COVID-19 medical therapy
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand, M.D.[2], Syed Hassan A. Kazmi BSc, MD [3],Sabawoon Mirwais, M.B.B.S, M.D.[4],
Overview
COVID-19 is an inflammatory hypercytokinemia disease. The aim of therapy is prevention of viral replication and controlling the inflammatory process.
Antiviral Agents
Remdesivir
- Remdesivir is a prodrug and inhibits viral RNA polymerase when intracellularly metabolized to an ATP analog.
- Remdesivir has been effective on MERS-COV,EBOLA, SARS-COV1 and also Covid-19 by this mechanism:
- Significant reduction in viral load in bronchoaleolar lavage
- Inhibition of SARS-COV-2 replication in nasal and bronchial airway epithelial cells.
- 5-day course of remdesivir in hospitalized patients with moderate Covid-19 had better clinical status compared with standard care at 11 days after starting the treatment.[1]
- Remdesivir indicates in the treatment of all hospitalized adult and pediatric patients with suspected or laboratory-confirmed COVID-19 , regardless of the severity of disease according to FDA emergency use authorization.
- The recommended dose of remdesivir in COVID-19 is::[2]
- Adult dosing (wt > 40 kg): 200 mg IV loading dose on day 1, then 100 mg IV daily maintenance dose
- Infuse each dose over 30-120 min
- 5-day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days
- 10-day course for patients on mechanical ventilation/ECMO
- Pediatric dosing (wt 3.5 - 40 kg): 5 mg/kg loading dose on day 1, then 2.5 mg/kg maintenance dose
- 5-day course if not on ventilation/ECMO. If no clinical improvement at 5 days, extend to 10 days
- 10 day course for patients on mechanical ventilation/ECMO
- Adult dosing (wt > 40 kg): 200 mg IV loading dose on day 1, then 100 mg IV daily maintenance dose
- Contraindications of remdesivir include :
- Severe renal impairment (eGFR <30 ml/min)
- Severe hepatic dysfunction or alanin transferase (ALT)ᐳ 5-times upper limit
Interferon-1
- Interferon-1 has been effective in the treatment of SARS-COV, MERS infection and multiple sclerosis.[3]
- Mechanism of action is the anti-inflammatory and immunomodulatory effect on viral activity and prevention of vascular leakage in the lung in SARS-COV2 infection.
- Interferon-1 is effective in the milder type of COVID-19 and there is no significant reduction in mortality in ARDS related SARS-COV2. [4]
- Atazanavir has been used for treatment of SARS-COV, HIV infection.[5]
- Mechanism of action in COVID-19 is anti-protease activity and prevention of viral replication and anti-inflammatory effect on IL-6 and TNF-alpha in COVID-19.
Hydroxychloroquine and Chloroquine
- Hydroxychloroquine has been effective in graft versus host disease ,lupus erythematosus, rheumatoid arthritis, and malaria.
- Due to cardiac side effects, recently FDA disapproved of the emergency use authorization of hydroxychloroquine if clinical trials are unavailable.
- Hydroxychloroquine for early treatment of adults with mild COVID-19 has not improved outcomes in a modest-sized unblinded randomized controlled trial.[6]
- In a modest-sized randomized trial of 1483 healthcare workers, pre-expose prophylaxis with hydroxychloroquine 2 times a week did not significantly reduce laboratory-confirmed Covid-19 or covid-19 compatible illness.[7]
- In the beginning of the COVID-19 pandemic,hydroxychloroquine was used due to inhibition of the entry of SARS-COV-2 and prevention of the fusion of viral spike protein to ACE2 receptor and reduction of the cytokine storm.
- Intracellular uptake of hydroxychloroquine was enhanced with combination with Zinc.[8]
- Hydroxychloroquine has cardiac side effects due to the QT prolongation effect.
- Efficacy of remdesivir is reduced in combination with hydroxychroroquine.
