Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats

DOI record: { "DOI": "10.1038/s41598-020-74084-y", "ISSN": [ "2045-2322" ], "URL": "http://dx.doi.org/10.1038/s41598-020-74084-y", "abstract": "<jats:title>Abstract</jats:title><jats:p>Ivermectin is a widely used antiparasitic drug with known efficacy against several single-strain RNA viruses. Recent data shows significant reduction of SARS-CoV-2 replication in vitro by ivermectin concentrations not achievable with safe doses orally. Inhaled therapy has been used with success for other antiparasitics. An ethanol-based ivermectin formulation was administered once to 14 rats using a nebulizer capable of delivering particles with alveolar deposition. Rats were randomly assigned into three target dosing groups, lower dose (80–90 mg/kg), higher dose (110–140 mg/kg) or ethanol vehicle only. A toxicology profile including behavioral and weight monitoring, full blood count, biochemistry, necropsy and histological examination of the lungs was conducted. The pharmacokinetic profile of ivermectin in plasma and lungs was determined in all animals. There were no relevant changes in behavior or body weight. There was a delayed elevation in muscle enzymes compatible with rhabdomyolysis, that was also seen in the control group and has been attributed to the ethanol dose which was up to 11 g/kg in some animals. There were no histological anomalies in the lungs of any rat. Male animals received a higher ivermectin dose adjusted by adipose weight and reached higher plasma concentrations than females in the same dosing group (mean C<jats:sub>max</jats:sub> 86.2 ng/ml vs. 26.2 ng/ml in the lower dose group and 152 ng/ml vs. 51.8 ng/ml in the higher dose group). All subjects had detectable ivermectin concentrations in the lungs at seven days post intervention, up to 524.3 ng/g for high-dose male and 27.3 ng/g for low-dose females. nebulized ivermectin can reach pharmacodynamic concentrations in the lung tissue of rats, additional experiments are required to assess the safety of this formulation in larger animals.</jats:p>", "alternative-id": [ "74084" ], "article-number": "17073", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "13 July 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "25 September 2020" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "13 October 2020" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "The authors declare no competing interests." } ], "author": [ { "affiliation": [], "family": "Chaccour", "given": "Carlos", "sequence": "first" }, { "affiliation": [], "family": "Abizanda", "given": "Gloria", "sequence": "additional" }, { "affiliation": [], "family": "Irigoyen-Barrio", "given": "Ángel", "sequence": "additional" }, { "affiliation": [], "family": "Casellas", "given": "Aina", "sequence": "additional" }, { "affiliation": [], "family": "Aldaz", "given": "Azucena", "sequence": "additional" }, { "affiliation": [], "family": "Martínez-Galán", "given": "Fernando", "sequence": "additional" }, { "affiliation": [], "family": "Hammann", "given": "Felix", "sequence": "additional" }, { "affiliation": [], "family": "Gil", "given": "Ana Gloria", "sequence": "additional" } ], "container-title": "Scientific Reports", "container-title-short": "Sci Rep", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2020, 10, 13 ] ], "date-time": "2020-10-13T10:05:00Z", "timestamp": 1602583500000 }, "deposited": { "date-parts": [ [ 2022, 12, 6 ] ], "date-time": "2022-12-06T21:17:19Z", "timestamp": 1670361439000 }, "funder": [ { "DOI": "10.13039/501100004435", "doi-asserted-by": "publisher", "name": "Universidad de Navarra" } ], "indexed": { "date-parts": [ [ 2024, 4, 15 ] ], "date-time": "2024-04-15T23:13:53Z", "timestamp": 1713222833183 }, "is-referenced-by-count": 29, "issue": "1", "issued": { "date-parts": [ [ 2020, 10, 13 ] ] }, "journal-issue": { "issue": "1", "published-online": { "date-parts": [ [ 2020, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 10, 13 ] ], "date-time": "2020-10-13T00:00:00Z", "timestamp": 1602547200000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2020, 10, 13 ] ], "date-time": "2020-10-13T00:00:00Z", "timestamp": 1602547200000 } } ], "link": [ { "URL": "https://www.nature.com/articles/s41598-020-74084-y.