1
|
Quintana JM, Larrea N, Menéndez L, Legarreta MJ, Gascon M, Garcia-Asensio J, España PP. Effectiveness of drugs employed in the treatment of COVID-19: real-world evidence. Expert Rev Respir Med 2025; 19:493-498. [PMID: 40186558 DOI: 10.1080/17476348.2025.2488966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 03/27/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
BACKGROUND Drugs used to treat patients with SARS-CoV-2 infection have been tested in different clinical trials but less in real-life studies. Our goal was to assess the effectiveness of several specific COVID-19 drugs. RESEARCH DESIGN AND METHODS Retrospective study of all patients testing positive for SARS-CoV-2 infection between 1 March 2020 and 9 January 2022. We extracted sociodemographic, basal comorbidities, specific medication for their COVID-19, COVID-19 vaccination data, and outcomes such as death and admission to hospital and intensive care unit (ICU) during the different periods of the pandemic. RESULTS The prescription of corticosteroids to out-of-hospital patients was related to a higher likelihood of hospital admission. Among the hospitalized patients, all of the drugs studied (dexamethasone, prednisone, methylprednisolone, remdesivir, ritonavir/lopinavir, and tocilizumab) were related to a higher likelihood of dying at 90 days or being admitted to an ICU. In patients admitted to an ICU, corticosteroids prevented intrahospital mortality (Odds ratio: 0.73; 95% confident intervals: 0.554-0.969). All drugs were related to longer length of hospital admission and ICU stays. CONCLUSIONS Most drugs used for COVID-19 patients had no clear benefit except in the case of corticosteroids, associated with a reduced risk of intrahospital mortality among ICU patients. TRIAL REGISTRATION The study is registered at ClinicalTrials.gov (CT.gov identifier: NCT04463706).
Collapse
Affiliation(s)
- Jose M Quintana
- Osakidetza Basque Health Service, Galdakao-Usansolo University Hospital, Research Unit, Galdakao, Spain
- Biosistemak Institute for Health System Research, Barakaldo, Spain
- Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), Bilbao, Spain
| | - Nere Larrea
- Osakidetza Basque Health Service, Galdakao-Usansolo University Hospital, Research Unit, Galdakao, Spain
- Biosistemak Institute for Health System Research, Barakaldo, Spain
- Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), Bilbao, Spain
| | - Lara Menéndez
- Osakidetza Basque Health Service, Galdakao-Usansolo University Hospital, Pharmacy Service, Galdakao, Spain
| | - Maria J Legarreta
- Osakidetza Basque Health Service, Galdakao-Usansolo University Hospital, Research Unit, Galdakao, Spain
- Biosistemak Institute for Health System Research, Barakaldo, Spain
- Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), Bilbao, Spain
| | - Maria Gascon
- Network for Research on Chronicity, Primary Care, and Health Promotion (RICAPPS), Bilbao, Spain
- Bioaraba Health Research Institute, Araba University Hospital, Research Unit, Vitoria-Gasteiz, Spain
| | - Julia Garcia-Asensio
- Basque Government Department of Health, Office of Healthcare Planning, Organization and Evaluation, Basque Country, Spain
| | - Pedro-Pablo España
- Osakidetza Basque Health Service, Galdakao-Usansolo University Hospital, Respiratory Service, Galdakao, Spain
- BioBizkaia Health Research Institute, Barakaldo, Spain
| |
Collapse
|
2
|
Petcherski A, Tingley BM, Martin A, Adams S, Brownstein AJ, Steinberg RA, Shabane B, Ngo J, Osto C, Garcia G, Veliova M, Arumugaswami V, Colby AH, Shirihai OS, Grinstaff MW. Endolysosome-targeted nanoparticle delivery of antiviral therapy for coronavirus infections. Life Sci Alliance 2025; 8:e202403182. [PMID: 39900438 PMCID: PMC11790838 DOI: 10.26508/lsa.202403182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/22/2025] [Accepted: 01/22/2025] [Indexed: 02/05/2025] Open
Abstract
SARS-CoV-2 can infect cells through endocytic uptake, a process that is targeted by inhibition of lysosomal proteases. However, clinically this approach to treat viral infections has afforded mixed results, with some studies detailing an oral regimen of hydroxychloroquine accompanied by significant off-target toxicities. We rationalized that an organelle-targeted approach will avoid toxicity while increasing the concentration of the drug at the target. Here, we describe a lysosome-targeted, mefloquine-loaded poly(glycerol monostearate-co-ε-caprolactone) nanoparticle (MFQ-NP) for pulmonary delivery via inhalation. Mefloquine is a more effective inhibitor of viral endocytosis than hydroxychloroquine in cellular models of COVID-19. MFQ-NPs are less toxic than molecular mefloquine, are 100-150 nm in diameter, and possess a negative surface charge, which facilitates uptake via endocytosis allowing inhibition of lysosomal proteases. MFQ-NPs inhibit coronavirus infection in mouse MHV-A59 and human OC43 coronavirus model systems and inhibit SARS-CoV-2 WA1 and its Omicron variant in a human lung epithelium model. Organelle-targeted delivery is an effective means to inhibit viral infection.
Collapse
Affiliation(s)
- Anton Petcherski
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Brett M Tingley
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Andrew Martin
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Sarah Adams
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Alexandra J Brownstein
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Molecular Cellular Integrative Physiology, University of California Los Angeles, Los Angeles, CA, USA
| | - Ross A Steinberg
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Byourak Shabane
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Jennifer Ngo
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Corey Osto
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Gustavo Garcia
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Michaela Veliova
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Vaithilingaraja Arumugaswami
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Aaron H Colby
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
| | - Orian S Shirihai
- Department of Medicine, Division of Endocrinology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Mark W Grinstaff
- Department of Biomedical Engineering, Boston University, Boston, MA, USA
- Department of Chemistry, Boston University, Boston, MA, USA
| |
Collapse
|
3
|
Paróczai D, Bikov A, Blidaru A, Bobu E, Lascu A, Mot CI, Mihaicuta S, Frent S. Comparative efficacy of repurposed drugs lopinavir-ritonavir and darunavir-ritonavir in hospitalised COVID-19 patients: insights from a tertiary centre cohort. Front Cell Infect Microbiol 2025; 14:1496176. [PMID: 39885967 PMCID: PMC11779713 DOI: 10.3389/fcimb.2024.1496176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 12/26/2024] [Indexed: 02/01/2025] Open
Abstract
Background Drug repurposing has become a widely adopted strategy to minimise research time, costs, and associated risks. Combinations of protease inhibitors such as lopinavir and darunavir with ritonavir have been repurposed as treatments for COVID-19. Although lopinavir-ritonavir (LPV/r) and darunavir-ritonavir (DRV/r) have shown in vitro efficacy against COVID-19, the results in human studies have been inconsistent. Therefore, our objective was to compare the efficacy of LPV/r and DRV/r in COVID-19 patients admitted to a tertiary centre in Romania. Research design and methods A clinical dataset from 417 hospitalised patients was analysed. Patients were assigned to the LPV/r, DRV/r, or control (standard-of-care) group based on clinical decisions made by the attending infectious disease specialists, aligned with national treatment protocols. Kaplan-Meier and Cox proportional hazards regression analyses were conducted to compare in-hospital mortality and to identify factors associated with clinical improvement or fatal outcomes. Results By day 10, more patients showed improvement with LPV/r and DRV/r (p=0.03 and 0.01, respectively), but only LPV/r was associated with improved survival compared to the control group (p=0.05). Factors associated with mortality included male gender (HR: 3.63, p=0.02), diabetes (HR: 2.49, p=0.03), oxygen saturation below 90% at admission (HR: 5.23, p<0.01), high blood glucose levels (HR: 3.68, p=0.01), age (HR: 1.04, p=0.02), and more than 25% lesion extension on chest CT scan (HR: 2.28, p=0.03). Conclusions LPV/r, but not DRV/r, showed a survival benefit in patients hospitalised with COVID-19, but these findings deserve further investigation in a randomised clinical trial.
Collapse
Affiliation(s)
- Dóra Paróczai
- Department of Medical Microbiology, University of Szeged, Szeged, Hungary
- Albert Szent-Györgyi Health Center, Pulmonology Clinic, University of Szeged, Deszk, Hungary
| | - András Bikov
- North West Lung Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
- Division of Immunology, Immunity to Infection and Respiratory Medicine, University of Manchester, Manchester, United Kingdom
| | - Andreea Blidaru
- Department of Infectious Diseases, Infectious Diseases and Pulmonology Clinical Hospital, Timisoara, Romania
| | - Emanuel Bobu
- Department of Pulmonology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Ana Lascu
- Department of Functional Sciences, Discipline of Pathophysiology, Centre for Translational Research and Systems Medicine, University of Medicine and Pharmacy Timisoara, Timisoara, Romania
- Institute for Cardiovascular Diseases of Timisoara, Clinic for Cardiovascular Surgery, Timisoara, Romania
| | - Cristian Ion Mot
- ENT Department, Municipal Emergency Hospital Timisoara, Timisoara, Romania
- Department of Surgery, University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Stefan Mihaicuta
- Department of Infectious Diseases, Infectious Diseases and Pulmonology Clinical Hospital, Timisoara, Romania
- Centre for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| | - Stefan Frent
- Department of Infectious Diseases, Infectious Diseases and Pulmonology Clinical Hospital, Timisoara, Romania
- Centre for Research and Innovation in Precision Medicine of Respiratory Diseases, Department of Pulmonology, University of Medicine and Pharmacy Timisoara, Timisoara, Romania
| |
Collapse
|
4
|
Behzadi P, Chandran D, Chakraborty C, Bhattacharya M, Saikumar G, Dhama K, Chakraborty A, Mukherjee S, Sarshar M. The dual role of toll-like receptors in COVID-19: Balancing protective immunity and immunopathogenesis. Int J Biol Macromol 2025; 284:137836. [PMID: 39613064 DOI: 10.1016/j.ijbiomac.2024.137836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 11/01/2024] [Accepted: 11/17/2024] [Indexed: 12/01/2024]
Abstract
Toll-like receptors (TLRs) of human are considered as the most critical immunological mediators of inflammatory pathogenesis of COVID-19. These immunoregulatory glycoproteins are located on the surface and/or intracellular compartment act as innate immune sensors. Upon binding with distinct SARS-CoV-2 ligand(s), TLRs signal activation of different transcription factors that induce expression of the proinflammatory mediators that collectively induce 'cytokine storm'. Similarly, TLR activation is also pivotal in conferring protection to infection and invasion as well as upregulating the tissue repair pathways. This dual role of the human TLRs in deciding the fate of SARS-CoV-2 has made these receptor proteins as the critical mediators of immunoprotective and immunopathogenic consequences associated with COVID-19. Herein, pathbreaking discoveries exploring the immunobiological importance of the TLRs in COVID-19 and developing TLR-directed therapeutic intervention have been reviewed by accessing the up-to-date literatures available in the public domain/databases. In accordance with our knowledge in association with the importance of TLRs' role against viruses and identification of viral particles, they have been recognized as suitable candidates with high potential as vaccine adjuvants. In this regard, the agonists of TLR4 and TLR9 have effective potential in vaccine technology while the others need further investigations. This comprehensive review suggests that basal level expression of TLRs can act as friends to keep our body safe from strangers but act as a foe via overexpression. Therefore, selective inhibition of the overexpressed TLRs appears to be a solution to counteract the cytokine storm while TLR-agonists as vaccine adjuvants could lessen the risk of infection in the naïve population.
Collapse
Affiliation(s)
- Payam Behzadi
- Department of Microbiology, Shahr-e-Qods Branch, Islamic Azad University, Tehran, 37541-374, Iran.
| | | | - Chiranjib Chakraborty
- Department of Biotechnology, School of Life Science and Biotechnology, Adamas University, Kolkata, 700126, West Bengal, India
| | - Manojit Bhattacharya
- Department of Zoology, Fakir Mohan University, VyasaVihar, Balasore, 756020, Odisha, India
| | - Guttula Saikumar
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Izatnagar, Uttar Pradesh, 243122, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, Izatnagar, Uttar Pradesh, 243122, India.
| | - Ankita Chakraborty
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, 713340, West Bengal, India
| | - Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol, 713340, West Bengal, India.
| | - Meysam Sarshar
- Research Laboratories, Bambino Gesù Children's Hospital-IRCCS, 00146, Rome, Italy
| |
Collapse
|
5
|
Peralta-Moreno MN, Mena Y, Ortega-Alarcon D, Jimenez-Alesanco A, Vega S, Abian O, Velazquez-Campoy A, Thomson TM, Pinto M, Granadino-Roldán JM, Santos Tomas M, Perez JJ, Rubio-Martinez J. Shedding Light on Dark Chemical Matter: The Discovery of a SARS-CoV-2 M pro Main Protease Inhibitor through Intensive Virtual Screening and In Vitro Evaluation. Int J Mol Sci 2024; 25:6119. [PMID: 38892306 PMCID: PMC11172690 DOI: 10.3390/ijms25116119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 05/23/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
The development of specific antiviral therapies targeting SARS-CoV-2 remains fundamental because of the continued high incidence of COVID-19 and limited accessibility to antivirals in some countries. In this context, dark chemical matter (DCM), a set of drug-like compounds with outstanding selectivity profiles that have never shown bioactivity despite being extensively assayed, appears to be an excellent starting point for drug development. Accordingly, in this study, we performed a high-throughput screening to identify inhibitors of the SARS-CoV-2 main protease (Mpro) using DCM compounds as ligands. Multiple receptors and two different docking scoring functions were employed to identify the best molecular docking poses. The selected structures were subjected to extensive conventional and Gaussian accelerated molecular dynamics. From the results, four compounds with the best molecular behavior and binding energy were selected for experimental testing, one of which presented inhibitory activity with a Ki value of 48 ± 5 μM. Through virtual screening, we identified a significant starting point for drug development, shedding new light on DCM compounds.