- Lopinavir-Ritonavir Inhibits the activity of the HIV-1 protease.
- In an open-label randomized controlled trial, the comparison between patients with COVID-19 received either lopinavir-ritonavir 400/100 mg, orally twice daily plus standard of care or standard care alone showed no benefit of administration of lopinavir-ritonavir.[9]
- Only one study in Korea in the initial phase of outbreak accepted using this combination.[10]
- Side effects: Diarrhea, nausea, asthenia
Umifenovir (Arbidol)
- Umifenovir has been used in treatment of Ebola virus, human herpesvirus 8 (HHV-8), hepatitis C virus (HCV), and Tacaribe arenavirus, influenza A,B.[11]
- Mechanism of action: inhibition of the virus fusion to the cell membrane and hydrogen binding to membrance phospholipids.[12]
- In a retrospective cohort study showed improvement in chest ct scan of COVID-19 patients received a combination of Umifenovir and lopinavir-ritonavir..[13]
- In a prospective study, umifenovir had inferior outcomes in the clinical recovery rate and relief of fever and cough compared with favipiravir.[14]
- Safety and efficacy in COVID-19 is under investigation in china with two randomized open trials.
Favipiravir (Avigan)
- Favipiravir has been used in 2014 in Japan for the treatment of influenza resistant to neuraminidase inhibitors and has been used in the treatment of infectious diseases caused by RNA viruses such as influenza, Ebola, and norovirus.[15] [16]
- Mechanism of action: after entering the infected cells and being phosphorylated, inhibits viral RNA replication.
- SARS-CoV-2 is an enveloped, positive-sense, single-strand RNA virus and studies showed the efficacy of favipiravir on SARS-COV-2.
- A randomized control trial has shown that COVID-19 patients treated with favipiravir have superior recovery rate (71.43%) than that treated with umifenovir (55.86%), and the duration of fever and cough relief time are significantly shorter in favipiravir group than in umifenovir group. [14]
- Two randomized and nonrandomized controlled trials are evaluating the safety and efficacy of favipiravir for treatment of COVID-19 disease.
Oseltamivir (Tamiflu)
- Oseltamivir has been approved for the treatment of influenza A, B viruses and inhibits neuraminidase glygoprotein which is essential for replication of influenza A and B viruses.[17]
- The study in Wuhan showed no positive outcomes were observed in COVID-19 patients after receiving osetamivir.[18]
- A clinical trial is investigating the efficacy of combination between Oseltamivir with chloroquine and favipiravir.[19]
Supportive Agents
Azithromycin
- Azithromycin has been effective in the treatment of Zika and Ebola viruses and prevented severe respiratory tract infection.[20]
- Mechanism of action is binding to 50S subunit of the bacteria ribosom,then inhibition of translation of mRNA.
- Effects of azithromycin in treatment of viral respiratory tract infection include:1. antibacterial coverage 2.immunomodulatory and anti-inflammatory effects.[21]
- A trial in france reported %100 viral clearance in nasopharengeal swap after recieving hydroxychloroquine with azithromycin.[21]
- Data about benefits of azithromycin in COVID-19 disease is still inadequate and needs further evaluation.
Vitamin C (Ascorbic Acid)
- Maturation of T lymphocytes and NK( natural killer) cells that are involved in the immune response to viral agents.
- Inhibition of reactive oxygen species (ROS) production
- Remodulation of the cytokine network in systemic inflammatory syndrome.
- Study in COVID-19 patients in china showed administration of high dose IV,Vitamin C (1500mg per day) in moderate and severe cases was correlated with improvement in oxygenation indexes and recovery.[23]
Vitamin D (Calcifediol)
Vitamin D may have role[24].
