COVID-19 medical therapy: Difference between revisions

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[[File:SARS-CoV-2 49534865371.jpg|thumb|Electron micrograph of SARS-CoV-2 virions with visible coronae]]
'''For COVID-19 frequently asked inpatient questions, click [[COVID-19 frequently asked inpatient questions|here]]'''<br>'''For COVID-19 frequently asked outpatient questions, click [[COVID-19 frequently asked outpatient questions|here]]'''<br>
__NOTOC__
__NOTOC__{{COVID-19}}
{{COVID-19}}
{{CMG}}; {{AE}} {{Sara.Zand}}, {{HK}},{{Sab}},  
{{CMG}} ; {{AE}}[[User:DrMars|Mohammadmain Rezazadehsaatlou]] [2],


==Overview==
==Overview==
[[COVID-19]] is an inflammatory [[hypercytokinemia]]  disease. The aim of therapy is prevention of [[viral replication]] and controlling the [[inflammatory]] process. On February 09, 2021 [[FDA]] approved [[emergency use authorization]] of [[monoclonal antibodies]] including [[bamlanivimab]] and [[etesevimab]] for mild to moderate [[covid-19]] patients who are high risk for progression of disease ( age > 65years, [[ medical comorbidities]]).


==COVID-19 medical therapy==
===Current Treatment===


==References==
====Corticosteroids====
 
* A [[meta-analysis]] of multiple trials ('''RECOVERY trial''') of [[corticosteroids]] 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" />
 
====Dexamethasone====
 
*Effects of [[Dexamethasone|dexamethasone]] in [[ARDS]] related [[COVID-19]] include:<ref name="pmid32043983">{{cite journal |vauthors=Russell CD, Millar JE, Baillie JK |title=Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury |journal=Lancet |volume=395 |issue=10223 |pages=473–475 |date=February 2020 |pmid=32043983 |pmc=7134694 |doi=10.1016/S0140-6736(20)30317-2 |url=}}</ref><ref name="pmid32043986">{{cite journal |vauthors=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 |title=Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial |journal=Lancet Respir Med |volume=8 |issue=3 |pages=267–276 |date=March 2020 |pmid=32043986 |doi=10.1016/S2213-2600(19)30417-5 |url=}}</ref>
 
#Decreased days of [[intubation]]
#Decreased [[mortality]]
 
====Methylprednisolone====
 
*Effects of low doses of [[methylprednisolone]] in [[COVID-19]] include:<ref name="pmid30097460">{{cite journal |vauthors=Lamontagne F, Rochwerg B, Lytvyn L, Guyatt GH, Møller MH, Annane D, Kho ME, Adhikari NKJ, 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 RAC |title=Corticosteroid therapy for sepsis: a clinical practice guideline |journal=BMJ |volume=362 |issue= |pages=k3284 |date=August 2018 |pmid=30097460 |pmc=6083439 |doi=10.1136/bmj.k3284 |url=}}</ref><ref name="pmid32043983">{{cite journal |vauthors=Russell CD, Millar JE, Baillie JK |title=Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury |journal=Lancet |volume=395 |issue=10223 |pages=473–475 |date=February 2020 |pmid=32043983 |pmc=7134694 |doi=10.1016/S0140-6736(20)30317-2 |url=}}</ref>
 
#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]]<ref name="pmid32167524">{{cite journal |vauthors=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 |title=Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China |journal=JAMA Intern Med |volume= |issue= |pages= |date=March 2020 |pmid=32167524 |pmc=7070509 |doi=10.1001/jamainternmed.2020.0994 |url=}}</ref>
 
====Inhaled corticosteroids====
Inhaled [[corticosteroids]] ([[budesonide]]) may improve recovery time and reducing hospital admission or [[death]] in high risk [[covid-19]] [[patients]] in the community.  <ref>Yu L-M et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): A randomised, controlled, open-label, adaptive platform trial. Lancet 2021 Aug 10; [e-pub]. https://doi.org/10.1016/S0140-6736(21)01744-X</ref>.
 
===Experimental Treatments===
 
===[[ Remdesivir]]===
 
*[[Remdesivir]] is a [[prodrug]] and inhibits viral [[RNA polymerase]] when intracellularly metabolized to an [[ATP analog|ATP analog.]]
 
*[[Remdesivir]] has been effective on [[MERS|MERS-COV]],[[EBOLA]], [[SARS-COV1]] and also [[Covid-19]] by these mechanisms:<ref name="pmid28124907">{{cite journal |vauthors=Siegel D, Hui HC, Doerffler E, Clarke MO, Chun K, Zhang L, Neville S, Carra E, Lew W, Ross B, Wang Q, Wolfe L, Jordan R, Soloveva V, Knox J, Perry J, Perron M, Stray KM, Barauskas O, Feng JY, Xu Y, Lee G, Rheingold AL, Ray AS, Bannister R, Strickley R, Swaminathan S, Lee WA, Bavari S, Cihlar T, Lo MK, Warren TK, Mackman RL |title=Discovery and Synthesis of a Phosphoramidate Prodrug of a Pyrrolo[2,1-f][triazin-4-amino] Adenine C-Nucleoside (GS-5734) for the Treatment of Ebola and Emerging Viruses |journal=J. Med. Chem. |volume=60 |issue=5 |pages=1648–1661 |date=March 2017 |pmid=28124907 |pmc=7202039 |doi=10.1021/acs.jmedchem.6b01594 |url=}}</ref
*<nowiki>[[Remdesivir]]</nowiki> has been effective on <nowiki>[[MERS|MERS-COV]]</nowiki>,<nowiki>[[EBOLA]]</nowiki>, <nowiki>[[SARS-COV1]]</nowiki>.
*Effects of [[remdesivir]] in [[COVID-19]] include:<ref name="GreinOhmagari2020"></nowiki>{{cite journal|last1=Grein|first1=Jonathan|last2=Ohmagari|first2=Norio|last3=Shin|first3=Daniel|last4=Diaz|first4=George|last5=Asperges|first5=Erika|last6=Castagna|first6=Antonella|last7=Feldt|first7=Torsten|last8=Green|first8=Gary|last9=Green|first9=Margaret L.|last10=Lescure|first10=François-Xavier|last11=Nicastri|first11=Emanuele|last12=Oda|first12=Rentaro|last13=Yo|first13=Kikuo|last14=Quiros-Roldan|first14=Eugenia|last15=Studemeister|first15=Alex|last16=Redinski|first16=John|last17=Ahmed|first17=Seema|last18=Bernett|first18=Jorge|last19=Chelliah|first19=Daniel|last20=Chen|first20=Danny|last21=Chihara|first21=Shingo|last22=Cohen|first22=Stuart H.|last23=Cunningham|first23=Jennifer|last24=D’Arminio Monforte|first24=Antonella|last25=Ismail|first25=Saad|last26=Kato|first26=Hideaki|last27=Lapadula|first27=Giuseppe|last28=L’Her|first28=Erwan|last29=Maeno|first29=Toshitaka|last30=Majumder|first30=Sumit|last31=Massari|first31=Marco|last32=Mora-Rillo|first32=Marta|last33=Mutoh|first33=Yoshikazu|last34=Nguyen|first34=Duc|last35=Verweij|first35=Ewa|last36=Zoufaly|first36=Alexander|last37=Osinusi|first37=Anu O.|last38=DeZure|first38=Adam|last39=Zhao|first39=Yang|last40=Zhong|first40=Lijie|last41=Chokkalingam|first41=Anand|last42=Elboudwarej|first42=Emon|last43=Telep|first43=Laura|last44=Timbs|first44=Leighann|last45=Henne|first45=Ilana|last46=Sellers|first46=Scott|last47=Cao|first47=Huyen|last48=Tan|first48=Susanna K.|last49=Winterbourne|first49=Lucinda|last50=Desai|first50=Polly|last51=Mera|first51=Robertino|last52=Gaggar|first52=Anuj|last53=Myers|first53=Robert P.|last54=Brainard|first54=Diana M.|last55=Childs|first55=Richard|last56=Flanigan|first56=Timothy|title=Compassionate Use of Remdesivir for Patients with Severe Covid-19|journal=New England Journal of Medicine|volume=382|issue=24|year=2020|pages=2327–2336|issn=0028-4793|doi=10.1056/NEJMoa2007016}}</ref>
 
