Conv. Plasma
Nigella Sativa

All ivermectin studies
Meta analysis
study COVID-19 treatment researchIvermectinIvermectin (more..)
Melatonin Meta
Metformin Meta
Azvudine Meta
Bromhexine Meta Molnupiravir Meta
Budesonide Meta
Colchicine Meta
Conv. Plasma Meta Nigella Sativa Meta
Curcumin Meta Nitazoxanide Meta
Famotidine Meta Paxlovid Meta
Favipiravir Meta Quercetin Meta
Fluvoxamine Meta Remdesivir Meta
Hydroxychlor.. Meta Thermotherapy Meta
Ivermectin Meta

All Studies   Meta Analysis    Recent:   

Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing

Kern et al., Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678
Mar 2021  
  Source   PDF   All Studies   Meta AnalysisMeta
Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,000+ studies for 60+ treatments.
Modeling study analyzing timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. The greatest benefits were seen when treatments were given immediately at the time of diagnosis. Authors state that "For IVM, no results of clinical trials regarding its effectiveness in COVID-19 have been published yet", which is inaccurate - there were 19 peer-reviewed trials published as of Mar 10, 2021 (43 including preprints).
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Jitobaom, Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Jitobaom, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), inhibits SARS-CoV-2 3CLpro Mody, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 via IMPase inhibition Jitobaom, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, may inhibit SARS-CoV-2 RdRp activity Parvez (B), may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), increases Bifidobacteria which play a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
Kern et al., 10 Mar 2021, peer-reviewed, 4 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing
Charlotte Kern, Verena Schöning, Carlos Chaccour, Felix Hammann
Frontiers in Pharmacology, doi:10.3389/fphar.2021.625678
Several repurposed drugs are currently under investigation in the fight against coronavirus disease 2019 (COVID-19). Candidates are often selected solely by their effective concentrations in vitro, an approach that has largely not lived up to expectations in COVID-19. Cell lines used in in vitro experiments are not necessarily representative of lung tissue. Yet, even if the proposed mode of action is indeed true, viral dynamics in vivo, host response, and concentration-time profiles must also be considered. Here we address the latter issue and describe a model of human SARS-CoV-2 viral kinetics with acquired immune response to investigate the dynamic impact of timing and dosing regimens of hydroxychloroquine, lopinavir/ritonavir, ivermectin, artemisinin, and nitazoxanide. We observed greatest benefits when treatments were given immediately at the time of diagnosis. Even interventions with minor antiviral effect may reduce host exposure if timed correctly. Ivermectin seems to be at least partially effective: given on positivity, peak viral load dropped by 0.3-0.6 log units and exposure by 8.8-22.3%. The other drugs had little to no appreciable effect. Given how well previous clinical trial results for hydroxychloroquine and lopinavir/ritonavir are explained by the models presented here, similar strategies should be considered in future drug candidate prioritization efforts.
AUTHOR CONTRIBUTIONS FH conceived the project; CK, VS, and FH performed the analyses; and FH, CK, and VS wrote the first draft of the manuscript. All authors revised and approved the final manuscript. SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: full#supplementary-material. Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2021 Kern, Schöning, Chaccour and Hammann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Annie, Sirbu, Frazier, Broce, Lucas, Hydroxychloroquine in hospitalized COVID-19 patients: real world experience assessing mortality, Pharmacotherapy, doi:10.1002/phar.2467
Arshad, Pertinez, Box, Tatham, Rajoli et al., Prioritization of anti-SARS-cov-2 drug repurposing opportunities based on plasma and target site concentrations derived from their established human pharmacokinetics, Clin. Pharmacol. Ther, doi:10.1002/cpt.1909
Atzori, Villani, Regazzi, Maruzzi, Cargnel, Detection of intrapulmonary concentration of lopinavir in an HIV-infected patient, AIDS, doi:10.1097/01.aids.0000076289.54156.32