Corticosteroids
- Meta-analysis of multiple trials confirmed lower 28-day all-cause mortality with systemic corticosteroid in critically ill patients with COVID-19.[25]
- Corticosteroids is administrated in patients on supplemental oxygen or receiving mechanical ventilation[2]
Methylprednisolone
- Effects of low doses of methylprednisolone in COVID-19 include:[26][27]
- Controlled of hypercytokinemia
- Anti-inflammatory effect in superimposed infection in COVID-19
- Increased blood pressure when it is low
- Decreased risk of death in ARDS related COVID-19[28]
Dexamethasone
- The recommended dose of dexamethasone for COVID-19 is 6 mg IV once daily or po x 10 days[2]
- Effects of dexamethason in ARDS related COVID-19 include:[27][29]
- Decreased days of intubation
- Decreased mortality
Niclosamide and Ivermectin
- Mechanism of action is the Inhibition of binding of coronavirus onto the cells.[30]
- Niclosamid inhibits replication of MERS-COV AND SARS-COV-2..[31]
- Ivermectin inhibits viral replication in dengue virus, flavivirus,influenza. [31]
- FDA approved Ivermectin for treatment of SARS-COV-2. The study showed Ivermectin inhibited SARS-COV-2 replication up to 5000 fold at 48 h in vitro.[32]
Convalescent Plasma
- Convalescent Plasma is the Transfusion of plasma loaded with antibodies after improvement from COVID-19.
- FDA confirmed emergency use authorization for administration of Convalescent Plasma for hospitalized COVID-19 patients.on AUGUST 23, 2020
- Studies in Taiwan and South Korea showed clinical benefits in severe cases of SARS-COV and MERS.[33]
- Pilot study in COVID19 showed symptoms improvement including fever, cough, tightness of breath,chest pain.[34]
- Serious side effects were not reported.[34]
- There is no randomized trial data to assess the efficacy of convalescent plasma in COVID-19.
Anticoagulation
- In COVID-19 hypercoagulable state induces micro-macro-vascular thrombosis.
- Predictors of poor outcome in COVID-19 include: Disseminated intravascular coagulation , high level of D-dimer.[35]
- A retrospective tudy showed anticoagulant therapy compared to prophylaxis dosage in COVID-19 hospitalized patients was associated with less mortality and intubation.<[36]
- A randomized controlled trial found benefits for intermediate outcomes[37].
- Efficacy of heparin in COVID-19 includes : 1.anti inflammatory properties,2. prevention of viral attachment via changing in covid 19 spike protein 3.anticoagulation effect. [38]
- Efficacy of low molecular weight heparin in COVID-19 includes:
- 1.Reduction in level of IL-6 and cytokine storm.[39]
- 2.Anticoagulation effect.
- Prophylactic anticoagulant therapy is necessary for all hospitalized COVID-19 patients.
- In patients with rapidly progressing respiratory distress and the probability of thrombosis, treatment doses of anticoagulant is considered.
Ibuprofen
- Ibuprofen is an anti-inflammatory drug (NSAID) and blocks the renin-angiotensin pathway.
- Ibuprofen is an Activator of ACE2 receptor.[40]
- There is No strong evidence between intake of NSAID and worsening COVID-19.
- Ibuprofen approved by FDA for treatment of COVID-19.
Tucilizumab (Actemra)
- Tocilizumab is a monoclonal antibody that binds to IL-6 receptor on the cells and prevents inflammatory response.[41]
- Tucilizumab has been used for the treatment of rheumatoid arthritis and juvenile idiopathic artheritis.
- Phase 3 IMPACTA clinical trial showed actemra reduced 44% the need for mechanical ventilation, in patients with Covid-19 association pneumonia and also Reduced mortality and the need for intubation (12.2% in actemra group compared with 19.3% in placebo group.