*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'''.<ref name="BeigelTomashek2020">{{cite journal|last1=Beigel|first1=John H.|last2=Tomashek|first2=Kay M.|last3=Dodd|first3=Lori E.|last4=Mehta|first4=Aneesh K.|last5=Zingman|first5=Barry S.|last6=Kalil|first6=Andre C.|last7=Hohmann|first7=Elizabeth|last8=Chu|first8=Helen Y.|last9=Luetkemeyer|first9=Annie|last10=Kline|first10=Susan|last11=Lopez de Castilla|first11=Diego|last12=Finberg|first12=Robert W.|last13=Dierberg|first13=Kerry|last14=Tapson|first14=Victor|last15=Hsieh|first15=Lanny|last16=Patterson|first16=Thomas F.|last17=Paredes|first17=Roger|last18=Sweeney|first18=Daniel A.|last19=Short|first19=William R.|last20=Touloumi|first20=Giota|last21=Lye|first21=David Chien|last22=Ohmagari|first22=Norio|last23=Oh|first23=Myoung-don|last24=Ruiz-Palacios|first24=Guillermo M.|last25=Benfield|first25=Thomas|last26=Fätkenheuer|first26=Gerd|last27=Kortepeter|first27=Mark G.|last28=Atmar|first28=Robert L.|last29=Creech|first29=C. Buddy|last30=Lundgren|first30=Jens|last31=Babiker|first31=Abdel G.|last32=Pett|first32=Sarah|last33=Neaton|first33=James D.|last34=Burgess|first34=Timothy H.|last35=Bonnett|first35=Tyler|last36=Green|first36=Michelle|last37=Makowski|first37=Mat|last38=Osinusi|first38=Anu|last39=Nayak|first39=Seema|last40=Lane|first40=H. Clifford|title=Remdesivir for the Treatment of Covid-19 — Final Report|journal=New England Journal of Medicine|year=2020|issn=0028-4793|doi=10.1056/NEJMoa2007764}}</ref>
*In a Phase 3 open label randomized trial, No clinical benefit was observed from the use of [[remdesivir]] in [[patients]] who were admitted to hospital for [[COVID19]],who were [[symptomatic]] for more than 7 days, and required [[oxygen]] support.(doi:10.1016/S1473-3099)
 
* 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.<ref name="SpinnerGottlieb2020">{{cite journal|last1=Spinner|first1=Christoph D.|last2=Gottlieb|first2=Robert L.|last3=Criner|first3=Gerard J.|last4=Arribas López|first4=José Ramón|last5=Cattelan|first5=Anna Maria|last6=Soriano Viladomiu|first6=Alex|last7=Ogbuagu|first7=Onyema|last8=Malhotra|first8=Prashant|last9=Mullane|first9=Kathleen M.|last10=Castagna|first10=Antonella|last11=Chai|first11=Louis Yi Ann|last12=Roestenberg|first12=Meta|last13=Tsang|first13=Owen Tak Yin|last14=Bernasconi|first14=Enos|last15=Le Turnier|first15=Paul|last16=Chang|first16=Shan-Chwen|last17=SenGupta|first17=Devi|last18=Hyland|first18=Robert H.|last19=Osinusi|first19=Anu O.|last20=Cao|first20=Huyen|last21=Blair|first21=Christiana|last22=Wang|first22=Hongyuan|last23=Gaggar|first23=Anuj|last24=Brainard|first24=Diana M.|last25=McPhail|first25=Mark J.|last26=Bhagani|first26=Sanjay|last27=Ahn|first27=Mi Young|last28=Sanyal|first28=Arun J.|last29=Huhn|first29=Gregory|last30=Marty|first30=Francisco M.|title=Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19|journal=JAMA|volume=324|issue=11|year=2020|pages=1048|issn=0098-7484|doi=10.1001/jama.2020.16349}}</ref>
*[[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 o]]<nowiki/>r [[alanin transferase]] (ALT)ᐳ 5-times upper limit
 
===[[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]].<ref name="pmid28769016">{{cite journal |vauthors=Furuta Y, Komeno T, Nakamura T |title=Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase |journal=Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. |volume=93 |issue=7 |pages=449–463 |date=2017 |pmid=28769016 |pmc=5713175 |doi=10.2183/pjab.93.027 |url=}}</ref> '''<ref name="pmid31389664">{{cite journal |vauthors=De Clercq E |title=New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections |journal=Chem Asian J |volume=14 |issue=22 |pages=3962–3968 |date=November 2019 |pmid=31389664 |pmc=7159701 |doi=10.1002/asia.201900841 |url=}}</ref>'''
*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]].<ref name="JoshiParkar2021">{{cite journal|last1=Joshi|first1=Shashank|last2=Parkar|first2=Jalil|last3=Ansari|first3=Abdul|last4=Vora|first4=Agam|last5=Talwar|first5=Deepak|last6=Tiwaskar|first6=Mangesh|last7=Patil|first7=Saiprasad|last8=Barkate|first8=Hanmant|title=Role of favipiravir in the treatment of COVID-19|journal=International Journal of Infectious Diseases|volume=102|year=2021|pages=501–508|issn=12019712|doi=10.1016/j.ijid.2020.10.069}}</ref>
* Safety and efficacy of [[favipiravir]] in both [[viral clearance]] and [[clinical improvement]] was shown in mild to moderate [[covid-19]] [[patients]].
*A multicenter randomized controlled study  showed that use of [[favipiravir]] in [[covid-19]] [[patients]] was associated with less [[hospitalization]] and the need for [[mechanical ventilation]].<ref name="pmid33492523">{{cite journal |vauthors=Dabbous HM, Abd-Elsalam S, El-Sayed MH, Sherief AF, Ebeid FFS, El Ghafar MSA, Soliman S, Elbahnasawy M, Badawi R, Tageldin MA |title=Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study |journal=Arch Virol |volume=166 |issue=3 |pages=949–954 |date=March 2021 |pmid=33492523 |pmc=7829645 |doi=10.1007/s00705-021-04956-9 |url=}}</ref>
*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. <ref name="ChenZhang2020">{{cite journal|last1=Chen|first1=Chang|last2=Zhang|first2=Yi|last3=Huang|first3=Jianying|last4=Yin|first4=Ping|last5=Cheng|first5=Zhenshun|last6=Wu|first6=Jianyuan|last7=Chen|first7=Song|last8=Zhang|first8=Yongxi|last9=Chen|first9=Bo|last10=Lu|first10=Mengxin|last11=Luo|first11=Yongwen|last12=Ju|first12=Lingao|last13=Zhang|first13=Jingyi|last14=Wang|first14=Xinghuan|year=2020|doi=10.1101/2020.03.17.20037432}}</ref>
 
