The Place of Ivermectin in the Management of Covid-19: State of the Evidence
Main Article Content
Abstract
Background and aims.
The covid 19 pandemic necessitated the use of old, repurposed, and new drugs, in addition to vaccines and public health measures. There are still many controversies about the efficacy and impact of some of the medications used, which need further elucidation.
We review the pharmacological properties and the place of the repurposed drug, Ivermectin (IVM) in the prophylaxis and treatment of SARS - CoV- 2 (severe acute respiratory syndrome coronavirus 2.) infection or Covid 19 disease.
Major findings: in-vitro, in-vivo, and human studies
In vitro studies in Vero/hSlam cells caused a 99.98 % inhibition of SARS - Cov-2 (5000-fold) within 48 hours. The IC50 (half maximal inhibitory concentration) for this virucidal action was 2.8μM, which was thought unattainable in humans in-vivo. Thus, there was initial skepticism on pharmacokinetic grounds as to possible efficacy of IVM in humans with Covid 19. There are, however, a multiplicity of anti-covid 19 mechanisms, beyond mere anti-viral effects, such as blockade of ACE2 receptor viral entry, and the anti-cytokine and anti-inflammatory effects of IVM. IVM has a long half-life of 18 - 24 hours, Mean Residence Time (MRT) of 3.4 days and a preferential site of lung accumulation.
In-vivo studies in Syrian Golden hamsters confirmed the symptomatic, anti-inflammatory, anti-cytokine, histopathological and survival benefit of IVM, which was more manifest in female animals.
In a January 2023 meta-analysis of studies (s) in total number of patients (n) for various parameters (p), the reduction in risk relative to placebo or controls were as follows:
- Overall improvement (s= 95) (n= 134,554) was 62% [95%CI 54-69].
- Mortality (s=48) (n=120,000) there was 51% reduction [95%CI 37-62].
- Hospitalization (s=29) (n = 44, 784), there was 34% reduction [ 95% CI 20-45].
- Viral clearance (s=20) (n= 3945) there was 45% reduction [95%CI 31-55].
- Prophylaxis (s=17) (n=19,764) showed 82% reduction [95%CI 73-88]
6 Randomised Control Trial (RCT) studies (s= 45) (n=2173) showed a 54 % mortality reduction [95% CI 39-65]
In addition, IVM has been shown in studies to cause a rapid reversal of hypoxemia (SPO2 < 94%) and a rapid increase in SPO2, an effect exhibiting a gender dichotomy. (SPO2 is the percentage of the maximum carrying capacity of the blood). This effect on SPO2 has been attributed to IVM’s reversal and prevention of SARS-CoV-2 virus induced hemagglutination. The dosage used for treatment of covid 19 varied widely within studies, but doses of 200-400 μg/kg twice weekly or daily for 5 consecutive days, caused significant viral clearance and clinical improvement, with minimal safety concerns. For prophylaxis, a dose of 200μg/kg for two consecutive days every 15 days was found effective in studies.
Conclusion: This review provides powerful evidence that IVM is efficacious singly or as a part of a regimen for covid 19. IVM could potentially be combined with newer oral anti-covid 19 agents, such as Paxlovid, for effective and life-saving regimen in patients infected with covid-19. The anti-viral properties of these drugs can synergize with the anti-inflammatory and anti-cytokine properties of Ivermectin. Ivermectin is also useful prophylactically, especially where vaccines are unavailable or undesirable.
Article Details
How to Cite
O.E., Babalola; A.A ., Ajayi.
The Place of Ivermectin in the Management of Covid-19: State of the Evidence.
Medical Research Archives, [S.l.], v. 11, n. 4, apr. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3778>. Date accessed: 21 nov. 2024.
doi: https://doi.org/10.18103/mra.v11i4.3778.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Wuhan Municipal Health and Health Commission’s Briefing on the Current Pneumonia Epidemic Situation in Our City. 2020. http://wjw.wuhan.gov.cn/ front/web/showDetail/ 2019123108989.Accessed 2nd May 2020.
2. Thacker PD. The covid-19 lab leak hypothesis: did the media fall victim to a misinformation campaign? BMJ2021;374doi:https://doi.org/10.1136/bmj.n1656(Published 08 July 2021) Cite this as:BMJ2021;374:n1656
3. WHO Coronavirus (COVID-19) Dashboard: https://covid19.who.int/. Accessed February 10th 2023
4. Centers for Disease control and Prevention. SARS-CoV2 variant classifications and definitions. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Assessed 29th January 2023)
5. The Nobel Prize in Physiology: https://www.nobelprize.org/prizes/medicine/2015/press-release/
6. Santin AD, Scheim DE, McCullough PA, Yagisawa M, Borody TJ. Ivermectin: a multifaceted drug of Nobel prize-honored distinction with indicated efficacy against a new global scourge, COVID-19. New Microbes and New Infections. 2021;43:100924.