- Study in Wuhan showed significant clinical improvement in severe COVID-19 patients.[42]
- Hypoxia
- Lung infiltration on CXR
- High inflammatory markers(CRP>3g/dl,ferritin>400ng/dl
- Clinical deterioration
- Contraindications of tocilizumab include as followings:
- Confirmed bacterial or fungal infection
- Platelet count<100000/cc
- Neutrophil count<2000/cc
- Alanin aminotrasferase or aspartat aminotransferase >5times upper limit normal
References
- ↑ Spinner, Christoph D.; Gottlieb, Robert L.; Criner, Gerard J.; Arribas López, José Ramón; Cattelan, Anna Maria; Soriano Viladomiu, Alex; Ogbuagu, Onyema; Malhotra, Prashant; Mullane, Kathleen M.; Castagna, Antonella; Chai, Louis Yi Ann; Roestenberg, Meta; Tsang, Owen Tak Yin; Bernasconi, Enos; Le Turnier, Paul; Chang, Shan-Chwen; SenGupta, Devi; Hyland, Robert H.; Osinusi, Anu O.; Cao, Huyen; Blair, Christiana; Wang, Hongyuan; Gaggar, Anuj; Brainard, Diana M.; McPhail, Mark J.; Bhagani, Sanjay; Ahn, Mi Young; Sanyal, Arun J.; Huhn, Gregory; Marty, Francisco M. (2020). "Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19". JAMA. 324 (11): 1048. doi:10.1001/jama.2020.16349. ISSN 0098-7484.
- ↑ 2.0 2.1 2.2 "Sanford Guide".
- ↑ Dong L, Hu S, Gao J (2020). "Discovering drugs to treat coronavirus disease 2019 (COVID-19)". Drug Discov Ther. 14 (1): 58–60. doi:10.5582/ddt.2020.01012. PMID 32147628 Check
|pmid=value (help). - ↑ Ranieri VM, Pettilä V, Karvonen MK, Jalkanen J, Nightingale P, Brealey D, Mancebo J, Ferrer R, Mercat A, Patroniti N, Quintel M, Vincent JL, Okkonen M, Meziani F, Bellani G, MacCallum N, Creteur J, Kluge S, Artigas-Raventos A, Maksimow M, Piippo I, Elima K, Jalkanen S, Jalkanen M, Bellingan G (February 2020). "Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial". JAMA. doi:10.1001/jama.2019.22525. PMID 32065831 Check
|pmid=value (help). - ↑ . doi:10.1101/2020.04.04.020925doi: bioRxiv preprint Check
|doi=value (help). Missing or empty|title=(help) - ↑ Skipper, Caleb P.; Pastick, Katelyn A.; Engen, Nicole W.; Bangdiwala, Ananta S.; Abassi, Mahsa; Lofgren, Sarah M.; Williams, Darlisha A.; Okafor, Elizabeth C.; Pullen, Matthew F.; Nicol, Melanie R.; Nascene, Alanna A.; Hullsiek, Kathy H.; Cheng, Matthew P.; Luke, Darlette; Lother, Sylvain A.; MacKenzie, Lauren J.; Drobot, Glen; Kelly, Lauren E.; Schwartz, Ilan S.; Zarychanski, Ryan; McDonald, Emily G.; Lee, Todd C.; Rajasingham, Radha; Boulware, David R. (2020). "Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19". Annals of Internal Medicine. doi:10.7326/M20-4207. ISSN 0003-4819.
- ↑ Rajasingham, Radha; Bangdiwala, Ananta S; Nicol, Melanie R; Skipper, Caleb P; Pastick, Katelyn A; Axelrod, Margaret L; Pullen, Matthew F; Nascene, Alanna A; Williams, Darlisha A; Engen, Nicole W; Okafor, Elizabeth C; Rini, Brian I; Mayer, Ingrid A; McDonald, Emily G; Lee, Todd C; Li, Peter; MacKenzie, Lauren J; Balko, Justin M; Dunlop, Stephen J; Hullsiek, Katherine H; Boulware, David R; Lofgren, Sarah M (2020). doi:10.1101/2020.09.18.20197327. Missing or empty
|title=(help) - ↑ Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ (2014). "Chloroquine is a zinc ionophore". PLoS ONE. 9 (10): e109180. doi:10.1371/journal.pone.0109180. PMC 4182877. PMID 25271834.
