardiovascular disease (CVD) is the leading cause of death in most developed countries, including the United States, with a significant economic impact. Lifestyle changes and the administration of antiplatelet medication, like aspirin, may significantly contribute to the secondary prevention of CVD in adults. For years, aspirin has been utilized for both secondary and primary cardiovascular disease prevention. Aspirin has been extensively used because of the belief that it may have a positive impact on primary prevention, despite the debate surrounding its usage. This study briefly examines usage patterns and discusses the potential variables and factors that can decrease the ability of aspirin to prevent cardiovascular disease. The present study also explore the key studies of aspirin use in the context of recent recommendations. The risk of bleeding has been observed to significantly rise, although large randomized clinical studies have demonstrated a reduction or absence of CVD events. Prevention strategies for cardiovascular disease with low-dose aspirin are no longer advised for persons at intermediate risk. To determine whether taking aspirin is worth the potential dangers, the benefits must be evaluated.Copyright © 2022 Novyi Russkii Universitet. All rights reserved.

A review on quality control, toxicity and clinical application of Amomum tsao-ko Crevost & Lemarie

The dried fruit of Amomum tsao-ko Crevost & Lemarie, a perennial herb of Cardamom in Zingiberaceae, has been widely used in food and as a folk medicine. It is used not only as an important food additive and spice for removing peculiar smell and improving taste, but also as a traditional Chinese medicine with significant efficacy in treating many kinds of disorders. Based on the high edible and medicinal value, large amounts of investigation have been reported for A. tsaoko in the past several years. This review specifically summarises its quality control, toxicology and clinical application, about which no literature had systematically reviewed, based on our best acknowledge. The current quality control of A. tsaoko is based on the content of volatile oil, which should be no less than 1.4% according to the Pharmacopoeia of the People's Republic of China (2020 edition), while a more possible Q-Markers should be developed to focus on either a specific bioactive ingredient or a component correlated with a certain clinical efficacy. Toxicity research suggests that A. tsaoko actually belongs to the non-toxic substance, although citral and 1,8-cineole, two main components of A. tsaoko, is hepatotoxic for the former and displays low acute toxicity and sub-chronic oral toxicity for the latter, but no obviously accumulative toxicity has so far been discovered for A. tsaoko. In clinical practice, A. tsaoko is often used in treatment of dampness/cold resistance, malaria, vomiting, fullness and epigastric distension across additional disorders, such as SARS, COVID-19 and hepatitis.Copyright © 2022 The Author(s)

Electronic, intermolecular, quantum computational investigations, molecular docking and simulation studies of the potent antiviral drug EIDD-2801

In this work, an analysis has been done to describe the molecular structure, spectroscopic, reduced density gradient, topological properties, atomic charges, Lipinski rule, Natural bond orbital analysis, docking and molecular dynamics simulation of the potent antiviral drug EIDD-2801 in the effective treatment against COVID-19. Intramolecular charge distribution is well understood by three schemes such as AIM, Mulliken and NBO analysis and non-covalent interactions have been understood through reduced density gradient. Topological properties, such as charge density and Laplacian of charge density along with the electron localization function, make it easy to obtain comprehensive information about bond strengths and critical points. The details obtained from the calculation of global reactivity descriptors and Lipinski rule are useful for understanding the nature of molecular reactivity and site selectivity. Electrostatic potentials help to identify potential electrophilic and nucleophilic sites for interaction between EIDD-2801 and target proteins. The molecular docking combined with molecular dynamic simulation studies enables us to get better picture about the ligand-protein interaction.Copyright © 2023 Indian Chemical Society

Vertex metric resolvability of COVID antiviral drug structures

In November of 2019 year, there was the first case of COVID-19 (Coronavirus) recorded, and up to 3rd of April of 2020, 1,116,643 confirmed positive cases, and around 59,158 dying were recorded. Novel antiviral structures of the 2019 pandemic disease Coronavirus are discussed in terms of the metric basis of their molecular graph. These structures are named arbidol, chloroquine, hydroxy-chloroquine, thalidomide, and theaflavin. Metric dimension or metric basis is a concept in which the whole vertex set of a structure is uniquely identified with a chosen subset named as resolving set. Moreover, the fault-tolerant concept of those structures is also included in this study. By this concept of vertex-metric resolvability of COVID antiviral drug structures are uniquely identified and help to study the structural properties of the structure. © 2023 - IOS Press. All rights reserved.

