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COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 86527

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Prof. Dr. George J. Kontoghiorghes

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Postgraduate Research Institute of Science, Technology, Environment and Medicine, CY-3021 Limassol, Cyprus
Interests: chelation therapy; chelation in medicine; chelating drugs; iron chelating drugs in thalassaemia and other diseases of iron overload or imbalance; chelator antioxidants in free radical pathology; chelators and antioxidants in cancer and neurodegenerative diseases; chelating drug design, development and clinical use
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Dr. Christina N. Kontoghiorghe

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Postgraduate Research Institute of Science, Technology, Environment and Medicine, CY-3021 Limassol, Cyprus
Interests: medicine; surgery; trauma; orthopaedics; global health; medicinal drugs; orphan drugs; risk/benefit assessment; sports medicine
Special Issues, Collections and Topics in MDPI journals

Dr. Annita Kolnagou

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Postgraduate Research Institute of Science, Technology, Environment and Medicine, CY-3021 Limassol, Cyprus
Interests: medicine; internal medicine; medicinal drugs; thalassaemia; Friedreich's Ataxia; infectious diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A high rate of morbidity and mortality has been observed worldwide as a result of the COVID-19 (coronavirus) pandemic. Currently, there is no available effective treatment. Many clinical trials with antiviral and other drugs are in progress, but the availability of an effective vaccine or the development of experimental drugs is not considered feasible for this year. The economic decline from the emergency restrictions is likely to cause unprecedented damage to living standards, including decline in healthcare systems and increases in morbidity and mortality worldwide, especially in developing countries. Emergency strategies and medicines are required to combat the COVID-19 pandemic, including unconventional approaches. There are many pathways involved in the initiation and progression of the COVID-19 infection, and many more associated with the severe acute respiratory syndrome (SARS) and other symptomatological side effects. The aim of this Special Issue is to propose possible therapeutics and the related mechanisms for targeting one or more pathways to combat the progress of the COVID-19 disease and/or associated symptoms. The proposal for therapeutics is only related to regulatory approved drugs and should include the INN name, mode of action, posology, therapeutic index, toxic side effects, ADMET characteristics, patient categories receiving the drug, drug interactions and use in adjuvant therapies. It is hoped that the findings and strategy adopted in this Special Issue will encourage clinical trials and the compassionate use of promising therapeutics against the COVID-19 infection.

Prof. Dr. George J. Kontoghiorghes
Dr. Christina N. Kontoghiorghe
Dr. Annita Kolnagou
Guest Editors

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Keywords

drug design, development and use
COVID-19 drugs
SARS-CoV-2
multi-target drugs
antiviral drugs
drugs for COVID-19 symptomatology
repurposing drugs
prophylactic drugs
emergency medicines
combination therapies
adjuvant therapies
drug risk/benefit assessment
compassionate use of drugs
ADMET of drugs

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review

4 pages, 190 KiB

Open AccessEditorial

Conventional and Unconventional Approaches for Innovative Drug Treatments in COVID-19: Looking Outside of Plato’s Cave

by George J. Kontoghiorghes, Annita Kolnagou, Stella Fetta and Christina N. Kontoghiorghe

Int. J. Mol. Sci. 2021, 22(13), 7208; https://doi.org/10.3390/ijms22137208 - 5 Jul 2021

Cited by 6 | Viewed by 2154

Abstract

Thousands of drugs and nutraceuticals along with their combinations can be used to select candidate therapeutics for targeting the transmission, proliferation and the fatal or severe symptoms of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in order to reduce the unacceptably high mortality rate observed in the coronavirus disease 2019 (COVID-19) pandemic and its associated negative effects on daily life worldwide [...] Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

Research

Jump to: Editorial, Review

17 pages, 2524 KiB

Open AccessArticle

Protective Effects of Meldonium in Experimental Models of Cardiovascular Complications with a Potential Application in COVID-19

by Reinis Vilskersts, Dana Kigitovica, Stanislava Korzh, Melita Videja, Karlis Vilks, Helena Cirule, Andris Skride, Marina Makrecka-Kuka, Edgars Liepinsh and Maija Dambrova

Int. J. Mol. Sci. 2022, 23(1), 45; https://doi.org/10.3390/ijms23010045 - 21 Dec 2021