7. Venco L, McCall JW, Guerrero J, Genchi C. Efficacy of long-term monthly administration of ivermectin on the progress of naturally acquired heartworm infections in dogs. Vet Parasitol. 2004 Oct 5;124(3-4):259-68. doi: 10.1016/j.vetpar.2004.06.024. PMID: 15381305.
8. Coffeng LE, Stolk WA, Zouré HG, Veerman JL, Agblewonu KB, Murdoch ME, Noma M, Fobi G, Richardus JH, Bundy DA, Habbema D, de Vlas SJ, Amazigo UV. African Programme For Onchocerciasis Control 1995-2015: model-estimated health impact and cost. PLoS Negl Trop Dis. 2013;7(1):e2032. doi: 10.1371/journal.pntd.0002032. Epub 2013 Jan 31. PMID: 23383355; PMCID: PMC3561133.
9. Crump A, Ōmura S. Ivermectin, 'wonder drug' from Japan: the human use perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(2):13-28. doi: 10.2183/pjab.87.13. PMID: 21321478; PMCID: PMC3043740.
10. MaratheA,ShiR,Mendez-LopezA, et al. Potential impact of 5 years of ivermectin mass drug administration on malaria outcomes in high burden countries. BMJ Global Health2021;6:e006424.
11. Suputtamongkol Y, Avirutnan P, Mairiang D, Angkasekwinai N, Niwattayakul K, Yamasmith E, Saleh-Arong FA, Songjaeng A, Prommool T, Tangthawornchaikul N, Puttikhunt C, Hunnangkul S, Komoltri C, Thammapalo S, Malasit P. Ivermectin Accelerates Circulating Nonstructural Protein 1 (NS1) Clearance in Adult Dengue Patients: A Combined Phase 2/3 Randomized Double-blinded Placebo Controlled Trial. Clin Infect Dis. 2021 May 18;72(10):e586-e593. doi: 10.1093/cid/ciaa1332. PMID: 33462580.
12. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3. PMID: 32251768; PMCID:
13. Georgi Momekov & Denitsa Momekova(2020)Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens,Biotechnology & Biotechnological Equipment,34:1,469-474,DOI:10.1080/13102818.2020.1775118ref.
14. Lehrer S, Rheinstein PH. Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2. Vivo 2020;34:3023–6. https://doi.org/10.21873/invivo.12134. PMID: 32871846; PMCID: PMC7652439
15. Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antivir Res. 2020;177:104760.
16. Arshad U, Pertinez H, Box H, 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 (2020), https://doi.org/10. 1002/cpt.1909
17. Seth C, Mas C, Conod A, Mueller J, Siems K, Kuciak M, et al. LongLasting WNT-TCF response blocking and epigenetic modifying activities of withanolide f in human cancer cells. PLoS One. 2016;11:e0168170.
18. Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res. 2008;57:524–9. https://doi.org/10. 1007/s00011-008-8007-8. [PMID: 19109745]
19. Matsuyama T, Kubli SP, Yoshinaga SK, et al. An aberrant STAT pathway is central to COVID-19. Cell Death Differ. 2020;27:3209–25. https://doi.org/10.1038/s41418-020-00633-7
20. Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of ivermectin against SARS-CoV-2-an extensive review. J Antibiot (Tokyo). 2022 Feb;75(2):60-71. doi: 10.1038/s41429-021-00491-6. Epub 2021 Dec 21. PMID: 34931048; PMCID: PMC8688140.
21. Yan S, Ci X, Chen N. Anti-Inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res. 2011;60:589–96.
22. Whitworth JA, Hay CR, McNicholas AM, Morgan D, Maude GH, Taylor DW.Coagulation abnormalities and ivermectin.Ann Trop Med Parasitol. 1992;86(3):301-305. [PubMed][Google Scholar]
23. Hay J, Arnott MA.Ivermectin and coagulation: an in vitro study.Ann Trop Med Parasitol. 1990;84(5):503-506. [PubMed][Google Scholar]
24. Richards F, JR, Mcneeley M, Bryan R, et al.Ivermectin and prothrombin time.The Lancet. 1989;333(8647):1139-1140.[Google Scholar]
25. Wagstaff et al., Ivermectin Global Summit, In vitro investigations of Ivermectin as an antiviral agent, https://vimeo.com/554860553#t=1h32m0s.
26. Dias de melo G, Lazarini F, Marchio A, Pineau P, Lecuit M, Lledoy P-M et al. Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin. Embo Molecular Medicine(2021) 13. doi: 10.15252/Emmm 202114122.)
27. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J. 2008;10(1):42-6. doi: 10.1208/s12248-007-9000-9. Epub 2008 Jan 25. PMID: 18446504; PMCID: PMC2751445.
28. Krolewiecki A, Lifschitz A, Moragas M, Travacio M, Valentini R, Alonso DF, et al. Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial. EClinicalMedicine. 2021 Jun 18;37:100959. doi:10.1016/j.eclinm.2021.100959. Erratum in: EClinicalMedicine. 2021 Sep;39:101119. PMID: 34189446; PMCID: PMC8225706.
29. Ivermectin treatment for COVID-19: Real- time meta- analysis of 64 studies. https:/ /ivmmeta.com/ (2021)
30. Behera P, Patro BK, Singh AK, Chandanshive PD, S. R. R, Pradhan SK, et al. (2021) Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study. PLoS ONE 16(2): e0247163. https://doi.org/10.1371/journal.pone.0247163
31. Behera P, Patro B K, Padhy B M, et al. (August 05, 2021) Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers. Cureus 13(8): e16897. doi:10.7759/cureus.16897.
32. Kerr L, Cadegiani F A, Baldi F, et al. (January 15, 2022) Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching. Cureus 14(1): e21272. doi:10.7759/cureus.21272
33. Alam MT, Murshed R, Gomes PF, Masud Z M, et al. (2020). Ivermectin as Pre-exposure Prophylaxis for COVID-19 among Healthcare Providers in a Selected Tertiary Hospital in Dhaka – An Observational Study.European Journal of Medical and Health Sciences,2(6). https://doi.org/10.24018/ejmed.2020.2.6.599
34. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin.Int J Antimicrob Agents. 2021;57(1):106248. doi:10.1016/j.ijantimicag.2020.106248.
35. Thairu Y, Babalola OE, Ajayi AA, et al. (2022) “A Comparison of Ivermectin and Non Ivermectin Based Regimen for COVID-19 in Abuja: Effects on Virus Clearance, Days-to-discharge and Mortality”,Journal of Pharmaceutical Research International, 34(44A), pp. 1-19. doi: 10.9734/jpri/2022/v34i44A36328
36. Kory P, Meduri GU,Varon J, Iglesias Jose, Marik PE. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19, American Journal of Therapeutics: May/June 2021 - Volume 28 - Issue 3 - p e299-e318 doi: 10.1097/MJT.0000000000001377
37. Justus RH. June 1, 2021 Updated Jun 7, 2021. Ivermectin obliterates 97% of Delhi cases. The Desert Review.
38. Babalola OE, Bode CO, Ajayi AA, Alakaloko FM, Akase IE, Otrofanowei E, Salu OB, Adeyemo WL, Ademuyiwa AO, Omilabu S. Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos,QJM: An International Journal of Medicine, 2021;, hcab035,https://doi.org/10.1093/qjmed/hcab035
39. Babalola OE, Ajayi A , Yunusa T, Ndanusa YA, Ogedengbe J, Omede O (2022) Ivermectin is associated with Increase in SPO2 in Hypoxemic SARS-CoV-2 Patients: Pharmacodynamic Profile and Correlates. J Clin Chem Lab Med. 5:222.
40. Stone JC, Ndarukwa P, Scheim DE, Dancis BM, Dancis J, Gill MG, Aldous C. Changes in SpO2 on Room Air for 34 Severe COVID-19 Patients after Ivermectin-Based Combination Treatment: 62% Normalization within 24 Hours.Biologics. 2022; 2(3):196-210. https://doi.org/10.3390/biologics2030015.
41. Hazan, S.; Dave, S.; Gunaratne, A.W.; Dolai, S.; Clancy, R.L.; McCullough, P.A.; Borody, T.J. Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.Future Microbiol.2022,17, 339–350.
42. Osman AM, Farouk S, Osman NM, Abdrabou AM (2020) Longitudinal assessment of chest computerized tomography and oxygen saturation for patients with COVID-19. The Egyptian Journal of Radiology and Nuclear Medicine 51: 255.
43. Annunziata A, Coppola A, Carannante N, Simioli F, Lanza M, et al. (2021) Home management of patients with moderate or severe respiratory failure secondary to COVID-19, using remote monitoring and oxygen with or without HFNC. Pathogens 10: 413.]
