Ivermectin is a widely used drug for the treatment and control of several neglected tropical diseases.The drug has an excellent safety profile, with more than 2.5 billion doses distributed in the last 30 years, and its potential to reduce malaria transmission by killing mosquitoes is under evaluation in several trials around the
world. Ivermectin inhibits the in vitro replication of some positive, single-stranded RNA viruses, namely, dengue virus (DNV), Zika virus, yellow fever virus, and others

Chaccour, Carlos

Hammann, Felix

Rabinovich, N Regina

Ramón-García, Santiago

American Journal of Tropical Medicine and Hygiene

English

Ramón García, Santiago

Rabinovich, Regina

Diposit Digital de la Universitat de Barcelona

Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in Times of Urgency.

Bern Open Repository and Information System (BORIS)

In order to provide our readers with timely access to new content, papers accepted by the American Journal of Tropical Medicine and Hygiene are posted online ahead of print publication.Papers that have been accepted for publication are peer-reviewed and copy edited but do not incorporate all corrections or constitute the final versions that will appear in the Journal. Final,corrected papers will be published online concurrent with the release of the print issue.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, providedthe original author and source are credited.Am. J. Trop. Med. Hyg., 00(0), 2020, pp. 1–2doi:10.4269/ajtmh.20-0271Copyright © 2020 by The American Society of Tropical Medicine and HygieneEditorialIvermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in Times of UrgencyCarlos Chaccour,1,2,3* Felix Hammann,4 Santiago Ramo´n-Garcı´a,5,6 and N. Regina Rabinovich1,71ISGlobal, Hospital Clı´nic - Universitat de Barcelona, Barcelona, Spain; 2Ifakara Health Institute, Ifakara, United Republic of Tanzania; 3Facultad deMedicina,UniversidaddeNavarra, Pamplona, Spain; 4DepartmentofGeneral InternalMedicine,Clinical Pharmacology andToxicology, Inselspital,BernUniversityHospital, UniversityofBern,Bern,Switzerland; 5Research&DevelopmentAgencyofAragon (ARAID) Foundation, Zaragoza, Spain;6Department ofMicrobiology,Mycobacterial GeneticsGroup, PreventiveMedicine andPublicHealth, Faculty ofMedicine, University of Zaragoza,Zaragoza, Spain; 7Harvard T.H. Chan School of Public Health, Boston, MassachusettsIvermectin is a widely used drug for the treatment and controlof severalneglected tropicaldiseases.1Thedrughasanexcellentsafety profile, with more than 2.5 billion doses distributed in thelast 30 years, and its potential to reducemalaria transmission bykillingmosquitoes is under evaluation in several trials around theworld.2 Ivermectin inhibits the invitro replicationofsomepositive,single-stranded RNA viruses, namely, dengue virus (DNV),3–5Zika virus,4,6 yellow fever virus,7,8 and others.4,7,9Caly et al.10 recently reported that ivermectin is a potent in-hibitor of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) replication in vitro.Given thecoronavirusdisease-19 (COVID-19) pandemic, this has understandably resonatedwidely in the global press.11Caly et al.10 report a 5,000-fold reduction inSARS-CoV-2RNAlevels, compared with those in controls, after infected Vero/hSLAM cells were incubated for 48 hours with 5 μM ivermectin.The ivermectin IC50 for the viruswas calculated at approximately2.5 μM. These concentrations are the equivalent of 4,370 and2,190 ng/mL, respectively, notably 50- to 100-fold the peakconcentration (Cmax) achieved in plasma after the single dose of200μg/kg (14mg ina70-kgadult) commonlyused for thecontrolof onchocerchiasis.12 Pharmacokinetic studies in healthy vol-unteers have suggested that single doses up to 120 mg of iver-mectin can be safe andwell tolerated.13 However, even with thisdose, which is 10-fold greater than those