===[[Atazanavir]]===
 
 
*[[Atazanavir]] has been used for treatment of [[SARS-CoV]], [[HIV]] infection.<ref>{{cite journal|doi=10.1101/2020.04.04.020925doi: bioRxiv preprint}}</ref>
 
*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]].
* In [[patients]] with [[Covid-19]] undergoing clinical trial, use of [[atazanavir]] alone or in combination with [[ritonavir]]  was associated with reduced level of [[IL-6]] or [[TNF-alpha]].
* In moderate and severe [[covid-19]], combination therapy of [[atazanavir]] and [[hydroxychloroquine]] did not improve [[mortality]], duration of [[hospital stay]] , [[discharge]] from the [[hospital]].<ref name="pmid32857301">{{cite journal |vauthors=Rahmani H, Davoudi-Monfared E, Nourian A, Nabiee M, Sadeghi S, Khalili H, Abbasian L, Ghiasvand F, Seifi A, Hasannezhad M, Ghaderkhani S, Mohammadi M, Yekaninejad MS |title=Comparing outcomes of hospitalized patients with moderate and severe COVID-19 following treatment with hydroxychloroquine plus atazanavir/ritonavir |journal=Daru |volume=28 |issue=2 |pages=625–634 |date=December 2020 |pmid=32857301 |pmc=7453126 |doi=10.1007/s40199-020-00369-2 |url=}}</ref>
 
===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]].<ref name="pmid26739045">{{cite journal |vauthors=Pécheur EI, Borisevich V, Halfmann P, Morrey JD, Smee DF, Prichard M, Mire CE, Kawaoka Y, Geisbert TW, Polyak SJ |title=The Synthetic Antiviral Drug Arbidol Inhibits Globally Prevalent Pathogenic Viruses |journal=J. Virol. |volume=90 |issue=6 |pages=3086–92 |date=January 2016 |pmid=26739045 |pmc=4810626 |doi=10.1128/JVI.02077-15 |url=}}</ref>
*Mechanism of action: inhibition of the virus fusion to the cell membrane and hydrogen binding to [[membrance phospholipids]].<ref name="pmid20527735">{{cite journal |vauthors=Villalaín J |title=Membranotropic effects of arbidol, a broad anti-viral molecule, on phospholipid model membranes |journal=J Phys Chem B |volume=114 |issue=25 |pages=8544–54 |date=July 2010 |pmid=20527735 |doi=10.1021/jp102619w |url=}}</ref>
*In a retrospective cohort study showed improvement in chest ct scan of COVID-19 patients received a combination of Umifenovir and lopinavir-ritonavir..<ref name="pmid32171872">{{cite journal |vauthors=Deng L, Li C, Zeng Q, Liu X, Li X, Zhang H, Hong Z, Xia J |title=Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study |journal=J. Infect. |volume=81 |issue=1 |pages=e1–e5 |date=July 2020 |pmid=32171872 |pmc=7156152 |doi=10.1016/j.jinf.2020.03.002 |url=}}</ref>
*In a prospective study, [[umifenovir]] had inferior outcomes in the clinical recovery rate and relief of fever and [[cough]] compared with [[favipiravir]].<ref name="ChenZhang2020">{{cite journal|last1=Chen|first1=Chang|last2=Zhang|first2=Yi|last3=Huang|first3=Jianying|last4=Yin|first4=Ping|last5=Cheng|first5=Zhenshun|last6=Wu|first6=Jianyuan|last7=Chen|first7=Song|last8=Zhang|first8=Yongxi|last9=Chen|first9=Bo|last10=Lu|first10=Mengxin|last11=Luo|first11=Yongwen|last12=Ju|first12=Lingao|last13=Zhang|first13=Jingyi|last14=Wang|first14=Xinghuan|year=2020|doi=10.1101/2020.03.17.20037432}}</ref>
* Use of [[umifenovir]] was not associated with improved outcome in [[covid-19]] [[patients]].<ref name="HuangYu2020">{{cite journal|last1=Huang|first1=Dong|last2=Yu|first2=He|last3=Wang|first3=Ting|last4=Yang|first4=Huan|last5=Yao|first5=Rong|last6=Liang|first6=Zongan|title=Efficacy and safety of umifenovir for coronavirus disease 2019 (COVID‐19): A systematic review and meta‐analysis|journal=Journal of Medical Virology|volume=93|issue=1|year=2020|pages=481–490|issn=0146-6615|doi=10.1002/jmv.26256}}</ref>
 
 
 
===[[Clofazimine]]===
*[[Clofazimine]] is an anti-[[leprosy]] drug<ref name="YuanYin2021">{{cite journal|last1=Yuan|first1=Shuofeng|last2=Yin|first2=Xin|last3=Meng|first3=Xiangzhi|last4=Chan|first4=Jasper Fuk-Woo|last5=Ye|first5=Zi-Wei|last6=Riva|first6=Laura|last7=Pache|first7=Lars|last8=Chan|first8=Chris Chun-Yiu|last9=Lai|first9=Pok-Man|last10=Chan|first10=Chris Chung-Sing|last11=Poon|first11=Vincent Kwok-Man|last12=Lee|first12=Andrew Chak-Yiu|last13=Matsunaga|first13=Naoko|last14=Pu|first14=Yuan|last15=Yuen|first15=Chun-Kit|last16=Cao|first16=Jianli|last17=Liang|first17=Ronghui|last18=Tang|first18=Kaiming|last19=Sheng|first19=Li|last20=Du|first20=Yushen|last21=Xu|first21=Wan|last22=Lau|first22=Chit-Ying|last23=Sit|first23=Ko-Yung|last24=Au|first24=Wing-Kuk|last25=Wang|first25=Runming|last26=Zhang|first26=Yu-Yuan|last27=Tang|first27=Yan-Dong|last28=Clausen|first28=Thomas Mandel|last29=Pihl|first29=Jessica|last30=Oh|first30=Juntaek|last31=Sze|first31=Kong-Hung|last32=Zhang|first32=Anna Jinxia|last33=Chu|first33=Hin|last34=Kok|first34=Kin-Hang|last35=Wang|first35=Dong|last36=Cai|first36=Xue-Hui|last37=Esko|first37=Jeffrey D.|last38=Hung|first38=Ivan Fan-Ngai|last39=Li|first39=Ronald Adolphus|last40=Chen|first40=Honglin|last41=Sun|first41=Hongzhe|last42=Jin|first42=Dong-Yan|last43=Sun|first43=Ren|last44=Chanda|first44=Sumit K.|last45=Yuen|first45=Kwok-Yung|title=Clofazimine broadly inhibits coronaviruses including SARS-CoV-2|journal=Nature|year=2021|issn=0028-0836|doi=10.1038/s41586-021-03431-4}}</ref>
* Effects of [[clofazimine]] on [[covid-19]] include:
:* Decreasing [[viral]] shedding in [[lung]] and [[feces]]
:* [[Anti-inflammation]] and controlling [[cytokine]] storm
* The efficacy of  [[clofazimine]]  for [[ prophylaxis]] and [[treatment]] of [[covid-19]] in under investigation.
 