44. Boschi C, Scheim DE, Bancod A, Militello M, Bideau ML, Colson P, Fantini J, Scola BL. SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects.International Journal of Molecular Sciences. 2022; 23(24):15480. https://doi.org/10.3390/ijms232415480
45. Scheim, D.E. A Deadly Embrace: Hemagglutination Mediated by SARS-CoV-2 Spike Protein at Its 22 N-Glycosylation Sites, Red Blood Cell Surface Sialoglycoproteins, and Antibody. Int. J.Mol.Sci.2022,23,2558. https:// doi.org/10.3390/ijms23052558
46. Zou R, Peng L, Shu D, Zhao L, Lan J, Tan G, Peng J, Yang X, Liu M, Zhang C, Yuan J, Wang H, Li S, Lu H, Zhong W, Liu Y. Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial. Front Pharmacol. 2022 Jun 15;13:939573. doi: 10.3389/fphar.2022.939573. PMID: 35784723; PMCID: PMC9248931.
47. Spagnuolo V, Voarino M, Tonelli M, Galli L, Poli A, Bruzzesi E, Racca S, Clementi N, Oltolini C, Tresoldi M, Rovere Querini P, Dagna L, Zangrillo A, Ciceri F, Clementi M, Castagna A. Impact of Remdesivir on SARS-CoV-2 Clearance in a Real-Life Setting: A Matched-Cohort Study.Drug Des Devel Ther. 2022;16:3645-3654
https://doi.org/10.2147/DDDT.S369473
48. Zhang X, Song Y, Ci X, An N, Ju Y, Li H. Ivermectin Inhibits LPS-induced Production of Inflammatory Cytokines and Improves LPS-induced Survival in Mice.Inflamm Res.2008;Nov;57:524–529. doi:10.1007/s00011-008-8007-8.
49. Yan Shuhan, Ci Xinxin, Na Chen, Chen Chi, Li Xiangchao, Chu Xiao. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma.Inflamm Res.2011;Jun;60:589–596. doi:10.1007/s00011-011-0307-8.
50. Shah MM, Joyce B, Plumb ID, et al. Paxlovid is associated with decreased hospitalization rate among adults with Covid-19- United States, April-September 2022. MMWR MORB MORTAL WKLY REP 2022;71:1531-1537. DOI: http://dx.doi.org/10.15585/mmwr.mm7148e2
51. Najjar-Debbiny R, Gronich N, Weber G, et al. Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients. Clin Infect Dis 2022;ciac443.https://doi.org/10.1093/cid/ciac443PMID:35653428
52. Butler CC et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. The Lancet: volume 401, issue 10373, Page 231-239, January 28, 2023.
53. WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. The Lancet. |VOLUME 399, ISSUE 10339,P1941-1953,MAY 21, 2022
54. Gottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G, Oguchi G, Ryan P, Nielsen BU, Brown M, Hidalgo A, Sachdeva Y, Mittal S, Osiyemi O, Skarbinski J, Juneja K, Hyland RH, Osinusi A, Chen S, Camus G, Abdelghany M, Davies S, Behenna-Renton N, Duff F, Marty FM, Katz MJ, Ginde AA, Brown SM, Schiffer JT, Hill JA; GS-US-540-9012 (PINETREE) Investigators. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022 Jan 27;386(4):305-315. doi: 10.1056/NEJMoa2116846. Epub 2021 Dec 22. PMID: 34937145; PMCID: PMC8757570.
55. Guerrero R et al : Covid 10: The Ivermectin African enigma Colomb Med ( Cali) 2020, 51(4) e 2014613, doi: 10.25100/cm.v51i4.4613.
56. Hazan S. Front Microbilogy 2022, 13: 952321 Mmicrobiome -based hypothesis on Ivermectin Mechanisms in COVID -19 : Ivermectin feeds bifidobacteria to boost immunity.
57. Ya'qoub L, Elgendy IY, Pepine CJ. Sex and gender differences in COVID-19: More to be learned! Am Heart J Plus. 2021 Mar;3:100011. doi: 10.1016/j.ahjo.2021.100011. Epub 2021 Apr 14. PMID: 34169297; PMCID: PMC8045422.
58. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. International Journal of Infectious Diseases,Volume 103,2021,Pages 214-216.ISSN 1201-9712. https://doi.org/10.1016/j.ijid.2020.11.191.(https://www.sciencedirect.com/science/article/pii/S1201971220325066)
59. Shouman W M et al., Journal of Clinical and Diagnostic Research, doi:10.7860/JCDR/2020/46795.0000, Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomised Clinical Trial,https://www.jcdr.net/articles/PDF/..Sh)_PF1(SY_OM)_PFA_(OM)_PN(KM).pdf.
60. Espitia-Hernandez G et al., Biomedical Research, 31:5, Effects of Ivermectin-azithromycin-cholecalciferol combined therapy on COVID-19 infected patients: A proof of concept study, https://www.biom edres.info/biomedi..-proof-of-concept-study14435.html.
