Nintedanib: a review of the properties, function, and usefulness to minimize COVID-19-induced lung injury.

INTRODUCTION: In severe COVID-19 patients, acute respiratory distress syndrome (ARDS)-induced lung injury regularly causes a pulmonary fibrotic phase. There is no approved therapy for the COVID-19-induced pulmonary fibrosis. However, administration of an anti-fibrotic agent, in the early acute phase of the severe COVID-19 with ARDS, may improve the infection outcomes. AREAS COVERED: In this review, the main characteristics of nintedanib and its usefulness to treat COVID-19-induced fibrosis were studied. In July 2022, a literature search was performed from PubMed, Google Scholar, and the WHO databases for studies focusing on the properties, function, efficacy, and safety of nintedanib against different lung injuries. EXPERT OPINION: Nintedanib interferes with lung fibrosis and tumor angiogenesis by targeting multiple receptor tyrosine kinases (RTKs). Loss of RTKs activity leads to blocking downstream signaling cascades and inhibiting the proliferation and migration of lung fibroblasts. Targeting RTKs may be useful in the treatment of COVID-19 lung fibrosis. Nintedanib may be a superior agent compared to pirfenidone for the treatment of COVID-19 ARDS-related pulmonary fibrosis. Investigation of the efficacy and safety of nintedanib in the early stages of COVID-19-induced ARDS is critical since it may decrease the oxygen dependency and degree of lung fibrosis after the hospital discharge.

A narrative review on tofacitinib: The properties, function, and usefulness to treat coronavirus disease 2019.

In coronavirus disease 2019 (COVID-19), the formation of cytokine storm may have a role in worsening of the disease. By attaching the cytokines like interleukin-6 to the cytokine receptors on a cell surface, Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway will be activated in the cytoplasm lead to hyperinflammatory conditions and acute respiratory distress syndrome. Inhibition of JAK/STAT pathway may be useful to prevent the formation of cytokine storm. Tofacitinib is a pan inhibitor of JAKs. In this review, the main characteristics of tofacitinib and its usefulness against COVID-19 pneumonia were reviewed. Tofacitinib may be a hopeful therapeutic candidate against COVID-19 respiratory injury since it inhibits a range of inflammatory pathways. Hence, the agent may be considered a potential therapeutic against the post-COVID-19 respiratory damage. Compared to other JAK inhibitors (JAKi), the administration of tofacitinib in COVID-19 patients may be safer and more effective. Other JAKi such as baricitinib are related to severe adverse events such as thrombotic events compared to more common side effects of tofacitinib.

A review on favipiravir: the properties, function, and usefulness to treat COVID-19.

INTRODUCTION: At this time, there is no specific therapeutic or vaccine for treatment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Hence, available drugs for treatment of other viral infections may be useful to treat COVID-19. AREAS COVERED: The focus of the current review was studying the main characteristics of favipiravir and its usefulness to treat COVID-19. An electronic search was done by using Pubmed and Google scholar. EXPERT OPINION: Based on the mechanism of action and safety of favipiravir, the drug may be a promising candidate for compassionate use against the SARS-CoV-2 infection. Favipiravir has a wide range of activity against many single-stranded RNA viruses, is well tolerated in humans and has a high barrier to resistance. However, high doses of the agent are necessary to obtain an efficient antiviral activity. Favipiravir is teratogen in pregnant women and associated with the hyperuricemia. Therefore, the administration of the drug should be well controlled. Investigating the antiviral prophylactic potency of favipiravir and search for its pro-drugs and/or analogs showing improved activity and/or safety are critical.

A Review on Remdesivir: A Possible Promising Agent for the Treatment of COVID-19.

The novel coronavirus 2019 (2019-nCoV), formally named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a novel human infectious coronavirus. The disease caused by SARS-CoV-2 is named COVID-19. Development and manufacturing of specific therapeutics and vaccines to treat COVID-19 are time-consuming processes. At this time, using available conventional therapeutics along with other treatment options may be useful to fight COVID-19. In different clinical trials, efficacy of remdesivir (GS-5734) against Ebola virus has been demonstrated. Moreover, remdesivir may be an effective therapy in vitro and in animal models infected by SARS and MERS coronaviruses. Hence, the drug may be theoretically effective against SARS-CoV-2. Remdesivir is a phosphoramidate prodrug of an adenosine C-nucleoside. By entrance into respiratory epithelial cells in human, the prodrug is metabolized to a nucleoside triphosphate as the active form. The nucleoside analog inhibits the viral RNA-dependent RNA polymerase (RdRp) by competing with the usual counterpart adenosine triphosphate (ATP). The nucleoside analog is incorporated into the generating RNA strand and causes a delayed stop in the viral replication process. Knowledge about the potential efficacy of remdesivir against coronaviruses has been restricted to in vitro studies and animal models. However, information related to COVID-19 is rapidly growing. Several clinical trials are ongoing for the management of COVID-19 using remdesivir. In this study, characteristics of remdesivir and its usage for treatment of COVID-19 are reviewed based on an electronic search using PubMed and Google Scholar.