approved by the USFood and Drug Administration, the Cmax values reported were∼250 ng/mL,13 one order of magnitude lower than effectivein vitro concentrations against SARS-CoV-2.These findings may seem to discourage follow-up clinicaltrials with ivermectin. However, some in vivo effect may bepossible even if efficacious in vitro concentrations are physi-ologically unattainable. A recent phase III clinical trial in den-gue patients in Thailand, in which a once-daily dose of 400μg/kg for 3 days was found to be safe but did not produce anyclinical benefit,14 showed a modest and indirect in vivo effectagainst DNV.14 Previous work by Wagstaff et al.5 reportedinhibition atmuchhigher in vitro concentrations (25μM) inDNV-infected Vero cells. Both pharmacokinetic considerations andthe relatively long incubation period of DNV might explain thelack of clinical efficacy. Until we have a better understanding ofivermectin’s antiviral mode of action and of appropriate in vitrosystems for testing, we caution against using findings in Verocells as more than a qualitative indicator of potential efficacy.Very recently, preliminary findings on a potential effect ofhydroxychloroquine combined with azithromycin againstSARS-CoV-2 were widely publicized,15 leading to a surge indemand and self-medication, which resulted in serious harmin some cases and a stock shortage that jeopardized drugavailability for other critical conditions for which hydroxy-chloroquine or chloroquine is the standard of care, that is, vivaxmalaria, rheumatoidarthritis, andsystemic lupuserythematosus.Efficacy claims for hydroxychloroquine against COVID-19 havebeen questioned in follow-up trials using similar dosingregimens,16,17 and we await results of randomized, con-trolled clinical trials exploring treatment efficacy.We believe the recent findings regarding ivermectin warrantrapidly implemented controlled clinical trials to assess its ef-ficacy against SARS-CoV-2. These trials may open a new fieldof research on the potential use of avermectin antiparasiticdrugs, including compounds with an improved pharmacoki-netic profile, as antivirals.18However, becauseof the followingpoints, extreme due diligence and regulatory review areneeded before testing ivermectin in severe disease.First, ivermectin, which targets glutamate-gated chlorinechannels in invertebrates, may cross-target the GABA-gatedchlorine channels present in the mammalian central nervoussystem (CNS) and cause neurotoxicity.19 This is normallyprevented by an intact blood–brain barrier (BBB), but in pa-tientswith a hyperinflammatory state, endothelial permeabilityat the BBB may be increased and cause leaking of drugs intothe CNS, potentially causing harm.20,21Second, boosted antiretrovirals such as lopinavir/ritonavirand darunavir/cobicistat, which have been widely used againstSARS-CoV-2based on limited evidence, and a number of otherdrugs, are potent inhibitors of cytochrome P450 3A4, the mainmetabolic pathway for ivermectin. Concurrent use of thesedrugs will result in increased systemic exposure to ivermectin.Furthermore, ritonavir and cobicistat can readily inhibit one ofthe main efflux pumps in the BBB, P-glycoprotein, further fa-voring neurotoxicity.22,23 However, it is encouraging that a re-cent analysis of ivermectin-related neurotoxic adverse eventsreported to theWHOProgram for International DrugMonitoringfound only one case of 1,668 reports in which concomitant useof antivirals was associated with neurotoxicity.24Third, as earlier, available evidence suggests that levels ofivermectin with meaningful activity against SARS-CoV-2would not be achieved without extraordinary, potentiallytoxic increases in ivermectin dosing levels in humans. How-ever, evidence from animal models showing up to 3-foldhigher levels in pulmonary tissue than in plasma 1 week afteroral dosing leaves the door open for