Collapse
Affiliation(s)
- Maria Nuria Peralta-Moreno
- Department of Materials Science and Physical Chemistry, Institut de Recerca en Quimica Teòrica i Computacional (IQTCUB), University of Barcelona (UB), 08028 Barcelona, Spain; (M.N.P.-M.); (Y.M.)
| | - Yago Mena
- Department of Materials Science and Physical Chemistry, Institut de Recerca en Quimica Teòrica i Computacional (IQTCUB), University of Barcelona (UB), 08028 Barcelona, Spain; (M.N.P.-M.); (Y.M.)
| | - David Ortega-Alarcon
- Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain; (D.O.-A.); (A.J.-A.); (S.V.); (O.A.); (A.V.-C.)
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain
| | - Ana Jimenez-Alesanco
- Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain; (D.O.-A.); (A.J.-A.); (S.V.); (O.A.); (A.V.-C.)
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain
| | - Sonia Vega
- Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain; (D.O.-A.); (A.J.-A.); (S.V.); (O.A.); (A.V.-C.)
| | - Olga Abian
- Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain; (D.O.-A.); (A.J.-A.); (S.V.); (O.A.); (A.V.-C.)
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS Aragon), 50009 Zaragoza, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas Digestivas (CIBERehd), 28029 Madrid, Spain;
| | - Adrian Velazquez-Campoy
- Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, Spain; (D.O.-A.); (A.J.-A.); (S.V.); (O.A.); (A.V.-C.)
- Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria de Aragón (IIS Aragon), 50009 Zaragoza, Spain
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas Digestivas (CIBERehd), 28029 Madrid, Spain;
| | - Timothy M. Thomson
- Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas Digestivas (CIBERehd), 28029 Madrid, Spain;
- Institute of Molecular Biology of Barcelona (IBMB-CSIC), 08028 Barcelona, Spain
- Instituto de investigaciones de la Altura, Universidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Lima 15102, Peru
| | - Marta Pinto
- AbbVie Deutschland GmbH & Co. KG, Computational Drug Discovery, Knollstrasse, 67061 Ludwigshafen, Germany;
| | - José M. Granadino-Roldán
- Departamento de Química Física y Analítica, Facultad de Ciencias Experimentales, Universidad de Jaén, Campus “Las Lagunillas” s/n, 23071 Jaén, Spain;
| | - Maria Santos Tomas
- Department of Architecture Technology, Universitat Politecnica de Catalunya (UPC), Av. Diagonal 649, 08028 Barcelona, Spain;
| | - Juan J. Perez
- Department of Chemical Engineering, Universitat Politecnica de Catalunya (UPC), Barcelona Tech. Av. Diagonal, 647, 08028 Barcelona, Spain;
| | - Jaime Rubio-Martinez
- Department of Materials Science and Physical Chemistry, Institut de Recerca en Quimica Teòrica i Computacional (IQTCUB), University of Barcelona (UB), 08028 Barcelona, Spain; (M.N.P.-M.); (Y.M.)
| |
Collapse
|
6
|
Alipour Z, Zarezadeh S, Ghotbi-Ravandi AA. The Potential of Anti-coronavirus Plant Secondary Metabolites in COVID-19 Drug Discovery as an Alternative to Repurposed Drugs: A Review. PLANTA MEDICA 2024; 90:172-203. [PMID: 37956978 DOI: 10.1055/a-2209-6357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2023]
Abstract
In early 2020, a global pandemic was announced due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to cause COVID-19. Despite worldwide efforts, there are only limited options regarding antiviral drug treatments for COVID-19. Although vaccines are now available, issues such as declining efficacy against different SARS-CoV-2 variants and the aging of vaccine-induced immunity highlight the importance of finding more antiviral drugs as a second line of defense against the disease. Drug repurposing has been used to rapidly find COVID-19 therapeutic options. Due to the lack of clinical evidence for the therapeutic benefits and certain serious side effects of repurposed antivirals, the search for an antiviral drug against SARS-CoV-2 with fewer side effects continues. In recent years, numerous studies have included antiviral chemicals from a variety of plant species. A better knowledge of the possible antiviral natural products and their mechanism against SARS-CoV-2 will help to develop stronger and more targeted direct-acting antiviral agents. The aim of the present study was to compile the current data on potential plant metabolites that can be investigated in COVID-19 drug discovery and development. This review represents a collection of plant secondary metabolites and their mode of action against SARS-CoV and SARS-CoV-2.
Collapse
Affiliation(s)
- Zahra Alipour
- Department of Plant Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Somayeh Zarezadeh
- Department of Plant Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Ali Akbar Ghotbi-Ravandi
- Department of Plant Sciences and Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| |
Collapse
|
7
|
Bege M, Borbás A. The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19. Pharmaceutics 2024; 16:217. [PMID: 38399271 PMCID: PMC10891713 DOI: 10.3390/pharmaceutics16020217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 01/26/2024] [Accepted: 01/31/2024] [Indexed: 02/25/2024] Open
Abstract
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has presented an enormous challenge to health care systems and medicine. As a result of global research efforts aimed at preventing and effectively treating SARS-CoV-2 infection, vaccines with fundamentally new mechanisms of action and some small-molecule antiviral drugs targeting key proteins in the viral cycle have been developed. The most effective small-molecule drug approved to date for the treatment of COVID-19 is PaxlovidTM, which is a combination of two protease inhibitors, nirmatrelvir and ritonavir. Nirmatrelvir is a reversible covalent peptidomimetic inhibitor of the main protease (Mpro) of SARS-CoV-2, which enzyme plays a crucial role in viral reproduction. In this combination, ritonavir serves as a pharmacokinetic enhancer, it irreversibly inhibits the cytochrome CYP3A4 enzyme responsible for the rapid metabolism of nirmatrelvir, thereby increasing the half-life and bioavailability of nirmatrelvir. In this tutorial review, we summarize the development and pharmaceutical chemistry aspects of Paxlovid, covering the evolution of protease inhibitors, the warhead design, synthesis and the mechanism of action of nirmatrelvir, as well as the synthesis of ritonavir and its CYP3A4 inhibition mechanism. The efficacy of Paxlovid to novel virus mutants is also overviewed.
Collapse
Affiliation(s)
- Miklós Bege
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
- HUN-REN-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
- Institute of Healthcare Industry, University of Debrecen, Nagyerdei krt 98, 4032 Debrecen, Hungary
| | - Anikó Borbás
- Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary;
- HUN-REN-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, 4032 Debrecen, Hungary
- National Laboratory of Virology, University of Pécs, Ifjúság útja 20, 7624 Pécs, Hungary
| |
Collapse
|
8
|
Hoseininezhad-Namin MS, Rahimpour E, Jouyban A. Favipiravir, remdesivir, and lopinavir: metabolites, degradation products and their analytical methods. Drug Metab Rev 2024; 56:127-144. [PMID: 38445647 DOI: 10.1080/03602532.2024.2326415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 02/23/2024] [Indexed: 03/07/2024]
Abstract
Severe acute respiratory syndrome 2 (SARS-CoV-2) caused the emergence of the COVID-19 pandemic all over the world. Several studies have suggested that antiviral drugs such as favipiravir (FAV), remdesivir (RDV), and lopinavir (LPV) may potentially prevent the spread of the virus in the host cells and person-to-person transmission. Simultaneously with the widespread use of these drugs, their stability and action mechanism studies have also attracted the attention of many researchers. This review focuses on the action mechanism, metabolites and degradation products of these antiviral drugs (FAV, RDV and LPV) and demonstrates various methods for their quantification and discrimination in the different biological samples. Herein, the instrumental methods for analysis of the main form of drugs or their metabolite and degradation products are classified into two types: optical and chromatography methods which the last one in combination with various detectors provides a powerful method for routine and stability analyses. Some representative studies are reported in this review and the details of them are carefully explained. It is hoped that this review will be a good guideline study and provide a better understanding of these drugs from the aspects investigated in this study.
Collapse
Affiliation(s)
- Mir Saleh Hoseininezhad-Namin
- Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elaheh Rahimpour
- Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abolghasem Jouyban
- Pharmaceutical Analysis Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
9
|
Sakellariou E, Argyropoulou E, Karampinas P, Galanis A, Varsamos I, Giannatos V, Vasiliadis E, Kaspiris A, Vlamis J, Pneumaticos S. A Comprehensive Review of COVID-19-Infection- and Steroid-Treatment-Associated Bone Avascular Necrosis: A Multi-Study Analysis. Diagnostics (Basel) 2024; 14:247. [PMID: 38337763 PMCID: PMC10855439 DOI: 10.3390/diagnostics14030247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
BACKGROUND The COVID-19 pandemic has presented numerous challenges to the global healthcare system and emerging evidence suggests a potential link between COVID-19 treatment, specifically steroid therapy, and the development of avascular necrosis (AVN) of the hip. This review aims to provide a comprehensive overview of recent studies and case reports investigating the relationship between COVID-19, corticosteroid therapy, and the development of AVN. Understanding the nuances of AVN in the context of COVID-19 is crucial for healthcare professionals to navigate treatment decisions and mitigate potential complications. MATERIALS AND METHODS The Preferred Reporting Items for Systematic Reviews and a Meta-Analysis (PRISMA) were used in the systematic review until 1 September 2023. The full texts of the remaining twenty-three (n = 23) articles were independently reviewed by the authors of this review. CONCLUSIONS The association between steroid therapy for COVID-19 and the development of hip AVN is a noteworthy concern even though no relationship is evident between the duration of treatment, cumulative dosage of medication, maximum daily dosage received, and presence of AVN. Further research with larger cohorts and long-term follow up is needed to better understand the causative relationship and optimal management strategies for hip AVN in the context of COVID-19 and steroid therapy.
Collapse
Affiliation(s)
- Evangelos Sakellariou
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| | - Evangelia Argyropoulou
- Department of Orthopaedics and Traumatology, University General Hospital of Patras, 26504 Patras, Greece;
| | - Panagiotis Karampinas
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| | - Athanasios Galanis
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| | - Iordanis Varsamos
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| | - Vasileios Giannatos
- Department of Orthopaedics and Traumatology, University General Hospital of Patras, 26504 Patras, Greece;
| | - Elias Vasiliadis
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| | - Angelos Kaspiris
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| | - John Vlamis
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| | - Spiros Pneumaticos
- Department of Orthopaedic Surgery, National & Kapodistrian University of Athens, KAT General Hospital, 14561 Athens, Greece; (E.S.); (P.K.); (A.G.); (I.V.); (E.V.); (A.K.); (J.V.); (S.P.)
| |
Collapse
|
10
|
Mia ME, Howlader M, Akter F, Hossain MM. Preclinical and Clinical Investigations of Potential Drugs and Vaccines for COVID-19 Therapy: A Comprehensive Review With Recent Update. CLINICAL PATHOLOGY (THOUSAND OAKS, VENTURA COUNTY, CALIF.) 2024; 17:2632010X241263054. [PMID: 39070952 PMCID: PMC11282570 DOI: 10.1177/2632010x241263054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Accepted: 06/03/2024] [Indexed: 07/30/2024]
Abstract
The COVID-19 pandemic-led worldwide healthcare crisis necessitates prompt societal, ecological, and medical efforts to stop or reduce the rising number of fatalities. Numerous mRNA based vaccines and vaccines for viral vectors have been licensed for use in emergencies which showed 90% to 95% efficacy in preventing SARS-CoV-2 infection. However, safety issues, vaccine reluctance, and skepticism remain major concerns for making mass vaccination a successful approach to treat COVID-19. Hence, alternative therapeutics is needed for eradicating the global burden of COVID-19 from developed and low-resource countries. Repurposing current medications and drug candidates could be a more viable option for treating SARS-CoV-2 as these therapies have previously passed a number of significant checkpoints for drug development and patient care. Besides vaccines, this review focused on the potential usage of alternative therapeutic agents including antiviral, antiparasitic, and antibacterial drugs, protease inhibitors, neuraminidase inhibitors, and monoclonal antibodies that are currently undergoing preclinical and clinical investigations to assess their effectiveness and safety in the treatment of COVID-19. Among the repurposed drugs, remdesivir is considered as the most promising agent, while favipiravir, molnupiravir, paxlovid, and lopinavir/ritonavir exhibited improved therapeutic effects in terms of elimination of viruses. However, the outcomes of treatment with oseltamivir, umifenovir, disulfiram, teicoplanin, and ivermectin were not significant. It is noteworthy that combining multiple drugs as therapy showcases impressive effectiveness in managing individuals with COVID-19. Tocilizumab is presently employed for the treatment of patients who exhibit COVID-19-related pneumonia. Numerous antiviral drugs such as galidesivir, griffithsin, and thapsigargin are under clinical trials which could be promising for treating COVID-19 individuals with severe symptoms. Supportive treatment for patients of COVID-19 may involve the use of corticosteroids, convalescent plasma, stem cells, pooled antibodies, vitamins, and natural substances. This study provides an updated progress in SARS-CoV-2 medications and a crucial guide for inventing novel interventions against COVID-19.