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41598-020-74084-y", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41598-020-74084-y.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1038", "published": { "date-parts": [ [ 2020, 10, 13 ] ] }, "published-online": { "date-parts": [ [ 2020, 10, 13 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "DOI": "10.7326/ACPJ202006160-063", "author": "P Yang", "doi-asserted-by": "publisher", "first-page": "JC63", "journal-title": "Ann. Intern. Med.", "key": "74084_CR1", "unstructured": "Yang, P., Tekwani, S. & Martin, G. S. In COVID-19, adding lopinavir-ritonavir to usual care did not shorten time to clinical improvement. Ann. Intern. Med. 172, JC63. https://doi.org/10.7326/ACPJ202006160-063 (2020).", "volume": "172", "year": "2020" }, { "DOI": "10.1056/NEJMoa2016638", "author": "DR Boulware", "doi-asserted-by": "publisher", "journal-title": "N. Engl. J. Med.", "key": "74084_CR2", "unstructured": "Boulware, D. R. et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for covid-19. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2016638 (2020).", "year": "2020" }, { "DOI": "10.1001/jamanetworkopen.2020.8857", "author": "MGS Borba", "doi-asserted-by": "publisher", "first-page": "e208857", "journal-title": "JAMA Netw. Open", "key": "74084_CR3", "unstructured": "Borba, M. G. S. et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw. Open 3, e208857. https://doi.org/10.1001/jamanetworkopen.2020.8857 (2020).", "volume": "3", "year": "2020" }, { "DOI": "10.1056/NEJMoa2007764", "author": "JH Beigel", "doi-asserted-by": "publisher", "journal-title": "N. Engl. J. Med.", "key": "74084_CR4", "unstructured": "Beigel, J. H. et al. Remdesivir for the treatment of covid-19—preliminary report. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2007764 (2020).", "year": "2020" }, { "DOI": "10.1101/2020.06.22.20137273", "author": "P Horby", "doi-asserted-by": "publisher", "journal-title": "medRxiv", "key": "74084_CR5", "unstructured": "Horby, P. et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv https://doi.org/10.1101/2020.06.22.20137273 (2020).", "year": "2020" }, { "DOI": "10.1042/BJ20120150", "author": "KM Wagstaff", "doi-asserted-by": "publisher", "first-page": "851", "journal-title": "Biochem. J.", "key": "74084_CR6", "unstructured": "Wagstaff, K. M., Sivakumaran, H., Heaton, S. M., Harrich, D. & Jans, D. A. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J. 443, 851–856. https://doi.org/10.1042/BJ20120150 (2012).", "volume": "443", "year": "2012" }, { "DOI": "10.1016/j.chom.2016.07.004", "author": "NJ Barrows", "doi-asserted-by": "publisher", "first-page": "259", "journal-title": "Cell Host Microbe", "key": "74084_CR7", "unstructured": "Barrows, N. J. et al. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe 20, 259–270. https://doi.org/10.1016/j.chom.2016.07.004 (2016).", "volume": "20", "year": "2016" }, { "DOI": "10.1093/jac/dks147", "author": "E Mastrangelo", "doi-asserted-by": "publisher", "first-page": "1884", "journal-title": "J. Antimicrob. Chemother.", "key": "74084_CR8", "unstructured": "Mastrangelo, E. et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J. Antimicrob. Chemother. 