Caspofungin: a review of its characteristics, activity, and use in intensive care units.

INTRODUCTION: Candidemia is the fourth frequent reason of healthcare-related bloodstream infections in critically ill patients. For initial management of (suspected) invasive candidiasis in critically ill patients, usage of an echinocandin, e.g. caspofungin, has been recommended. AREAS COVERED: In this study, characteristics of caspofungin and its use in intensive care unit (ICU) patients are reviewed based on an electronic search using PubMed and Google scholar. EXPERT OPINION: Caspofungin is a semisynthetic derivative from pneumocandin B and the first member of the echinocandins that was approved by the U.S. Food and Drug Administration (FDA) to fight fungal infection. Caspofungin inhibits the enzyme ß(1,3)-D-glucan synthase of the fungal cell wall resulted in inhibition of the synthesis of ß(1,3)-D-glucan. For critically ill patients, inter- and intraindividual variations affect the caspofungin concentration. The incidence rates and densities of candidemia in surgical ICUs may be higher than medical ICUs resulting in a higher burden of candidemia in surgical ICUs. However, the mortality rate in surgical ICU patients with candidemia is higher than that medical ICU patients due to differences in their underlying conditions.

Virtual screening for potential inhibitors of ß(1,3)-D-glucan synthase as drug candidates against fungal cell wall.

Background: To enhance the outcome in patients with invasive candidiasis, initiation of an efficient antifungal treatment in a suitable dosage is necessary. Echinocandins (e.g. caspofungin) inhibit the enzyme ß(1,3)-D-glucan synthase of the fungal cell wall. Compared to azoles and other antifungal agents, echinocandins have lower adverse effects and toxicity in humans. Echinocandins are available in injectable (intravenous) form. Methods: In this study, to identify the novel oral drug-like compounds that affect the fungal cell wall, downloaded oral drug-like compounds from the ZINC database were processed with a virtual screening procedure. The docking free energies were calculated and compared with the known inhibitor caspofungin. Four molecules were selected as the most potent ligands and subjected to hydrogen bonds analysis. Results: Considering the hydrogen bond analysis, two compounds (ZINC71336662 and ZINC40910772) were predicted to better interact with the active site of ß(1,3)-D-glucan synthase compared with caspofungin. Conclusion: The introduced compound in this study may be valuable to analyze experimentally as a novel oral drug candidate targeting fungal cell walls.

A review on modafinil: the characteristics, function, and use in critical care.

In critically ill patients, sleep is generally interrupted. Some factors that lead to such sleep interruption include the intensive care unit (ICU) circumstance, primary medical disease itself, mental stress, and impacts of many drugs and other managements utilized to treat ICU patients. Another illness that may cause profound daytime somnolence is narcolepsy. Modafinil, methylphenidate and amphetamines are used as stimulants to treat symptoms, such as extreme daytime sleepiness, cataplexy and nocturnal sleep disruption. Such stimulants can increase awareness, improve perception and thinking, as well as assist in keeping people awake. The exact mechanism of action of modafinil is unclear. In vitro studies have demonstrated that binding of modafinil to the dopamine reuptake pump can prevent the reuptake of dopamine, resulting in a boost in extracellular dopamine. Modafinil is a racemic compound containing l and d isomers. Peak plasma concentrations of the drug occur at 2-4 h after administration; therefore, the absorption of modafinil is considered fast. Modafinil is properly distributed in tissues by binding to plasma proteins moderately. Despite the likely role of modafinil in improving cognition and arousal in critically ill patients, the available data on the use of modafinil in the ICU setting is limited. The aim of the study was to review the novel usage of modafinil for alleviation of fatigue, excessive daytime somnolence (EDS), and/or depression in critically ill patients.

Fosfomycin: the characteristics, activity, and use in critical care.

Fosfomycin (C3H7O4P) is a phosphonic acid derivative representing an epoxide class of antibiotics. The drug is a re-emerging bactericidal antibiotic with a wide range of actions against several Gram-positive and Gram-negative bacteria. Among the existing antibacterial agents, fosfomycin has the lowest molecular weight (138 Da), which is not structurally associated with other classes of antibiotics. In intensive care unit (ICU) patients, severe soft tissue infections (STIs) may lead to serious life-threatening problems, and therefore, appropriate antibiotic therapy and often intensive care management (ICM) coupled with surgical intervention are necessary. Fosfomycin is an antibiotic primarily utilized for the treatment of STIs in ICUs. Recently, fosfomycin has attracted renewed interest for the treatment of serious systemic infections caused by multidrug-resistant Enterobacteriaceae. In some countries, intravenous fosfomycin has been prescribed for various serious systemic infections, such as acute osteomyelitis, nosocomial lower respiratory tract infections, complicated urinary tract infections, bacterial meningitis, and bacteremia. Administration of intravenous fosfomycin can result in a sufficient concentration of the drug at different body regions. Dose modification is not required in hepatic deficiency because fosfomycin is not subjected to enterohepatic circulation.

