COVID-19 medical therapy: Difference between revisions
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* A [[meta-analysis]] of multiple trials ('''RECOVERY trial''') confirmed 36% reduction in 28-day [[mortality]] with [[ dexamethasone]] in ventilated patients and by 18% in other [[COVID-19]] patients recieving [[oxygen]].<ref name="SterneMurthy2020">{{cite journal|last1=Sterne|first1=Jonathan A. C.|last2=Murthy|first2=Srinivas|last3=Diaz|first3=Janet V.|last4=Slutsky|first4=Arthur S.|last5=Villar|first5=Jesús|last6=Angus|first6=Derek C.|last7=Annane|first7=Djillali|last8=Azevedo|first8=Luciano Cesar Pontes|last9=Berwanger|first9=Otavio|last10=Cavalcanti|first10=Alexandre B.|last11=Dequin|first11=Pierre-Francois|last12=Du|first12=Bin|last13=Emberson|first13=Jonathan|last14=Fisher|first14=David|last15=Giraudeau|first15=Bruno|last16=Gordon|first16=Anthony C.|last17=Granholm|first17=Anders|last18=Green|first18=Cameron|last19=Haynes|first19=Richard|last20=Heming|first20=Nicholas|last21=Higgins|first21=Julian P. T.|last22=Horby|first22=Peter|last23=Jüni|first23=Peter|last24=Landray|first24=Martin J.|last25=Le Gouge|first25=Amelie|last26=Leclerc|first26=Marie|last27=Lim|first27=Wei Shen|last28=Machado|first28=Flávia R.|last29=McArthur|first29=Colin|last30=Meziani|first30=Ferhat|last31=Møller|first31=Morten Hylander|last32=Perner|first32=Anders|last33=Petersen|first33=Marie Warrer|last34=Savovic|first34=Jelena|last35=Tomazini|first35=Bruno|last36=Veiga|first36=Viviane C.|last37=Webb|first37=Steve|last38=Marshall|first38=John C.|title=Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19|journal=JAMA|year=2020|issn=0098-7484|doi=10.1001/jama.2020.17023}}</ref> | * A [[meta-analysis]] of multiple trials ('''RECOVERY trial''') confirmed 36% reduction in 28-day [[mortality]] with [[ dexamethasone]] in ventilated patients and by 18% in other [[COVID-19]] patients recieving [[oxygen]].<ref name="SterneMurthy2020">{{cite journal|last1=Sterne|first1=Jonathan A. C.|last2=Murthy|first2=Srinivas|last3=Diaz|first3=Janet V.|last4=Slutsky|first4=Arthur S.|last5=Villar|first5=Jesús|last6=Angus|first6=Derek C.|last7=Annane|first7=Djillali|last8=Azevedo|first8=Luciano Cesar Pontes|last9=Berwanger|first9=Otavio|last10=Cavalcanti|first10=Alexandre B.|last11=Dequin|first11=Pierre-Francois|last12=Du|first12=Bin|last13=Emberson|first13=Jonathan|last14=Fisher|first14=David|last15=Giraudeau|first15=Bruno|last16=Gordon|first16=Anthony C.|last17=Granholm|first17=Anders|last18=Green|first18=Cameron|last19=Haynes|first19=Richard|last20=Heming|first20=Nicholas|last21=Higgins|first21=Julian P. T.|last22=Horby|first22=Peter|last23=Jüni|first23=Peter|last24=Landray|first24=Martin J.|last25=Le Gouge|first25=Amelie|last26=Leclerc|first26=Marie|last27=Lim|first27=Wei Shen|last28=Machado|first28=Flávia R.|last29=McArthur|first29=Colin|last30=Meziani|first30=Ferhat|last31=Møller|first31=Morten Hylander|last32=Perner|first32=Anders|last33=Petersen|first33=Marie Warrer|last34=Savovic|first34=Jelena|last35=Tomazini|first35=Bruno|last36=Veiga|first36=Viviane C.|last37=Webb|first37=Steve|last38=Marshall|first38=John C.|title=Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19|journal=JAMA|year=2020|issn=0098-7484|doi=10.1001/jama.2020.17023}}</ref> | ||
*[[Corticosteroids]] is administrated in patients on supplemental [[oxygen]] or receiving [[mechanical ventilation]]<ref name="urlSanford Guide" /> | *[[Corticosteroids]] is administrated in patients on supplemental [[oxygen]] or receiving [[mechanical ventilation]]<ref name="urlSanford Guide" /> | ||
====Dexamethasone==== | ====Dexamethasone==== | ||
Revision as of 10:51, 1 November 2020
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
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COVID-19 Microchapters |
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COVID-19 medical therapy On the Web |
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American Roentgen Ray Society Images of COVID-19 medical therapy |
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Risk calculators and risk factors for COVID-19 medical therapy |
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.
In the non peer reviewing WHO SOLIDARITY trial which was conducted in 405 hospitals in 30 countries, showed Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens have NO effect on hospitalized covid-19 as include by overall mortality, initiation of ventilation and duration of hospital days.The result is in contrast with recent study about Remdesivir.
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 these mechanisms:
- Significant reduction in viral load in bronchoaleolar lavage
- Inhibition of SARS-COV-2 replication in nasal and bronchial airway epithelial cells.
- Remdesivir is approved by FDA on 22 October 2020 for all hospitalized adult and pediatric older than 12 years of age and weighing at least 40 kg (88 pounds).
- Remdesivir was effective in shortening the time of recovery about 32% and survival benefit in adult hospitalized covid-19 patients according to ACTT-1 trial.[1]
- The combination of Remdesivir and Baricitinib reduced recovery time in hospitalized covid-19 patients according to ACTT-2 trial.
- Safety and efficacy of the combination of Remdesivir and interferon b-1a is under investigation according to ACTT-3 trial.
