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COVID-19 Therapeutics: Use, Mechanism of Action, and Toxicity (Xenobiotics).
Chary, MA, Barbuto, AF, Izadmehr, S, Tarsillo, M, Fleischer, E, Burns, MM
Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2023;(1):26-36
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Abstract
SARS-CoV-2 emerged in 2019 and led to the COVID-19 pandemic. Efforts to develop therapeutics against SARS-Cov-2 led to both new treatments and attempts to repurpose existing medications. Here, we provide a narrative review of the xenobiotics and alternative remedies used or proposed to treat COVID-19. Most repositioned xenobiotics have had neither the feared toxicity nor the anticipated efficacy. Repurposed viral replication inhibitors are not efficacious and frequently associated with nausea, vomiting, and diarrhea. Antiviral medications designed specifically against SARS-CoV-2 may prevent progression to severe disease in at-risk individuals and appear to have a wide therapeutic index. Colloidal silver, zinc, and ivermectin have no demonstrated efficacy. Ivermectin has a wide therapeutic index but is not efficacious and acquiring it from veterinary sources poses additional danger. Chloroquine has a narrow therapeutic index and no efficacy. A companion review covers vaccines, monoclonal antibodies, and immunotherapies. Together, these two reviews form an update to our 2020 review.
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The BNT162b2 mRNA SARS-CoV-2 vaccine induces transient afucosylated IgG1 in naive but not in antigen-experienced vaccinees.
Van Coillie, J, Pongracz, T, Rahmöller, J, Chen, HJ, Geyer, CE, van Vught, LA, Buhre, JS, Šuštić, T, van Osch, TLJ, Steenhuis, M, et al
EBioMedicine. 2023;:104408
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Abstract
BACKGROUND Afucosylated IgG1 responses have only been found against membrane-embedded epitopes, including anti-S in SARS-CoV-2 infections. These responses, intrinsically protective through enhanced FcγRIIIa binding, can also trigger exacerbated pro-inflammatory responses in severe COVID-19. We investigated if the BNT162b2 SARS-CoV-2 mRNA also induced afucosylated IgG responses. METHODS Blood from vaccinees during the first vaccination wave was collected. Liquid chromatography-Mass spectrometry (LC-MS) was used to study anti-S IgG1 Fc glycoprofiles. Responsiveness of alveolar-like macrophages to produce proinflammatory cytokines in presence of sera and antigen was tested. Antigen-specific B cells were characterized and glycosyltransferase levels were investigated by Fluorescence-Activated Cell Sorting (FACS). FINDINGS Initial transient afucosylated anti-S IgG1 responses were found in naive vaccinees, but not in antigen-experienced ones. All vaccinees had increased galactosylated and sialylated anti-S IgG1. Both naive and antigen-experienced vaccinees showed relatively low macrophage activation potential, as expected, due to the low antibody levels for naive individuals with afucosylated IgG1, and low afucosylation levels for antigen-experienced individuals with high levels of anti-S. Afucosylation levels correlated with FUT8 expression in antigen-specific plasma cells in naive individuals. Interestingly, low fucosylation of anti-S IgG1 upon seroconversion correlated with high anti-S IgG levels after the second dose. INTERPRETATION Here, we show that BNT162b2 mRNA vaccination induces transient afucosylated anti-S IgG1 responses in naive individuals. This observation warrants further studies to elucidate the clinical context in which potent afucosylated responses would be preferred. FUNDING LSBR1721, 1908; ZonMW10430012010021, 09150161910033, 10430012010008; DFG398859914, 400912066, 390884018; PMI; DOI4-Nr. 3; H2020-MSCA-ITN 721815.
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Addendum to vitamin D deficiency aggravates COVID-19: systematic review and meta-analysis.
Damascena, AD, Azevedo, LMG, Oliveira, TA, Santana, JDM, Pereira, M
Critical reviews in food science and nutrition. 2023;(4):557-562
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Flavonoids as a therapeutical option for the treatment of thrombotic complications associated with COVID-19.