Linezolid: a review of its properties, function, and use in critical care.

Linezolid can be considered as the first member of the class of oxazolidinone antibiotics. The compound is a synthetic antibiotic that inhibits bacterial protein synthesis through binding to rRNA. It also inhibits the creation of the initiation complex during protein synthesis which can reduce the length of the developed peptide chains, and decrease the rate of reaction of translation elongation. Linezolid has been approved for the treatment of infections caused by vancomycin-resistant Enterococcus faecium, hospital-acquired pneumonia caused by Staphylococcus aureus, complicated skin and skin structure infections (SSSIs), uncomplicated SSSIs caused by methicillin-susceptible S. aureus or Streptococcus pyogenes, and community-acquired pneumonia caused by Streptococcus pneumoniae. Analysis of high-resolution structures of linezolid has demonstrated that it binds a deep cleft of the 50S ribosomal subunit that is surrounded by 23S rRNA nucleotides. Mutation of 23S rRNA was shown to be a linezolid resistance mechanism. Besides, mutations in specific regions of ribosomal proteins uL3 and uL4 are increasingly associated with linezolid resistance. However, these proteins are located further away from the bound drug. The methicillin-resistant S. aureus and vancomycin-resistant enterococci are considered the most common Gram-positive bacteria found in intensive care units (ICUs), and linezolid, as an antimicrobial drug, is commonly utilized to treat infected ICU patients. The drug has favorable in vitro and in vivo activity against the mentioned organisms and is considered as a useful antibiotic to treat infections in the ICU.

Computer-aided design of amino acid-based therapeutics: a review.

During the last two decades, the pharmaceutical industry has progressed from detecting small molecules to designing biologic-based therapeutics. Amino acid-based drugs are a group of biologic-based therapeutics that can effectively combat the diseases caused by drug resistance or molecular deficiency. Computational techniques play a key role to design and develop the amino acid-based therapeutics such as proteins, peptides and peptidomimetics. In this study, it was attempted to discuss the various elements for computational design of amino acid-based therapeutics. Protein design seeks to identify the properties of amino acid sequences that fold to predetermined structures with desirable structural and functional characteristics. Peptide drugs occupy a middle space between proteins and small molecules and it is hoped that they can target "undruggable" intracellular protein-protein interactions. Peptidomimetics, the compounds that mimic the biologic characteristics of peptides, present refined pharmacokinetic properties compared to the original peptides. Here, the elaborated techniques that are developed to characterize the amino acid sequences consistent with a specific structure and allow protein design are discussed. Moreover, the key principles and recent advances in currently introduced computational techniques for rational peptide design are spotlighted. The most advanced computational techniques developed to design novel peptidomimetics are also summarized.

Virtual Screening for Potential Inhibitors of CTX-M-15 Protein of Klebsiella pneumoniae.

The Gram-negative bacterium Klebsiella pneumoniae, responsible for a wide variety of nosocomial infections in immuno-deficient patients, involves the respiratory, urinary and gastrointestinal tract infections and septicemia. Extended spectrum ß-lactamases (ESBL) belong to ß-lactamases capable of conferring antibiotic resistance in Gram-negative bacteria. CTX-M-15, a prevalent ESBL reported from Enterobacteriaceae including K. pneumoniae, was selected as a potent anti-bacterial target. To identify the novel drug-like compounds, structure-based screening procedure was employed against downloaded drug-like compounds from ZINC database. An acronym for "ZINC" is not commercial. The docking free energy values were investigated and compared to the known inhibitor Avibactam. Six best novel drug-like compounds were selected and their hydrogen bindings with the receptor were determined. Based on the binding efficiency mode, three among these six identified most potential inhibitors, ZINC21811621, ZINC93091917 and ZINC19488569, were predicted as potential competitive inhibitors against CTX-M-15 compared to Avibactam. These three inhibitors may provide a framework for the experimental studies to develop anti-Klebsiella novel drug candidates targeting CTX-M-15.

In silico phylogenetic analysis of Vibrio cholerae isolates based on three housekeeping genes.

Vibrio cholera, a gram-negative bacterium, has been categorised into clinical and environmental species. Phylogenetic studies have been performed to investigate the relationships of the V. cholerae populations in worldwide. In this study, phylogenetic relationship between V. cholerae isolates from Iran and other regions of the world was determined, based on three housekeeping genes analysis. Results for Iranian strains showed that congruency of asd and hlyA phylogenetic trees were remarkably higher than recA tree. Iranian strains displayed 2-3%, 1-14% and 3-5% deference in asd, hlyA and recA nucleotide sequences, respectively. Sequence similarity degrees were variable between Iranian and other region's strains. Furthermore, the non-congruence in the phylogeny of the pathogenic clones in cladograms is probably due to horizontal gene transfer. Finally, results of this study suggest that monitoring of surface waters for housekeeping genes of V. cholerae in the cholera endemic areas may be valuable for forecasting the expected cholera outbreaks.