- ↑ Cao, Bin; Wang, Yeming; Wen, Danning; Liu, Wen; Wang, Jingli; Fan, Guohui; Ruan, Lianguo; Song, Bin; Cai, Yanping; Wei, Ming; Li, Xingwang; Xia, Jiaan; Chen, Nanshan; Xiang, Jie; Yu, Ting; Bai, Tao; Xie, Xuelei; Zhang, Li; Li, Caihong; Yuan, Ye; Chen, Hua; Li, Huadong; Huang, Hanping; Tu, Shengjing; Gong, Fengyun; Liu, Ying; Wei, Yuan; Dong, Chongya; Zhou, Fei; Gu, Xiaoying; Xu, Jiuyang; Liu, Zhibo; Zhang, Yi; Li, Hui; Shang, Lianhan; Wang, Ke; Li, Kunxia; Zhou, Xia; Dong, Xuan; Qu, Zhaohui; Lu, Sixia; Hu, Xujuan; Ruan, Shunan; Luo, Shanshan; Wu, Jing; Peng, Lu; Cheng, Fang; Pan, Lihong; Zou, Jun; Jia, Chunmin; Wang, Juan; Liu, Xia; Wang, Shuzhen; Wu, Xudong; Ge, Qin; He, Jing; Zhan, Haiyan; Qiu, Fang; Guo, Li; Huang, Chaolin; Jaki, Thomas; Hayden, Frederick G.; Horby, Peter W.; Zhang, Dingyu; Wang, Chen (2020). "A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19". New England Journal of Medicine. 382 (19): 1787–1799. doi:10.1056/NEJMoa2001282. ISSN 0028-4793.
- ↑ Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, Choe KW, Kang YM, Lee B, Park SJ (February 2020). "Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR". J. Korean Med. Sci. 35 (6): e79. doi:10.3346/jkms.2020.35.e79. PMC 7025910 Check
|pmc=value (help). PMID 32056407 Check|pmid=value (help). - ↑ Pécheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ (January 2016). "The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses". J. Virol. 90 (6): 3086–92. doi:10.1128/JVI.02077-15. PMC 4810626. PMID 26739045.
- ↑ Villalaín J (July 2010). "Membranotropic effects of arbidol, a broad anti-viral molecule, on phospholipid model membranes". J Phys Chem B. 114 (25): 8544–54. doi:10.1021/jp102619w. PMID 20527735.
- ↑ Deng L, Li C, Zeng Q, Liu X, Li X, Zhang H, Hong Z, Xia J (July 2020). "Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study". J. Infect. 81 (1): e1–e5. doi:10.1016/j.jinf.2020.03.002. PMC 7156152 Check
|pmc=value (help). PMID 32171872 Check|pmid=value (help). - ↑ 14.0 14.1 Chen, Chang; Zhang, Yi; Huang, Jianying; Yin, Ping; Cheng, Zhenshun; Wu, Jianyuan; Chen, Song; Zhang, Yongxi; Chen, Bo; Lu, Mengxin; Luo, Yongwen; Ju, Lingao; Zhang, Jingyi; Wang, Xinghuan (2020). doi:10.1101/2020.03.17.20037432. Missing or empty
|title=(help) - ↑ Furuta Y, Komeno T, Nakamura T (2017). "Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase". Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 93 (7): 449–463. doi:10.2183/pjab.93.027. PMC 5713175. PMID 28769016.
- ↑ De Clercq E (November 2019). "New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections". Chem Asian J. 14 (22): 3962–3968. doi:10.1002/asia.201900841. PMC 7159701 Check
|pmc=value (help). PMID 31389664. - ↑ McClellan K, Perry CM (2001). "Oseltamivir: a review of its use in influenza". Drugs. 61 (2): 263–83. doi:10.2165/00003495-200161020-00011. PMID 11270942.