Cited by 7 | Viewed by 5266

Abstract

Right ventricular (RV) and left ventricular (LV) dysfunction is common in a significant number of hospitalized coronavirus disease 2019 (COVID-19) patients. This study was conducted to assess whether the improved mitochondrial bioenergetics by cardiometabolic drug meldonium can attenuate the development of ventricular dysfunction in experimental RV and LV dysfunction models, which resemble ventricular dysfunction in COVID-19 patients. Effects of meldonium were assessed in rats with pulmonary hypertension-induced RV failure and in mice with inflammation-induced LV dysfunction. Rats with RV failure showed decreased RV fractional area change (RVFAC) and hypertrophy. Treatment with meldonium attenuated the development of RV hypertrophy and increased RVFAC by 50%. Mice with inflammation-induced LV dysfunction had decreased LV ejection fraction (LVEF) by 30%. Treatment with meldonium prevented the decrease in LVEF. A decrease in the mitochondrial fatty acid oxidation with a concomitant increase in pyruvate metabolism was noted in the cardiac fibers of the rats and mice with RV and LV failure, respectively. Meldonium treatment in both models restored mitochondrial bioenergetics. The results show that meldonium treatment prevents the development of RV and LV systolic dysfunction by enhancing mitochondrial function in experimental models of ventricular dysfunction that resembles cardiovascular complications in COVID-19 patients. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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18 pages, 1754 KiB

Open AccessArticle

Platelet Lysate Nebulization Protocol for the Treatment of COVID-19 and Its Sequels: Proof of Concept and Scientific Rationale

by Maider Beitia, Diego Delgado, Pello Sánchez, Ana Vallejo de la Cueva, José Ramón Cugat and Mikel Sánchez

Int. J. Mol. Sci. 2021, 22(4), 1856; https://doi.org/10.3390/ijms22041856 - 12 Feb 2021

Cited by 9 | Viewed by 3753

Abstract

One of the most severe effects of coronavirus disease 2019 (COVID-19) is lung disorders such as acute respiratory distress syndrome. In the absence of effective treatments, it is necessary to search for new therapies and therapeutic targets. Platelets play a fundamental role in respiratory disorders resulting from viral infections, being the first line of defense against viruses and essential in maintaining lung function. The direct application of platelet lysate (PL) obtained from the platelet-rich plasma of healthy donors could help in the improvement of the patient due its anti-inflammatory, immunomodulatory, antifibrotic, and repairing effects. This work evaluates PL nebulization by analyzing its levels of growth factors and its biological activity on lung fibroblast cell cultures, besides describing a scientific basis for its use in this kind of pathology. The data of the work suggest that the molecular levels and biological activity of the PL are maintained after nebulization. Airway administration would allow acting directly on the lung tissue modulating inflammation and stimulating reparative processes on key structures such as the alveolocapillary barrier, improving the disease and sequels. The protocol developed in this work is a first step for the study of nebulized PL both in animal experimentation and in clinical trials. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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15 pages, 5103 KiB

Open AccessArticle

Nicotinic Cholinergic System and COVID-19: In Silico Identification of an Interaction between SARS-CoV-2 and Nicotinic Receptors with Potential Therapeutic Targeting Implications

by Konstantinos Farsalinos, Elias Eliopoulos, Demetres D. Leonidas, Georgios E. Papadopoulos, Socrates Tzartos and Konstantinos Poulas

Int. J. Mol. Sci. 2020, 21(16), 5807; https://doi.org/10.3390/ijms21165807 - 13 Aug 2020

Cited by 62 | Viewed by 20737

Abstract

While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine other potential interactions between the virus and other cell receptors. Based on the clinical observation of low prevalence of smoking among hospitalized COVID-19 patients, we examined and identified a “toxin-like” amino acid (aa) sequence in the Receptor Binding Domain of the Spike Glycoprotein of SARS-CoV-2 (aa 375–390), which is homologous to a sequence of the Neurotoxin homolog NL1, one of the many snake venom toxins that are known to interact with nicotinic acetylcholine receptors (nAChRs). We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein and the superposition of the modelled structure of the Neurotoxin homolog NL1 and the SARS-CoV-2 Spike Glycoprotein. We also performed computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 Spike Glycoprotein and the extracellular domain of the nAChR α9 subunit. We identified a main interaction between the aa 381–386 of the SARS-CoV-2 Spike Glycoprotein and the aa 189–192 of the extracellular domain of the nAChR α9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the α9 nAChR and α-bungarotoxin. A similar interaction was observed between the pentameric α7 AChR chimera and SARS-CoV-2 Spike Glycoprotein. The findings raise the possibility that SARS-CoV-2 may interact with nAChRs, supporting the hypothesis of dysregulation of the nicotinic cholinergic system being implicated in the pathophysiology of COVID-19. Nicotine and other nicotinic cholinergic agonists may protect nAChRs and thus have therapeutic value in COVID-19 patients. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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Review