- 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.[2]
- 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 (EUA) issued on 1 may 2020.
- 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 reduced in combination with hydroxychloroquine
- 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]
- The randomised clinical trial showed combination of azithromycin with hydroxychroquin was not effective in clinical improvement or mortality reduction in severe covid-19 pateints.[22]
- In the begining of covid-19 pandemic a trial in France reported %100 viral clearance in nasopharengeal swap after recieving hydroxychloroquine with azithromycin.[21]
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.[24]
Corticosteroids
- A meta-analysis of multiple trials (RECOVERY trial) confirmed 36% reduction in 28-day mortality with dexamethasone in ventilated patients and by 18% in other COVID-19 patients recieving oxygen.[25]
- Corticosteroids is administrated in patients on supplemental oxygen or receiving mechanical ventilation[26]
Dexamethasone
- Effects of dexamethason in ARDS related COVID-19 include:[27][28]
- Decreased days of intubation
- Decreased mortality
Methylprednisolone
- Effects of low doses of methylprednisolone in COVID-19 include:[29][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[30]
Niclosamide and Ivermectin
- Mechanism of action is the Inhibition of binding of coronavirus onto the cells.[31]
- Niclosamid inhibits replication of MERS-COV AND SARS-COV-2..[32]
- Ivermectin inhibits viral replication in dengue virus, flavivirus,influenza. [32]
- 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.[33]
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.[34]
- Pilot study in COVID19 showed symptoms improvement including fever, cough, tightness of breath,chest pain.[35]
- Serious side effects were not reported.[35]
- 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.[36]
- A retrospective Study showed anticoagulant therapy compared to prophylaxis dosage in COVID-19 hospitalized patients was associated with less mortality and intubation.<[37]
- A randomized controlled trial found in covid-19 hospitalized patients, therapeutic anticoagulalation was associated with reduction in mortality and the need for ventilation[38].
- 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. [39]
- Efficacy of low molecular weight heparin in COVID-19 includes:
- 1.Reduction in level of IL-6 and cytokine storm.[40]
- 2.Anticoagulation effect.
- Prophylactic anticoagulant therapy is necessary for all hospitalized COVID-19 patients.[41].
- 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.[42]
- 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.[43]
- Tucilizumab has been used for the treatment of rheumatoid arthritis and juvenile idiopathic artheritis.
- In a randomized, double-blind, placebo-controlled trial involving patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), tocilizumab was not effective for preventing intubation or death. [44]
- 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.[45]
- 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
- ↑ Beigel, John H.; Tomashek, Kay M.; Dodd, Lori E.; Mehta, Aneesh K.; Zingman, Barry S.; Kalil, Andre C.; Hohmann, Elizabeth; Chu, Helen Y.; Luetkemeyer, Annie; Kline, Susan; Lopez de Castilla, Diego; Finberg, Robert W.; Dierberg, Kerry; Tapson, Victor; Hsieh, Lanny; Patterson, Thomas F.; Paredes, Roger; Sweeney, Daniel A.; Short, William R.; Touloumi, Giota; Lye, David Chien; Ohmagari, Norio; Oh, Myoung-don; Ruiz-Palacios, Guillermo M.; Benfield, Thomas; Fätkenheuer, Gerd; Kortepeter, Mark G.; Atmar, Robert L.; Creech, C. Buddy; Lundgren, Jens; Babiker, Abdel G.; Pett, Sarah; Neaton, James D.; Burgess, Timothy H.; Bonnett, Tyler; Green, Michelle; Makowski, Mat; Osinusi, Anu; Nayak, Seema; Lane, H. Clifford (2020). "Remdesivir for the Treatment of Covid-19 — Final Report". New England Journal of Medicine. doi:10.1056/NEJMoa2007764. ISSN 0028-4793.
- ↑ 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.
- ↑ 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.
- ↑ . doi:10.1016/S0140-6736(20)31862_6. Missing or empty
|title=(help) - ↑ 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
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|pmid=value (help). - ↑ 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 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.
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|pmc=value (help). PMID 16183666. - ↑ 35.0 35.1 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) - ↑ https://app.magicapp.org/#/guideline/L4Q5An/section/j29ONE
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|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). - ↑ Stone, John H.; Frigault, Matthew J.; Serling-Boyd, Naomi J.; Fernandes, Ana D.; Harvey, Liam; Foulkes, Andrea S.; Horick, Nora K.; Healy, Brian C.; Shah, Ruta; Bensaci, Ana Maria; Woolley, Ann E.; Nikiforow, Sarah; Lin, Nina; Sagar, Manish; Schrager, Harry; Huckins, David S.; Axelrod, Matthew; Pincus, Michael D.; Fleisher, Jorge; Sacks, Chana A.; Dougan, Michael; North, Crystal M.; Halvorsen, Yuan-Di; Thurber, Tara K.; Dagher, Zeina; Scherer, Allison; Wallwork, Rachel S.; Kim, Arthur Y.; Schoenfeld, Sara; Sen, Pritha; Neilan, Tomas G.; Perugino, Cory A.; Unizony, Sebastian H.; Collier, Deborah S.; Matza, Mark A.; Yinh, Janeth M.; Bowman, Kathryn A.; Meyerowitz, Eric; Zafar, Amna; Drobni, Zsofia D.; Bolster, Marcy B.; Kohler, Minna; D’Silva, Kristin M.; Dau, Jonathan; Lockwood, Megan M.; Cubbison, Caroline; Weber, Brittany N.; Mansour, Michael K. (2020). "Efficacy of Tocilizumab in Patients Hospitalized with Covid-19". New England Journal of Medicine. doi:10.1056/NEJMoa2028836. ISSN 0028-4793.
- ↑ 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.