Baccam, Beauchemin, Macken, Hayden, Perelson, Kinetics of influenza A virus infection in humans, J Virol, doi:10.1128/JVI.01623-05
Balderas-Acata, Ríos-Rogríguezbueno, Pérez-Becerril, Espinosa-Martínez, Burke-Fraga et al., Bioavailability of two oral-suspension formulations of a single dose of nitazoxanide 500 mg: an open-label, randomized-sequence, two-period crossover, comparison in healthy fasted Mexican adult volunteers, J Bioequiv Availab, doi:10.1016/j.clinthera.2009.08.004
Beauchemin, Handel, A review of mathematical models of influenza A infections within a host or cell culture: lessons learned and challenges ahead, BMC Public Health, doi:10.1186/1471-2458-11-S1-S7
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of covid-19 -preliminary report, N Engl J Med, doi:10.1056/NEJMoa2007764
Birgersson, Van Toi, Truong, Dung, Ashton et al., Population pharmacokinetic properties of artemisinin in healthy male Vietnamese volunteers, Malar J, doi:10.1186/s12936-016-1134-8
Boffito, Hoggard, Lindup, Bonora, Sinicco et al., Lopinavir protein binding in vivo through the 12-hour dosing interval, Ther. Drug Monit, doi:10.1097/00007691-200402000-00008
Boulware, Pullen, Bangdiwala, Pastick, Lofgren et al., A randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19, New England Journal of Medicine, doi:10.1056/NEJMoa2016638
Bray, Rayner, Noël, Jans, Wagstaff, Ivermectin and COVID-19: a report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors' responses, Antiviral Res, doi:10.1016/j.antiviral.2020.104805
Caly, Druce, Catton, Jans, Wagstaff, The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro, Antiviral Res, doi:10.1016/j.antiviral.2020.104787
Canini, Perelson, Viral kinetic modeling: state of the art, J Pharmacokinet Pharmacodyn, doi:10.1007/s10928-014-9363-3
Cao, Hu, Li, Wang, Xu et al., Anti-SARS-CoV-2 potential of artemisinins in vitro, ACS Infect Dis, doi:10.1021/acsinfecdis.0c00522
Cao, Wang, Wen, Liu, Wang et al., A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19, New England J. Medicine, doi:10.1056/NEJMoa2001282
Cavalcanti, Zampieri, Rosa, Azevedo, Veiga et al., hydroxychloroquine with or without azithromycin in mild-to-moderate covid-19, N Engl J Med, doi:10.1056/NEJMoa2019014.E
Chaccour, Hammann, Rabinovich, Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety, Malar J, doi:10.1186/s12936-017-1801-4
Chandler, Serious neurological adverse events after ivermectin-do they occur beyond the indication of onchocerciasis?, Am J Trop Med Hyg, doi:10.4269/ajtmh.17-0042
Chandwani, Shuter, Lopinavir/ritonavir in the treatment of HIV-1 infection: a review, Ther Clin Risk Manag, doi:10.2147/tcrm.s3285
Choy, Wong, Kaewpreedee, Sia, Chen et al., Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro, Antiviral Res, doi:10.1016/j.antiviral.2020.104786
Chu, Pan, Cheng, Hui, Krishnan et al., Molecular diagnosis of a novel coronavirus (2019-nCoV) causing an outbreak of pneumonia, Clin Chem, doi:10.1093/clinchem/hvaa029
Czuppon, Débarre, Gonçalves, Tenaillon, Perelson et al., Predicted success of prophylactic antiviral therapy to block or delay SARS-CoV-2 infection depends on the targeted mechanism, medRxiv, doi:10.1101/2020.05.07.20092965
Degani-Katzav, Klein, Har-Even, Gortler, Tobi et al., Trapping of ivermectin by a pentameric ligand-gated ion channel upon open-to-closed isomerization, Sci Rep, doi:10.1038/srep42481
Dickinson, Boffito, Back, Else, Von Hentig et al., Sequential population pharmacokinetic modeling of lopinavir and ritonavir in healthy volunteers and assessment of different dosing strategies, Antimicrob Agents Chemother, doi:10.1128/AAC.00887-10
Duthaler, Leisegang, Karlsson, Krähenbühl, Hammann, The effect of food on the pharmacokinetics of oral ivermectin, J. Antimicrobial Chemotherapy, doi:10.1093/jac/dkz466
Fajnzylber, Regan, Coxen, Corry, Wong et al., SARS-CoV-2 viral load is associated with increased disease severity and mortality, Nat Commun, doi:10.1038/s41467-020-19057-5
Fan, Beitler, Brochard, Calfee, Ferguson et al., COVID-19-associated acute respiratory distress syndrome: is a different approach to management warranted?, Lancet Respir Med, doi:10.1016/S2213-2600(20)30304-0
Fda, Prescribing INFORMATION: Alinia ® (nitazoxanide) Tablets (nitazoxanide) for oral suspension
Fda, Prescribing INFORMATION: KALETRA (lopinavir/ritonavir) tablet, film coated for oral use, KALETRA (lopinavir/ritonavir) solution for oral use