- ↑ Wang, Dawei; Hu, Bo; Hu, Chang; Zhu, Fangfang; Liu, Xing; Zhang, Jing; Wang, Binbin; Xiang, Hui; Cheng, Zhenshun; Xiong, Yong; Zhao, Yan; Li, Yirong; Wang, Xinghuan; Peng, Zhiyong (2020). "Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China". JAMA. 323 (11): 1061. doi:10.1001/jama.2020.1585. ISSN 0098-7484.
- ↑ Rosa S, Santos WC (2020). "Clinical trials on drug repositioning for COVID-19 treatment". Rev. Panam. Salud Publica. 44: e40. doi:10.26633/RPSP.2020.40. PMC 7105280 Check
|pmc=value (help). PMID 32256547 Check|pmid=value (help). Vancouver style error: initials (help) - ↑ Retallack H, Di Lullo E, Arias C, Knopp KA, Laurie MT, Sandoval-Espinosa C, Mancia Leon WR, Krencik R, Ullian EM, Spatazza J, Pollen AA, Mandel-Brehm C, Nowakowski TJ, Kriegstein AR, DeRisi JL (December 2016). "Zika virus cell tropism in the developing human brain and inhibition by azithromycin". Proc. Natl. Acad. Sci. U.S.A. 113 (50): 14408–14413. doi:10.1073/pnas.1618029113. PMC 5167169. PMID 27911847.
- ↑ 21.0 21.1 Gautret, Philippe; Lagier, Jean-Christophe; Parola, Philippe; Hoang, Van Thuan; Meddeb, Line; Mailhe, Morgane; Doudier, Barbara; Courjon, Johan; Giordanengo, Valérie; Vieira, Vera Esteves; Dupont, Hervé Tissot; Honoré, Stéphane; Colson, Philippe; Chabrière, Eric; La Scola, Bernard; Rolain, Jean-Marc; Brouqui, Philippe; Raoult, Didier (2020). "Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial". International Journal of Antimicrobial Agents: 105949. doi:10.1016/j.ijantimicag.2020.105949. ISSN 0924-8579.
- ↑ van Gorkom G, Klein Wolterink R, Van Elssen C, Wieten L, Germeraad W, Bos G (March 2018). "Influence of Vitamin C on Lymphocytes: An Overview". Antioxidants (Basel). 7 (3). doi:10.3390/antiox7030041. PMC 5874527. PMID 29534432. Vancouver style error: initials (help)
- ↑ Cheng RZ (March 2020). "Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?". Med Drug Discov. 5: 100028. doi:10.1016/j.medidd.2020.100028. PMC 7167497 Check
|pmc=value (help). PMID 32328576 Check|pmid=value (help). - ↑ Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R; et al. (2020). ""Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study"". J Steroid Biochem Mol Biol. 203: 105751. doi:10.1016/j.jsbmb.2020.105751. PMC 7456194 Check
|pmc=value (help). PMID 32871238 Check|pmid=value (help). - ↑ Sterne, Jonathan A. C.; Murthy, Srinivas; Diaz, Janet V.; Slutsky, Arthur S.; Villar, Jesús; Angus, Derek C.; Annane, Djillali; Azevedo, Luciano Cesar Pontes; Berwanger, Otavio; Cavalcanti, Alexandre B.; Dequin, Pierre-Francois; Du, Bin; Emberson, Jonathan; Fisher, David; Giraudeau, Bruno; Gordon, Anthony C.; Granholm, Anders; Green, Cameron; Haynes, Richard; Heming, Nicholas; Higgins, Julian P. T.; Horby, Peter; Jüni, Peter; Landray, Martin J.; Le Gouge, Amelie; Leclerc, Marie; Lim, Wei Shen; Machado, Flávia R.; McArthur, Colin; Meziani, Ferhat; Møller, Morten Hylander; Perner, Anders; Petersen, Marie Warrer; Savovic, Jelena; Tomazini, Bruno; Veiga, Viviane C.; Webb, Steve; Marshall, John C. (2020). "Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19". JAMA. doi:10.1001/jama.2020.17023. ISSN 0098-7484.