Collapse
Affiliation(s)
- Md. Easin Mia
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Mithu Howlader
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Farzana Akter
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md. Murad Hossain
- Department of Biotechnology and Genetic Engineering, Noakhali Science and Technology University, Noakhali, Bangladesh
| |
Collapse
|
11
|
Arman BY, Brun J, Hill ML, Zitzmann N, von Delft A. An Update on SARS-CoV-2 Clinical Trial Results-What We Can Learn for the Next Pandemic. Int J Mol Sci 2023; 25:354. [PMID: 38203525 PMCID: PMC10779148 DOI: 10.3390/ijms25010354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/21/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic has claimed over 7 million lives worldwide, providing a stark reminder of the importance of pandemic preparedness. Due to the lack of approved antiviral drugs effective against coronaviruses at the start of the pandemic, the world largely relied on repurposed efforts. Here, we summarise results from randomised controlled trials to date, as well as selected in vitro data of directly acting antivirals, host-targeting antivirals, and immunomodulatory drugs. Overall, repurposing efforts evaluating directly acting antivirals targeting other viral families were largely unsuccessful, whereas several immunomodulatory drugs led to clinical improvement in hospitalised patients with severe disease. In addition, accelerated drug discovery efforts during the pandemic progressed to multiple novel directly acting antivirals with clinical efficacy, including small molecule inhibitors and monoclonal antibodies. We argue that large-scale investment is required to prepare for future pandemics; both to develop an arsenal of broad-spectrum antivirals beyond coronaviruses and build worldwide clinical trial networks that can be rapidly utilised.
Collapse
Affiliation(s)
- Benediktus Yohan Arman
- Antiviral Drug Discovery Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; (J.B.); (N.Z.)
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
| | - Juliane Brun
- Antiviral Drug Discovery Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; (J.B.); (N.Z.)
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
| | - Michelle L. Hill
- Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK;
| | - Nicole Zitzmann
- Antiviral Drug Discovery Unit, Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK; (J.B.); (N.Z.)
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
| | - Annette von Delft
- Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QU, UK
- Centre for Medicine Discovery, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK
| |
Collapse
|
12
|
Bostanghadiri N, Ziaeefar P, Mofrad MG, Yousefzadeh P, Hashemi A, Darban-Sarokhalil D. COVID-19: An Overview of SARS-CoV-2 Variants-The Current Vaccines and Drug Development. BIOMED RESEARCH INTERNATIONAL 2023; 2023:1879554. [PMID: 37674935 PMCID: PMC10480030 DOI: 10.1155/2023/1879554] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 07/07/2023] [Accepted: 08/04/2023] [Indexed: 09/08/2023]
Abstract
The world is presently in crisis facing an outbreak of a health-threatening microorganism known as COVID-19, responsible for causing uncommon viral pneumonia in humans. The virus was first reported in Wuhan, China, in early December 2019, and it quickly became a global concern due to the pandemic. Challenges in this regard have been compounded by the emergence of several variants such as B.1.1.7, B.1.351, P1, and B.1.617, which show an increase in transmission power and resistance to therapies and vaccines. Ongoing researches are focused on developing and manufacturing standard treatment strategies and effective vaccines to control the pandemic. Despite developing several vaccines such as Pfizer/BioNTech and Moderna approved by the U.S. Food and Drug Administration (FDA) and other vaccines in phase 4 clinical trials, preventive measures are mandatory to control the COVID-19 pandemic. In this review, based on the latest findings, we will discuss different types of drugs as therapeutic options and confirmed or developing vaccine candidates against SARS-CoV-2. We also discuss in detail the challenges posed by the variants and their effect on therapeutic and preventive interventions.
Collapse
Affiliation(s)
- Narjess Bostanghadiri
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Pardis Ziaeefar
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Morvarid Golrokh Mofrad
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | - Parsa Yousefzadeh
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Hashemi
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Darban-Sarokhalil
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
13
|
Alabdalaali MM, Hadi AM. A Comparative Study of Antiretroviral (Lopinavir/Ritonavir) and Remdesivir Used in the Pandemic in Iraq on the Clinical Outcome in Patients with SARS-CoV-2. ARCHIVES OF RAZI INSTITUTE 2023; 78:935-941. [PMID: 38028857 PMCID: PMC10657950 DOI: 10.22092/ari.2022.360354.2574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/26/2022] [Indexed: 12/01/2023]
Abstract
The SARS-CoV-2 virus, which emerged in December 2019, has infected millions worldwide and caused many deaths. Due to its high mortality rate, several studies assessed the effectiveness of different drugs against COVID-19, mainly in reducing the hospitalization rate among the elderly and compromised patients. Lopinavir-ritonavir combination and remdesivir were among the medications used to treat COVID-19. Due to considerable differences in the effectiveness and clinical outcomes of the two treatments, this study aimed to compare the clinical outcomes between COVID-19 patients treated with antiretrovirals (lopinavir-ritonavir) and remdesivir. A total of 33 patients on lopinavir-ritonavir and 35 on remdesivir were selected for this study. A retrospective comparative analysis was conducted based on demographic characteristics, hospital stay, laboratory parameters of C-reactive protein (CRP) and plasma blood oxygen saturation (SPO2), clinical treatment, and a clinical outcome assessment extracted from hospital archive data. Both treatments improved patient outcomes, yet there was a significant difference between lopinavir-ritonavir and remdesivir groups in platelet count, CRP, SPO2, and monocyte results, with remdesivir showing better clinical outcomes. No significant difference was reported in white blood cells, lymphopenia, and lactate dehydrogenase between the two treatments. It is still necessary to conduct further research to determine how effective the two treatments are in treating severe COVID-19 cases due to the limited number of available studies and the inconsistency in research methods and measurements.
Collapse
Affiliation(s)
| | - A M Hadi
- College of Pharmacy, University of Basra, Basra, Iraq
| |
Collapse
|
14
|
Hashemian SMR, Sheida A, Taghizadieh M, Memar MY, Hamblin MR, Bannazadeh Baghi H, Sadri Nahand J, Asemi Z, Mirzaei H. Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy? Biomed Pharmacother 2023; 162:114367. [PMID: 37018987 PMCID: PMC9899776 DOI: 10.1016/j.biopha.2023.114367] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/22/2023] [Accepted: 02/03/2023] [Indexed: 02/08/2023] Open
Abstract
Despite the need for novel, effective therapeutics for the COVID-19 pandemic, no curative regimen is yet available, therefore patients are forced to rely on supportive and nonspecific therapies. Some SARS-CoV-2 proteins, like the 3 C-like protease (3CLpro) or the major protease (Mpro), have been identified as promising targets for antiviral drugs. The Mpro has major a role in protein processing as well as pathogenesis of the virus, and could be a useful therapeutic target. The antiviral drug nirmatrelvir can keep SARS-CoV-2 from replicating through inhibiting Mpro. Nirmatrelvir was combined with another HIV protease inhibitor, ritonavir, to create Paxlovid (Nirmatrelvir/Ritonavir). The metabolizing enzyme cytochrome P450 3 A is inhibited by ritonavir to lengthen the half-life of nirmatrelvir, so rintonavir acts as a pharmacological enhancer. Nirmatrelvir exhibits potent antiviral activity against current coronavirus variants, despite significant alterations in the SARS-CoV-2 viral genome. Nevertheless, there are still several unanswered questions. This review summarizes the current literature on nirmatrelvir and ritonavir efficacy in treating SARS-CoV-2 infection, and also their safety and possible side effects.
Collapse
Affiliation(s)
- Seyed Mohammad Reza Hashemian
- Critical Care Department, National Research Institute ofTuberculosis and Lung Disease, Shahid Beheshti University of Medical Science,Tehran, Iran; Chronic Respiratory Disease Research Center, National ResearchInstitute of Tuberculosis and Lung Disease, Shahid Beheshti University ofMedical Science, Tehran, Iran
| | - Amirhossein Sheida
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan Universityof Medical Sciences, Kashan, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women'sHealth Research Zahra, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research Center, Tabriz Universityof Medical Sciences, Tabriz, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Hossein Bannazadeh Baghi
- Infectious and Tropical Diseases Research Center, Tabriz Universityof Medical Sciences, Tabriz, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz Universityof Medical Sciences, Tabriz, Iran.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
| |
Collapse
|
15
|
Bavaro DF, Diella L, Belati A, Metrangolo G, De Santis L, Spada V, Camporeale M, Dargenio A, Brindicci G, Balena F, Fiordelisi D, Signorile F, Loseto G, Pasciolla C, Minoia C, Attolico I, Perrone T, Simone S, Rendina M, Giovine N, Di Gennaro F, Musto P, Guarini A, Di Leo A, Gesualdo L, Dell'Aera M, Saracino A. Efficacy of Remdesivir and Neutralizing Monoclonal Antibodies in Monotherapy or Combination Therapy in Reducing the Risk of Disease Progression in Elderly or Immunocompromised Hosts Hospitalized for COVID-19: A Single Center Retrospective Study. Viruses 2023; 15:v15051199. [PMID: 37243285 DOI: 10.3390/v15051199] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2023] [Revised: 05/16/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
INTRODUCTION Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking. METHODS All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate-multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed. RESULTS Overall, 331 subjects were included; their median (q1-q3) age was 71 (51-80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3-11%) and 14% (95%CI = 3-25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02-0.77) when compared with monotherapy. CONCLUSIONS REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.
Collapse
Affiliation(s)
- Davide Fiore Bavaro
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Lucia Diella
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Alessandra Belati
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Giuliana Metrangolo
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Laura De Santis
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Vito Spada
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Michele Camporeale
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Angelo Dargenio
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Gaetano Brindicci
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Flavia Balena
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Deborah Fiordelisi
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Fabio Signorile
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Giacomo Loseto
- Hematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy
| | - Crescenza Pasciolla
- Hematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy
| | - Carla Minoia
- Hematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy
| | - Immacolata Attolico
- Unit of Hematology and Stem Cell Transplantation, AOUC Policlinic, 70124 Bari, Italy
| | - Tommasina Perrone
- Unit of Hematology and Stem Cell Transplantation, AOUC Policlinic, 70124 Bari, Italy
| | - Simona Simone
- Nephrology Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Maria Rendina
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
| | - Nicoletta Giovine
- Hospital Pharmacy Department, University Hospital of Bari, 70124 Bari, Italy
| | - Francesco Di Gennaro
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| | - Pellegrino Musto
- Unit of Hematology and Stem Cell Transplantation, AOUC Policlinic, 70124 Bari, Italy
- Department of Precision and Regenerative Medicine and Ionian Area University of Bari and Unit of Hematology and Stem Cell Transplantation, AOUC Policlinico, 70124 Bari, Italy
| | - Attilio Guarini
- Hematology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy
| | - Alfredo Di Leo
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy
| | - Loreto Gesualdo
- Nephrology Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, 70124 Bari, Italy
| | - Maria Dell'Aera
- Hospital Pharmacy Department, University Hospital of Bari, 70124 Bari, Italy
| | - Annalisa Saracino
- Clinic of Infectious Diseases, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Piazza G. Cesare 11, 70124 Bari, Italy
| |
Collapse
|
16
|
Domínguez-García P, Rodríguez RR, Barata C, Gómez-Canela C. Presence and toxicity of drugs used to treat SARS-CoV-2 in Llobregat River, Catalonia, Spain. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:49487-49497. [PMID: 36780086 PMCID: PMC9924204 DOI: 10.1007/s11356-023-25512-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 01/19/2023] [Indexed: 04/16/2023]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the on-going COVID-19 pandemic. In March 2020, it was declared global pandemic, causing millions of deaths. An evident tendency of global pharmaceutical consumption due to COVID-19 pandemic should be seen worldwide, and this increase might suppose an environmental threat. Pharmaceuticals administrated at home or in pharmacies are excreted by faeces and urine after consumption, and wastewater treatment plants (WWTPs) are not able to remove all pharmaceuticals residues that eventually will end up in the aquatic media (rivers and sea). For this reason, analytical techniques such as liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) have become prominent to identify and quantify pharmaceuticals residues in aquatic matrices. In view of the scarce data on the occurrence of pharmaceuticals used as COVID-19 treatment, the aim of the present study was to evaluate the presence of these class of pharmaceuticals in river water which were dexamethasone, prednisone, ciprofloxacin, levofloxacin, remdesivir, ritonavir, lopinavir, acetaminophen, hydroxychloroquine, chloroquine and cloperastine, their toxicity in the aquatic environment using D. magna and to perform an exhaustive risk assessment in seven points of the Llobregat river basin. Dexamethasone, cloperastine and acetaminophen were the pharmaceuticals with higher concentrations, showing mean levels between 313 and 859 ng L-1.