Furst, Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases, Lupus
Gautret, Lagier, Parola, Hoang, Meddeb et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial, Inter. J. Antimicrobial Agents, doi:10.1016/j.ijantimicag.2020.105949
Goldman, Gilman, Hollenback, Kato, Premack et al., Hydroxychloroquine inhibits calcium signals in T cells: a new mechanism to explain its immunomodulatory properties, Blood, doi:10.1182/blood.v95.11.3460
Gonçalves, Bertrand, Ke, Comets, De Lamballerie et al., Timing of antiviral treatment initiation is critical to reduce SARS-CoV-2 viral load, CPT: Pharm. Syst. Pharm, doi:10.1002/psp4.12543
Gordon, Jang, Bouhaddou, Xu, Obernier et al., A SARS-CoV-2 protein interaction map reveals targets for drug repurposing, Nature, doi:10.1038/s41586-020-2286-9
Guzzo, Furtek, Porras, Chen, Tipping et al., Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects, J Clin Pharmacol, doi:10.1177/009127002401382731
Hernandez-Vargas, Chapter 3 -model parameter estimation
Hernandez-Vargas, Velasco-Hernandez, In-host mathematical modelling of COVID-19 in humans, Annu Rev Control, doi:10.1016/j.arcontrol.2020.09.006
Hoffmann, Mösbauer, Hofmann-Winkler, Kaul, Kleine-Weber et al., Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, Nature, doi:10.1038/s41586-020-2575-3
Jagdev, Sidhu, Single-dose, comparative study of venous, capillary and salivary artemisinin concentrations in healthy, male adults, The American Journal of Tropical Medicine and Hygiene, doi:10.4269/ajtmh.1997.56.13
Kim, Ejima, Ito, Iwanami, Ohashi et al., Modelling SARS-CoV-2 dynamics: implications for therapy, MedRxiv, doi:10.1101/2020.03.23.20040493
Kim, Ko, Kim, Kim, Kim et al., Viral load kinetics of SARS-CoV-2 infection in first two patients in korea, J Korean Med Sci, doi:10.3346/jkms.2020.35.e86
Klok, Kruip, Van Der Meer, Arbous, Gommers et al., Incidence of thrombotic complications in critically ill ICU patients with COVID-19, Thromb Res, doi:10.1016/j.thromres.2020.04.013
Klotz, Ogbuokiri, Okonkwo, Ivermectin binds avidly to plasma proteins, Eur J Clin Pharmacol, doi:10.1007/BF00316107
Lauer, Grantz, Bi, Jones, Zheng et al., The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application, Ann Intern Med, doi:10.7326/M20-0504
Li, Chen, Zhang, Guo, Wang et al., Identification of natural compounds with antiviral activities against SARSassociated coronavirus, Antiviral Res, doi:10.1016/j.antiviral.2005.02.007
Li, Li, Zhang, Wang, Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues, Infect Dis Poverty, doi:10.1186/s40249-020-00662-x
Li, Xu, Liu, Zhou, The within-host viral kinetics of SARS-CoV-2, Math Biosci Eng, doi:10.3934/mbe.2020159
Lifschitz, Virkel, Sallovitz, Sutra, Galtier et al., Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle, Vet Parasitol, doi:10.1016/s0304-4017(99)00175-2
Lim, Im, Cho, Bae, Klein et al., Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax, Antimicrob Agents Chemother, doi:10.1128/AAC.00339-08
Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov, doi:10.1038/s41421-020-0156-0
Long, Liu, Deng, Wu, Deng et al., Antibody responses to SARS-CoV-2 in patients with COVID-19, Nat Med, doi:10.1038/s41591-020-0897-1
Magleby, Westblade, Trzebucki, Simon, Rajan et al., Impact of SARS-CoV-2 viral load on risk of intubation and mortality among hospitalized patients with coronavirus disease 2019, Clin Infect Dis, doi:10.1093/cid/ciaa851
Maisonnasse, Guedj, Contreras, Behillil, Solas et al., Hydroxychloroquine in the treatment and prophylaxis of SARS-CoV-2 infection in non-human primates, Virology, doi:10.21203/
Mao, Jin, Wang, Hu, Chen et al., Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China, JAMA Neurol, doi:10.1001/jamaneurol.2020.1127
Martins-Filho, Barreto-Alves, Fakhouri, Potential role for nitazoxanide in treating SARS-CoV-2 infection, American Journal of Physiology-Lung Cellular and Molecular Physiology, doi:10.1152/ajplung.00170.2020
Mastrangelo, Pezzullo, De Burghgraeve, Kaptein, Pastorino et al., Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug, J Antimicrob Chemother, doi:10.1093/jac/dks147
Molento, COVID-19 and the rush for self-medication and self-dosing with ivermectin: a word of caution, One Health, doi:10.1016/j.onehlt.2020.100148
Molina, Delaugerre, Le Goff, Mela-Lima, Ponscarme et al., No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe COVID-19 infection, Med Mal Infect, doi:10.1016/j.medmal.2020.03.006
