Current pharmacological treatments for COVID‐19: What's next?

Since December 2019 SARS‐Cov‐2 was found responsible for the disease COVID‐19, which has spread worldwide. No specific therapies/vaccines are yet available for the treatment of COVID‐19. Drug repositioning may offer a strategy and a number of drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir and tocilizumab. This paper describes the main pharmacological properties of such drugs administered to patients with COVID‐19, focusing on their antiviral, immune‐modulatory and/or anti‐inflammatory actions. Where available, data from clinical trials involving patients with COVID‐19 are reported. Preliminary clinical trials seem to support their benefit. However, such drugs in COVID‐19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds. Nevertheless, while waiting for effective preventive measures i.e. vaccines, many clinical trials on drugs belonging to different therapeutic classes are currently underway. Their results will help us in defining the best way to treat COVID‐19 and reducing its symptoms and complications.

[1]  Jianjun Gao,et al.  Discovering drugs to treat coronavirus disease 2019 (COVID-19). , 2020, Drug discoveries & therapeutics.

[2]  W. Phoolcharoen,et al.  Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). , 2020, Asian Pacific journal of allergy and immunology.

[3]  Yan Zhao,et al.  The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China , 2020, Clinical Immunology.

[4]  J. Behr,et al.  Inhalation of vasoactive intestinal peptide in pulmonary hypertension , 2008, European Respiratory Journal.

[5]  Arthur Christopoulos,et al.  THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein‐coupled receptors , 2019, British journal of pharmacology.

[6]  Alasdair J. G. Gray,et al.  The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY , 2017, Nucleic Acids Res..

[7]  M. Easterbrook The ocular safety of hydroxychloroquine. , 1993, Seminars in arthritis and rheumatism.

[8]  D. Wang,et al.  The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status , 2020, Military Medical Research.

[9]  S. Ju,et al.  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): a review , 2020, Molecular Cancer.

[10]  S. Lindstrom,et al.  First Case of 2019 Novel Coronavirus in the United States , 2020, The New England journal of medicine.

[11]  V. Wong,et al.  Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak , 2004, Thorax.

[12]  S. Jawhara Could Intravenous Immunoglobulin Collected from Recovered Coronavirus Patients Protect against COVID-19 and Strengthen the Immune System of New Patients? , 2020, International journal of molecular sciences.

[13]  J. Vanden Eynde,et al.  Baricitinib: A 2018 Novel FDA-Approved Small Molecule Inhibiting Janus Kinases , 2019, Pharmaceuticals.

[14]  Xiao-dong Zhu,et al.  Emerging agents and regimens for hepatocellular carcinoma , 2019, Journal of Hematology & Oncology.

[15]  Bo Chen,et al.  Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial , 2020, medRxiv.

[16]  M. Dayer,et al.  Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study , 2017 .

[17]  W. Lim,et al.  Corticosteroids as adjunctive therapy in the treatment of influenza. , 2019, The Cochrane database of systematic reviews.

[18]  S. Perlman,et al.  Coronaviruses: An Overview of Their Replication and Pathogenesis , 2015, Methods in molecular biology.

[19]  Lisa E. Gralinski,et al.  Complement Activation Contributes to Severe Acute Respiratory Syndrome Coronavirus Pathogenesis , 2018, mBio.

[20]  Sharon Einav,et al.  A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19 , 2020, Journal of Critical Care.

[21]  Hartmut H. Malluche,et al.  Food and Drug Administration Center for Drug Evaluation and Research , 1996 .

[22]  R. Kruse Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China , 2020, F1000Research.

[23]  D. Gemsa,et al.  Inhibition of LPS-induced tumor necrosis factor-alpha production by colchicine and other microtubule disrupting drugs. , 1996, Immunobiology.

[24]  N. Seidah,et al.  Chloroquine is a potent inhibitor of SARS coronavirus infection and spread , 2005, Virology Journal.

[25]  D. Jans,et al.  The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro , 2020, Antiviral Research.

[26]  Kome Gbinigie,et al.  Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review , 2020, BJGP open.

[27]  Philippe Brouqui,et al.  Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 , 2020, International Journal of Antimicrobial Agents.

[28]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[29]  E. Deeks Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide: A Review in HIV-1 Infection , 2016, Drugs.

[30]  M. A. Machado,et al.  Novel thalidomide analogues from diamines inhibit pro-inflammatory cytokine production and CD80 expression while enhancing IL-10. , 2012, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[31]  J. Dye,et al.  Anticancer kinase inhibitors impair intracellular viral trafficking and exert broad-spectrum antiviral effects , 2017, The Journal of clinical investigation.

[32]  A. Elfiky,et al.  Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study , 2020, Life Sciences.