Jump to: Editorial, Research

22 pages, 748 KiB

Open AccessReview

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology

by George J. Kontoghiorghes

Int. J. Mol. Sci. 2022, 23(12), 6735; https://doi.org/10.3390/ijms23126735 - 16 Jun 2022

Cited by 10 | Viewed by 3054

Abstract

The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a “magic bullet” drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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25 pages, 2057 KiB

Open AccessReview

Immunomodulatory and Anti-Inflammatory Properties of Selenium-Containing Agents: Their Role in the Regulation of Defense Mechanisms against COVID-19

by Valentina N. Mal’tseva, Michael V. Goltyaev, Egor A. Turovsky and Elena G. Varlamova

Int. J. Mol. Sci. 2022, 23(4), 2360; https://doi.org/10.3390/ijms23042360 - 21 Feb 2022

Cited by 43 | Viewed by 5065

Abstract

The review presents the latest data on the role of selenium-containing agents in the regulation of diseases of the immune system. We mainly considered the contributions of selenium-containing compounds such as sodium selenite, methylseleninic acid, selenomethionine, and methylselenocysteine, as well as selenoproteins and selenium nanoparticles in the regulation of defense mechanisms against various viral infections, including coronavirus infection (COVID-19). A complete description of the available data for each of the above selenium compounds and the mechanisms underlying the regulation of immune processes with the active participation of these selenium agents, as well as their therapeutic and pharmacological potential, is presented. The main purpose of this review is to systematize the available information, supplemented by data obtained in our laboratory, on the important role of selenium compounds in all of these processes. In addition, the presented information makes it possible to understand the key differences in the mechanisms of action of these compounds, depending on their chemical and physical properties, which is important for obtaining a holistic picture and prospects for creating drugs based on them. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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16 pages, 527 KiB

Open AccessReview

A Patent Review on the Therapeutic Application of Monoclonal Antibodies in COVID-19

by Syed Mohammed Basheeruddin Asdaq, Syed Imam Rabbani, Meshary Alkahtani, Meshal Meshary Aldohyan, Abdullah Mohammad Alabdulsalam, Majed Sadun Alshammari, Saleh Ahmad Alajlan, Aljawharah Binrokan, Yahya Mohzari, Ahmed Alrashed, Mohammed Kanan Alshammari, Mohd. Imran and Naira Nayeem

Int. J. Mol. Sci. 2021, 22(21), 11953; https://doi.org/10.3390/ijms222111953 - 4 Nov 2021

Cited by 10 | Viewed by 4865

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contains spike proteins that assist the virus in entering host cells. In the absence of a specific intervention, efforts are afoot throughout the world to find an effective treatment for SARS-CoV-2. Through innovative techniques, monoclonal antibodies (MAbs) are being designed and developed to block a particular pathway of SARS-CoV-2 infection. More than 100 patent applications describing the development of MAbs and their application against SARS-CoV-2 have been registered. Most of them target the receptor binding protein so that the interaction between virus and host cell can be prevented. A few monoclonal antibodies are also being patented for the diagnosis of SARS-CoV-2. Some of them, like Regeneron^® have already received emergency use authorization. These protein molecules are currently preferred for high-risk patients such as those over 65 years old with compromised immunity and those with metabolic disorders such as obesity. Being highly specific in action, monoclonal antibodies offer one of the most appropriate interventions for both the prevention and treatment of SARS-CoV-2. Technological advancement has helped in producing highly efficacious MAbs. However, these agents are known to induce immunogenic and non-immunogenic reactions. More research and testing are required to establish the suitability of administering MAbs to all patients at risk of developing a severe illness. This patent study is focused on MAbs as a therapeutic option for treating COVID-19, as well as their invention, patenting information, and key characteristics. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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24 pages, 5025 KiB

Open AccessReview

Mechanics Insights of Alpha-Lipoic Acid against Cardiovascular Diseases during COVID-19 Infection

by Luc Rochette and Steliana Ghibu

Int. J. Mol. Sci. 2021, 22(15), 7979; https://doi.org/10.3390/ijms22157979 - 26 Jul 2021