Investigating novel thiazolyl-indazole derivatives as scaffolds for SARS-CoV-2 MPro inhibitors

COVID-19 is a global pandemic caused by infection with the SARS-CoV-2 virus. Remdesivir, a SARS-CoV-2 RNA polymerase inhibitor, is the only drug to have received widespread approval for treatment of COVID-19. The SARS-CoV-2 main protease enzyme (MPro), essential for viral replication and transcription, remains an active target in the search for new treatments. In this study, the ability of novel thiazolyl-indazole derivatives to inhibit MPro is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with (R)-carvone, (R)-pulegone and (R)-menthone thiosemicarbazones. The binding affinity and binding interactions of each compound were evaluated through Schrodinger Glide docking, AMBER molecular dynamics simulations, and MM-GBSA free energy estimation, and these results were compared with similar calculations of MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified MPro tight-binder X77. From these simulations, we can see that binding is driven by residue specific interactions such as pi-stacking with His41, and S/pi interactions with Met49 and Met165. The compounds were also experimentally evaluated in a MPro biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC50 of 92.9 muM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future MPro inhibitors.Copyright © 2022 The Authors

Mechanism-based approaches of 1,3,4 thiadiazole scaffolds as potent enzyme inhibitors for cytotoxicity and antiviral activity

Significant progress in understanding cancer pathogenesis, it remains one of the leading causes of death after cardiovascular diseases. Similarly viral infections have emerged from wildlife or re-emerged, generating serious threats to the global health. As a result, there is an urgent need for the development of novel, more effective anticancer and antiviral therapeutics. Scientists, medicinal chemists and researchers are continuously finding novel targets, mechanisms and molecules against theses severe and dangerous infections. Therefore, ongoing extensively study and research emphasizes 1,3,4 thiadiazole pharmacophore have versatile pharmacological actions. Due to mesoionic behaviour of 1,3,4 thiadiazole pharmacophore allows to enter and easily cross biological membrane which allow to interact various biological proteins. In this review study an attempt has been made of various mechanisms involved in cancer and viral prevalence with updated studies done so far. This review study also findings the role of 1,3,4 thiadiazole motif in the management of various cancers and viral infection. This study also highlighting research statics on clinical trials and various patents containing 1,3,4 thiadiazole derivatives. © 2022 The Author(s)

Highly Efficient Base-Catalyzed Synthesisof Piperidine-4-Imine Lead Molecules for SARS-Cov-2 Mutant Spike Proteasevia in Silico Method

For the discovery of drugs to SARS-CoV-2 pandemics, we have developed a new series of piperidine-4-imines as the central core owing to significant pharmaceuticaldemands on it. The synthesis of piperidine-4-imines involvesatwo-step base-catalyzed reaction, namely (i)condensations followed by cyclization with aromatic aldehyde, aliphatic ketone, and ammonia to yield piperidine-4-ketone core, and (ii) a simple Schiff base/piperidine-4-imines formation between piperidine-4-ketone andvarious aromatic primary amines. All the synthesized intermediate and target piperidine-4-imines molecular structures were well characterized by NMR, FT-IR, and mass spectral studies. Further, the ground state geometry of synthesized molecules was optimized using density function theory (DFT) with basis set of b3lyp 6-31g (d,p) in Gaussian 09 program. Using this molecular geometry, we docked against SARS-CoV-2 mutant spike protease of delta, delta plus, and omicron, which shows an effective binding ability. In addition, Lipinski's rule, pre ADME and toxicity studies also reveal drug-likeness properties. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Role of Hyaluronic acid in various diseases with special emphasis on Periodontal inflammation - A review