[33]  D. Raoult,et al.  Hydroxychloroquine and Azithromycin as a treatment of COVID-19: preliminary results of an open-label non-randomized clinical trial , 2020, medRxiv.

[34]  Bevacizumab in Severe or Critical Patients With COVID-19 Pneumonia , 2020, Case Medical Research.

[35]  G. Kaplan,et al.  Thalidomide and thalidomide analogs reduce HIV type 1 replication in human macrophages in vitro. , 1997, AIDS research and human retroviruses.

[36]  H. Feldmann,et al.  Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection , 2020, Proceedings of the National Academy of Sciences.

[37]  Y. Furuta,et al.  Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase , 2017, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[38]  Xinhao Li,et al.  Molecular Modeling Evaluation of the Binding Effect of Ritonavir, Lopinavir and Darunavir to Severe Acute Respiratory Syndrome Coronavirus 2 Proteases , 2020, bioRxiv.

[39]  Xiaohu Zheng,et al.  Effective treatment of severe COVID-19 patients with tocilizumab , 2020, Proceedings of the National Academy of Sciences.

[40]  R. Baric,et al.  Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV , 2020, Nature Communications.

[41]  Xiaotao Lu,et al.  Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease , 2018, mBio.

[42]  Chengyu Jiang,et al.  Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model , 2012, Cell Research.

[43]  Yifan Rao,et al.  The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines , 2020, npj Vaccines.

[44]  F. Ingegnoli,et al.  COVID-19 infection and rheumatoid arthritis: Faraway, so close! , 2020, Autoimmunity Reviews.

[45]  World Health Organization,et al.  Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. Interim guidance , 2020, Pediatria i Medycyna Rodzinna.

[46]  L. Delang,et al.  Favipiravir as a potential countermeasure against neglected and emerging RNA viruses , 2018, Antiviral research.

[47]  Jing Zhao,et al.  Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia , 2020, The New England journal of medicine.

[48]  A. Rismanbaf,et al.  Liver and Kidney Injuries in COVID-19 and Their Effects on Drug Therapy; a Letter to Editor , 2020, Archives of academic emergency medicine.

[49]  Yixiao Lin,et al.  Persistence and clearance of viral RNA in 2019 novel coronavirus disease rehabilitation patients , 2020, Chinese medical journal.

[50]  S. Said Vasoactive intestinal peptide in pulmonary arterial hypertension. , 2012, American journal of respiratory and critical care medicine.

[51]  Arturo Casadevall,et al.  The convalescent sera option for containing COVID-19. , 2020, The Journal of clinical investigation.

[52]  P. Maes,et al.  Antiviral Activity of Chloroquine against Human Coronavirus OC43 Infection in Newborn Mice , 2009, Antimicrobial Agents and Chemotherapy.

[53]  Hanxiong Guan,et al.  Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression , 2020, American Journal of Transplantation.

[54]  S. N. Timasheff,et al.  Tubulin bound to colchicine forms polymers different from microtubules. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Congress Report Riassunto delle Caratteristiche del Prodotto , 2007 .

[56]  Fingolimod in COVID-19 , 2020, Case Medical Research.

[57]  Ping Zhu,et al.  Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial , 2020, medRxiv.

[58]  J. Sung,et al.  Influence of FcγRIIA and MBL polymorphisms on severe acute respiratory syndrome , 2005, Tissue antigens.

[59]  Jon Cohen,et al.  Vaccine designers take first shots at COVID-19. , 2020, Science.

[60]  M. Shinoda,et al.  Acute eosinophilic pneumonia caused by camostat mesilate: The first case report , 2016, Respiratory medicine case reports.

[61]  L. Berrino,et al.  Current pharmacological treatments for COVID‐19: What's next? , 2020, British journal of pharmacology.

[62]  Huixia Yang,et al.  Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records , 2020, The Lancet.

[63]  Study to Evaluate the Safety and Antiviral Activity of Remdesivir (GS-5734™) in Participants With Moderate Coronavirus Disease (COVID-19) Compared to Standard of Care Treatment , 2020, Case Medical Research.

[64]  A. Millar,et al.  Vascular Endothelial Growth Factor in Acute Lung Injury and Acute Respiratory Distress Syndrome , 2013, Respiration.

[65]  N. Dalbeth,et al.  Mechanism of action of colchicine in the treatment of gout. , 2014, Clinical therapeutics.

[66]  H. Kwon,et al.  Two cases of immune reconstitution inflammatory syndrome in HIV patients treated with thalidomide , 2019, International journal of STD & AIDS.

[67]  Marc Van Ranst,et al.  In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine , 2004, Biochemical and Biophysical Research Communications.

[68]  H. Mou Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China [version 2; peer review: 2 approved] , 2020 .

[69]  Z. Memish,et al.  Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial , 2020, Trials.