further research, in par-ticular for the treatment of respiratory viruses.25,26The discovery of ivermectin’s activity against SARS-CoV-2gives reason for hope, but off-label and compassionate userequires careful risk–benefit considerations,27 especially in* Address correspondence to Carlos Chaccour, ISGlobal, HospitalClı´nic - Universitat deBarcelona, Rosello 132, 5a 2a, Barcelona 08036,Spain. E-mail: carlos.chaccour@isglobal.org1source: https://doi.org/10.7892/boris.143758 | downloaded: 13.5.2020critically ill patients. A path to consider is evaluation first ofimpacts on virologic outcomes in uncomplicated, low-riskpatients early in the course of the disease. Well-conductedclinical trials informed by robust pharmacokinetic modelsshould be considered to validate the impact before the use ofivermectin to treat SARS-CoV-2 is implemented.Received April 8, 2020. Accepted for publication April 10, 2020.Published online April 16, 2020.Authors’ addresses: Carlos Chaccour, ISGlobal, Hospital Clı´nic -Universitat de Barcelona, Barcelona, Spain, Ifakara Health Institute,Ifakara, United Republic of Tanzania, and Facultad de Medicina,Universidad de Navarra, Pamplona, Spain, E-mail: carlos.chaccour@isglobal.org. Felix Hammann, Department of General Internal Medi-cine, Clinical Pharmacology and Toxicology, Inselspital, Bern Uni-versity Hospital, University of Bern, Bern, Switzerland, E-mail:felix.hammann@insel.ch. Santiago Ramo´n-Garcı´a, Research & De-velopment Agency of Aragon (ARAID) Foundation, Spain and De-partment of Microbiology, Mycobacterial Genetics Group, PreventiveMedicine and Public Health, Faculty of Medicine, University of Zar-agoza, Spain, E-mail: santiramon@unizar.es. N. Regina Rabinovich,ISGlobal, Hospital Clı´nic - Universitat de Barcelona, Barcelona, Spainand Harvard T.H. Chan School of Public Health, Boston, MA, E-mail:rrabinov@hsph.harvard.edu.This is an open-access article distributed under the terms of theCreative Commons Attribution (CC-BY) License, which permits un-restricted use, distribution, and reproduction in anymedium, providedthe original author and source are credited.REFERENCES1. Omura S, Crump A, 2014. Ivermectin: panacea for resource-poorcommunities? Trends Parasitol 30: 445–455.2. The Ivermectin Roadmappers, 2020. A roadmap for the devel-opment of ivermectin as a complementary malaria vectorcontrol tool. Am J Trop Med Hyg 102: 3–24.3. Tay MY, Fraser JE, ChanWK, Moreland NJ, Rathore AP, Wang CVasudevan SG, Jans DA, 2013. Nuclear localization of denguevirus (DENV) 1-4 non-structural protein 5; protection against all4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res 99:301–306.4. Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, BorgNA, Jans DA, 2020. The broad spectrum antiviral ivermectintargets the host nuclear transport importin alpha/beta1 heter-odimer. Antiviral Res 177: 104760.5. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA,2012. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 anddengue virus. Biochem J 443: 851–856.6. Barrows NJ et al., 2016. A screen of FDA-approved drugs forinhibitorsof Zika virus infection.CellHostMicrobe20:259–270.7. Varghese FS, Kaukinen P, Glasker S, Bespalov M, Hanski L,Wennerberg K Ku¨mmerer BM, Ahola T 2016. Discovery ofberberine, abamectin and ivermectin as antivirals against chi-kungunya and other alphaviruses. Antiviral Res 126: 117–124.8. Mastrangelo E et al., 2012. Ivermectin is a potent inhibitor of fla-vivirus replication specifically targeting NS3 helicase activity:new prospects for an old drug. J Antimicrob Chemother 67:1884–1894.9. Lee YJ, Lee C, 2016. Ivermectin inhibits porcine reproductive andrespiratory syndrome virus in cultured porcine alveolar mac-rophages. Arch Virol 161: 257–268.10. Caly L, Druce J, Catton M, Jans D, KM W, 2020. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2in vitro.Antiviral Res. Available at: https://www.sciencedirect.com/science/article/pii/S0166354220302011.11. Slisco A, 2020. Anti-parasite Drug Used since 1980s May HelpStop Coronavirus, New Study Says. Newsweek. April, 04.Available at: https://www.newsweek.com/anti-parasite-drug-used-since-1980s-may-help-stop-coronavirus-new-study-says-1496083. Accessed April 5, 2020.12. Chaccour C, Hammann F, Rabinovich NR, 2017. Ivermectin toreduce malaria transmission I. Pharmacokinetic and pharma-codynamic considerations regarding efficacy and safety.MalarJ 16: 161.13. GuzzoCA, FurtekCI, PorrasAG, ChenC, TippingR, ClineschmidtCM, Sciberras DG, Hsieh JY, Lasseter KC, 2002. Safety, tol-erability, and pharmacokinetics of escalating high doses ofivermectin in healthy adult subjects. J Clin Pharmacol 42:1122–1133.14. YamasmithEet al., 2018.EfficacyandSafetyof Ivermectin againstDengue Infection: A Phase III, Randomized, Double-blind,Placebo-controlled Trial. He 34th Annual Meeting the RoyalCollege of Physicians of Thailand- ‘Internal Medicine and OneHealth’: Chonburi, Thailand. Registry. Available at: https://clinicaltrials.gov/ct2/show/NCT02045069. Accessed Aplri 5,2020.15. Gautret P et al., 2020. Hydroxychloroquine and azithromycinas a treatment of COVID-19: results of an open-labelnon-randomized clinical trial. Int J Antimicrob Agents. Avail-able at: https://www.sciencedirect.com/science/article/pii/S0924857920300996.16. Song S, Zhang D, Qian Z, Li T, Shen Y, Hongzh L, 2020. A PilotStudy of Hydroxychloroquine in Treatment of Patients withCommon Coronavirus Disease-19 (COVID-19). Available at:http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf. Accessed April 5,2020. Journal of Zhejiang University, 3.17. Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D,Goldwirt L, de Castro N, 2020 No evidence of rapid antiviralclearance or clinical benefit with the combination of hydroxy-chloroquineandazithromycin in patientswith severeCOVID-19infection.Me´d Mal Infect 9: S0399-077X(20)30085-8.18. Scherr N, Pluschke G, Thompson CJ, Ramon-Garcia S, 2015.Selamectin is the avermectin with the best potential for buruliulcer treatment. PLoS Negl Trop Dis 9: e0003996.19. Menez C, Sutra JF, Prichard R, Lespine A, 2012. Relative neuro-toxicity of ivermectin and moxidectin in Mdr1ab (-/-) mice andeffects on mammalian GABA(A) channel activity. PLoS NeglTrop Dis 6: e1883.20. Varatharaj A, Galea I, 2017. The blood-brain barrier in systemicinflammation. Brain Behav Immun 60: 1–12.21. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B,2020. COVID-19–associated acute hemorrhagic necrotizingencephalopathy: CT andMRI features. Radiology. Available at:https://pubs.rsna.org/doi/pdf/10.1148/radiol.2020201187.22. Lepist EI, Phan TK, Roy A, Tong L, Maclennan K, Murray B, RayAS, 2012. Cobicistat boosts the intestinal absorption of trans-port substrates, includingHIVprotease inhibitorsandGS-7340,in vitro. Antimicrob Agents Chemother 56: 5409–5413.23. Drewe J, Gutmann H, Fricker G, TorokM, Beglinger C, Huwyler J,1999. HIV protease inhibitor ritonavir: a more potent inhibitor ofP-glycoprotein than the cyclosporine analog SDZ PSC 833.Biochem Pharmacol 57: 1147–1152.24. Chandler RE, 2018. Serious neurological adverse events afterivermectin-do they occur beyond the indication of onchocer-ciasis? Am J Trop Med Hyg 98: 382–388.25. LespineA,AlvinerieM,Sutra JF,Pors I, ChartierC, 2005. Influenceof the route of administration on efficacy and tissue distributionof ivermectin in goat. Vet Parasitol 128: 251–260.26. Chiu SH, Lu AY, 1989.Metabolism and tissue residues. CampbellWC, ed. Ivermectin and Abamectin. New York, NY: Springer-Verlag, 131–143.27. Kalil AC, 2020. Treating COVID-19-off-label drug use, compas-sionate use, and randomized clinical trials during pandemics.JAMA. Available at: https://jamanetwork.com/journals/jama/fullarticle/2763802.2 CHACCOUR AND OTHERS