- ↑ Lamontagne F, Rochwerg B, Lytvyn L, Guyatt GH, Møller MH, Annane D, Kho ME, Adhikari N, Machado F, Vandvik PO, Dodek P, Leboeuf R, Briel M, Hashmi M, Camsooksai J, Shankar-Hari M, Baraki MK, Fugate K, Chua S, Marti C, Cohen D, Botton E, Agoritsas T, Siemieniuk R (August 2018). "Corticosteroid therapy for sepsis: a clinical practice guideline". BMJ. 362: k3284. doi:10.1136/bmj.k3284. PMC 6083439. PMID 30097460. Vancouver style error: initials (help)
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|pmc=value (help). PMID 32043983 Check|pmid=value (help). - ↑ Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, Huang H, Zhang L, Zhou X, Du C, Zhang Y, Song J, Wang S, Chao Y, Yang Z, Xu J, Zhou X, Chen D, Xiong W, Xu L, Zhou F, Jiang J, Bai C, Zheng J, Song Y (March 2020). "Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China". JAMA Intern Med. doi:10.1001/jamainternmed.2020.0994. PMC 7070509 Check
|pmc=value (help). PMID 32167524 Check|pmid=value (help). - ↑ Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, Aguilar G, Alba F, González-Higueras E, Conesa LA, Martín-Rodríguez C, Díaz-Domínguez FJ, Serna-Grande P, Rivas R, Ferreres J, Belda J, Capilla L, Tallet A, Añón JM, Fernández RL, González-Martín JM (March 2020). "Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial". Lancet Respir Med. 8 (3): 267–276. doi:10.1016/S2213-2600(19)30417-5. PMID 32043986 Check
|pmid=value (help). - ↑ Wu CJ, Jan JT, Chen CM, Hsieh HP, Hwang DR, Liu HW, Liu CY, Huang HW, Chen SC, Hong CF, Lin RK, Chao YS, Hsu JT (July 2004). "Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide". Antimicrob. Agents Chemother. 48 (7): 2693–6. doi:10.1128/AAC.48.7.2693-2696.2004. PMC 434198. PMID 15215127.
- ↑ 31.0 31.1 Gassen NC, Niemeyer D, Muth D, Corman VM, Martinelli S, Gassen A, Hafner K, Papies J, Mösbauer K, Zellner A, Zannas AS, Herrmann A, Holsboer F, Brack-Werner R, Boshart M, Müller-Myhsok B, Drosten C, Müller MA, Rein T (December 2019). "SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection". Nat Commun. 10 (1): 5770. doi:10.1038/s41467-019-13659-4. PMC 6920372 Check
|pmc=value (help). PMID 31852899. - ↑ Caly, Leon; Druce, Julian D.; Catton, Mike G.; Jans, David A.; Wagstaff, Kylie M. (2020). "The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro". Antiviral Research. 178: 104787. doi:10.1016/j.antiviral.2020.104787. ISSN 0166-3542.