61. Carvallo H et al., Journal of Biomedical Research and Clinical Investigation, doi:10.31546/2633-8653.1007, Study of the Efficacy and Safety of Topical Ivermectin + Iota-Carrageenan in the Prophylaxis against COVID-19 in Health Personnel, https://medicalpressopenaccess.com/upload/1605709669_1007.pdf.
62. Ajayi AAL. Drugs Shown to Inhibit SARS-CoV-2 in COVID-19 Disease: Comparative Basic and Clinical Pharmacology of Molnupiravir and Ivermectin. Austin J Pharmacol Ther. 2021; 9(5).1149.
63. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J. 2008;10(1):42-6. doi: 10.1208/s12248-007-9000-9. Epub 2008 Jan 25. PMID: 18446504; PMCID: PMC2751445.
64. Mohan A, Tiwari P, Suri TM et al. Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial. Journal of Infection and Chemotherapy,Volume 27, Issue 12,2021,Pages 1743-1749,ISSN 1341-321X,https://doi.org/10.1016/j.jiac.2021.08.021. (https://www.sciencedirect.com/science/article/pii/S1341321X21002397)
2. Thacker PD. The covid-19 lab leak hypothesis: did the media fall victim to a misinformation campaign? BMJ2021;374doi:https://doi.org/10.1136/bmj.n1656(Published 08 July 2021) Cite this as:BMJ2021;374:n1656
3. WHO Coronavirus (COVID-19) Dashboard: https://covid19.who.int/. Accessed February 10th 2023
4. Centers for Disease control and Prevention. SARS-CoV2 variant classifications and definitions. https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html. Assessed 29th January 2023)
5. The Nobel Prize in Physiology: https://www.nobelprize.org/prizes/medicine/2015/press-release/
6. Santin AD, Scheim DE, McCullough PA, Yagisawa M, Borody TJ. Ivermectin: a multifaceted drug of Nobel prize-honored distinction with indicated efficacy against a new global scourge, COVID-19. New Microbes and New Infections. 2021;43:100924.
7. Venco L, McCall JW, Guerrero J, Genchi C. Efficacy of long-term monthly administration of ivermectin on the progress of naturally acquired heartworm infections in dogs. Vet Parasitol. 2004 Oct 5;124(3-4):259-68. doi: 10.1016/j.vetpar.2004.06.024. PMID: 15381305.
8. Coffeng LE, Stolk WA, Zouré HG, Veerman JL, Agblewonu KB, Murdoch ME, Noma M, Fobi G, Richardus JH, Bundy DA, Habbema D, de Vlas SJ, Amazigo UV. African Programme For Onchocerciasis Control 1995-2015: model-estimated health impact and cost. PLoS Negl Trop Dis. 2013;7(1):e2032. doi: 10.1371/journal.pntd.0002032. Epub 2013 Jan 31. PMID: 23383355; PMCID: PMC3561133.
9. Crump A, Ōmura S. Ivermectin, 'wonder drug' from Japan: the human use perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(2):13-28. doi: 10.2183/pjab.87.13. PMID: 21321478; PMCID: PMC3043740.
10. MaratheA,ShiR,Mendez-LopezA, et al. Potential impact of 5 years of ivermectin mass drug administration on malaria outcomes in high burden countries. BMJ Global Health2021;6:e006424.
11. Suputtamongkol Y, Avirutnan P, Mairiang D, Angkasekwinai N, Niwattayakul K, Yamasmith E, Saleh-Arong FA, Songjaeng A, Prommool T, Tangthawornchaikul N, Puttikhunt C, Hunnangkul S, Komoltri C, Thammapalo S, Malasit P. Ivermectin Accelerates Circulating Nonstructural Protein 1 (NS1) Clearance in Adult Dengue Patients: A Combined Phase 2/3 Randomized Double-blinded Placebo Controlled Trial. Clin Infect Dis. 2021 May 18;72(10):e586-e593. doi: 10.1093/cid/ciaa1332. PMID: 33462580.
12. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020 Jun;178:104787. doi: 10.1016/j.antiviral.2020.104787. Epub 2020 Apr 3. PMID: 32251768; PMCID:
13. Georgi Momekov & Denitsa Momekova(2020)Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view: antiviral levels are not likely attainable with known dosing regimens,Biotechnology & Biotechnological Equipment,34:1,469-474,DOI:10.1080/13102818.2020.1775118ref.
14. Lehrer S, Rheinstein PH. Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2. Vivo 2020;34:3023–6. https://doi.org/10.21873/invivo.12134. PMID: 32871846; PMCID: PMC7652439
15. Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antivir Res. 2020;177:104760.