Ivermectin is a widely used drug for the treatment and control of severalneglectedtropical diseases.1 Thedrughas anexcellent safety profile, with more than 2.5 billion doses distributed in the last 30 years, and its potential to reducemalaria transmission by killingmosquitoes is under evaluation in several trials around the world.2 Ivermectin inhibits the in vitro replicationof somepositive, single-stranded RNA viruses, namely, dengue virus (DNV),3–5 Zika virus,4,6 yellow fever virus,7,8 and others.4,7,9 Caly et al.10 recently reported that ivermectin is a potent inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro.Given the coronavirus disease- 19 (COVID-19) pandemic, this has understandably resonated widely in the global press.11
Caly et al.10 report a 5,000-fold reduction inSARS-CoV-2RNA levels, compared with those in controls, after infected Vero/ hSLAM cells were incubated for 48 hours with 5 µM ivermectin. The ivermectin IC50 for the viruswas calculated at approximately 2.5 µM. These concentrations are the equivalent of 4,370 and 2,190 ng/mL, respectively, notably 50- to 100-fold the peak concentration (Cmax) achieved in plasma after the single dose of 200 µg/kg (14mg in a 70-kg adult) commonly used for the control of onchocerchiasis.12 Pharmacokinetic studies in healthy volunteers have suggested that single doses up to 120 mg of ivermectin can be safe and well tolerated.13 However, even with this dose, which is 10-fold greater than those approved by the US..