===[[Lopinavir]]-[[Ritonavir]] or [[kalerta]]===
*Lopinavir-Ritonavir Inhibits the activity of the HIV-1 protease.
*In the  '''Recovery Trial''' [[kaletra]] was not effective in reducing of [[mortality]], duration of [[hospitalization]] or prevention of [[ventilation]].<ref name="HorbyMafham2020">{{cite journal|last1=Horby|first1=Peter W|last2=Mafham|first2=Marion|last3=Bell|first3=Jennifer L|last4=Linsell|first4=Louise|last5=Staplin|first5=Natalie|last6=Emberson|first6=Jonathan|last7=Palfreeman|first7=Adrian|last8=Raw|first8=Jason|last9=Elmahi|first9=Einas|last10=Prudon|first10=Benjamin|last11=Green|first11=Christopher|last12=Carley|first12=Simon|last13=Chadwick|first13=David|last14=Davies|first14=Matthew|last15=Wise|first15=Matthew P|last16=Baillie|first16=J Kenneth|last17=Chappell|first17=Lucy C|last18=Faust|first18=Saul N|last19=Jaki|first19=Thomas|last20=Jefferey|first20=Katie|last21=Lim|first21=Wei Shen|last22=Montgomery|first22=Alan|last23=Rowan|first23=Kathryn|last24=Juszczak|first24=Edmund|last25=Haynes|first25=Richard|last26=Landray|first26=Martin J|title=Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial|journal=The Lancet|volume=396|issue=10259|year=2020|pages=1345–1352|issn=01406736|doi=10.1016/S0140-6736(20)32013-4}}</ref>
*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]].<ref name="CaoWang2020">{{cite journal|last1=Cao|first1=Bin|last2=Wang|first2=Yeming|last3=Wen|first3=Danning|last4=Liu|first4=Wen|last5=Wang|first5=Jingli|last6=Fan|first6=Guohui|last7=Ruan|first7=Lianguo|last8=Song|first8=Bin|last9=Cai|first9=Yanping|last10=Wei|first10=Ming|last11=Li|first11=Xingwang|last12=Xia|first12=Jiaan|last13=Chen|first13=Nanshan|last14=Xiang|first14=Jie|last15=Yu|first15=Ting|last16=Bai|first16=Tao|last17=Xie|first17=Xuelei|last18=Zhang|first18=Li|last19=Li|first19=Caihong|last20=Yuan|first20=Ye|last21=Chen|first21=Hua|last22=Li|first22=Huadong|last23=Huang|first23=Hanping|last24=Tu|first24=Shengjing|last25=Gong|first25=Fengyun|last26=Liu|first26=Ying|last27=Wei|first27=Yuan|last28=Dong|first28=Chongya|last29=Zhou|first29=Fei|last30=Gu|first30=Xiaoying|last31=Xu|first31=Jiuyang|last32=Liu|first32=Zhibo|last33=Zhang|first33=Yi|last34=Li|first34=Hui|last35=Shang|first35=Lianhan|last36=Wang|first36=Ke|last37=Li|first37=Kunxia|last38=Zhou|first38=Xia|last39=Dong|first39=Xuan|last40=Qu|first40=Zhaohui|last41=Lu|first41=Sixia|last42=Hu|first42=Xujuan|last43=Ruan|first43=Shunan|last44=Luo|first44=Shanshan|last45=Wu|first45=Jing|last46=Peng|first46=Lu|last47=Cheng|first47=Fang|last48=Pan|first48=Lihong|last49=Zou|first49=Jun|last50=Jia|first50=Chunmin|last51=Wang|first51=Juan|last52=Liu|first52=Xia|last53=Wang|first53=Shuzhen|last54=Wu|first54=Xudong|last55=Ge|first55=Qin|last56=He|first56=Jing|last57=Zhan|first57=Haiyan|last58=Qiu|first58=Fang|last59=Guo|first59=Li|last60=Huang|first60=Chaolin|last61=Jaki|first61=Thomas|last62=Hayden|first62=Frederick G.|last63=Horby|first63=Peter W.|last64=Zhang|first64=Dingyu|last65=Wang|first65=Chen|title=A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe Covid-19|journal=New England Journal of Medicine|volume=382|issue=19|year=2020|pages=1787–1799|issn=0028-4793|doi=10.1056/NEJMoa2001282}}</ref>
*Only one study in Korea in the initial phase of outbreak accepted using this combination.<ref name="pmid32056407">{{cite journal |vauthors=Lim J, Jeon S, Shin HY, Kim MJ, Seong YM, Lee WJ, Choe KW, Kang YM, Lee B, Park SJ |title=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 |journal=J. Korean Med. Sci. |volume=35 |issue=6 |pages=e79 |date=February 2020 |pmid=32056407 |pmc=7025910 |doi=10.3346/jkms.2020.35.e79 |url=}}</ref>
*Side effects: [[Diarrhea]], [[nausea]], [[asthenia]]
===[[Niclosamide]] and [[Ivermectin]]===
 
*Mechanism of action is the Inhibition of binding of [[Coronavirus, SARS associated|coronavirus]] onto the cells.<ref name="pmid15215127">{{cite journal |vauthors=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 |title=Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide |journal=Antimicrob. Agents Chemother. |volume=48 |issue=7 |pages=2693–6 |date=July 2004 |pmid=15215127 |pmc=434198 |doi=10.1128/AAC.48.7.2693-2696.2004 |url=}}</ref>
 
*[[Niclosamid]] inhibits replication of [[MERS-COV]] AND [[SARS-COV-2|SARS-COV-2.]].<ref name="pmid31852899">{{cite journal |vauthors=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 |title=SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection |journal=Nat Commun |volume=10 |issue=1 |pages=5770 |date=December 2019 |pmid=31852899 |pmc=6920372 |doi=10.1038/s41467-019-13659-4 |url=}}</ref>
 
*[[Ivermectin]] inhibits viral replication in dengue virus, [[flavivirus]],[[influenza]] and is a cheap [[drug]] with low side effect. <ref name="pmid31852899">{{cite journal |vauthors=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 |title=SKP2 attenuates autophagy through Beclin1-ubiquitination and its inhibition reduces MERS-Coronavirus infection |journal=Nat Commun |volume=10 |issue=1 |pages=5770 |date=December 2019 |pmid=31852899 |pmc=6920372 |doi=10.1038/s41467-019-13659-4 |url=}}</ref>
* The study showed [[Ivermectin]] inhibited [[SARS-COV-2]]  replication up to 5000 fold at 48 h in vitro.<ref name="CalyDruce2020">{{cite journal|last1=Caly|first1=Leon|last2=Druce|first2=Julian D.|last3=Catton|first3=Mike G.|last4=Jans|first4=David A.|last5=Wagstaff|first5=Kylie M.|title=The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro|journal=Antiviral Research|volume=178|year=2020|pages=104787|issn=01663542|doi=10.1016/j.antiviral.2020.104787}}</ref>
* Experimental study showed early use of [[ivermectin]] in the clinical course of [[covid-19]] may reduce progression to severe disease.
* The efficacy of [[ivermectin]] for prophylaxis and treatment of [[covid-19]] is under investigation.<ref name="pmid34145166">{{cite journal |vauthors=Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, Tham TC |title=Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines |journal=Am J Ther |volume=28 |issue=4 |pages=e434–e460 |date=June 2021 |pmid=34145166 |pmc=8248252 |doi=10.1097/MJT.0000000000001402 |url=}}</ref>
 