16. Arshad U, Pertinez H, Box H, 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 (2020), https://doi.org/10. 1002/cpt.1909
17. Seth C, Mas C, Conod A, Mueller J, Siems K, Kuciak M, et al. LongLasting WNT-TCF response blocking and epigenetic modifying activities of withanolide f in human cancer cells. PLoS One. 2016;11:e0168170.
18. Zhang X, Song Y, Ci X, et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm Res. 2008;57:524–9. https://doi.org/10. 1007/s00011-008-8007-8. [PMID: 19109745]
19. Matsuyama T, Kubli SP, Yoshinaga SK, et al. An aberrant STAT pathway is central to COVID-19. Cell Death Differ. 2020;27:3209–25. https://doi.org/10.1038/s41418-020-00633-7
20. Zaidi AK, Dehgani-Mobaraki P. The mechanisms of action of ivermectin against SARS-CoV-2-an extensive review. J Antibiot (Tokyo). 2022 Feb;75(2):60-71. doi: 10.1038/s41429-021-00491-6. Epub 2021 Dec 21. PMID: 34931048; PMCID: PMC8688140.
21. Yan S, Ci X, Chen N. Anti-Inflammatory effects of ivermectin in mouse model of allergic asthma. Inflamm Res. 2011;60:589–96.
22. Whitworth JA, Hay CR, McNicholas AM, Morgan D, Maude GH, Taylor DW.Coagulation abnormalities and ivermectin.Ann Trop Med Parasitol. 1992;86(3):301-305. [PubMed][Google Scholar]
23. Hay J, Arnott MA.Ivermectin and coagulation: an in vitro study.Ann Trop Med Parasitol. 1990;84(5):503-506. [PubMed][Google Scholar]
24. Richards F, JR, Mcneeley M, Bryan R, et al.Ivermectin and prothrombin time.The Lancet. 1989;333(8647):1139-1140.[Google Scholar]
25. Wagstaff et al., Ivermectin Global Summit, In vitro investigations of Ivermectin as an antiviral agent, https://vimeo.com/554860553#t=1h32m0s.
26. Dias de melo G, Lazarini F, Marchio A, Pineau P, Lecuit M, Lledoy P-M et al. Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin. Embo Molecular Medicine(2021) 13. doi: 10.15252/Emmm 202114122.)
27. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J. 2008;10(1):42-6. doi: 10.1208/s12248-007-9000-9. Epub 2008 Jan 25. PMID: 18446504; PMCID: PMC2751445.
28. Krolewiecki A, Lifschitz A, Moragas M, Travacio M, Valentini R, Alonso DF, et al. Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial. EClinicalMedicine. 2021 Jun 18;37:100959. doi:10.1016/j.eclinm.2021.100959. Erratum in: EClinicalMedicine. 2021 Sep;39:101119. PMID: 34189446; PMCID: PMC8225706.
29. Ivermectin treatment for COVID-19: Real- time meta- analysis of 64 studies. https:/ /ivmmeta.com/ (2021)
30. Behera P, Patro BK, Singh AK, Chandanshive PD, S. R. R, Pradhan SK, et al. (2021) Role of ivermectin in the prevention of SARS-CoV-2 infection among healthcare workers in India: A matched case-control study. PLoS ONE 16(2): e0247163. https://doi.org/10.1371/journal.pone.0247163
31. Behera P, Patro B K, Padhy B M, et al. (August 05, 2021) Prophylactic Role of Ivermectin in Severe Acute Respiratory Syndrome Coronavirus 2 Infection Among Healthcare Workers. Cureus 13(8): e16897. doi:10.7759/cureus.16897.
32. Kerr L, Cadegiani F A, Baldi F, et al. (January 15, 2022) Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching. Cureus 14(1): e21272. doi:10.7759/cureus.21272
33. Alam MT, Murshed R, Gomes PF, Masud Z M, et al. (2020). Ivermectin as Pre-exposure Prophylaxis for COVID-19 among Healthcare Providers in a Selected Tertiary Hospital in Dhaka – An Observational Study.European Journal of Medical and Health Sciences,2(6). https://doi.org/10.24018/ejmed.2020.2.6.599
34. Hellwig MD, Maia A. A COVID-19 prophylaxis? Lower incidence associated with prophylactic administration of ivermectin.Int J Antimicrob Agents. 2021;57(1):106248. doi:10.1016/j.ijantimicag.2020.106248.