Collapse
Affiliation(s)
- Pol Domínguez-García
- Department of Analytical and Applied Chemistry, School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, Via Augusta 390, 08017, Barcelona, Spain
| | - Reinerio Rolando Rodríguez
- Department of Analytical and Applied Chemistry, School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, Via Augusta 390, 08017, Barcelona, Spain
| | - Carlos Barata
- Institute for Environmental Assessment and Water Research (IDAEA-CSIC), Jordi Girona 18, 08034, Barcelona, Spain
| | - Cristian Gómez-Canela
- Department of Analytical and Applied Chemistry, School of Engineering, Institut Químic de Sarrià-Universitat Ramon Llull, Via Augusta 390, 08017, Barcelona, Spain.
| |
Collapse
|
17
|
Gildea DT, Woo SM, O’Connor CE, Rangnekar AS. COVID-19-Associated Liver Injury. Hepat Med 2023; 15:1-9. [PMID: 36852138 PMCID: PMC9960793 DOI: 10.2147/hmer.s384108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 02/11/2023] [Indexed: 03/01/2023] Open
Abstract
This review analyzes data regarding liver injury associated with COVID-19 infection. We discuss reported effects on the liver from both COVID-19 and COVID-19 treatment as well as pathophysiology, review the potential role of drug-induced liver injury as an etiology of COVID-19-associated liver injury, and touch on other reports of significant outcomes including COVID-19 cholangiopathy and autoimmune hepatitis. Finally, we review the implications of COVID-19 infection in liver transplant recipients.
Collapse
Affiliation(s)
- Daniel T Gildea
- Department of Internal Medicine, MedStar Georgetown University Hospital, Washington, DC, USA,Correspondence: Daniel T Gildea, Tel +1 302-985-7777, Email
| | - Stephanie M Woo
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC, USA
| | | | - Amol S Rangnekar
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC, USA
| |
Collapse
|
18
|
Almeida B, Domingues C, Mascarenhas-Melo F, Silva I, Jarak I, Veiga F, Figueiras A. The Role of Cyclodextrins in COVID-19 Therapy-A Literature Review. Int J Mol Sci 2023; 24:2974. [PMID: 36769299 PMCID: PMC9918006 DOI: 10.3390/ijms24032974] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/05/2023] Open
Abstract
Coronavirus disease-19 (COVID-19) emerged in December 2019 and quickly spread, giving rise to a pandemic crisis. Therefore, it triggered tireless efforts to identify the mechanisms of the disease, how to prevent and treat it, and to limit and hamper its global dissemination. Considering the above, the search for prophylactic approaches has led to a revolution in the reglementary pharmaceutical pipeline, with the approval of vaccines against COVID-19 in an unprecedented way. Moreover, a drug repurposing scheme using regulatory-approved antiretroviral agents is also being pursued. However, their physicochemical characteristics or reported adverse events have sometimes limited their use. Hence, nanotechnology has been employed to potentially overcome some of these challenges, particularly cyclodextrins. Cyclodextrins are cyclic oligosaccharides that present hydrophobic cavities suitable for complexing several drugs. This review, besides presenting studies on the inclusion of antiviral drugs in cyclodextrins, aims to summarize some currently available prophylactic and therapeutic schemes against COVID-19, highlighting those that already make use of cyclodextrins for their complexation. In addition, some new therapeutic approaches are underscored, and the potential application of cyclodextrins to increase their promising application against COVID-19 will be addressed. This review describes the instances in which the use of cyclodextrins promotes increased bioavailability, antiviral action, and the solubility of the drugs under analysis. The potential use of cyclodextrins as an active ingredient is also covered. Finally, toxicity and regulatory issues as well as future perspectives regarding the use of cyclodextrins in COVID-19 therapy will be provided.
Collapse
Affiliation(s)
- Beatriz Almeida
- Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Cátia Domingues
- Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
- LAQV-REQUIMTE, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
- Institute for Clinical and Biomedical Research (iCBR) Area of Environment Genetics and Oncobiology (CIMAGO), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Filipa Mascarenhas-Melo
- Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
- LAQV-REQUIMTE, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Inês Silva
- Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ivana Jarak
- Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Francisco Veiga
- Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
- LAQV-REQUIMTE, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| | - Ana Figueiras
- Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
- LAQV-REQUIMTE, Laboratory of Drug Development and Technologies, Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal
| |
Collapse
|
19
|
Parchwani D, Sonagra AD, Dholariya S, Motiani A, Singh R. COVID-19-related liver injury: Focus on genetic and drug-induced perspectives. World J Virol 2023; 12:53-67. [PMID: 36743658 PMCID: PMC9896591 DOI: 10.5501/wjv.v12.i1.53] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/15/2022] [Accepted: 12/01/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Empirical use of potentially hepatotoxic drugs in the management of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is considered as one of the major etiopathogenetic factors for liver injury. Recent evidence has shown that an underlying genetic factor may also occur. Hence, it is important to understand the host genetics and iatrogenic-based mechanisms for liver dysfunction to make timely remedial measures. AIM To investigate drug-induced and genetic perspectives for the development of coronavirus disease 2019 (COVID-19)-related liver injury. METHODS Reference Citation Analysis, PubMed, Google Scholar and China National Knowledge Infrastructure were searched by employing the relevant MeSH keywords and pertaining data of the duration, site and type of study, sample size with any subgroups and drug-induced liver injury outcome. Genetic aspects were extracted from the most current pertinent publications. RESULTS In all studies, the hepatic specific aminotransferase and other biochemical indices were more than their prescribed upper normal limit in COVID-19 patients and were found to be significantly related with the gravity of disease, hospital stay, number of COVID-19 treatment drugs and worse clinical outcomes. In addition, membrane bound O-acyltransferase domain containing 7 rs641738, rs11385942 G>GA at chromosome 3 gene cluster and rs657152 C>A at ABO blood locus was significantly associated with severity of livery injury in admitted SARS-CoV-2 patients. CONCLUSION Hepatic dysfunction in SARS-CoV-2 infection could be the result of individual drugs or due to drug-drug interactions and may be in a subset of patients with a genetic propensity. Thus, serial estimation of hepatic indices in hospitalized SARS-CoV-2 patients should be done to make timely corrective actions for iatrogenic causes to avoid clinical deterioration. Additional molecular and translational research is warranted in this regard.
Collapse
Affiliation(s)
- Deepak Parchwani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Amit D Sonagra
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Sagar Dholariya
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Anita Motiani
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| | - Ragini Singh
- Department of Biochemistry, All India Institute of Medical Sciences, Rajkot 360001, India
| |
Collapse
|
20
|
Pauly I, Kumar Singh A, Kumar A, Singh Y, Thareja S, Kamal MA, Verma A, Kumar P. Current Insights and Molecular Docking Studies of the Drugs under Clinical Trial as RdRp Inhibitors in COVID-19 Treatment. Curr Pharm Des 2023; 28:3677-3705. [PMID: 36345244 DOI: 10.2174/1381612829666221107123841] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/08/2022] [Accepted: 09/19/2022] [Indexed: 11/10/2022]
Abstract
Study Background & Objective: After the influenza pandemic (1918), COVID-19 was declared a Vth pandemic by the WHO in 2020. SARS-CoV-2 is an RNA-enveloped single-stranded virus. Based on the structure and life cycle, Protease (3CLpro), RdRp, ACE2, IL-6, and TMPRSS2 are the major targets for drug development against COVID-19. Pre-existing several drugs (FDA-approved) are used to inhibit the above targets in different diseases. In coronavirus treatment, these drugs are also in different clinical trial stages. Remdesivir (RdRp inhibitor) is the only FDA-approved medicine for coronavirus treatment. In the present study, by using the drug repurposing strategy, 70 preexisting clinical or under clinical trial molecules were used in scrutiny for RdRp inhibitor potent molecules in coronavirus treatment being surveyed via docking studies. Molecular simulation studies further confirmed the binding mechanism and stability of the most potent compounds. MATERIAL AND METHODS Docking studies were performed using the Maestro 12.9 module of Schrodinger software over 70 molecules with RdRp as the target and remdesivir as the standard drug and further confirmed by simulation studies. RESULTS The docking studies showed that many HIV protease inhibitors demonstrated remarkable binding interactions with the target RdRp. Protease inhibitors such as lopinavir and ritonavir are effective. Along with these, AT-527, ledipasvir, bicalutamide, and cobicistat showed improved docking scores. RMSD and RMSF were further analyzed for potent ledipasvir and ritonavir by simulation studies and were identified as potential candidates for corona disease. CONCLUSION The drug repurposing approach provides a new avenue in COVID-19 treatment.
Collapse
Affiliation(s)
- Irine Pauly
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Yogesh Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Mohammad A Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jaddah, Saudi Arabia.,Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia.,Novel Global Community Educational Foundation, Australia Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, Australia
| | - Amita Verma
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| |
Collapse
|
21
|
Nag A, Dasgupta A, Sengupta S, Lai TK, Acharya K. An in-silico pharmacophore-based molecular docking study to evaluate the inhibitory potentials of novel fungal triterpenoid Astrakurkurone analogues against a hypothetical mutated main protease of SARS-CoV-2 virus. Comput Biol Med 2023; 152:106433. [PMID: 36565483 PMCID: PMC9767885 DOI: 10.1016/j.compbiomed.2022.106433] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 11/21/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND The main protease is an important structural protein of SARS-CoV-2, essential for its survivability inside a human host. Considering current vaccines' limitations and the absence of approved therapeutic targets, Mpro may be regarded as the potential candidate drug target. Novel fungal phytocompound Astrakurkurone may be studied as the potential Mpro inhibitor, considering its medicinal properties reported elsewhere. METHODS In silico molecular docking was performed with Astrakurkurone and its twenty pharmacophore-based analogues against the native Mpro protein. A hypothetical Mpro was also constructed with seven mutations and targeted by Astrakurkurone and its analogues. Furthermore, multiple parameters such as statistical analysis (Principal Component Analysis), pharmacophore alignment, and drug likeness evaluation were performed to understand the mechanism of protein-ligand molecular interaction. Finally, molecular dynamic simulation was done for the top-ranking ligands to validate the result. RESULT We identified twenty Astrakurkurone analogues through pharmacophore screening methodology. Among these twenty compounds, two analogues namely, ZINC89341287 and ZINC12128321 showed the highest inhibitory potentials against native and our hypothetical mutant Mpro, respectively (-7.7 and -7.3 kcal mol-1) when compared with the control drug Telaprevir (-5.9 and -6.0 kcal mol-1). Finally, we observed that functional groups of ligands namely two aromatic and one acceptor groups were responsible for the residual interaction with the target proteins. The molecular dynamic simulation further revealed that these compounds could make a stable complex with their respective protein targets in the near-native physiological condition. CONCLUSION To conclude, Astrakurkurone analogues ZINC89341287 and ZINC12128321 can be potential therapeutic agents against the highly infectious SARS-CoV-2 virus.
Collapse
Affiliation(s)
- Anish Nag
- Department of Life Sciences, CHRIST (Deemed to be University), Bangalore, Karnataka, India
| | - Adhiraj Dasgupta
- Department of Botany, University of Calcutta, Kolkata, West Bengal, India
| | - Sutirtha Sengupta
- Department of Life Sciences, CHRIST (Deemed to be University), Bangalore, Karnataka, India
| | - Tapan Kumar Lai
- Department of Chemistry, Vidyasagar Metropolitan College, Kolkata, West Bengal, India
| | - Krishnendu Acharya
- Department of Botany, University of Calcutta, Kolkata, West Bengal, India.
| |
Collapse
|
22
|
Sahebkar A, Jamialahmadi T, Rahmoune H, Guest PC. Long-Term Vaccination and Treatment Strategies for COVID-19 Disease and Future Coronavirus Pandemics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1412:27-49. [PMID: 37378760 DOI: 10.1007/978-3-031-28012-2_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
The appearance of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased infectivity and immune escape capabilities has allowed continuation of the COVID-19 pandemic for the foreseeable future. This review describes the worldwide efforts aimed at developing new vaccination and treatment strategies to keep pace with these variants as they emerge. In the case of vaccines and monoclonal antibody-based therapeutics, we describe the development of variant-specific, multivalent, and universal coronavirus directed approaches. Existing treatment approaches consist of repurposed medicines, such as antiviral compounds and anti-inflammatory agents, although efforts are underway to develop new ways of preventing or minimizing the effects of infection with the use of small molecules that disrupt binding the SARS-CoV-2 virus to host cells. Finally, we discuss the preclinical and clinical testing of natural products from medicinal herbs and spices, which have demonstrated anti-inflammatory and antiviral properties and therefore show potential as novel and safe COVID-19 treatment approaches.