Hyaluronic acid is a naturally occurring polysaccharide of extracellular matrix of connective tissues, synovial fluid, and other body tissues. It has an important role in regulating interactions intra and extracellularly between different growth factors, in addition to regulating osmotic pressure, maintaining tissue volume and lubrication. Periodontitis is an multifactorial inflammatory disease that affects teeth supporting structures which results in teeth loss. It is considered a wide world cause of teeth loss in adults. In addition to its local effect, teeth loss, it can have systemic impacts on many systemic organs. Although its main cause is bacteria, exaggerated host response and risk factors such as smoking, diabetes mellitus, HIV/AIDS, family history, and certain medications increase the disease progress. Hence teeth supporting structures are connective tissues and hyaluronic acid is a main component of connective tissues, a correlation of both in health and disease is explained in this article. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Machine Learning and Deep Learning Strategies in Drug Repositioning

Drug repositioning invovles exploring novel usages for existing drugs. It plays an important role in drug discovery, especially in the pre-clinical stages. Compared with the traditional drug discovery approaches, computational approaches can save time and reduce cost significantly. Since drug repositioning relies on existing drug-, disease-, and target-centric data, many machine learning (ML) approaches have been proposed to extract useful information from multiple data resources. Deep learning (DL) is a subset of ML and appears in drug repositioning much later than basic ML. Nevertheless, DL methods have shown great performance in predicting potential drugs in many studies. In this article, we review the commonly used basic ML and DL approaches in drug repositioning. Firstly, the related databases are introduced, while all of them are publicly available for researchers. Two types of preprocessing steps, calculating similarities and constructing networks based on those data, are discussed. Secondly, the basic ML and DL strategies are illustrated separately. Thirdly, we review the latest studies focused on the applications of basic ML and DL in identifying potential drugs through three paths: drug-disease associations, drug-drug interactions, and drug-target interactions. Finally, we discuss the limitations in current studies and suggest several directions of future work to address those limitations.

Partition dimension of COVID antiviral drug structures.

In November 2019, there was the first case of COVID-19 (Coronavirus) recorded, and up to 3$ ^{rd }$ of April 2020, 1,116,643 confirmed positive cases, and around 59,158 dying were recorded. Novel antiviral structures of the SARS-COV-2 virus is discussed in terms of the metric basis of their molecular graph. These structures are named arbidol, chloroquine, hydroxy-chloroquine, thalidomide, and theaflavin. Partition dimension or partition metric basis is a concept in which the whole vertex set of a structure is uniquely identified by developing proper subsets of the entire vertex set and named as partition resolving set. By this concept of vertex-metric resolvability of COVID-19 antiviral drug structures are uniquely identified and helps to study the structural properties of structure.

Challenges and Promises for Obtaining New Antiprotozoal Drugs: What’s Going Wrong?

Infections by protozoa can cause some of the most serious human diseases, particularly in tropical regions. However, the number of available drugs used to treat such diseases tends to be limited with relatively high toxicity, and the vast majority of such drugs were developed in the 1920s to 1970s. The development of antiprotozoal drugs has been hindered owing in part to: (1) the highly complicated life cycles of such organisms and their ability to avoid innate immune defences;(2) challenges associated with culturing such organisms particularly in different phases of their growth and amplification;and (3) a lack of investment in biomedical research aimed at developing treatments for tropical diseases that do not tend to affect more affluent countries. Indeed, only three new drugs have entered into clinical trials in recent times, highlighting the tremendous gap in knowledge that should be bridged to more effectively treat protozoal infections.