==Supportive Agents==
==='''[[Tocilizumab]] (Actemra)'''===
 
*[[Tocilizumab]] is a monoclonal antibody that binds to  [[IL-6  receptor]] on the cells and prevents inflammatory response.<ref name="pmid32290839">{{cite journal |vauthors=Fu B, Xu X, Wei H |title=Why tocilizumab could be an effective treatment for severe COVID-19? |journal=J Transl Med |volume=18 |issue=1 |pages=164 |date=April 2020 |pmid=32290839 |pmc=7154566 |doi=10.1186/s12967-020-02339-3 |url=}}</ref>
**[[Tocilizumab]] has been used for the treatment of [[rheumatoid arthritis]] and [[juvenile idiopathic artheritis]].
* Use of [[Tocilizumab]] in hospitalized [[covid-19]] [[patients]] was associated with reduced likelihood of progression to [[mechanical ventilation]] and [[death]]. <ref name="SalamaHan2021">{{cite journal|last1=Salama|first1=Carlos|last2=Han|first2=Jian|last3=Yau|first3=Linda|last4=Reiss|first4=William G.|last5=Kramer|first5=Benjamin|last6=Neidhart|first6=Jeffrey D.|last7=Criner|first7=Gerard J.|last8=Kaplan-Lewis|first8=Emma|last9=Baden|first9=Rachel|last10=Pandit|first10=Lavannya|last11=Cameron|first11=Miriam L.|last12=Garcia-Diaz|first12=Julia|last13=Chávez|first13=Victoria|last14=Mekebeb-Reuter|first14=Martha|last15=Lima de Menezes|first15=Ferdinando|last16=Shah|first16=Reena|last17=González-Lara|first17=Maria F.|last18=Assman|first18=Beverly|last19=Freedman|first19=Jamie|last20=Mohan|first20=Shalini V.|title=Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia|journal=New England Journal of Medicine|volume=384|issue=1|year=2021|pages=20–30|issn=0028-4793|doi=10.1056/NEJMoa2030340}}</ref>
 
 
* For hospitalized [[covid-19]] patients preliminary results of '''Recovery Trial''' for [[tocilizumab]] showed less [[mortality]], shortened time to [[hospital]] discharge, reduced need for [[mechanical ventilation]].
* 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. <ref name="StoneFrigault2020">{{cite journal|last1=Stone|first1=John H.|last2=Frigault|first2=Matthew J.|last3=Serling-Boyd|first3=Naomi J.|last4=Fernandes|first4=Ana D.|last5=Harvey|first5=Liam|last6=Foulkes|first6=Andrea S.|last7=Horick|first7=Nora K.|last8=Healy|first8=Brian C.|last9=Shah|first9=Ruta|last10=Bensaci|first10=Ana Maria|last11=Woolley|first11=Ann E.|last12=Nikiforow|first12=Sarah|last13=Lin|first13=Nina|last14=Sagar|first14=Manish|last15=Schrager|first15=Harry|last16=Huckins|first16=David S.|last17=Axelrod|first17=Matthew|last18=Pincus|first18=Michael D.|last19=Fleisher|first19=Jorge|last20=Sacks|first20=Chana A.|last21=Dougan|first21=Michael|last22=North|first22=Crystal M.|last23=Halvorsen|first23=Yuan-Di|last24=Thurber|first24=Tara K.|last25=Dagher|first25=Zeina|last26=Scherer|first26=Allison|last27=Wallwork|first27=Rachel S.|last28=Kim|first28=Arthur Y.|last29=Schoenfeld|first29=Sara|last30=Sen|first30=Pritha|last31=Neilan|first31=Tomas G.|last32=Perugino|first32=Cory A.|last33=Unizony|first33=Sebastian H.|last34=Collier|first34=Deborah S.|last35=Matza|first35=Mark A.|last36=Yinh|first36=Janeth M.|last37=Bowman|first37=Kathryn A.|last38=Meyerowitz|first38=Eric|last39=Zafar|first39=Amna|last40=Drobni|first40=Zsofia D.|last41=Bolster|first41=Marcy B.|last42=Kohler|first42=Minna|last43=D’Silva|first43=Kristin M.|last44=Dau|first44=Jonathan|last45=Lockwood|first45=Megan M.|last46=Cubbison|first46=Caroline|last47=Weber|first47=Brittany N.|last48=Mansour|first48=Michael K.|title=Efficacy of Tocilizumab in Patients Hospitalized with Covid-19|journal=New England Journal of Medicine|year=2020|issn=0028-4793|doi=10.1056/NEJMoa2028836}}</ref>
 
* 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.<ref name="pmid32350134">{{cite journal |vauthors=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 |title=Effective treatment of severe COVID-19 patients with tocilizumab |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=117 |issue=20 |pages=10970–10975 |date=May 2020 |pmid=32350134 |pmc=7245089 |doi=10.1073/pnas.2005615117 |url=}}</ref>
 
*[[Tocilizumab]] indicates in [[COVID-19]] patients with the following criteria:<ref name="KewanCovut2020">{{cite journal|last1=Kewan|first1=Tariq|last2=Covut|first2=Fahrettin|last3=Al–Jaghbeer|first3=Mohammed J.|last4=Rose|first4=Lori|last5=Gopalakrishna|first5=K.V.|last6=Akbik|first6=Bassel|title=Tocilizumab for treatment of patients with severe COVID–19: A retrospective cohort study|journal=EClinicalMedicine|year=2020|pages=100418|issn=25895370|doi=10.1016/j.eclinm.2020.100418}}</ref>
 
#[[Hypoxia]]
#[[Lung]] infiltration on [[CXR]]
#High [[inflammatory markers]] ([[CRP]]>3g/dl, [[ferritin]]>400ng/dl
#Clinical deterioration
 
*Contraindications of [[tocilizumab]] include as follows:
 
#Confirmed [[bacterial]] or [[fungal]] infection
#[[Platelet count]]<100000/cc
#[[Neutrophil]] count<2000/cc
#[[Alanin aminotrasferase]] or [[aspartat aminotransferase]] >5times upper limit normal<br />
===[[Bamlanivimab]],[[Etesevimab]]===
*  Efficacy of [[Neutralized monoclonal antibodies]] in [[covid-19]] [[patients]] who are in risk of progression to severe [[disease]]  were investigated in '''BLAZE-1''' clinical trial.
* In mild to moderate ambulatory [[covid-19]] [[patients]], use of [[bamlanivimab]] plus [[etesevimab]] decreasd [[hospitalization]] and [[death]].
===[[Casirivimab]], [[Imdevimab]]===
* On  November 21,2020 [[FDA]] approved [[emergency use authorizarion]] for use of [[casirivimab]] plus [[imdevimab]] for [[mild]] to moderate [[covid-19]] [[patients]] who are high risk for progression to severe disease (in the presence of [[comorbidities]], age≥ 65 years old).
===Sotrovimab===
* On May 26,2021 [[FDA]] approved [[emergency use authorization]] for use of this [[monoclonal antibody]] for mild to moderate [[covid-19]] [[patients]] who are high risk for progression to severe diseae.
* Use of [[monoclonal antibodies]] in [[hospitalized]] [[severe]] [[covid-19]] [[patients]] was associated with worse clinical outcome.
 