35. Thairu Y, Babalola OE, Ajayi AA, et al. (2022) “A Comparison of Ivermectin and Non Ivermectin Based Regimen for COVID-19 in Abuja: Effects on Virus Clearance, Days-to-discharge and Mortality”,Journal of Pharmaceutical Research International, 34(44A), pp. 1-19. doi: 10.9734/jpri/2022/v34i44A36328
36. Kory P, Meduri GU,Varon J, Iglesias Jose, Marik PE. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19, American Journal of Therapeutics: May/June 2021 - Volume 28 - Issue 3 - p e299-e318 doi: 10.1097/MJT.0000000000001377
37. Justus RH. June 1, 2021 Updated Jun 7, 2021. Ivermectin obliterates 97% of Delhi cases. The Desert Review.
38. Babalola OE, Bode CO, Ajayi AA, Alakaloko FM, Akase IE, Otrofanowei E, Salu OB, Adeyemo WL, Ademuyiwa AO, Omilabu S. Ivermectin shows clinical benefits in mild to moderate COVID19: a randomized controlled double-blind, dose-response study in Lagos,QJM: An International Journal of Medicine, 2021;, hcab035,https://doi.org/10.1093/qjmed/hcab035
39. Babalola OE, Ajayi A , Yunusa T, Ndanusa YA, Ogedengbe J, Omede O (2022) Ivermectin is associated with Increase in SPO2 in Hypoxemic SARS-CoV-2 Patients: Pharmacodynamic Profile and Correlates. J Clin Chem Lab Med. 5:222.
40. Stone JC, Ndarukwa P, Scheim DE, Dancis BM, Dancis J, Gill MG, Aldous C. Changes in SpO2 on Room Air for 34 Severe COVID-19 Patients after Ivermectin-Based Combination Treatment: 62% Normalization within 24 Hours.Biologics. 2022; 2(3):196-210. https://doi.org/10.3390/biologics2030015.
41. Hazan, S.; Dave, S.; Gunaratne, A.W.; Dolai, S.; Clancy, R.L.; McCullough, P.A.; Borody, T.J. Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.Future Microbiol.2022,17, 339–350.
42. Osman AM, Farouk S, Osman NM, Abdrabou AM (2020) Longitudinal assessment of chest computerized tomography and oxygen saturation for patients with COVID-19. The Egyptian Journal of Radiology and Nuclear Medicine 51: 255.
43. Annunziata A, Coppola A, Carannante N, Simioli F, Lanza M, et al. (2021) Home management of patients with moderate or severe respiratory failure secondary to COVID-19, using remote monitoring and oxygen with or without HFNC. Pathogens 10: 413.]
44. Boschi C, Scheim DE, Bancod A, Militello M, Bideau ML, Colson P, Fantini J, Scola BL. SARS-CoV-2 Spike Protein Induces Hemagglutination: Implications for COVID-19 Morbidities and Therapeutics and for Vaccine Adverse Effects.International Journal of Molecular Sciences. 2022; 23(24):15480. https://doi.org/10.3390/ijms232415480
45. Scheim, D.E. A Deadly Embrace: Hemagglutination Mediated by SARS-CoV-2 Spike Protein at Its 22 N-Glycosylation Sites, Red Blood Cell Surface Sialoglycoproteins, and Antibody. Int. J.Mol.Sci.2022,23,2558. https:// doi.org/10.3390/ijms23052558
46. Zou R, Peng L, Shu D, Zhao L, Lan J, Tan G, Peng J, Yang X, Liu M, Zhang C, Yuan J, Wang H, Li S, Lu H, Zhong W, Liu Y. Antiviral Efficacy and Safety of Molnupiravir Against Omicron Variant Infection: A Randomized Controlled Clinical Trial. Front Pharmacol. 2022 Jun 15;13:939573. doi: 10.3389/fphar.2022.939573. PMID: 35784723; PMCID: PMC9248931.
47. Spagnuolo V, Voarino M, Tonelli M, Galli L, Poli A, Bruzzesi E, Racca S, Clementi N, Oltolini C, Tresoldi M, Rovere Querini P, Dagna L, Zangrillo A, Ciceri F, Clementi M, Castagna A. Impact of Remdesivir on SARS-CoV-2 Clearance in a Real-Life Setting: A Matched-Cohort Study.Drug Des Devel Ther. 2022;16:3645-3654
https://doi.org/10.2147/DDDT.S369473
48. Zhang X, Song Y, Ci X, An N, Ju Y, Li H. Ivermectin Inhibits LPS-induced Production of Inflammatory Cytokines and Improves LPS-induced Survival in Mice.Inflamm Res.2008;Nov;57:524–529. doi:10.1007/s00011-008-8007-8.
49. Yan Shuhan, Ci Xinxin, Na Chen, Chen Chi, Li Xiangchao, Chu Xiao. Anti-inflammatory effects of ivermectin in mouse model of allergic asthma.Inflamm Res.2011;Jun;60:589–596. doi:10.1007/s00011-011-0307-8.