Cited by 26 | Viewed by 7958

Abstract

Coronavirus disease 2019 (COVID-19) was first reported in Wuhan, China, in late December 2019. Since then, COVID-19 has spread rapidly worldwide and was declared a global pandemic on 20 March 2020. Cardiovascular complications are rapidly emerging as a major peril in COVID-19 in addition to respiratory disease. The mechanisms underlying the excessive effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with cardiovascular comorbidities remain only partly understood. SARS-CoV-2 infection is caused by binding of the viral surface spike (S) protein to the human angiotensin-converting enzyme 2 (ACE2), followed by the activation of the S protein by transmembrane protease serine 2 (TMPRSS2). ACE2 is expressed in the lung (mainly in type II alveolar cells), heart, blood vessels, small intestine, etc., and appears to be the predominant portal to the cellular entry of the virus. Based on current information, most people infected with SARS-CoV-2 virus have a good prognosis, while a few patients reach critical condition, especially the elderly and those with chronic underlying diseases. The “cytokine storm” observed in patients with severe COVID-19 contributes to the destruction of the endothelium, leading to “acute respiratory distress syndrome” (ARDS), multiorgan failure, and death. At the origin of the general proinflammatory state may be the SARS-CoV-2-mediated redox status in endothelial cells via the upregulation of ACE/Ang II/AT1 receptors pathway or the increased mitochondrial reactive oxygen species (mtROS) production. Furthermore, this vicious circle between oxidative stress (OS) and inflammation induces endothelial dysfunction, endothelial senescence, high risk of thrombosis and coagulopathy. The microvascular dysfunction and the formation of microthrombi in a way differentiate the SARS-CoV-2 infection from the other respiratory diseases and bring it closer to cardiovascular diseases like myocardial infarction and stroke. Due the role played by OS in the evolution of viral infection and in the development of COVID-19 complications, the use of antioxidants as adjuvant therapy seems appropriate in this new pathology. Alpha-lipoic acid (ALA) could be a promising candidate that, through its wide tissue distribution and versatile antioxidant properties, interferes with several signaling pathways. Thus, ALA improves endothelial function by restoring the endothelial nitric oxide synthase activity and presents an anti-inflammatory effect dependent or independent of its antioxidant properties. By improving mitochondrial function, it can sustain the tissues’ homeostasis in critical situation and by enhancing the reduced glutathione it could indirectly strengthen the immune system. This complex analysis could open a new therapeutic perspective for ALA in COVID-19 infection. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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26 pages, 2824 KiB

Open AccessReview

Existing Drugs Considered as Promising in COVID-19 Therapy

by Edyta Janik, Marcin Niemcewicz, Marcin Podogrocki, Joanna Saluk-Bijak and Michal Bijak

Int. J. Mol. Sci. 2021, 22(11), 5434; https://doi.org/10.3390/ijms22115434 - 21 May 2021

Cited by 24 | Viewed by 7085

Abstract

COVID-19 is a respiratory disease caused by newly discovered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease at first was identified in the city of Wuhan, China in December 2019. Being a human infectious disease, it causes high fever, cough, breathing problems. In some cases it can be fatal, especially in people with comorbidities like heart or kidney problems and diabetes. The current COVID-19 treatment is based on symptomatic therapy, so finding an appropriate drug against COVID-19 remains an immediate and crucial target for the global scientific community. Two main processes are thought to be responsible for the COVID-19 pathogenesis. In the early stages of infection, disease is determined mainly by virus replication. In the later stages of infection, by an excessive immune/inflammatory response, leading to tissue damage. Therefore, the main treatment options are antiviral and immunomodulatory/anti-inflammatory agents. Many clinical trials have been conducted concerning the use of various drugs in COVID-19 therapy, and many are still ongoing. The majority of trials examine drug reposition (repurposing), which seems to be a good and effective option. Many drugs have been repurposed in COVID-19 therapy including remdesivir, favipiravir, tocilizumab and baricitinib. The aim of this review is to highlight (based on existing and accessible clinical evidence on ongoing trials) the current and available promising drugs for COVID-19 and outline their characteristics. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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36 pages, 5961 KiB

Open AccessReview

Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19

by Gustavo José da Silva Pereira, Anderson Henrique França Figueredo Leão, Adolfo Garcia Erustes, Ingrid Beatriz de Melo Morais, Talita Aparecida de Moraes Vrechi, Lucas dos Santos Zamarioli, Cássia Arruda Souza Pereira, Laís de Oliveira Marchioro, Letícia Paulino Sperandio, Ísis Valeska Freire Lins, Mauro Piacentini, Gian Maria Fimia, Patrícia Reckziegel, Soraya Soubhi Smaili and Claudia Bincoletto

Int. J. Mol. Sci. 2021, 22(8), 4067; https://doi.org/10.3390/ijms22084067 - 15 Apr 2021