 
 
===[[Interferon-1]]===
*Interferon-1 has been effective in the treatment of [[SARS-COV]], [[ MERS ]] infection and  [[multiple sclerosis]].<ref name="pmid32147628">{{cite journal |vauthors=Dong L, Hu S, Gao J |title=Discovering drugs to treat coronavirus disease 2019 (COVID-19) |journal=Drug Discov Ther |volume=14 |issue=1 |pages=58–60 |date=2020 |pmid=32147628 |doi=10.5582/ddt.2020.01012 |url=}}</ref>
*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]]. <ref name="pmid32065831">{{cite journal |vauthors=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 |title=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 |journal=JAMA |volume= |issue= |pages= |date=February 2020 |pmid=32065831 |doi=10.1001/jama.2019.22525 |url=}}</ref>
 
===[[Azithromycin]]===
 
*[[Azithromycin]] has been effective in the treatment of [[Zika]] and [[Ebola]] viruses and prevented severe respiratory tract infection.<ref name="pmid27911847">{{cite journal |vauthors=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 |title=Zika virus cell tropism in the developing human brain and inhibition by azithromycin |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=113 |issue=50 |pages=14408–14413 |date=December 2016 |pmid=27911847 |pmc=5167169 |doi=10.1073/pnas.1618029113 |url=}}</ref>
*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.<ref name="GautretLagier2020">{{cite journal|last1=Gautret|first1=Philippe|last2=Lagier|first2=Jean-Christophe|last3=Parola|first3=Philippe|last4=Hoang|first4=Van Thuan|last5=Meddeb|first5=Line|last6=Mailhe|first6=Morgane|last7=Doudier|first7=Barbara|last8=Courjon|first8=Johan|last9=Giordanengo|first9=Valérie|last10=Vieira|first10=Vera Esteves|last11=Dupont|first11=Hervé Tissot|last12=Honoré|first12=Stéphane|last13=Colson|first13=Philippe|last14=Chabrière|first14=Eric|last15=La Scola|first15=Bernard|last16=Rolain|first16=Jean-Marc|last17=Brouqui|first17=Philippe|last18=Raoult|first18=Didier|title=Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial|journal=International Journal of Antimicrobial Agents|year=2020|pages=105949|issn=09248579|doi=10.1016/j.ijantimicag.2020.105949}}</ref>
*The  randomised clinical  trial showed  combination of [[azithromycin]] with [[hydroxychroquin]]  was not effective in clinical improvement or [[mortality]] reduction in severe [[covid-19]] pateints.<ref>{{cite journal|doi=10.1016/S0140-6736(20)31862_6}}</ref>
 
* In the absence of indications, routine use of [[azithromycin]] in [[covid-19]] [[disease]] is not recommended due to increased risk of [[antibiotic]] [[resistance]]. <ref name="ButlerDorward2021">{{cite journal|last1=Butler|first1=Christopher C|last2=Dorward|first2=Jienchi|last3=Yu|first3=Ly-Mee|last4=Gbinigie|first4=Oghenekome|last5=Hayward|first5=Gail|last6=Saville|first6=Benjamin R|last7=Van Hecke|first7=Oliver|last8=Berry|first8=Nick|last9=Detry|first9=Michelle|last10=Saunders|first10=Christina|last11=Fitzgerald|first11=Mark|last12=Harris|first12=Victoria|last13=Patel|first13=Mahendra G|last14=de Lusignan|first14=Simon|last15=Ogburn|first15=Emma|last16=Evans|first16=Philip H|last17=Thomas|first17=Nicholas PB|last18=Hobbs|first18=FD Richard|title=Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial|journal=The Lancet|volume=397|issue=10279|year=2021|pages=1063–1074|issn=01406736|doi=10.1016/S0140-6736(21)00461-X}}</ref>
 
===[[Vitamin C]] (Ascorbic Acid)===
 
*Effects of [[Vitamin C]] in viral agents include:<ref name="pmid29534432">{{cite journal |vauthors=van Gorkom GNY, Klein Wolterink RGJ, Van Elssen CHMJ, Wieten L, Germeraad WTV, Bos GMJ |title=Influence of Vitamin C on Lymphocytes: An Overview |journal=Antioxidants (Basel) |volume=7 |issue=3 |pages= |date=March 2018 |pmid=29534432 |pmc=5874527 |doi=10.3390/antiox7030041 |url=}}</ref>
 
#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.<ref name="pmid32328576">{{cite journal |vauthors=Cheng RZ |title=Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)? |journal=Med Drug Discov |volume=5 |issue= |pages=100028 |date=March 2020 |pmid=32328576 |pmc=7167497 |doi=10.1016/j.medidd.2020.100028 |url=}}</ref>
 
 
 
===Convalescent Plasma===
 
*Convalescent Plasma is the Transfusion of [[plasma]] loaded with antibodies after improvement from [[COVID-19]].
* In severe [[covid-19]] [[pneumonia]] there was not any improvement in [[clinical]] status or [[mortality]] by [[convalescent]] plasma.<ref name="SimonovichBurgos Pratx2021">{{cite journal|last1=Simonovich|first1=Ventura A.|last2=Burgos Pratx|first2=Leandro D.|last3=Scibona|first3=Paula|last4=Beruto|first4=María V.|last5=Vallone|first5=Marcelo G.|last6=Vázquez|first6=Carolina|last7=Savoy|first7=Nadia|last8=Giunta|first8=Diego H.|last9=Pérez|first9=Lucía G.|last10=Sánchez|first10=Marisa del L.|last11=Gamarnik|first11=Andrea Vanesa|last12=Ojeda|first12=Diego S.|last13=Santoro|first13=Diego M.|last14=Camino|first14=Pablo J.|last15=Antelo|first15=Sebastian|last16=Rainero|first16=Karina|last17=Vidiella|first17=Gabriela P.|last18=Miyazaki|first18=Erica A.|last19=Cornistein|first19=Wanda|last20=Trabadelo|first20=Omar A.|last21=Ross|first21=Fernando M.|last22=Spotti|first22=Mariano|last23=Funtowicz|first23=Gabriel|last24=Scordo|first24=Walter E.|last25=Losso|first25=Marcelo H.|last26=Ferniot|first26=Inés|last27=Pardo|first27=Pablo E.|last28=Rodriguez|first28=Eulalia|last29=Rucci|first29=Pablo|last30=Pasquali|first30=Julieta|last31=Fuentes|first31=Nora A.|last32=Esperatti|first32=Mariano|last33=Speroni|first33=Gerardo A.|last34=Nannini|first34=Esteban C.|last35=Matteaccio|first35=Alejandra|last36=Michelangelo|first36=Hernán G.|last37=Follmann|first37=Dean|last38=Lane|first38=H. Clifford|last39=Belloso|first39=Waldo H.|title=A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia|journal=New England Journal of Medicine|volume=384|issue=7|year=2021|pages=619–629|issn=0028-4793|doi=10.1056/NEJMoa2031304}}</ref>
* Earlier, [[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]].<ref name="pmid16183666">{{cite journal |vauthors=Yeh KM, Chiueh TS, Siu LK, Lin JC, Chan PK, Peng MY, Wan HL, Chen JH, Hu BS, Perng CL, Lu JJ, Chang FY |title=Experience of using convalescent plasma for severe acute respiratory syndrome among healthcare workers in a Taiwan hospital |journal=J. Antimicrob. Chemother. |volume=56 |issue=5 |pages=919–22 |date=November 2005 |pmid=16183666 |pmc=7110092 |doi=10.1093/jac/dki346 |url=}}</ref>
*Serious side effects were not reported.<ref name="pmid32253318">{{cite journal |vauthors=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 |title=Effectiveness of convalescent plasma therapy in severe COVID-19 patients |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=117 |issue=17 |pages=9490–9496 |date=April 2020 |pmid=32253318 |pmc=7196837 |doi=10.1073/pnas.2004168117 |url=}}</ref>
 