Quintal Martínez, JP, Segura Campos, MR
Phytotherapy research : PTR. 2023;(3):1092-1114
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Abstract
The SARS-CoV-2 outbreak has been one of the largest public health crises globally, while thrombotic complications have emerged as an important factor contributing to mortality. Therefore, compounds that regulate the processes involved in thrombosis could represent a dietary strategy to prevent thrombotic complications involved in COVID-19. In August 2022, various databases were consulted using the keywords "flavonoids", "antiplatelet", "anticoagulant", "fibrinolytic", and "nitric oxide". Studies conducted between 2019 and 2022 were chosen. Flavonoids, at concentrations mainly between 2 and 300 μM, are capable of regulating platelet aggregation, blood coagulation, fibrinolysis, and nitric oxide production due to their action on multiple receptors and enzymes. Most of the studies have been carried out through in vitro and in silico models, and limited studies have reported the in vivo and clinical effect of flavonoids. Currently, quercetin has been the only flavonoid evaluated clinically in patients with COVID-19 for its effect on D-dimer levels. Therefore, clinical studies in COVID-19 patients analyzing the effect on platelet, coagulant, fibrinolytic, and nitric oxide parameters are required. In addition, further high-quality studies that consider cytotoxic safety and bioavailability are required to firmly propose flavonoids as a treatment for the thrombotic complications implicated in COVID-19.
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Harm of early dexamethasone for COVID-19 and bias in randomized trials.
Núñez, I, Caro-Vega, Y, Soto-Mota, A
European journal of internal medicine. 2023;:100-101
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COVID-19 Vaccines and the Virus: Impact on Drug Metabolism and Pharmacokinetics.
McColl, ER, Croyle, MA, Zamboni, WC, Honer, WG, Heise, M, Piquette-Miller, M, Goralski, KB
Drug metabolism and disposition: the biological fate of chemicals. 2023;(1):130-141
Abstract
This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12 billion vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amid an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. SIGNIFICANCE STATEMENT Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver cytochrome P450 metabolism of small molecules, enhanced innate immune system metabolism of complex molecules, and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety, and effectiveness and fetal neurodevelopment.
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In silico screening and covalent binding of phytochemicals of Ocimum sanctum against SARS-CoV-2 (COVID 19) main protease.
Mohapatra, PK, Chopdar, KS, Dash, GC, Mohanty, AK, Raval, MK
Journal of biomolecular structure & dynamics. 2023;(2):435-444
Abstract
Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has compelled the scientific community to search for an effective drug that can cure or a vaccine that can prevent the disease. Alternatively, symptomatic treatment and traditional immunity boosters are prescribed. Holy Tulsi (Ocimum sanctum) has been known as an ancient remedy for cure of common cold and respiratory ailment. Several reports have come on virtual screening of phytochemicals including those of Tulsi against various enzymes of the virus. We undertook in silico analysis of the ethanol extracted phytochemicals of Tulsi as inhibitors of SARS-CoV-2 (2019-nCoV) main protease with an approach to look into the possibility of covalent ligand binding with the catalytic residue Cys145, which makes the report unique. The results suggest that the flavonoids and polyphenolic compounds of Tulsi, have potential to covalently bind to the catalytic residue Cys145 of main protease and irreversibly inhibit the viral enzyme. Luteolin-7-O-glucuronide is specially considered for its optimum properties, namely, low toxicity (LD50 5000 mg/kg body weight), high drug-likeness score (0.71), the active site binding free energy (ΔGbind) -19.19 kcal/mol by GBSA method and covalent binding energy -24.23 kcal/mol. Further experimental validations are required to establish the theoretical findings.Communicated by Ramaswamy H. Sarma.
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Multi-OMICs landscape of SARS-CoV-2-induced host responses in human lung epithelial cells.