Chaccour, C.

Hammann, F.

Ramon-Garcia, S.

Rabinovich, N.R.

Repositorio Universidad de Zaragoza

Am. J. Trop. Med. Hyg., 102(6), 2020, pp. 1156–1157doi:10.4269/ajtmh.20-0271Copyright © 2020 by The American Society of Tropical Medicine and HygieneEditorialIvermectin and COVID-19: Keeping Rigor in Times of UrgencyCarlos Chaccour,1,2,3* Felix Hammann,4 Santiago Ramón-Garcı́a,5,6 and N. Regina Rabinovich1,71ISGlobal, Hospital Clı́nic - Universitat de Barcelona, Barcelona, Spain; 2Ifakara Health Institute, Ifakara, United Republic of Tanzania; 3Facultad deMedicina,UniversidaddeNavarra,Pamplona,Spain; 4DepartmentofGeneral InternalMedicine,Clinical Pharmacology andToxicology, Inselspital,BernUniversityHospital, UniversityofBern,Bern,Switzerland; 5Research&DevelopmentAgencyofAragon (ARAID) Foundation, Zaragoza, Spain;6Department ofMicrobiology,Mycobacterial GeneticsGroup, PreventiveMedicine andPublicHealth, Faculty ofMedicine, University of Zaragoza,Zaragoza, Spain; 7Harvard T.H. Chan School of Public Health, Boston, MassachusettsIvermectin is a widely used drug for the treatment and controlof severalneglected tropicaldiseases.1Thedrughasanexcellentsafety profile, with more than 2.5 billion doses distributed in thelast 30 years, and its potential to reducemalaria transmission bykillingmosquitoes is under evaluation in several trials around theworld.2 Ivermectin inhibits the invitro replicationofsomepositive,single-stranded RNA viruses, namely, dengue virus (DNV),3–5Zika virus,4,6 yellow fever virus,7,8 and others.4,7,9Caly et al.10 recently reported that ivermectin is a potent in-hibitor of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) replication in vitro.Given thecoronavirusdisease-19 (COVID-19) pandemic, this has understandably resonatedwidely in the global press.11Caly et al.10 report a 5,000-fold reduction inSARS-CoV-2RNAlevels, compared with those in controls, after infected Vero/hSLAM cells were incubated for 48 hours with 5 μM ivermectin.The ivermectin IC50 for the viruswas calculated at approximately2.5 μM. These concentrations are the equivalent of 4,370 and2,190 ng/mL, respectively, notably 50- to 100-fold the peakconcentration (Cmax) achieved in plasma after the single dose of200μg/kg (14mg ina70-kgadult) commonlyused for thecontrolof onchocerchiasis.12 Pharmacokinetic studies in healthy vol-unteers have suggested that single doses up to 120 mg of iver-mectin can be safe andwell tolerated.13 However, even with thisdose, which is 10-fold greater than those approved by the USFood and Drug Administration, the Cmax values reported were∼250 ng/mL,13 one order of magnitude lower than effectivein vitro concentrations against SARS-CoV-2.These findings may seem to discourage follow-up clinicaltrials with ivermectin. However, some in vivo effect may bepossible even if efficacious in vitro concentrations are physi-ologically unattainable. A recent phase III clinical trial in den-gue patients in Thailand, in which a once-daily dose of 400μg/kg for 3 days was found to be safe but did not produce anyclinical benefit,14 showed a modest and indirect in vivo effectagainst DNV.14 Previous work by Wagstaff et al.5 reportedinhibition atmuchhigher in vitro concentrations (25μM) inDNV-infected Vero cells. Both pharmacokinetic considerations andthe relatively long incubation period of DNV might explain thelack of clinical efficacy. Until we have a better understanding ofivermectin’s antiviral mode of action and of appropriate in vitrosystems for testing, we caution against using findings in Verocells as more than a qualitative indicator of potential efficacy.Very recently, preliminary findings on a potential effect ofhydroxychloroquine combined with azithromycin againstSARS-CoV-2 were widely publicized,15 leading to a surge indemand and self-medication, which resulted in serious harmin some cases and a stock shortage that jeopardized drugavailability for other critical conditions for which hydroxy-chloroquine or chloroquine is the standard of care, that is, vivaxmalaria, rheumatoidarthritis, andsystemic lupuserythematosus.Efficacy claims for hydroxychloroquine against COVID-19 havebeen questioned in follow-up trials using similar dosingregimens,16,17 and we await results of randomized, con-trolled clinical trials exploring treatment efficacy.We believe the recent findings regarding ivermectin warrantrapidly implemented controlled clinical trials to assess its ef-ficacy against SARS-CoV-2. These trials may open a new fieldof research on the potential use of avermectin antiparasiticdrugs, including compounds with an improved pharmacoki-netic profile, as antivirals.18However, becauseof the followingpoints, extreme due diligence and regulatory review areneeded before testing ivermectin in severe disease.First, ivermectin, which