===[[Anticoagulation]]===
In [[COVID-19]] [[hypercoagulable state]] induces micro-macro-vascular [[thrombosis]].
 
 
 
*Predictors of poor outcome in [[COVID-19]] include: Disseminated intravascular [[Coagulopathy|coagulation]] , high level of [[D-dimer]].<ref name="pmid32073213">{{cite journal |vauthors=Tang N, Li D, Wang X, Sun Z |title=Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia |journal=J. Thromb. Haemost. |volume=18 |issue=4 |pages=844–847 |date=April 2020 |pmid=32073213 |pmc=7166509 |doi=10.1111/jth.14768 |url=}}</ref>
*A retrospective Study showed [[anticoagulant therapy]] compared to prophylaxis dosage in [[COVID-19]] hospitalized patients was associated with less [[mortality]] and [[intubation]].<<ref name="pmid32860872">{{cite journal| author=Nadkarni GN, Lala A, Bagiella E, Chang HL, Moreno P, Pujadas E | display-authors=etal| title=Anticoagulation, Mortality, Bleeding and Pathology Among Patients Hospitalized with COVID-19: A Single Health System Study. | journal=J Am Coll Cardiol | year= 2020 | volume=  | issue=  | pages=  | pmid=32860872 | doi=10.1016/j.jacc.2020.08.041 | pmc=7449655 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32860872  }} </ref>
* A randomized controlled trial found in [[covid-19]] hospitalized patients, therapeutic [[anticoagulalation]] was associated with reduction in [[mortality]] and the need for [[ventilation]]<ref name="pmid32977137">{{cite journal| author=Lemos ACB, do Espírito Santo DA, Salvetti MC, Gilio RN, Agra LB, Pazin-Filho A | display-authors=etal| title=Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). | journal=Thromb Res | year= 2020 | volume= 196 | issue=  | pages= 359-366 | pmid=32977137 | doi=10.1016/j.thromres.2020.09.026 | pmc=7503069 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=32977137  }} </ref>.
 
* Efficacy of [[heparin]] in [[COVID-19]] includes &nbsp;: 1.anti inflammatory properties,2. prevention of [[viral]] attachment via changing in [[covid 19]] spike protein 3.anticoagulation effect. <ref name="Mycroft-WestSu2020">{{cite journal|last1=Mycroft-West| first1=Courtney|last2=Su|first2=Dunhao| last3=Elli|first3=Stefano|last4=Li|first4=Yong|last5=Guimond| first5=Scott|last6=Miller|first6=Gavin|last7=Turnbull|first7=Jeremy|last8=Yates|first8=Edwin|last9=Guerrini|first9=Marco|last10=Fernig|first10=David|last11=Lima|first11=Marcelo|last12=Skidmore|first12=Mark|year=2020|doi=10.1101/2020.02.29.971093}}</ref>
 
*<nowiki/>Efficacy of [[low molecular weight hepari]]<nowiki/>n in [[COVID-19]] includes:
*<nowiki/>1.Reduction in level of [[IL-6]] and [[cytokin|cytok]][[cytokin|i]]<nowiki/>[[cytokin|ne storm]].<ref name="ShiWang2020">{{cite journal|last1=Shi|first1=Chen|last2=Wang|first2=Cong|last3=Wang|first3=Hanxiang|last4=Yang|first4=Chao|last5=Cai|first5=Fei|last6=Zeng|first6=Fang|last7=Cheng|first7=Fang|last8=Liu|first8=Yihui|last9=Zhou|first9=Taotao|last10=Deng|first10=Bin|last11=Vlodavsky|first11=Israel|last12=Li|first12=Jinping|last13=Zhang|first13=Yu|year=2020|doi=10.1101/2020.03.28.20046144}}</ref>
*<nowiki/>2.[[Anticoagulation]] effect.
*Prophylactic [[anticoagulant ]]therapy is n<nowiki/>ecessary for all hospitalized  [[COVID-19]] patients.<ref>https://app.magicapp.org/#/guideline/L4Q5An/section/j29ONE</ref>.
*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.<ref name="pmid16007097">{{cite journal |vauthors=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 |title=A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury |journal=Nat. Med. |volume=11 |issue=8 |pages=875–9 |date=August 2005 |pmid=16007097 |pmc=7095783 |doi=10.1038/nm1267 |url=}}</ref>
*There is No strong evidence between intake of NSAID and worsening [[COVID-19]].
*[[Ibuprofen]] approved by [[Food and Drug Administration|FDA]] for treatment of [[COVID-19]].
 