LL37 antimicrobial peptide: Structure and function

The human cathelicidin LL-37 plays a major role in the innate immune system for protection against bacterial infections. LL-37 can interact with molecules of the cell wall, perforate cell membranes, and finally lead to bacterial cell death. Moreover, LL-37 participates in immune regulation, chemotaxis of immune cells, and tissue repair. This peptide is produced by white blood cells (mainly neutrophils) and different epithelial cells (in the testicles, epidermis, intestinal system, respiratory system), and may be detected all over the body. LL-37 peptide has dual effects: a) it can increase inflammation and immunological responses and possess anti-infective and anti-cancer properties;b) it can suppress inflammation and enhance carcinogenesis. LL-37 is related to the risk of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis atherosclerosis, and psoriasis. This peptide binds to self-DNA, and acts as an autoantigen. On the other hand, targeting the antiviral and immunomodulatory activities of LL37 peptide can reduce virus transmission and pathogenicity such as human immunodeficiency virus (HIV-1) and the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). This peptide and its variants can directly attach to HIV-1 reverse transcriptase and inhibit its function in a dose-dependent approach. Moreover, in silico studies showed the potency of LL-37 as a therapeutic agent against SARS-CoV-2 infection. It is interesting that vitamin D, a candidate preventive molecule against coronavirus disease 2019 (COVID-19), can upregulate the expression of LL-37. The LL-37 cationic peptide can also penetrate the membrane of eukaryotic cells likely through lipid rafts. Indeed, it can transport the nucleic acid to endosomes, and facilitate oligonucleotide delivery to the cells. Regarding major functions of LL-37 peptide in body, this review will concentrate on its structure and functions as the only cathelicidin-derived defensive peptide identified in human.

Brensocatib: Dipeptidyl peptidase 1 (DPP1) inhibitor Treatment of non-cystic fibrosis bronchiectasis

Neutrophils, which are among the first immune cells to respond to both infection and injury, when activated can release pre-stored serine proteases such as neutrophil elastase, cathepsin G and proteinase 3. An abundant release of these proteolytic enzymes in the alveolar compartment as well as the airways can trigger collateral pulmonary tissue damage. Indeed, much of the tissue destruction that characterizes non-cystic fibrosis bronchiectasis appears to be caused by serine proteases. The transitory pharmacological inhibition of bone marrow dipeptidyl peptidase 1 (DPP1), which converts neutrophil proteolytic enzymes into their mature active form, is a therapeutic possibility to decrease the constitutively produced serine protease pool of neutrophils. Brensocatib (also called INS-1007 or AZD-7986) is a potent reversible DPP1 inhibitor that has been successfully evaluated in a phase II trial as a treatment for non-cystic fibrosis bronchiectasis and, consequently, has been granted breakthrough therapy designation by the U.S. Food and Drug Administration and Priority Medicines (PRIME) designation by the European Medicines Agency.

Antiviral Strategies Using Natural Source-Derived Sulfated Polysaccharides in the Light of the COVID-19 Pandemic and Major Human Pathogenic Viruses.

Only a mere fraction of the huge variety of human pathogenic viruses can be targeted by the currently available spectrum of antiviral drugs. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has highlighted the urgent need for molecules that can be deployed quickly to treat novel, developing or re-emerging viral infections. Sulfated polysaccharides are found on the surfaces of both the susceptible host cells and the majority of human viruses, and thus can play an important role during viral infection. Such polysaccharides widely occurring in natural sources, specifically those converted into sulfated varieties, have already proved to possess a high level and sometimes also broad-spectrum antiviral activity. This antiviral potency can be determined through multifold molecular pathways, which in many cases have low profiles of cytotoxicity. Consequently, several new polysaccharide-derived drugs are currently being investigated in clinical settings. We reviewed the present status of research on sulfated polysaccharide-based antiviral agents, their structural characteristics, structure-activity relationships, and the potential of clinical application. Furthermore, the molecular mechanisms of sulfated polysaccharides involved in viral infection or in antiviral activity, respectively, are discussed, together with a focus on the emerging methodology contributing to polysaccharide-based drug development.