Collapse
Affiliation(s)
- Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Medicine, The University of Western Australia, Perth, WA, Australia
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hassan Rahmoune
- Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK
| | - Paul C Guest
- Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
- Department of Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
- Laboratory of Translational Psychiatry, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
| |
Collapse
|
23
|
Khwaza V, Buyana B, Nqoro X, Peter S, Mbese Z, Feketshane Z, Alven S, Aderibigbe BA. Strategies for delivery of antiviral agents. VIRAL INFECTIONS AND ANTIVIRAL THERAPIES 2023:407-492. [DOI: 10.1016/b978-0-323-91814-5.00018-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
|
24
|
Zemskov DN, Balykova LA, Radaeva OA, Zaslavskaya KY, Bely PA, Semenova EV, Shirmankina MV, Koryanova KN. CURRENT ASPECTS OF ETIOTROPIC COVID-19 THERAPY. PHARMACY & PHARMACOLOGY 2022. [DOI: 10.19163/2307-9266-2022-10-5-432-445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Since the beginning of the pandemic, repeated attempts have been made to develop etiotropic therapy for a novel coronavirus infection. Hydroxychloroquine, lopinavir/ritonavir, etc. derivatives were used as antiviral agents, however, they demonstrated a low efficiency and an insufficient safety. In this connection, other groups of drugs with a more effective and safe pharmacological profile are currently being actively used.The aim of the study was to analyze the literature references on the efficacy and safety of antiviral drugs for the COVID-19 treatment.Materials and methods. When searching for the materials for the review article writing, such abstract databases as PubMed, Google Scholar, e-Library were used. The search was carried out on publications for the period from January 2020 to september 2022. The key queries were: COVID-19, etiotropic therapy; immunological drugs; antiviral drugs; interferons.Results. Currently, there are various degrees of effective etiotropic drugs for the treatment of COVID-19 patients. The review has considered a few groups of drugs that are of interest from the point of view of etiotropic therapy: immunological drugs (anticovid plasma, the drugs based on antiviral antibodies, the drugs of recombinant interferons-α2 and -β1, as well as interferon inducers, i.e., the drugs based on double-stranded RNA sodium salt, and others); drugs that block the penetration of the virus into the cell (umifenovir); the drugs that disrupt the process of the viral replication (favipiravir, remdesivir, molnupiravir, nirmatrelvir/ritonavir).Conclusion. Synthetic antivirals, in particular favipiravir, molnupiravir, remdesivir, and nirmatrelvir/ritonavir, have the largest evidence base for their efficacy and safety. The search for new effective and safe etiotropic drugs for the treatment of COVID-19, as well as the collection and analysis of post-registration data on the drugs already used in clinical practice, continues.
Collapse
Affiliation(s)
| | | | | | | | - P. A. Bely
- Evdokimov Moscow State Medical and Dental University
| | | | | | - K. N. Koryanova
- Pyatigorsk Medical and Pharmaceutical Institute – branch of Volgograd State Medical University
| |
Collapse
|
25
|
Gholizadeh O, Yasamineh S, Amini P, Afkhami H, Delarampour A, Akbarzadeh S, Karimi Matloub R, Zahedi M, Hosseini P, Hajiesmaeili M, Poortahmasebi V. Therapeutic and diagnostic applications of nanoparticles in the management of COVID-19: a comprehensive overview. Virol J 2022; 19:206. [PMID: 36463213 PMCID: PMC9719161 DOI: 10.1186/s12985-022-01935-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/25/2022] [Indexed: 12/04/2022] Open
Abstract
In December 2019, Coronavirus Disease 2019 (COVID-19) was reported in Wuhan, China. Comprehensive strategies for quick identification, prevention, control, and remedy of COVID-19 have been implemented until today. Advances in various nanoparticle-based technologies, including organic and inorganic nanoparticles, have created new perspectives in this field. These materials were extensively used to control COVID-19 because of their specific attribution to preparing antiviral face masks, various safety sensors, etc. In this review, the most current nanoparticle-based technologies, applications, and achievements against the coronavirus were summarized and highlighted. This paper also offers nanoparticle preventive, diagnostic, and treatment options to combat this pandemic.
Collapse
Affiliation(s)
- Omid Gholizadeh
- Department of Bacteriology and Virology, Faculty of Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Parya Amini
- Department of Microbiology, School of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hamed Afkhami
- Department of Medical Microbiology, Faculty of Medicine, Shahed University of Medical Science, Tehran, Iran
| | - Abbasali Delarampour
- Microbiology Department, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
| | - Sama Akbarzadeh
- Department of Animal Biology, Faculty of Natural Science, University of Tabriz, Tabriz, Iran
| | | | - Mahlagha Zahedi
- Department of Pathology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Parastoo Hosseini
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrnaz Hajiesmaeili
- Department of Microbiology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Vahdat Poortahmasebi
- Department of Bacteriology and Virology, Faculty of Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
26
|
Takayama S, Namiki T, Arita R, Ono R, Kikuchi A, Ohsawa M, Saito N, Suzuki S, Nakae H, Kobayashi S, Yoshino T, Ishigami T, Tanaka K, Nochioka K, Takagi A, Mimura M, Yamaguchi T, Ishii T, Hisanaga A, Mitani K, Ito T. Multicenter, randomized controlled trial of traditional Japanese medicine, kakkonto with shosaikotokakikyosekko, for mild and moderate coronavirus disease patients. Front Pharmacol 2022; 13:1008946. [PMID: 36438822 PMCID: PMC9682103 DOI: 10.3389/fphar.2022.1008946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/07/2022] [Indexed: 07/30/2023] Open
Abstract
The traditional Japanese (Kampo) medicine, kakkonto with shosaikotokakikyosekko, has antiviral and anti-inflammatory effects. In this randomized trial, patients with mild and moderate coronavirus disease (COVID-19) were randomly allocated to the control group receiving conventional treatment for symptom relief such as antipyretics and antitussives or the Kampo group receiving mixed extract granules of kakkonto (2.5 g) and shosaikotokakikyosekko (2.5 g) three times a day for 14 days in addition to conventional treatment. The main outcome was the number of days until total symptom relief. The secondary outcome was the number of days until each symptom's relief and whether the disease progressed to respiratory failure. We enrolled a total of 161 patients (Kampo group, n = 81; control group, n = 80). The results from Kaplan-Meier estimates of symptom relief showed that there are no significant differences between the groups. However, covariate-adjusted cumulative incidence of fever relief considering competitive risk showed that the recovery was significantly faster in the Kampo group than in the control group (HR 1.76, 95% CI 1.03-3.01). Additionally, the risk of disease progression to moderate COVID-19 requiring oxygen inhalation was lower in the Kampo group than in the control group (Risk Difference -0.13, 95% CI -0.27-0.01). No significant drug-related side effects were observed. Kakkonto with shosaikotokakikyosekko is effective for fever relief with suppression of disease progression in COVID-19 patients. Clinical Trial Registration: https://jrct.niph.go.jp/en-latest-detail/jRCTs021200020, identifier [jRCTs021200020].
Collapse
Affiliation(s)
- Shin Takayama
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | - Takao Namiki
- Department of Japanese-Oriental (Kampo) Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Ryutaro Arita
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | - Rie Ono
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | - Akiko Kikuchi
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | - Minoru Ohsawa
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | - Natsumi Saito
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | - Satoko Suzuki
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | - Hajime Nakae
- Department of Emergency and Critical Care Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Seiichi Kobayashi
- Department of Respiratory Medicine, Japanese Red Cross Ishinomaki Hospital, Ishinomaki, Japan
| | - Tetsuhiro Yoshino
- Center for Kampo Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tomoaki Ishigami
- Department of Cardiology, Yokohama City University Hospital, Yokohama, Japan
| | - Koichiro Tanaka
- Department of Traditional Medicine, Faculty of Medicine, Toho University, Tokyo, Japan
| | - Kotaro Nochioka
- Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Airi Takagi
- Clinical Research Data Center, Tohoku University Hospital, Sendai, Japan
| | - Masaru Mimura
- Center for Kampo Medicine, Keio University School of Medicine, Tokyo, Japan
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Takuhiro Yamaguchi
- Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tadashi Ishii
- Department of Education and Support for Regional Medicine (General and Kampo medicine), Tohoku University Hospital, Sendai, Japan
| | | | - Kazuo Mitani
- Medical Corporation Mitani Family Clinic, Osaka, Japan
| | | |
Collapse
|
27
|
Abadi B, Aarabi Jeshvaghani AH, Fathalipour H, Dehghan L, Rahimi Sirjani K, Forootanfar H. Therapeutic Strategies in the Fight against COVID-19: From Bench to Bedside. IRANIAN JOURNAL OF MEDICAL SCIENCES 2022; 47:517-532. [PMID: 36380976 PMCID: PMC9652495 DOI: 10.30476/ijms.2021.92662.2396] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/17/2021] [Accepted: 12/10/2021] [Indexed: 06/16/2023]
Abstract
In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China. This virus rapidly spread worldwide and was declared a global pandemic by the World Health Organization (WHO) in March 2020. High incidence, long incubation period, and diverse clinical signs of the disease posed a huge challenge globally. The efforts of health systems have been focused on repurposing existing drugs or developing innovative therapies to reduce the morbidity and mortality associated with SARS-CoV-2. In addition, most of the large pharmaceutical companies are intensely working on vaccine development to swiftly deliver safe and effective vaccines to prevent further spread of the virus. In this review, we will discuss the latest data on therapeutic strategies undergoing clinical trials. Additionally, we will provide a summary of vaccines currently under development.
Collapse
Affiliation(s)
- Banafshe Abadi
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Brain Cancer Research Core, Universal Scientific Education and Research Network, Tehran, Iran
| | | | - Hadis Fathalipour
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
| | - Leili Dehghan
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Hamid Forootanfar
- Pharmaceutical Sciences and Cosmetic Products Research Center, Kerman University of Medical Sciences, Kerman, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| |
Collapse
|
28
|
Lu D, Liu D, Wang X, Liu Y, Liu Y, Ren R, Pang G. Kinetics of Drug Molecule Interactions with a Newly Developed Nano-Gold-Modified Spike Protein Electrochemical Receptor Sensor. BIOSENSORS 2022; 12:888. [PMID: 36291025 PMCID: PMC9599096 DOI: 10.3390/bios12100888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/15/2022] [Accepted: 10/16/2022] [Indexed: 06/16/2023]
Abstract
In March 2020, the World Health Organization (WHO) declared COVID-19 a pandemic, and the spike protein has been reported to be an important drug target for anti-COVID-19 treatment. As such, in this study, we successfully developed a novel electrochemical receptor biosensor by immobilizing the SARS-CoV-2 spike protein and using AuNPs-HRP as an electrochemical signal amplification system. Moreover, the time-current method was used to quantify seven antiviral drug compounds, such as arbidol and chloroquine diphosphate. The results show that the spike protein and the drugs are linearly correlated within a certain concentration range and that the detection sensitivity of the sensor is extremely high. In the low concentration range of linear response, the kinetics of receptor-ligand interactions are similar to that of an enzymatic reaction. Among the investigated drug molecules, bromhexine exhibits the smallest Ka value, and thus, is most sensitively detected by the sensor. Hydroxychloroquine exhibits the largest Ka value. Molecular docking simulations of the spike protein with six small-molecule drugs show that residues of this protein, such as Asp, Trp, Asn, and Gln, form hydrogen bonds with the -OH or -NH2 groups on the branched chains of small-molecule drugs. The electrochemical receptor biosensor can directly quantify the interaction between the spike protein and drugs such as abidor and hydroxychloroquine and perform kinetic studies with a limit of detection 3.3 × 10-20 mol/L, which provides a new research method and idea for receptor-ligand interactions and pharmacodynamic evaluation.