===Failed therapies===
 
===[[Hydroxychloroquine]] and [[Chloroquine]]===


*[[Hydroxychloroquine]] has been effective in [[graft versus host disease]], [[lupus erythematosus]], [[rheumatoid arthritis]], and [[malaria]].
*Due to [[cardiac]] side effects in [[covid-19]] [[patients]], recently [[FDA]]  disapproved of the emergency use authorization of [[hydroxychloroquine]] if clinical trials are unavailable.
* The result of '''Recovery Trial''' showed [[hydroxychloroquine]] did not reduce incidence of death at 28 days in [[hospitalized]] [[patients]] with [[covid-19]]. 
*[[Hydroxychloroquine]] for early treatment of [[adults]] with mild  [[COVID-19]] has not improved outcomes in a modest-sized unblinded randomized controlled trial.<ref name="SkipperPastick2020">{{cite journal|last1=Skipper|first1=Caleb P.|last2=Pastick|first2=Katelyn A.|last3=Engen|first3=Nicole W.|last4=Bangdiwala|first4=Ananta S.|last5=Abassi|first5=Mahsa|last6=Lofgren|first6=Sarah M.|last7=Williams|first7=Darlisha A.|last8=Okafor|first8=Elizabeth C.|last9=Pullen|first9=Matthew F.|last10=Nicol|first10=Melanie R.|last11=Nascene|first11=Alanna A.|last12=Hullsiek|first12=Kathy H.|last13=Cheng|first13=Matthew P.|last14=Luke|first14=Darlette|last15=Lother|first15=Sylvain A.|last16=MacKenzie|first16=Lauren J.|last17=Drobot|first17=Glen|last18=Kelly|first18=Lauren E.|last19=Schwartz|first19=Ilan S.|last20=Zarychanski|first20=Ryan|last21=McDonald|first21=Emily G.|last22=Lee|first22=Todd C.|last23=Rajasingham|first23=Radha|last24=Boulware|first24=David R.|title=Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19|journal=Annals of Internal Medicine|year=2020|issn=0003-4819|doi=10.7326/M20-4207}}</ref>
* 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.<ref name="RajasinghamBangdiwala2020">{{cite journal|last1=Rajasingham|first1=Radha|last2=Bangdiwala|first2=Ananta S|last3=Nicol|first3=Melanie R|last4=Skipper|first4=Caleb P|last5=Pastick|first5=Katelyn A|last6=Axelrod|first6=Margaret L|last7=Pullen|first7=Matthew F|last8=Nascene|first8=Alanna A|last9=Williams|first9=Darlisha A|last10=Engen|first10=Nicole W|last11=Okafor|first11=Elizabeth C|last12=Rini|first12=Brian I|last13=Mayer|first13=Ingrid A|last14=McDonald|first14=Emily G|last15=Lee|first15=Todd C|last16=Li|first16=Peter|last17=MacKenzie|first17=Lauren J|last18=Balko|first18=Justin M|last19=Dunlop|first19=Stephen J|last20=Hullsiek|first20=Katherine H|last21=Boulware|first21=David R|last22=Lofgren|first22=Sarah M|year=2020|doi=10.1101/2020.09.18.20197327}}</ref>
*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]].<ref name="pmid25271834">{{cite journal |vauthors=Xue J, Moyer A, Peng B, Wu J, Hannafon BN, Ding WQ |title=Chloroquine is a zinc ionophore |journal=PLoS ONE |volume=9 |issue=10 |pages=e109180 |date=2014 |pmid=25271834 |pmc=4182877 |doi=10.1371/journal.pone.0109180 |url=}}</ref>
*[[Hydroxychloroquine]]  has [[cardiac]] side effects due to the [[QT prolongation]] effect.
*Efficacy of [[remdesivir]] reduced in combination with [[hydroxychloroquine]]


[[Category: Infectious disease]]
==References==
{{reflist|2}}
<references />

Latest revision as of 06:36, 31 October 2021

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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. On February 09, 2021 FDA approved emergency use authorization of monoclonal antibodies including bamlanivimab and etesevimab for mild to moderate covid-19 patients who are high risk for progression of disease ( age > 65years, medical comorbidities).

Current Treatment

Corticosteroids

Dexamethasone

  1. Decreased days of intubation
  2. Decreased mortality

Methylprednisolone

  1. Controlled of hypercytokinemia
  2. Anti-inflammatory effect in superimposed infection in COVID-19
  3. Increased blood pressure when it is low
  4. Decreased risk of death in ARDS related COVID-19[6]

Inhaled corticosteroids

Inhaled corticosteroids (budesonide) may improve recovery time and reducing hospital admission or death in high risk covid-19 patients in the community. [7].

Experimental Treatments

Remdesivir

  • 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.[8]
  • In a Phase 3 open label randomized trial, No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID19,who were symptomatic for more than 7 days, and required oxygen support.(doi:10.1016/S1473-3099)
  • 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.[9]
  • 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.
  1. Severe renal impairment (eGFR <30 ml/min)
  2. Severe hepatic dysfunction or alanin transferase (ALT)ᐳ 5-times upper limit

Favipiravir (Avigan)

Atazanavir

Umifenovir (Arbidol)


Clofazimine

Lopinavir-Ritonavir or kalerta

  • Lopinavir-Ritonavir Inhibits the activity of the HIV-1 protease.
  • In the Recovery Trial kaletra was not effective in reducing of mortality, duration of hospitalization or prevention of ventilation.[22]
  • 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.[23]
  • Only one study in Korea in the initial phase of outbreak accepted using this combination.[24]
  • Side effects: Diarrhea, nausea, asthenia

Niclosamide and Ivermectin

  • Mechanism of action is the Inhibition of binding of coronavirus onto the cells.[25]

Supportive Agents

Tocilizumab (Actemra)


  1. Hypoxia
  2. Lung infiltration on CXR
  3. High inflammatory markers (CRP>3g/dl, ferritin>400ng/dl
  4. Clinical deterioration
  1. Confirmed bacterial or fungal infection
  2. Platelet count<100000/cc
  3. Neutrophil count<2000/cc
  4. Alanin aminotrasferase or aspartat aminotransferase >5times upper limit normal

Bamlanivimab,Etesevimab

Casirivimab, Imdevimab

Sotrovimab


Interferon-1

Azithromycin

Vitamin C (Ascorbic Acid)

  1. Maturation of T lymphocytes and NK( natural killer) cells that are involved in the immune response to viral agents.
  2. Inhibition of reactive oxygen species (ROS) production
  3. 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.[41]


Convalescent Plasma

Anticoagulation

In COVID-19 hypercoagulable state induces micro-macro-vascular thrombosis.


  • 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. [48]

Ibuprofen

Failed therapies

Hydroxychloroquine and Chloroquine

References

  1. ↑ 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.
  2. ↑
  3. ↑ 3.0 3.1 Russell CD, Millar JE, Baillie JK (February 2020). "Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury". Lancet. 395 (10223): 473–475. doi:10.1016/S0140-6736(20)30317-2. PMC 7134694 Check |pmc= value (help). PMID 32043983 Check |pmid= value (help).
  4. ↑ 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).
  5. ↑ 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)
  6. ↑ 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).
  7. ↑ Yu L-M et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): A randomised, controlled, open-label, adaptive platform trial. Lancet 2021 Aug 10; [e-pub]. https://doi.org/10.1016/S0140-6736(21)01744-X
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ Joshi, Shashank; Parkar, Jalil; Ansari, Abdul; Vora, Agam; Talwar, Deepak; Tiwaskar, Mangesh; Patil, Saiprasad; Barkate, Hanmant (2021). "Role of favipiravir in the treatment of COVID-19". International Journal of Infectious Diseases. 102: 501–508. doi:10.1016/j.ijid.2020.10.069. ISSN 1201-9712.
  13. ↑ Dabbous HM, Abd-Elsalam S, El-Sayed MH, Sherief AF, Ebeid F, El Ghafar M, Soliman S, Elbahnasawy M, Badawi R, Tageldin MA (March 2021). "Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study". Arch Virol. 166 (3): 949–954. doi:10.1007/s00705-021-04956-9. PMC 7829645 Check |pmc= value (help). PMID 33492523 Check |pmid= value (help). Vancouver style error: initials (help)
  14. ↑ 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)
  15. ↑ . doi:10.1101/2020.04.04.020925doi: bioRxiv preprint Check |doi= value (help). Missing or empty |title= (help)
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  33. ↑ 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.
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  54. ↑ 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.
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