targets glutamate-gated chlorinechannels in invertebrates, may cross-target the GABA-gatedchlorine channels present in the mammalian central nervoussystem (CNS) and cause neurotoxicity.19 This is normallyprevented by an intact blood–brain barrier (BBB), but in pa-tientswith a hyperinflammatory state, endothelial permeabilityat the BBB may be increased and cause leaking of drugs intothe CNS, potentially causing harm.20,21Second, boosted antiretrovirals such as lopinavir/ritonavirand darunavir/cobicistat, which have been widely used againstSARS-CoV-2based on limited evidence, and a number of otherdrugs, are potent inhibitors of cytochrome P450 3A4, the mainmetabolic pathway for ivermectin. Concurrent use of thesedrugs will result in increased systemic exposure to ivermectin.Furthermore, ritonavir and cobicistat can readily inhibit one ofthe main efflux pumps in the BBB, P-glycoprotein, further fa-voring neurotoxicity.22,23 However, it is encouraging that a re-cent analysis of ivermectin-related neurotoxic adverse eventsreported to theWHOProgram for International DrugMonitoringfound only one case of 1,668 reports in which concomitant useof antivirals was associated with neurotoxicity.24Third, as earlier, available evidence suggests that levels ofivermectin with meaningful activity against SARS-CoV-2would not be achieved without extraordinary, potentiallytoxic increases in ivermectin dosing levels in humans. How-ever, evidence from animal models showing up to 3-foldhigher levels in pulmonary tissue than in plasma 1 week afteroral dosing leaves the door open for further research, in par-ticular for the treatment of respiratory viruses.25,26The discovery of ivermectin’s activity against SARS-CoV-2gives reason for hope, but off-label and compassionate userequires careful risk–benefit considerations,27 especially in* Address correspondence to Carlos Chaccour, ISGlobal, HospitalClı́nic - Universitat deBarcelona, Rosello 132, 5a 2a, Barcelona 08036,Spain. E-mail: carlos.chaccour@isglobal.org1156critically ill patients. A path to consider is evaluation first ofimpacts on virologic outcomes in uncomplicated, low-riskpatients early in the course of the disease. Well-conductedclinical trials informed by robust pharmacokinetic modelsshould be considered to validate the impact before the use ofivermectin to treat SARS-CoV-2 is implemented.Received April 8, 2020. Accepted for publication April 10, 2020.Published online April 16, 2020.Authors’ addresses: Carlos Chaccour, ISGlobal, Hospital Clı́nic -Universitat de Barcelona, Barcelona, Spain, Ifakara Health Institute,Ifakara, United Republic of Tanzania, and Facultad de Medicina,Universidad de Navarra, Pamplona, Spain, E-mail: carlos.chaccour@isglobal.org. Felix Hammann, Department of General Internal Medi-cine, Clinical Pharmacology and Toxicology, Inselspital, Bern Uni-versity Hospital, University of Bern, Bern, Switzerland, E-mail:felix.hammann@insel.ch. Santiago Ramón-Garcı́a, Research & De-velopment Agency of Aragon (ARAID) Foundation, Spain and De-partment of Microbiology, Mycobacterial Genetics Group, PreventiveMedicine and Public Health, Faculty of Medicine, University of Zar-agoza, Spain, E-mail: santiramon@unizar.es. N. Regina Rabinovich,ISGlobal, Hospital Clı́nic - Universitat de Barcelona, Barcelona, Spainand Harvard T.H. Chan School of Public Health, Boston, MA, E-mail:rrabinov@hsph.harvard.edu.This is an open-access article distributed under the terms of theCreative Commons Attribution (CC-BY) License, which permits un-restricted use, distribution, and reproduction in anymedium, providedthe original author and source are credited.REFERENCES1. Omura S, Crump A, 2014. Ivermectin: panacea for resource-poorcommunities? Trends Parasitol 30: 445–455.2. The Ivermectin Roadmappers, 2020. A roadmap for the devel-opment of ivermectin as a complementary malaria vectorcontrol tool. Am J Trop Med Hyg 102: 3–24.3. Tay MY, Fraser JE, ChanWK, Moreland NJ, Rathore AP, Wang CVasudevan SG, Jans DA, 2013. Nuclear localization of denguevirus (DENV) 1-4 non-structural protein 5; protection against all4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res 99:301–306.4. Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, BorgNA, Jans DA, 2020. The broad spectrum antiviral ivermectintargets the host nuclear transport importin alpha/beta1 heter-odimer. Antiviral Res 177: 104760.5. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA,2012. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 anddengue virus. Biochem J 443: 851–856.6. Barrows NJ et al., 2016. A screen of FDA-approved drugs forinhibitorsof Zika virus infection.CellHostMicrobe20:259–270.7. Varghese FS, Kaukinen P, Glasker S, Bespalov M, Hanski L,Wennerberg K Kümmerer BM, Ahola T 2016. Discovery ofberberine, abamectin and ivermectin as antivirals against chi-kungunya and other alphaviruses. Antiviral Res 126: 117–124.8. Mastrangelo E et al., 2012. Ivermectin is a potent inhibitor of fla-vivirus replication specifically targeting NS3 helicase activity:new prospects for an old drug. J Antimicrob Chemother 67:1884–1894.9. Lee YJ, Lee C, 2016. Ivermectin inhibits porcine reproductive andrespiratory syndrome virus in cultured porcine alveolar mac-rophages. Arch Virol 161: 257–268.10. Caly L, Druce J, Catton M, Jans D, KM W, 2020. The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2in vitro.Antiviral Res. Available at: https://www.sciencedirect.com/science/article/pii/S0166354220302011.11. Slisco A, 2020. Anti-parasite Drug Used since 1980s May HelpStop Coronavirus, New Study Says. Newsweek. April, 04.Available at: https://www.newsweek.com/anti-parasite-drug-used-since-1980s-may-help-stop-coronavirus-new-study-says-1496083. Accessed April 5, 2020.12. Chaccour C, Hammann F, Rabinovich NR, 2017. Ivermectin toreduce malaria transmission I. Pharmacokinetic and pharma-codynamic considerations regarding efficacy and safety.MalarJ 16: 161.13. GuzzoCA, FurtekCI, PorrasAG,ChenC, TippingR, ClineschmidtCM, Sciberras DG, Hsieh JY, Lasseter KC, 2002. Safety, tol-erability, and pharmacokinetics of escalating high doses ofivermectin in healthy adult subjects. J Clin Pharmacol 42:1122–1133.14. YamasmithEet al., 2018.EfficacyandSafety of Ivermectin againstDengue Infection: A Phase III, Randomized, Double-blind,Placebo-controlled Trial. He 34th Annual Meeting the RoyalCollege of Physicians of Thailand- ‘Internal Medicine and OneHealth’: Chonburi, Thailand. Registry. Available at: https://clinicaltrials.gov/ct2/show/NCT02045069. Accessed Aplri 5,2020.15. Gautret P et al., 2020. Hydroxychloroquine and azithromycinas a treatment of COVID-19: results of an open-labelnon-randomized clinical trial. Int J Antimicrob Agents. Avail-able at: https://www.sciencedirect.com/science/article/pii/S0924857920300996.16. Song S, Zhang D, Qian Z, Li T, Shen Y, Hongzh L, 2020. A PilotStudy of Hydroxychloroquine in Treatment of Patients withCommon Coronavirus Disease-19 (COVID-19). Available at:http://subject.med.wanfangdata.com.cn/UpLoad/Files/202003/43f8625d4dc74e42bbcf24795de1c77c.pdf. Accessed April 5,2020. Journal of Zhejiang University, 3.17. Molina JM, Delaugerre C, Goff JL, Mela-Lima B, Ponscarme D,Goldwirt L, de Castro N, 2020 No evidence of rapid antiviralclearance or clinical benefit with the combination of hydroxy-chloroquineandazithromycin in patientswith severeCOVID-19infection.Méd Mal Infect 9: S0399-077X(20)30085-8.18. Scherr N, Pluschke G, Thompson CJ, Ramon-Garcia S, 2015.Selamectin is the avermectin with the best potential for buruliulcer treatment. PLoS Negl Trop Dis 9: e0003996.19. Menez C, Sutra JF, Prichard R, Lespine A, 2012. Relative neuro-toxicity of ivermectin and moxidectin in Mdr1ab (-/-) mice andeffects on mammalian GABA(A) channel activity. PLoS NeglTrop Dis 6: e1883.20. Varatharaj A, Galea I, 2017. The blood-brain barrier in systemicinflammation. Brain Behav Immun 60: 1–12.21. Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B,2020. COVID-19–associated acute hemorrhagic necrotizingencephalopathy: CT andMRI features.Radiology. Available at:https://pubs.rsna.org/doi/pdf/10.1148/radiol.2020201187.22. Lepist EI, Phan TK, Roy A, Tong L, Maclennan K, Murray B, RayAS, 2012. Cobicistat boosts the intestinal absorption of trans-port substrates, includingHIVprotease inhibitorsandGS-7340,in vitro. Antimicrob Agents Chemother 56: 5409–5413.23. Drewe J, GutmannH, Fricker G, TorokM, Beglinger C, Huwyler J,1999. HIV protease inhibitor ritonavir: a more potent inhibitor ofP-glycoprotein than the cyclosporine analog SDZ PSC 833.Biochem Pharmacol 57: 1147–1152.24. Chandler RE, 2018. Serious neurological adverse events afterivermectin-do they occur beyond the indication of onchocer-ciasis? Am J Trop Med Hyg 98: 382–388.25. LespineA,AlvinerieM,Sutra JF,Pors I, ChartierC, 2005. Influenceof the route of administration on efficacy and tissue distributionof ivermectin in goat. Vet Parasitol 128: 251–260.26. Chiu SH, Lu AY, 1989.Metabolism and tissue residues. CampbellWC, ed. Ivermectin and Abamectin. New York, NY: Springer-Verlag, 131–143.27. Kalil AC, 2020. Treating COVID-19-off-label drug use, compas-sionate use, and randomized clinical trials during pandemics.JAMA. Available at: https://jamanetwork.com/journals/jama/fullarticle/2763802.IVERMECTIN AND COVID-19: KEEPING RIGOR IN TIMES OF URGENCY 1157

Ivermectin and COVID-19: Keeping Rigor in Times of Urgency

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Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in Times of Urgency.

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