Cited by 35 | Viewed by 5890

Abstract

The family of coronaviruses (CoVs) uses the autophagy machinery of host cells to promote their growth and replication; thus, this process stands out as a potential target to combat COVID-19. Considering the different roles of autophagy during viral infection, including SARS-CoV-2 infection, in this review, we discuss several clinically used drugs that have effects at different stages of autophagy. Among them, we mention (1) lysosomotropic agents, which can prevent CoVs infection by alkalinizing the acid pH in the endolysosomal system, such as chloroquine and hydroxychloroquine, azithromycin, artemisinins, two-pore channel modulators and imatinib; (2) protease inhibitors that can inhibit the proteolytic cleavage of the spike CoVs protein, which is necessary for viral entry into host cells, such as camostat mesylate, lopinavir, umifenovir and teicoplanin and (3) modulators of PI3K/AKT/mTOR signaling pathways, such as rapamycin, heparin, glucocorticoids, angiotensin-converting enzyme inhibitors (IECAs) and cannabidiol. Thus, this review aims to highlight and discuss autophagy-related drugs for COVID-19, from in vitro to in vivo studies. We identified specific compounds that may modulate autophagy and exhibit antiviral properties. We hope that research initiatives and efforts will identify novel or “off-label” drugs that can be used to effectively treat patients infected with SARS-CoV-2, reducing the risk of mortality. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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16 pages, 1749 KiB

Open AccessReview

Therapeutic Role of Tocilizumab in SARS-CoV-2-Induced Cytokine Storm: Rationale and Current Evidence

by Corrado Pelaia, Cecilia Calabrese, Eugenio Garofalo, Andrea Bruni, Alessandro Vatrella and Girolamo Pelaia

Int. J. Mol. Sci. 2021, 22(6), 3059; https://doi.org/10.3390/ijms22063059 - 17 Mar 2021

Cited by 40 | Viewed by 9444

Abstract

Among patients suffering from coronavirus disease 2019 (COVID-19) syndrome, one of the worst possible scenarios is represented by the critical lung damage caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced cytokine storm, responsible for a potentially very dangerous hyperinflammatory condition. Within such a context, interleukin-6 (IL-6) plays a key pathogenic role, thus being a suitable therapeutic target. Indeed, the IL-6-receptor antagonist tocilizumab, already approved for treatment of refractory rheumatoid arthritis, is often used to treat patients with severe COVID-19 symptoms and lung involvement. Therefore, the aim of this review article is to focus on the rationale of tocilizumab utilization in the SARS-CoV-2-triggered cytokine storm, as well as to discuss current evidence and future perspectives, especially with regard to ongoing trials referring to the evaluation of tocilizumab’s therapeutic effects in patients with life-threatening SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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27 pages, 3846 KiB

Open AccessReview

Cardiovascular Complications Associated with COVID-19 and Potential Therapeutic Strategies

by Arun Samidurai and Anindita Das

Int. J. Mol. Sci. 2020, 21(18), 6790; https://doi.org/10.3390/ijms21186790 - 16 Sep 2020

Cited by 55 | Viewed by 9220

Abstract

The outbreak of coronavirus disease 2019 (COVID-19), an infectious disease with severe acute respiratory syndrome, has now become a worldwide pandemic. Despite the respiratory complication, COVID-19 is also associated with significant multiple organ dysfunction, including severe cardiac impairment. Emerging evidence reveals a direct interplay between COVID-19 and dire cardiovascular complications, including myocardial injury, heart failure, heart attack, myocarditis, arrhythmias as well as blood clots, which are accompanied with elevated risk and adverse outcome among infected patients, even sudden death. The proposed pathophysiological mechanisms of myocardial impairment include invasion of SARS-CoV-2 virus via angiotensin-converting enzyme 2 to cardiovascular cells/tissue, which leads to endothelial inflammation and dysfunction, de-stabilization of vulnerable atherosclerotic plaques, stent thrombosis, cardiac stress due to diminish oxygen supply and cardiac muscle damage, and myocardial infarction. Several promising therapeutics are under investigation to the overall prognosis of COVID-19 patients with high risk of cardiovascular impairment, nevertheless to date, none have shown proven clinical efficacy. In this comprehensive review, we aimed to highlight the current integrated therapeutic approaches for COVID-19 and we summarized the potential therapeutic options, currently under clinical trials, with their mechanisms of action and associated adverse cardiac events in highly infectious COVID-19 patients. Full article

(This article belongs to the Special Issue COVID-19 Innovative Drug Treatments: Looking Outside of Plato’s Cave)

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