Nair, Huang, Fidock, Polyak, Wagoner et al., Artemisia annua L. extracts prevent in vitro replication of SARS-CoV-2, bioRxiv, doi:10.1101/2021.01.08.425825
Nordling, Unproven herbal remedy against COVID-19 could fuel drugresistant malaria, scientists warn
Oakes, Fuchs, Gardner, Lazartigues, Yue, Nicotine and the renin-angiotensin system, Am. J. physiol. Regul. Integr. Comp. Physiol, doi:10.1152/ajpregu.00099.2018
Owens, Excitement around hydroxychloroquine for treating COVID-19 causes challenges for rheumatology, Lancet Rheumatol, doi:10.1016/S2665-9913(20)30089-8
Pan, Peto, Karim, Alejandria, Henao-Restrepo et al., Repurposed antiviral drugs for COVID-19 -interim WHO SOLIDARITY trial results, medRxiv, doi:10.1101/2020.10.15.20209817
Quiros Roldan, Biasiotto, Magro, Zanella, The possible mechanisms of action of 4-aminoquinolines (chloroquine/ hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): a role for iron homeostasis?, Pharmacol Res, doi:10.1016/j.phrs.2020.104904
Rajasingham, Bangdiwala, Nicol, Skipper, Pastick et al., Hydroxychloroquine as pre-exposure prophylaxis for COVID-19 in healthcare workers: a randomized trial, Clin. Infect. Dis, doi:10.1093/cid/ciaa1571
Rajoli, Pertinez, Arshad, Box, Tatham et al., Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis, medRxiv, doi:10.1101/2020.05.01.20087130
Sanders, Monogue, Jodlowski, Cutrell, Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review, JAMA, doi:10.1001/jama.2020.6019
Schmith, Zhou, Lohmer, The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19, Cli. Pharmacol. Ther, doi:10.1002/cpt.1889
Sehailia, Chemat, Antimalarial-agent artemisinin and derivatives portray more potent binding to Lys353 and Lys31-binding hotspots of SARS-CoV-2 spike protein than hydroxychloroquine: potential repurposing of artenimol for COVID-19, J Biomol Struct Dyn, doi:10.1080/07391102.2020.1796809
Struyf, Deeks, Dinnes, Takwoingi, Davenport et al., Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19 disease, Cochrane Database Syst Rev, doi:10.1002/14651858.CD013665
Sze, Pan, Nevill, Gray, Martin et al., Ethnicity and clinical outcomes in COVID-19: a systematic review and metaanalysis, EClinicalMedicine, doi:10.1016/j.eclinm.2020.100630
Tang, Cao, Han, Wang, Chen et al., Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial, BMJ, doi:10.1136/bmj.m1849
Tang, Liu, Zhang, Xu, Ji et al., Cytokine storm in COVID-19: the current evidence and treatment strategies, Frontiers in Immunology, doi:10.3389/fimmu.2020.01708
To, Tsang, Leung, Tam, Wu et al., Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study, Lancet Infect Dis, doi:10.1016/S1473-3099(20)30196-1
Tripathy, Dassarma, Roy, Chabalala, Matsabisa, A review on possible modes of action of chloroquine/hydroxychloroquine: repurposing against SAR-CoV-2 (COVID-19) pandemic, Int J Antimicrob Agents, doi:10.1016/j.ijantimicag.2020.106028
Wagstaff, Sivakumaran, Heaton, Harrich, Jans, Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus, Biochem J, doi:10.1042/BJ20120150
Walsh, Jordan, Clyne, Rohde, Drummond et al., SARS-CoV-2 detection, viral load and infectivity over the course of an infection, J. Infect, doi:10.1016/j.jinf.2020.06.067
Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res, doi:10.1038/s41422-020-0282-0
Wang, Xu, Gao, Lu, Han et al., Detection of SARS-CoV-2 in different types of clinical specimens, JAMA, doi:10.1001/jama.2020.3786
Welle, COVID-19: Tests for 'miracle cure' herb Artemisia begin
Who, Emergence and spread of artemisinin resistance calls for intensified efforts to withdraw oral artemisinin monotherapy from the market
Who, Solidarity" clinical trial for COVID-19 treatments
Wu, Wang, Kuo, Shannar, Peter et al., An update on current therapeutic drugs treating COVID-19, Current Pharmacology Reports, doi:10.1007/s40495-020-00216-7
Yamasmith, Saleh-Arong, .-H, Avirutnan, Angkasekwinai et al., Efficacy and safety of ivermectin against dengue infection: a phase III, randomized, double-blind, placebo-controlled trial
Young, Ong, Kalimuddin, Low, Tan et al., Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore, JAMA, doi:10.1001/jama.2020.3204
Zhang, Xiao, Zhang, Xia, Cao et al., Coagulopathy and antiphospholipid antibodies in patients with covid-19
Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
  or use drag and drop