Collapse
Affiliation(s)
- Dingqiang Lu
- College of Biotechnology & Food Science, Tianjin University of Commerce, Tianjin 300134, China
- Tianjin Key Laboratory of Food Biotechnology, Tianjin 300134, China
| | - Danyang Liu
- College of Biotechnology & Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Xinqian Wang
- College of Biotechnology & Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Yujiao Liu
- College of Biotechnology & Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Yixuan Liu
- College of Biotechnology & Food Science, Tianjin University of Commerce, Tianjin 300134, China
| | - Ruijuan Ren
- Tianjin Institute for Food Safety Inspection Technology, Tianjin 300134, China
| | - Guangchang Pang
- College of Biotechnology & Food Science, Tianjin University of Commerce, Tianjin 300134, China
- Tianjin Key Laboratory of Food Biotechnology, Tianjin 300134, China
| |
Collapse
|
29
|
Sahin G, Akbal-Dagistan O, Culha M, Erturk A, Basarir NS, Sancar S, Yildiz-Pekoz A. Antivirals and the Potential Benefits of Orally Inhaled Drug Administration in COVID-19 Treatment. J Pharm Sci 2022; 111:2652-2661. [PMID: 35691607 PMCID: PMC9181835 DOI: 10.1016/j.xphs.2022.06.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 06/05/2022] [Accepted: 06/05/2022] [Indexed: 12/25/2022]
Abstract
Coronavirus Disease 2019 (COVID-19) pandemic has been on the agenda of humanity for more than 2 years. In the meantime, the pandemic has caused economic shutdowns, halt of daily lives and global mobility, overcrowding of the healthcare systems, panic, and worse, more than 6 million deaths. Today, there is still no specific therapy for COVID-19. Research focuses on repurposing of antiviral drugs that are licensed or currently in the research phase, with a known systemic safety profile. However, local safety profile should also be evaluated depending on the new indication, administration route and dosage form. Additionally, various vaccines have been developed. But the causative virus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has undergone multiple variations, too. The premise that vaccines may suffice to eradicate new and all variants is unreliable, as they are based on earlier versions of the virus. Therefore, a specific medication therapy for COVID-19 is crucial and needed in order to prevent severe complications of the disease. Even though there is no specific drug that inhibits the replication of the disease-causing virus, among the current treatment options, systemic antivirals are the most medically appropriate. As SARS-CoV-2 directly targets the lungs and initiates lung damage, treating COVID-19 with inhalants can offer many advantages over the enteral/parenteral administration. Inhaled drug delivery provides higher drug concentration, specifically in the pulmonary system. This enables the reduction of systemic side effects and produces a rapid clinical response. In this article, the most frequently (systemically) used antiviral compounds are reviewed including Remdesivir, Favipiravir, Molnupiravir, Lopinavir-Ritonavir, Umifenovir, Chloroquine, Hydroxychloroquine and Heparin. A comprehensive literature search was conducted to provide insight into the potential inhaled use of these antiviral drugs and the current studies on inhalation therapy for COVID-19 was presented. A brief evaluation was also made on the use of inhaler devices in the treatment of COVID-19. Inhaled antivirals paired with suitable inhaler devices should be considered for COVID-19 treatment options.
Collapse
Affiliation(s)
- Gokben Sahin
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey; Trakya University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey
| | - Ozlem Akbal-Dagistan
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey
| | - Meltem Culha
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey
| | - Aybige Erturk
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey; Istinye University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey
| | - Nur Sena Basarir
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey
| | - Serap Sancar
- Istanbul University, Faculty of Science, Department of Molecular Biology, Turkey
| | - Ayca Yildiz-Pekoz
- Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Turkey.
| |
Collapse
|
30
|
Saini J, Kaur P, Malik N, Lakhawat SS, Sharma PK. Antimicrobial peptides: A promising tool to combat multidrug resistance in SARS CoV2 era. Microbiol Res 2022; 265:127206. [PMID: 36162150 PMCID: PMC9491010 DOI: 10.1016/j.micres.2022.127206] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/26/2022] [Accepted: 09/16/2022] [Indexed: 10/25/2022]
Abstract
COVID-19 (Coronavirus Disease 2019), a life-threatening viral infection, is caused by a highly pathogenic virus named SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2). Currently, no treatment is available for COVID-19; hence there is an urgent need to find effective therapeutic drugs to combat COVID-19 pandemic. Considering the fact that the world is facing a major issue of antimicrobial drug resistance, naturally occurring compounds have the potential to achieve this goal. Antimicrobial peptides (AMPs) are naturally occurring antimicrobial agents which are effective against a wide variety of microbial infections. Therefore, the use of AMPs is an attractive therapeutic strategy for the treatment of SARS-CoV-2 infection. This review sheds light on the potential of antimicrobial peptides as antiviral agents followed by a comprehensive description of effective antiviral peptides derived from various natural sources found to be effective against SARS-CoV and other respiratory viruses. It also highlights the mechanisms of action of antiviral peptides with special emphasis on their effectiveness against SARS-CoV-2 infection.
Collapse
Affiliation(s)
- Jasleen Saini
- Department of Biotechnology, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab, India
| | - Pritpal Kaur
- Department of Biotechnology, Sri Guru Granth Sahib World University, Fatehgarh Sahib, Punjab, India
| | - Naveen Malik
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, India
| | | | | |
Collapse
|
31
|
George N, Imran M, Alam Khan S, Al Balushi K, Asdaq SMB, Jomah S. A Spotlight on the Development, Pharmaceutical Trends, Innovations and Patents of Nirmatrelvir (PaxlovidTM). INT J PHARMACOL 2022. [DOI: 10.3923/ijp.2022.1340.1352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
|
32
|
Assmus F, Driouich JS, Abdelnabi R, Vangeel L, Touret F, Adehin A, Chotsiri P, Cochin M, Foo CS, Jochmans D, Kim S, Luciani L, Moureau G, Park S, Pétit PR, Shum D, Wattanakul T, Weynand B, Fraisse L, Ioset JR, Mowbray CE, Owen A, Hoglund RM, Tarning J, de Lamballerie X, Nougairède A, Neyts J, Sjö P, Escudié F, Scandale I, Chatelain E. Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19. Microorganisms 2022; 10:1639. [PMID: 36014057 PMCID: PMC9460261 DOI: 10.3390/microorganisms10081639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 08/03/2022] [Accepted: 08/04/2022] [Indexed: 12/15/2022] Open
Abstract
In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform.
Collapse
Affiliation(s)
- Frauke Assmus
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LG, UK
| | - Jean-Sélim Driouich
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - Rana Abdelnabi
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
| | - Laura Vangeel
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
| | - Franck Touret
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - Ayorinde Adehin
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LG, UK
| | - Palang Chotsiri
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Maxime Cochin
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - Caroline S. Foo
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
| | - Dirk Jochmans
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
| | - Seungtaek Kim
- Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si 13488, Korea
| | - Léa Luciani
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - Grégory Moureau
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - Soonju Park
- Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si 13488, Korea
| | - Paul-Rémi Pétit
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - David Shum
- Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si 13488, Korea
| | - Thanaporn Wattanakul
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Birgit Weynand
- Departmet of Imaging and Pathology, Katholieke Universiteit Leuven, Translational Cell and Tissue Research, 3000 Leuven, Belgium
| | - Laurent Fraisse
- Drugs for Neglected Diseases Initiative (DNDi), 1202 Geneva, Switzerland
| | - Jean-Robert Ioset
- Drugs for Neglected Diseases Initiative (DNDi), 1202 Geneva, Switzerland
| | - Charles E. Mowbray
- Drugs for Neglected Diseases Initiative (DNDi), 1202 Geneva, Switzerland
| | - Andrew Owen
- Centre for Excellence in Long-Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool L69 7ZX, UK
| | - Richard M. Hoglund
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LG, UK
| | - Joel Tarning
- Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7LG, UK
| | - Xavier de Lamballerie
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - Antoine Nougairède
- Unité des Virus Émergents (UVE), Institut de Recherche pour le Développement (IRD), Aix-Marseille University, 190-Inserm 1207, 13005 Marseille, France
| | - Johan Neyts
- Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
- Global Virus Network (GVN), Baltimore, MD 21201, USA
| | - Peter Sjö
- Drugs for Neglected Diseases Initiative (DNDi), 1202 Geneva, Switzerland
| | - Fanny Escudié
- Drugs for Neglected Diseases Initiative (DNDi), 1202 Geneva, Switzerland
| | - Ivan Scandale
- Drugs for Neglected Diseases Initiative (DNDi), 1202 Geneva, Switzerland
| | - Eric Chatelain
- Drugs for Neglected Diseases Initiative (DNDi), 1202 Geneva, Switzerland
| |
Collapse
|
33
|
Postacute sequelae of SARS-CoV-2 infection. Osteonecrosis must not be overlooked. Int J Infect Dis 2022; 121:11-13. [PMID: 35462037 PMCID: PMC9022373 DOI: 10.1016/j.ijid.2022.04.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 04/14/2022] [Accepted: 04/14/2022] [Indexed: 12/14/2022] Open
Abstract
Recovery from COVID-19 is not always uneventful, especially in critically ill hospitalized patients. Persistent symptoms including fatigue/ weakness, shortness of breath, anxiety, and depression have been described at one-year follow-up. Furthermore, symptoms from the musculoskeletal system like joint pain or stiffness are underreported in studies with long-term follow-up of up to one year. Infection with SARS-CoV-2 itself has been associated with endothelial damage, and together with high-dose corticosteroid treatment, it is predisposed to the dissemination of microthrombi and the development of femoral head osteonecrosis (FHOn), as it has been shown during the previous (2003-2004) coronavirus outbreaks. A resurgence of FHOn cases is anticipated but this is not reflected in the existing studies with long-term follow-up. Prompt diagnosis is critical for early treatment and possibly for the hip joint preservation. Patients with COVID-19 treated with corticosteroids should be screened for avascular necrosis early after discharge from the hospital. Every healthcare worker involved in the management of these patients should maintain a high level of suspicion and should be alert when patients report symptoms such as vague aches at the buttocks, hip area, adductors, and/or above the knee. Studies are needed to identify risk factors for FHOn including disease severity, type of steroid, cumulative dose, and duration of treatment.
Collapse
|
34
|
Dzinamarira T, Murewanhema G, Chitungo I, Ngara B, Nkambule SJ, Madziva R, Herrera H, Mukwenha S, Cuadros DF, Iradukunda PG, Mashora M, Tungwarara N, Rwibasira GN, Musuka G. Risk of mortality in HIV-infected COVID-19 patients: A systematic review and meta-analysis. J Infect Public Health 2022; 15:654-661. [PMID: 35617829 PMCID: PMC9110010 DOI: 10.1016/j.jiph.2022.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 04/27/2022] [Accepted: 05/10/2022] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND The relationship between HIV infection and COVID-19 clinical outcomes remains a significant public health research problem. We aimed to determine the association of HIV comorbidity with COVID-19 mortality. METHODS We searched PubMed, Google Scholar and World Health Organization library databases for relevant studies. All searches were conducted from 1st to 7th December 2021. Title, abstract and full text screening was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The relative risk of mortality in HIV-infected COVID-19 patients was computed using a random-effects model. All analyses were performed using Meta and Metasens statistical packages available in R version 4.2.1 software package. The quality of included studies was assessed using the GRADE approach, Egger's test was employed to determine the risk of bias. RESULTS A total of 16 studies were included in this review. Among the COVID-19 patients with HIV infection, the mortality rate due to COVID-19 was 7.97% (4 287/53,801), and among the COVID-19 patients without HIV infection, the mortality rate due to COVID-19 was 0.69% (127, 961/18, 513, 747). In the random effects model, we found no statistically significant relative risk of mortality in HIV-infected COVID-19 patients (RR 1.07, 95% CI 0.86-1.32). The between-studies heterogeneity was substantial (I2 = 91%, P < 0.01), while the risk of publication bias was not significant. CONCLUSION Findings did not link HIV infection with an increased risk of COVID-19 mortality. Our results add to the conflicting data on the relationship between COVID-19 and HIV infection.
Collapse
Affiliation(s)
- Tafadzwa Dzinamarira
- School of Health Systems & Public Health, University of Pretoria, Pretoria 0002, South Africa; ICAP at Columbia University, Harare, Zimbabwe.
| | - Grant Murewanhema
- Unit of Obstetrics and Gynaecology, Department of Primary Health Care Sciences, Faculty of Medicine and Health Sciences, University of Zimbabwe, Zimbabwe
| | - Itai Chitungo
- Faculty of Medicine, College of Medicine and Health Sciences, University of Zimbabwe, Harare, Zimbabwe
| | - Bernard Ngara
- Faculty of Medicine, College of Medicine and Health Sciences, University of Zimbabwe, Harare, Zimbabwe
| | - Sphamandla Josias Nkambule
- Department of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban 4001, South Africa
| | | | | | | | | | | | | | - Nigel Tungwarara
- Department of Health Studies, University of South Africa, South Africa
| | | | | |
Collapse
|
35
|
Zhang C, Yang M. Newly Emerged Antiviral Strategies for SARS-CoV-2: From Deciphering Viral Protein Structural Function to the Development of Vaccines, Antibodies, and Small Molecules. Int J Mol Sci 2022; 23:6083. [PMID: 35682761 PMCID: PMC9181103 DOI: 10.3390/ijms23116083] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 01/09/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the most severe health crisis, causing extraordinary economic disruption worldwide. SARS-CoV-2 is a single-stranded RNA-enveloped virus. The process of viral replication and particle packaging is finished in host cells. Viral proteins, including both structural and nonstructural proteins, play important roles in the viral life cycle, which also provides the targets of treatment. Therefore, a better understanding of the structural function of virus proteins is crucial to speed up the development of vaccines and therapeutic strategies. Currently, the structure and function of proteins encoded by the SARS-CoV-2 genome are reviewed by several studies. However, most of them are based on the analysis of SARS-CoV-1 particles, lacking a systematic review update for SARS-CoV-2. Here, we specifically focus on the structure and function of proteins encoded by SARS-CoV-2. Viral proteins that contribute to COVID-19 infection and disease pathogenesis are reviewed according to the most recent research findings. The structure-function correlation of viral proteins provides a fundamental rationale for vaccine development and targeted therapy. Then, current antiviral vaccines are updated, such as inactive viral vaccines and protein-based vaccines and DNA, mRNA, and circular RNA vaccines. A summary of other therapeutic options is also reviewed, including monoclonal antibodies such as a cross-neutralizer antibody, a constructed cobinding antibody, a dual functional monoclonal antibody, an antibody cocktail, and an engineered bispecific antibody, as well as peptide-based inhibitors, chemical compounds, and clustered regularly interspaced short palindromic repeats (CRISPR) exploration. Overall, viral proteins and their functions provide the basis for targeted therapy and vaccine development.