[70]  Michael R Hamblin,et al.  Quantity does not equal quality: Scientific principles cannot be sacrificed , 2020, International Immunopharmacology.

[71]  A. Park,et al.  CENTER FOR DRUG EVALUATION AND RESEARCH , 2009 .

[72]  A. Inglot Comparison of the antiviral activity in vitro of some non-steroidal anti-inflammatory drugs. , 1969, The Journal of general virology.

[73]  Z. Memish,et al.  Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-β1b (MIRACLE trial): study protocol for a randomized controlled trial , 2018, Trials.

[74]  E. Soliman,et al.  Boosted protease inhibitors and the electrocardiographic measures of QT and PR durations , 2011, AIDS.

[75]  D. Cook,et al.  The influence of corticosteroid treatment on the outcome of influenza A(H1N1pdm09)-related critical illness , 2016, Critical Care.

[76]  Arthur Christopoulos,et al.  THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets , 2019, British journal of pharmacology.

[77]  Yuan Wei,et al.  A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19 , 2020, The New England journal of medicine.

[78]  Silvia Angeletti,et al.  The 2019‐new coronavirus epidemic: Evidence for virus evolution , 2020, Journal of medical virology.

[79]  P. Sfikakis,et al.  Retinal toxicity in long term hydroxychloroquine treatment. , 1996, Annals of the rheumatic diseases.

[80]  G. Funk,et al.  Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension. , 2003, The Journal of clinical investigation.

[81]  L. Manchikanti,et al.  Expanded Umbilical Cord Mesenchymal Stem Cells (UC-MSCs) as a Therapeutic Strategy in Managing Critically Ill COVID-19 Patients: The Case for Compassionate Use. , 2020, Pain physician.

[82]  Wu Zhong,et al.  Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro , 2020, Cell Research.

[83]  David Gottlieb,et al.  Mechanism of Action , 2012, Antibiotics.

[84]  E. Brown,et al.  Complement activation. , 1981, Immunology today.

[85]  The Efficacy and Safety of Thalidomide in the Adjuvant Treatment of Moderate New Coronavirus (COVID-19) Pneumonia , 2020, Case Medical Research.

[86]  Yan Zhao,et al.  Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. , 2020, JAMA.

[87]  J. Sung,et al.  Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome , 2004, Clinical and experimental immunology.

[88]  P. Mehta,et al.  COVID-19: consider cytokine storm syndromes and immunosuppression , 2020, The Lancet.

[89]  L. Scott Tocilizumab: A Review in Rheumatoid Arthritis , 2017, Drugs.

[90]  K. Demirkan,et al.  COVID-19 Drug Interactions , 2020 .

[91]  Joanna L. Sharman,et al.  The IUPHAR/BPS Guide to PHARMACOLOGY database (GtoPdb) in 2018: new features and updates , 2018 .

[92]  D. Raoult,et al.  Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial , 2020, International Journal of Antimicrobial Agents.

[93]  G. Herrler,et al.  SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor , 2020, Cell.

[94]  Jianjun Gao,et al.  Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. , 2020, Bioscience trends.

[95]  Ivan Griffin,et al.  COVID-19: combining antiviral and anti-inflammatory treatments , 2020, The Lancet Infectious Diseases.

[96]  Eculizumab (Soliris) in Covid-19 Infected Patients , 2020, Case Medical Research.

[97]  Sidney R. Cohen,et al.  Vasoactive intestinal peptide , 1989, Digestive Diseases and Sciences.

[98]  Yanchen Zhou,et al.  Protease inhibitors targeting coronavirus and filovirus entry , 2015, Antiviral Research.

[99]  Longxiang Xie,et al.  Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV , 2020, Viruses.

[100]  Hongzhou Lu,et al.  [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. , 2020, Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences.

[101]  Paul Garner,et al.  SARS: Systematic Review of Treatment Effects , 2006, PLoS medicine.

[102]  A. Phelan,et al.  Baricitinib as potential treatment for 2019-nCoV acute respiratory disease , 2020, The Lancet.

[103]  R. Wunderink,et al.  MERS, SARS and other coronaviruses as causes of pneumonia , 2017, Respirology.

[104]  Adekunle Ajasin Darunavir Disrupts Critical Nodes in Metastable 2019-nCoV-RBD/ACE-2 Complex , 2020 .

[105]  J. Peiris,et al.  Mannose-Binding Lectin in Severe Acute Respiratory Syndrome Coronavirus Infection , 2005, The Journal of infectious diseases.

[106]  S. Keam,et al.  Camrelizumab: First Global Approval , 2019, Drugs.

[107]  J. Harper,et al.  Colchicine suppresses neutrophil superoxide production in a murine model of gouty arthritis: a rationale for use of low‐dose colchicine , 2008, British journal of pharmacology.