- ↑ Yeh KM, Chiueh TS, Siu LK, Lin JC, Chan PK, Peng MY, Wan HL, Chen JH, Hu BS, Perng CL, Lu JJ, Chang FY (November 2005). "Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital". J. Antimicrob. Chemother. 56 (5): 919–22. doi:10.1093/jac/dki346. PMC 7110092 Check
|pmc=value (help). PMID 16183666. - ↑ 34.0 34.1 Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, Zhou M, Chen L, Meng S, Hu Y, Peng C, Yuan M, Huang J, Wang Z, Yu J, Gao X, Wang D, Yu X, Li L, Zhang J, Wu X, Li B, Xu Y, Chen W, Peng Y, Hu Y, Lin L, Liu X, Huang S, Zhou Z, Zhang L, Wang Y, Zhang Z, Deng K, Xia Z, Gong Q, Zhang W, Zheng X, Liu Y, Yang H, Zhou D, Yu D, Hou J, Shi Z, Chen S, Chen Z, Zhang X, Yang X (April 2020). "Effectiveness of convalescent plasma therapy in severe COVID-19 patients". Proc. Natl. Acad. Sci. U.S.A. 117 (17): 9490–9496. doi:10.1073/pnas.2004168117. PMC 7196837 Check
|pmc=value (help). PMID 32253318 Check|pmid=value (help). - ↑ Tang N, Li D, Wang X, Sun Z (April 2020). "Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia". J. Thromb. Haemost. 18 (4): 844–847. doi:10.1111/jth.14768. PMC 7166509 Check
|pmc=value (help). PMID 32073213 Check|pmid=value (help). - ↑ Nadkarni GN, Lala A, Bagiella E, Chang HL, Moreno P, Pujadas E; et al. (2020). "Anticoagulation, Mortality, Bleeding and Pathology Among Patients Hospitalized with COVID-19: A Single Health System Study". J Am Coll Cardiol. doi:10.1016/j.jacc.2020.08.041. PMC 7449655 Check
|pmc=value (help). PMID 32860872 Check|pmid=value (help). - ↑ Lemos ACB, do Espírito Santo DA, Salvetti MC, Gilio RN, Agra LB, Pazin-Filho A; et al. (2020). "Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID)". Thromb Res. 196: 359–366. doi:10.1016/j.thromres.2020.09.026. PMC 7503069 Check
|pmc=value (help). PMID 32977137 Check|pmid=value (help). - ↑ Mycroft-West, Courtney; Su, Dunhao; Elli, Stefano; Li, Yong; Guimond, Scott; Miller, Gavin; Turnbull, Jeremy; Yates, Edwin; Guerrini, Marco; Fernig, David; Lima, Marcelo; Skidmore, Mark (2020). doi:10.1101/2020.02.29.971093. Missing or empty
|title=(help) - ↑ Shi, Chen; Wang, Cong; Wang, Hanxiang; Yang, Chao; Cai, Fei; Zeng, Fang; Cheng, Fang; Liu, Yihui; Zhou, Taotao; Deng, Bin; Vlodavsky, Israel; Li, Jinping; Zhang, Yu (2020). doi:10.1101/2020.03.28.20046144. Missing or empty
|title=(help) - ↑ Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM (August 2005). "A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury". Nat. Med. 11 (8): 875–9. doi:10.1038/nm1267. PMC 7095783 Check
|pmc=value (help). PMID 16007097. - ↑ Fu B, Xu X, Wei H (April 2020). "Why tocilizumab could be an effective treatment for severe COVID-19?". J Transl Med. 18 (1): 164. doi:10.1186/s12967-020-02339-3. PMC 7154566 Check
|pmc=value (help). PMID 32290839 Check|pmid=value (help). - ↑ Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, Zhang X, Pan A, Wei H (May 2020). "Effective treatment of severe COVID-19 patients with tocilizumab". Proc. Natl. Acad. Sci. U.S.A. 117 (20): 10970–10975. doi:10.1073/pnas.2005615117. PMC 7245089 Check
|pmc=value (help). PMID 32350134 Check|pmid=value (help). - ↑ Kewan, Tariq; Covut, Fahrettin; Al–Jaghbeer, Mohammed J.; Rose, Lori; Gopalakrishna, K.V.; Akbik, Bassel (2020). "Tocilizumab for treatment of patients with severe COVID–19: A retrospective cohort study". EClinicalMedicine: 100418. doi:10.1016/j.eclinm.2020.100418. ISSN 2589-5370.