Collapse
Affiliation(s)
- Chunye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, USA;
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, USA
| |
Collapse
|
36
|
Caufriez A, Tabernilla A, Van Campenhout R, Cooreman A, Leroy K, Sanz Serrano J, Kadam P, dos Santos Rodrigues B, Lamouroux A, Ballet S, Vinken M. Effects of Drugs Formerly Suggested for COVID-19 Repurposing on Pannexin1 Channels. Int J Mol Sci 2022; 23:ijms23105664. [PMID: 35628472 PMCID: PMC9146942 DOI: 10.3390/ijms23105664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/12/2022] [Accepted: 05/17/2022] [Indexed: 02/01/2023] Open
Abstract
Although many efforts have been made to elucidate the pathogenesis of COVID-19, the underlying mechanisms are yet to be fully uncovered. However, it is known that a dysfunctional immune response and the accompanying uncontrollable inflammation lead to troublesome outcomes in COVID-19 patients. Pannexin1 channels are put forward as interesting drug targets for the treatment of COVID-19 due to their key role in inflammation and their link to other viral infections. In the present study, we selected a panel of drugs previously tested in clinical trials as potential candidates for the treatment of COVID-19 early on in the pandemic, including hydroxychloroquine, chloroquine, azithromycin, dexamethasone, ribavirin, remdesivir, favipiravir, lopinavir, and ritonavir. The effect of the drugs on pannexin1 channels was assessed at a functional level by means of measurement of extracellular ATP release. Immunoblot analysis and real-time quantitative reversetranscription polymerase chain reaction analysis were used to study the potential of the drugs to alter pannexin1 protein and mRNA expression levels, respectively. Favipiravir, hydroxychloroquine, lopinavir, and the combination of lopinavir with ritonavir were found to inhibit pannexin1 channel activity without affecting pannexin1 protein or mRNA levels. Thusthree new inhibitors of pannexin1 channels were identified that, though currently not being used anymore for the treatment of COVID-19 patients, could be potential drug candidates for other pannexin1-related diseases.
Collapse
Affiliation(s)
- Anne Caufriez
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
- Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; (A.L.); (S.B.)
| | - Andrés Tabernilla
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Raf Van Campenhout
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Axelle Cooreman
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Kaat Leroy
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Julen Sanz Serrano
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Prashant Kadam
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Bruna dos Santos Rodrigues
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
| | - Arthur Lamouroux
- Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; (A.L.); (S.B.)
| | - Steven Ballet
- Departments of Chemistry and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium; (A.L.); (S.B.)
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, Belgium; (A.C.); (A.T.); (R.V.C.); (A.C.); (K.L.); (J.S.S.); (P.K.); (B.d.S.R.)
- Correspondence: ; Tel.: +32-2477-4587
| |
Collapse
|
37
|
Ho WS, Zhang R, Tan YL, Chai CLL. COVID-19 and the promise of small molecule therapeutics: Are there lessons to be learnt? Pharmacol Res 2022; 179:106201. [PMID: 35367622 PMCID: PMC8970615 DOI: 10.1016/j.phrs.2022.106201] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/17/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022]
Abstract
The coronavirus disease 2019 (COVID-19) pandemic had grounded the world to a standstill. As the disease continues to rage two years on, it is apparent that effective therapeutics are critical for a successful endemic living with COVID-19. A dearth in suitable antivirals has prompted researchers and healthcare professionals to investigate existing and developmental drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although some of these drugs initially appeared to be promising for the treatment of COVID-19, they were ultimately found to be ineffective. In this review, we provide a retrospective analysis on the merits and limitations of some of these drugs that were tested against SARS-CoV-2 as well as those used for adjuvant therapy. While many of these drugs are no longer part of our arsenal for the treatment of COVID-19, important lessons can be learnt. The recent inclusion of molnupiravir and Paxlovid™ as treatment options for COVID-19 represent our best hope to date for endemic living with COVID-19. Our viewpoints on these two drugs and their prospects as current and future antiviral agents will also be provided.
Collapse
Affiliation(s)
- Wei Shen Ho
- Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
| | - Ruirui Zhang
- Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
| | - Yeong Lan Tan
- Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore
| | - Christina Li Lin Chai
- Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
| |
Collapse
|
38
|
Vegivinti CTR, Evanson KW, Lyons H, Akosman I, Barrett A, Hardy N, Kane B, Keesari PR, Pulakurthi YS, Sheffels E, Balasubramanian P, Chibbar R, Chittajallu S, Cowie K, Karon J, Siegel L, Tarchand R, Zinn C, Gupta N, Kallmes KM, Saravu K, Touchette J. Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials. BMC Infect Dis 2022; 22:107. [PMID: 35100985 PMCID: PMC8802260 DOI: 10.1186/s12879-022-07068-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 01/14/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Coronavirus disease 2019 (COVID-19) continues to pose a significant threat to public health worldwide. The purpose of this study was to review current evidence obtained from randomized clinical trials on the efficacy of antivirals for COVID-19 treatment. METHODS A systematic literature search was performed using PubMed to identify randomized controlled trials published up to September 4, 2021 that examined the efficacy of antivirals for COVID-19 treatment. Studies that were not randomized controlled trials or that did not include treatment of COVID-19 with approved antivirals were excluded. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) method. Due to study heterogeneity, inferential statistics were not performed and data were expressed as descriptive statistics. RESULTS Of the 2,284 articles retrieved, 31 (12,440 patients) articles were included. Overall, antivirals were more effective when administered early in the disease course. No antiviral treatment demonstrated efficacy at reducing COVID-19 mortality. Sofosbuvir/daclatasvir results suggested clinical improvement, although statistical power was low. Remdesivir exhibited efficacy in reducing time to recovery, but results were inconsistent across trials. CONCLUSIONS Although select antivirals have exhibited efficacy to improve clinical outcomes in COVID-19 patients, none demonstrated efficacy in reducing mortality. Larger RCTs are needed to conclusively establish efficacy.
Collapse
Affiliation(s)
- Charan Thej Reddy Vegivinti
- Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, 1400 Pelham Pkwy S, Bronx, NY, USA
| | - Kirk W Evanson
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA
| | - Hannah Lyons
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
- Ohio University Heritage College of Osteopathic Medicine, 6775 Bobcat Way, Dublin, OH, 43016, USA
| | - Izzet Akosman
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
- Weill Cornell Medical College, 1300 York Ave, New York, NY, 10065, USA
| | - Averi Barrett
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Nicole Hardy
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Bernadette Kane
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA
| | - Praneeth Reddy Keesari
- Kamineni Academy of Medical Sciences and Research Center, Hyderabad, Telangana, 500068, India
| | | | - Erin Sheffels
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA.
| | - Prasanth Balasubramanian
- Department of Internal Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, 1400 Pelham Pkwy S, Bronx, NY, USA
| | - Richa Chibbar
- Department of Medicine, Lakeridge Health, 1 Hospital Crt, Oshawa, ON, L1G 2B9, Canada
| | | | - Kathryn Cowie
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - J Karon
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Lauren Siegel
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Ranita Tarchand
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Caleb Zinn
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Nitin Gupta
- Department of Infectious Disease, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
- Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Kevin M Kallmes
- Nested Knowledge, 1430 Avon Street N, Saint Paul, MN, 55117, USA
| | - Kavitha Saravu
- Department of Infectious Disease, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
- Manipal Center for Infectious Diseases, Prasanna School of Public Health, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Jillienne Touchette
- Superior Medical Experts, 1425 Minnehaha Ave E, P.O. Box 6000545, St Paul, MN, 55106, USA
| |
Collapse
|
39
|
Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective. Molecules 2022; 27:molecules27030658. [PMID: 35163923 PMCID: PMC8838458 DOI: 10.3390/molecules27030658] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 01/17/2022] [Accepted: 01/19/2022] [Indexed: 02/01/2023] Open
Abstract
In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.
Collapse
|
40
|
Hosseini NF, Dalirfardouei R, Aliramaei MR, Najafi R. Stem cells or their exosomes: which is preferred in COVID-19 treatment? Biotechnol Lett 2022; 44:159-177. [PMID: 35043287 PMCID: PMC8765836 DOI: 10.1007/s10529-021-03209-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
It only took 8 months for the pneumonia caused by a previously unknown coronavirus to turn into a global pandemic of unprecedentedly far-reaching implications. Failure of the already discovered treatment measures opened up a new opportunity to evaluate the potentials of mesenchymal stem cells and their extracellular vesicles (EVs), exosomes in particular. Eventually, the initial success experienced after the use of MSCs in treating the new pneumonia by Lnge and his team backed up the idea of MSC-based therapies and pushed them closer to becoming a reality. However, MSC-related concerns regarding safety such as abnormal differentiation, spontaneous malignant and the formation of ectopic tissues have triggered the replacement of MSCs by their secreted exosomes. The issue has been further strengthened by the fact that the exosomes leave similar treatment impacts when compared to their parental cells. In recent years, much attention has been paid to the use of MSC-derived exosomes in the treatment of a variety of diseases. With a primary focus on COVID-19 and its current treatment methods, the present review looks into the potentials of MSCs and MSC-derived exosomes in battling the ongoing pandemic. Finally, the research will draw an analogy between exosomes and their parental cells, when it comes to the progresses and challenges in using exosomes as a large-scale treatment method.
Collapse
Affiliation(s)
- Nashmin Fayazi Hosseini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Dalirfardouei
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
| |
Collapse
|
41
|
Fomenko VV, Rudometova NB, Yarovaya OI, Rogachev AD, Fando AA, Zaykovskaya AV, Komarova NI, Shcherbakov DN, Pyankov OV, Pokrovsky AG, Karpenko LI, Maksyutov RA, Salakhutdinov NF. Synthesis and In Vitro Study of Antiviral Activity of Glycyrrhizin Nicotinate Derivatives against HIV-1 Pseudoviruses and SARS-CoV-2 Viruses. Molecules 2022; 27:295. [PMID: 35011529 PMCID: PMC8746574 DOI: 10.3390/molecules27010295] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 12/30/2021] [Accepted: 12/30/2021] [Indexed: 02/04/2023] Open
Abstract
When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502-8 μM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9-27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.
Collapse
Affiliation(s)
- Vladislav V. Fomenko
- Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia; (V.V.F.); (A.D.R.); (N.I.K.); (N.F.S.)
| | - Nadezhda B. Rudometova
- State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia; (N.B.R.); (A.V.Z.); (D.N.S.); (O.V.P.); (L.I.K.); (R.A.M.)
| | - Olga I. Yarovaya
- Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia; (V.V.F.); (A.D.R.); (N.I.K.); (N.F.S.)
- Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogov Str. 1, 630090 Novosibirsk, Russia; (A.A.F.); (A.G.P.)
| | - Artem D. Rogachev
- Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia; (V.V.F.); (A.D.R.); (N.I.K.); (N.F.S.)
- Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogov Str. 1, 630090 Novosibirsk, Russia; (A.A.F.); (A.G.P.)
| | - Anastasia A. Fando
- Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogov Str. 1, 630090 Novosibirsk, Russia; (A.A.F.); (A.G.P.)
| | - Anna V. Zaykovskaya
- State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia; (N.B.R.); (A.V.Z.); (D.N.S.); (O.V.P.); (L.I.K.); (R.A.M.)
| | - Nina I. Komarova
- Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia; (V.V.F.); (A.D.R.); (N.I.K.); (N.F.S.)
| | - Dmitry N. Shcherbakov
- State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia; (N.B.R.); (A.V.Z.); (D.N.S.); (O.V.P.); (L.I.K.); (R.A.M.)
| | - Oleg V. Pyankov
- State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia; (N.B.R.); (A.V.Z.); (D.N.S.); (O.V.P.); (L.I.K.); (R.A.M.)
| | - Andrey G. Pokrovsky
- Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogov Str. 1, 630090 Novosibirsk, Russia; (A.A.F.); (A.G.P.)
| | - Larisa I. Karpenko
- State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia; (N.B.R.); (A.V.Z.); (D.N.S.); (O.V.P.); (L.I.K.); (R.A.M.)
| | - Rinat A. Maksyutov
- State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559 Koltsovo, Russia; (N.B.R.); (A.V.Z.); (D.N.S.); (O.V.P.); (L.I.K.); (R.A.M.)
| | - Nariman F. Salakhutdinov
- Department of Medicinal Chemistry, N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Lavrentiev Ave. 9, 630090 Novosibirsk, Russia; (V.V.F.); (A.D.R.); (N.I.K.); (N.F.S.)
- Zelman Institute for Medicine and Psychology, Novosibirsk State University, Pirogov Str. 1, 630090 Novosibirsk, Russia; (A.A.F.); (A.G.P.)
| |
Collapse
|
42
|
Rahmah L, Abarikwu SO, Arero AG, Essouma M, Jibril AT, Fal A, Flisiak R, Makuku R, Marquez L, Mohamed K, Ndow L, Zarębska-Michaluk D, Rezaei N, Rzymski P. Oral antiviral treatments for COVID-19: opportunities and challenges. Pharmacol Rep 2022; 74:1255-1278. [PMID: 35871712 PMCID: PMC9309032 DOI: 10.1007/s43440-022-00388-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/24/2022] [Accepted: 07/06/2022] [Indexed: 01/18/2023]
Abstract
The use of antiviral COVID-19 medications can successfully inhibit SARS-CoV-2 replication and prevent disease progression to a more severe form. However, the timing of antiviral treatment plays a crucial role in this regard. Oral antiviral drugs provide an opportunity to manage SARS-CoV-2 infection without a need for hospital admission, easing the general burden that COVID-19 can have on the healthcare system. This review paper (i) presents the potential pharmaceutical antiviral targets, including various host-based targets and viral-based targets, (ii) characterizes the first-generation anti-SARS-CoV-2 oral drugs (nirmatrelvir/ritonavir and molnupiravir), (iii) summarizes the clinical progress of other oral antivirals for use in COVID-19, (iv) discusses ethical issues in such clinical trials and (v) presents challenges associated with the use of oral antivirals in clinical practice. Oral COVID-19 antivirals represent a part of the strategy to adapt to long-term co-existence with SARS-CoV-2 in a manner that prevents healthcare from being overwhelmed. It is pivotal to ensure equal and fair global access to the currently available oral antivirals and those authorized in the future.
Collapse
Affiliation(s)
- Laila Rahmah
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Jakarta, Indonesia
| | - Sunny O. Abarikwu
- Department of Biochemistry, University of Port Harcourt, Choba, Nigeria ,Universal Scientific Education and Research Network (USERN), Choba, Nigeria
| | - Amanuel Godana Arero
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Addis Ababa, Ethiopia
| | - Mickael Essouma
- Department of Internal Medicine and Specialties, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon ,Universal Scientific Education and Research Network, Yaoundé, Cameroon
| | - Aliyu Tijani Jibril
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran ,Nutritional and Health Team (NHT), Universal Scientific Education and Research Network (USERN), Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Accra, Ghana
| | - Andrzej Fal
- Department of Population Health, Division of Public Health, Wroclaw Medical University, Wroclaw, Poland ,Collegium Medicum, Warsaw Faculty of Medicine, Cardinal Stefan Wyszyński University, Warsaw, Poland ,Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University of Białystok, Białystok, Poland
| | - Rangarirai Makuku
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Harare, Zimbabwe
| | - Leander Marquez
- College of Social Sciences and Philosophy, University of the Philippines Diliman, Quezon City, Philippines ,Education and Research Network (USERN), Universal Scientific, Quezon City, Philippines
| | - Kawthar Mohamed
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Universal Scientific Education and Research Network (USERN), Manama, Bahrain
| | - Lamin Ndow
- National Health Laboratory Service, Kotu, Gambia ,Universal Scientific Education and Research Network (USERN), Banjul, Gambia
| | | | - Nima Rezaei
- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran ,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran ,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Piotr Rzymski
- Integrated Science Association (ISA), Universal Scientific Education and Research Network (USERN), Poznań, Poland ,Department of Environmental Medicine, Poznan University of Medical Sciences, Poznań, Poland
| |
Collapse
|
43
|
Sodeifian F, Seyedalhosseini ZS, Kian N, Eftekhari M, Najari S, Mirsaeidi M, Farsi Y, Nasiri MJ. Drug-Induced Liver Injury in COVID-19 Patients: A Systematic Review. Front Med (Lausanne) 2021; 8:731436. [PMID: 34616757 PMCID: PMC8488138 DOI: 10.3389/fmed.2021.731436] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction: The severity of COVID-19 may be correlated with the risk of liver injury development. An increasing number of studies indicate that degrees of hepatotoxicity has been associated with using some medications in the management of COVID-19 patients. However, limited studies had systematically investigated the evidence of drug-induced liver injury (DILI) in COVID-19 patients. Thus, this study aimed to examine DILI in COVID-19 patients. Methods: A systematic search was carried out in PubMed/Medline, EMBASE, and Web of Science up to December 30, 2020. Search items included "SARS-CoV-2", "Coronavirus," COVID-19, and liver injury. Results: We included 22 related articles. Among included studies, there was five case report, five case series, four randomizes control trial (RCT), seven cohort studies, and one cross-sectional study. The drugs included in this systematic review were remdesivir, favipiravir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir. Among included studies, some studies revealed a direct role of drugs, while others couldn't certainly confirm that the liver injury was due to SARS-CoV-2 itself or administration of medications. However, a significant number of studies reported that liver injury could be attributable to drug administration. Discussion: Liver injury in COVID-19 patients could be caused by the virus itself or the administration of some types of drug. Intensive liver function monitoring should be considered for patients, especially patients who are treated with drugs such as remdesivir, lopinavir/ritonavir, and tocilizumab.
Collapse
Affiliation(s)
- Fatemeh Sodeifian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Sadat Seyedalhosseini
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naghmeh Kian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahya Eftekhari
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shaghayegh Najari
- School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mirsaeidi
- Division of Pulmonary and Critical Care, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Pulmonary and Critical Care, Miami VA Medical Center, Miami, FL, United States
| | - Yeganeh Farsi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Javad Nasiri
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
44
|
Crespillo C, Moreno S. Antiviral therapy and immunotherapy of COVID-19. REVISTA ESPANOLA DE QUIMIOTERAPIA : PUBLICACION OFICIAL DE LA SOCIEDAD ESPANOLA DE QUIMIOTERAPIA 2021; 34 Suppl 1:57-59. [PMID: 34598429 PMCID: PMC8683015 DOI: 10.37201/req/s01.17.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The pharmacological treatment of COVID-19 has evolved in the months since the description of the disease. Published observational studies and, above all, clinical trials have highlighted drugs that are useful as well as ruled out any benefit from other drugs used at the beginning of the pandemic. The pathogenesis of the disease has suggested that patients may benefit from the administration of both antivirals, mainly in the earliest stages, and anti-inflammatory/immunomodulatory medications in more advanced stages. We present a short review of the drugs used and under investigation for the treatment of COVID-19.
Collapse
Affiliation(s)
| | - S Moreno
- Santiago Moreno Guillén, Servicio de Enfermedades Infecciosas, Hospital Universitario Ramón y Cajal, Madrid, Spain.
| |
Collapse
|
45
|
Spini A, Giudice V, Brancaleone V, Morgese MG, De Francia S, Filippelli A, Ruggieri A, Ziche M, Ortona E, Cignarella A, Trabace L. Sex-tailored pharmacology and COVID-19: Next steps towards appropriateness and health equity. Pharmacol Res 2021; 173:105848. [PMID: 34454035 PMCID: PMC8387562 DOI: 10.1016/j.phrs.2021.105848] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 08/21/2021] [Accepted: 08/22/2021] [Indexed: 12/12/2022]
Abstract
Making gender bias visible allows to fill the gaps in knowledge and understand health records and risks of women and men. The coronavirus disease 2019 (COVID-19) pandemic has shown a clear gender difference in health outcomes. The more severe symptoms and higher mortality in men as compared to women are likely due to sex and age differences in immune responses. Age-associated decline in sex steroid hormone levels may mediate proinflammatory reactions in older adults, thereby increasing their risk of adverse outcomes, whereas sex hormones and/or sex hormone receptor modulators may attenuate the inflammatory response and provide benefit to COVID-19 patients. While multiple pharmacological options including anticoagulants, glucocorticoids, antivirals, anti-inflammatory agents and traditional Chinese medicine preparations have been tested to treat COVID-19 patients with varied levels of evidence in terms of efficacy and safety, information on sex-targeted treatment strategies is currently limited. Women may have more benefit from COVID-19 vaccines than men, despite the occurrence of more frequent adverse effects, and long-term safety data with newly developed vectors are eagerly awaited. The prevalent inclusion of men in randomized clinical trials (RCTs) with subsequent extrapolation of results to women needs to be addressed, as reinforcing sex-neutral claims into COVID-19 research may insidiously lead to increased inequities in health care. The huge worldwide effort with over 3000 ongoing RCTs of pharmacological agents should focus on improving knowledge on sex, gender and age as pillars of individual variation in drug responses and enforce appropriateness.
Collapse
Affiliation(s)
- Andrea Spini
- University of Siena, Department of Medicine, Surgery and Neuroscience, 53100 Siena, Italy; University of Bordeaux, Bordeaux Population Health Center, UMR 1219, 33000 Bordeaux, France
| | - Valentina Giudice
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy
| | - Vincenzo Brancaleone
- Department of Science, University of Basilicata, via Ateneo Lucano, 85100 Potenza, Italy
| | - Maria Grazia Morgese
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Silvia De Francia
- Department of Clinical and Biological Sciences, S. Luigi Hospital, University of Turin, Italy
| | - Amelia Filippelli
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, 84081 Baronissi, Italy
| | - Anna Ruggieri
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Marina Ziche
- University of Siena, Department of Medicine, Surgery and Neuroscience, 53100 Siena, Italy; University of Bordeaux, Bordeaux Population Health Center, UMR 1219, 33000 Bordeaux, France; Centro Studi Nazionale Salute e Medicina di Genere, Italy
| | - Elena Ortona
- Center for Gender Specific Medicine, Istituto Superiore di Sanità, Rome, Italy; Centro Studi Nazionale Salute e Medicina di Genere, Italy
| | - Andrea Cignarella
- Department of Medicine, University of Padova, via Giustiniani 2, 35128 Padova, Italy; Centro Studi Nazionale Salute e Medicina di Genere, Italy
| | - Luigia Trabace
- Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy; Centro Studi Nazionale Salute e Medicina di Genere, Italy.
| |
Collapse
|
46
|
Gil Martínez V, Avedillo Salas A, Santander Ballestín S. Antiviral Therapeutic Approaches for SARS-CoV-2 Infection: A Systematic Review. Pharmaceuticals (Basel) 2021; 14:736. [PMID: 34451833 PMCID: PMC8398077 DOI: 10.3390/ph14080736] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/20/2021] [Accepted: 07/23/2021] [Indexed: 12/12/2022] Open
Abstract
Due to the lack of an etiologic treatment for SARS-CoV-2 and the difficulties involved in developing new drugs, some drugs already approved for other diseases or with efficacy against SARS and MERS, have been used in patients with COVID-19. This systematic review aims to summarize evidence on the efficacy and safety of five antivirals applied to patients with COVID-19, that have proven to be effective either in vitro studies or in studies on SARS-CoV and MERS.; An intensive search of different databases (Pub Med, WoS, MEDLINE and Cochrane COVID-19 Study Register) has been carried out until the end of April 2021. This systematic review has been conducted according to the PRISMA statement. From each of the included studies, the characteristics of the intervention and comparison groups, demographic data and results were extracted independently; Remdesivir is well tolerated and helps to accelerate clinical improvement but is ineffective in reducing mortality. Favipiravir is safe and shows promising results regarding symptom resolution but does not improve viral clearance. The use of lopinavir/ritonavir has been associated with an increased risk of gastrointestinal adverse events and it has not proven to be effective. No significant differences were observed between patients treated with ribavirin or umifenovir and their respective control groups; Remdesivir and favipiravir are well tolerated and effective in accelerating clinical improvement. This systematic review does not support the use of lopinavir/ritonavir, ribavirin and umifenovir in hospitalized patients with COVID-19.
Collapse
Affiliation(s)
| | | | - Sonia Santander Ballestín
- Department of Pharmacology, Physiology and Legal and Forensic Medicine, Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain; (V.G.M.); (A.A.S.)
| |
Collapse
|