50. Shah MM, Joyce B, Plumb ID, et al. Paxlovid is associated with decreased hospitalization rate among adults with Covid-19- United States, April-September 2022. MMWR MORB MORTAL WKLY REP 2022;71:1531-1537. DOI: http://dx.doi.org/10.15585/mmwr.mm7148e2
51. Najjar-Debbiny R, Gronich N, Weber G, et al. Effectiveness of Paxlovid in reducing severe coronavirus disease 2019 and mortality in high-risk patients. Clin Infect Dis 2022;ciac443.https://doi.org/10.1093/cid/ciac443PMID:35653428
52. Butler CC et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. The Lancet: volume 401, issue 10373, Page 231-239, January 28, 2023.
53. WHO Solidarity Trial Consortium. Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses. The Lancet. |VOLUME 399, ISSUE 10339,P1941-1953,MAY 21, 2022
54. Gottlieb RL, Vaca CE, Paredes R, Mera J, Webb BJ, Perez G, Oguchi G, Ryan P, Nielsen BU, Brown M, Hidalgo A, Sachdeva Y, Mittal S, Osiyemi O, Skarbinski J, Juneja K, Hyland RH, Osinusi A, Chen S, Camus G, Abdelghany M, Davies S, Behenna-Renton N, Duff F, Marty FM, Katz MJ, Ginde AA, Brown SM, Schiffer JT, Hill JA; GS-US-540-9012 (PINETREE) Investigators. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med. 2022 Jan 27;386(4):305-315. doi: 10.1056/NEJMoa2116846. Epub 2021 Dec 22. PMID: 34937145; PMCID: PMC8757570.
55. Guerrero R et al : Covid 10: The Ivermectin African enigma Colomb Med ( Cali) 2020, 51(4) e 2014613, doi: 10.25100/cm.v51i4.4613.
56. Hazan S. Front Microbilogy 2022, 13: 952321 Mmicrobiome -based hypothesis on Ivermectin Mechanisms in COVID -19 : Ivermectin feeds bifidobacteria to boost immunity.
57. Ya'qoub L, Elgendy IY, Pepine CJ. Sex and gender differences in COVID-19: More to be learned! Am Heart J Plus. 2021 Mar;3:100011. doi: 10.1016/j.ahjo.2021.100011. Epub 2021 Apr 14. PMID: 34169297; PMCID: PMC8045422.
58. Ahmed S, Karim MM, Ross AG, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. International Journal of Infectious Diseases,Volume 103,2021,Pages 214-216.ISSN 1201-9712. https://doi.org/10.1016/j.ijid.2020.11.191.(https://www.sciencedirect.com/science/article/pii/S1201971220325066)
59. Shouman W M et al., Journal of Clinical and Diagnostic Research, doi:10.7860/JCDR/2020/46795.0000, Use of Ivermectin as a Potential Chemoprophylaxis for COVID-19 in Egypt: A Randomised Clinical Trial,https://www.jcdr.net/articles/PDF/..Sh)_PF1(SY_OM)_PFA_(OM)_PN(KM).pdf.
60. Espitia-Hernandez G et al., Biomedical Research, 31:5, Effects of Ivermectin-azithromycin-cholecalciferol combined therapy on COVID-19 infected patients: A proof of concept study, https://www.biom edres.info/biomedi..-proof-of-concept-study14435.html.
61. Carvallo H et al., Journal of Biomedical Research and Clinical Investigation, doi:10.31546/2633-8653.1007, Study of the Efficacy and Safety of Topical Ivermectin + Iota-Carrageenan in the Prophylaxis against COVID-19 in Health Personnel, https://medicalpressopenaccess.com/upload/1605709669_1007.pdf.
62. Ajayi AAL. Drugs Shown to Inhibit SARS-CoV-2 in COVID-19 Disease: Comparative Basic and Clinical Pharmacology of Molnupiravir and Ivermectin. Austin J Pharmacol Ther. 2021; 9(5).1149.
63. González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J. 2008;10(1):42-6. doi: 10.1208/s12248-007-9000-9. Epub 2008 Jan 25. PMID: 18446504; PMCID: PMC2751445.
64. Mohan A, Tiwari P, Suri TM et al. Single-dose oral ivermectin in mild and moderate COVID-19 (RIVET-COV): A single-centre randomized, placebo-controlled trial. Journal of Infection and Chemotherapy,Volume 27, Issue 12,2021,Pages 1743-1749,ISSN 1341-321X,https://doi.org/10.1016/j.jiac.2021.08.021. (https://www.sciencedirect.com/science/article/pii/S1341321X21002397)