Pinto, SM, Subbannayya, Y, Kim, H, Hagen, L, Górna, MW, Nieminen, AI, Bjørås, M, Espevik, T, Kainov, D, Kandasamy, RK
iScience. 2023;(1):105895
Abstract
COVID-19 pandemic continues to remain a global health concern owing to the emergence of newer variants. Several multi-Omics studies have produced extensive evidence on host-pathogen interactions and potential therapeutic targets. Nonetheless, an increased understanding of host signaling networks regulated by post-translational modifications and their ensuing effect on the cellular dynamics is critical to expanding the current knowledge on SARS-CoV-2 infections. Through an unbiased transcriptomics, proteomics, acetylomics, phosphoproteomics, and exometabolome analysis of a lung-derived human cell line, we show that SARS-CoV-2 Norway/Trondheim-S15 strain induces time-dependent alterations in the induction of type I IFN response, activation of DNA damage response, dysregulated Hippo signaling, among others. We identified interplay of phosphorylation and acetylation dynamics on host proteins and its effect on the altered release of metabolites, especially organic acids and ketone bodies. Together, our findings serve as a resource of potential targets that can aid in designing novel host-directed therapeutic strategies.
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A 'health message' on sustainable physical and mental health for the prolonged COVID-19 and other pandemics.
So, B, Kwon, KH
Postgraduate medicine. 2023;(1):13-30
Abstract
The world has been living with another pandemic physical inactivity (PI) and sedentary behavior (SB) and of other nature for years. As social measures to prevent the spread of COVID-19 have been strengthened, the physical activity (PA) barrier has been hit and the PI/SB pandemic has been exacerbated, and in the current situation, triggered by its prolonged period, it is emerging as a problem to be considered in order to combat the PI/SB pandemic through PA and to maintain continuous physical and mental health. This review aims to summarize existing and recent studies on the effects of PA/SB on physical and mental health in preparation for the context of prolonged COVID-19 and provides an easy and fun way to motivate, access PA, and PA recommendations for maintaining physical and mental health. We performed search strategies on PubMed, Medline, Scopus, and Google Scholar databases, and used a literature review of the current available literature on the COVID-19 and the effects of PI, SB, and PA on physical and mental health. The clinical relevance of this review shows that integrating PA into daily life and reducing prolonged sitting time is an important strategy for continuing a healthy life physically and mentally. As a result, for those who have not yet incorporated exercise as part of their daily routine, fun and easy access to PA suggests that in the long run, may be an opportunity to implement newer habits. In addition, in an emergency such as the COVID-19 quarantine period or other pandemics, it is essential for one to maintain health through PA at home, and underscore the 'health message' of the current review that reducing SB, progressively increasing PA, and doing more PA regularly in the current context prolonged COVID-19 can bring significant benefits to long-term habits and physical and mental health.
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Commiphora myrrh: a phytochemical and pharmacological update.
Batiha, GE, Wasef, L, Teibo, JO, Shaheen, HM, Zakariya, AM, Akinfe, OA, Teibo, TKA, Al-Kuraishy, HM, Al-Garbee, AI, Alexiou, A, et al
Naunyn-Schmiedeberg's archives of pharmacology. 2023;(3):405-420
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Abstract
Medicinal plants have a long track record of use in history, and one of them is Commiphora myrrh which is commonly found in the southern part of Arabia, the northeastern part of Africa, in Somalia, and Kenya. Relevant literatures were accessed via Google Scholar, PubMed, Scopus, and Web of Science to give updated information on the phytochemical constituents and pharmacological action of Commiphora myrrh. It has been used traditionally for treating wounds, mouth ulcers, aches, fractures, stomach disorders, microbial infections, and inflammatory diseases. It is used as an antiseptic, astringent, anthelmintic, carminative, emmenagogue, and as an expectorant. Phytochemical studies have shown that it contains terpenoids (monoterpenoids, sesquiterpenoids, and volatile/essential oil), diterpenoids, triterpenoids, and steroids. Its essential oil has applications in cosmetics, aromatherapy, and perfumery. Research has shown that it exerts various biological activities such as anti-inflammatory, antioxidant, anti-microbial, neuroprotective, anti-diabetic, anti-cancer, analgesic, anti-parasitic, and recently, it was found to work against respiratory infections like COVID-19. With the advancement in drug development, hopefully, its rich phytochemical components can be explored for drug development as an insecticide due to its great anti-parasitic activity. Also, its interactions with drugs can be fully elucidated.This review highlights an updated information on the history, distribution, traditional uses, phytochemical components, pharmacology, and various biological activities of Commiphora myrrh. Graphical summary of the phytochemical and pharmacological update of Commiphora myrrh.