67, 1884–1894. https://doi.org/10.1093/jac/dks147 (2012).", "volume": "67", "year": "2012" }, { "DOI": "10.1016/j.antiviral.2020.104760", "author": "SNY Yang", "doi-asserted-by": "publisher", "journal-title": "Antiviral Res.", "key": "74084_CR9", "unstructured": "Yang, S. N. Y. et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antiviral Res. https://doi.org/10.1016/j.antiviral.2020.104760 (2020).", "year": "2020" }, { "DOI": "10.1016/j.antiviral.2020.104787", "author": "L Caly", "doi-asserted-by": "publisher", "journal-title": "Antivir. Res.", "key": "74084_CR10", "unstructured": "Caly, L., Druce, J., Catton, M., Jans, D. & Wagstaff, K. M. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir. Res. https://doi.org/10.1016/j.antiviral.2020.104787 (2020) (in Press, Journal Pre-proof).", "year": "2020" }, { "DOI": "10.4269/ajtmh.20-0271", "author": "C Chaccour", "doi-asserted-by": "publisher", "journal-title": "Am. J. Trop. Med. Hyg.", "key": "74084_CR11", "unstructured": "Chaccour, C., Hammann, F., Ramon-Garcia, S. & Rabinovich, N. R. Ivermectin and novel coronavirus disease (COVID-19): keeping rigor in times of urgency. Am. J. Trop. Med. Hyg. https://doi.org/10.4269/ajtmh.20-0271 (2020).", "year": "2020" }, { "DOI": "10.1007/s00011-008-8007-8", "author": "X Zhang", "doi-asserted-by": "publisher", "first-page": "524", "journal-title": "Inflamm. Res.", "key": "74084_CR12", "unstructured": "Zhang, X. et al. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm. Res. 57, 524–529. https://doi.org/10.1007/s00011-008-8007-8 (2008).", "volume": "57", "year": "2008" }, { "DOI": "10.1111/j.1472-8206.2009.00684.x", "author": "X Ci", "doi-asserted-by": "publisher", "first-page": "449", "journal-title": "Fundam. Clin. Pharmacol.", "key": "74084_CR13", "unstructured": "Ci, X. et al. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam. Clin. Pharmacol. 23, 449–455. https://doi.org/10.1111/j.1472-8206.2009.00684.x (2009).", "volume": "23", "year": "2009" }, { "DOI": "10.5802/crbiol.8", "author": "J Changeux", "doi-asserted-by": "publisher", "journal-title": "C. R. Biol.", "key": "74084_CR14", "unstructured": "Changeux, J., Amoura, Z., Rey, F. & Miyara, M. A nicotinic hypothesis for Covid-19 with preventive and therapeutic implications. C. R. Biol. https://doi.org/10.5802/crbiol.8 (2020).", "year": "2020" }, { "DOI": "10.1183/13993003.01116-2020", "author": "P Russo", "doi-asserted-by": "publisher", "first-page": "2001116", "journal-title": "Eur. Respir. J.", "key": "74084_CR15", "unstructured": "Russo, P. et al. COVID-19 and smoking: is nicotine the hidden link?. Eur. Respir. J. 55, 2001116. https://doi.org/10.1183/13993003.01116-2020 (2020).", "volume": "55", "year": "2020" }, { "DOI": "10.1124/mol.53.2.283", "author": "RM Krause", "doi-asserted-by": "publisher", "first-page": "283", "journal-title": "Mol. Pharmacol.", "key": "74084_CR16", "unstructured": "Krause, R. M. et al. Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53, 283–294. https://doi.org/10.1124/mol.53.2.283 (1998).", "volume": "53", "year": "1998" }, { "DOI": "10.1016/s0140-6736(87)91794-6", "author": "AB Montgomery", "doi-asserted-by": "publisher", "first-page": "480", "journal-title": "Lancet", "key": "74084_CR17", "unstructured": "Montgomery, A. B. et al. Aerosolised pentamidine as sole therapy for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet 2, 480–483. https://doi.org/10.1016/s0140-6736(87)91794-6 (1987).", "volume": "2", "year": "1987" }, { "DOI": "10.1378/chest.110.1.141", "author": "RA McIvor", "doi-asserted-by": "publisher", "first-page": "141", "journal-title": "Chest", "key": "74084_CR18", "unstructured": "McIvor, R. A., Berger, P., Pack, L. L., Rachlis, A. & Chan, C. K. An effectiveness community-based clinical trial of Respirgard II and Fisoneb nebulizers for Pneumocystis carinii prophylaxis with aerosol pentamidine in HIV-infected individuals. Toronto Aerosol Pentamidine Study (TAPS) Group. Chest 110, 141–146. https://doi.org/10.1378/chest.110.1.141 (1996).", "volume": "110", "year": "1996" }, { "author": "JI Lei", "first-page": "70", "journal-title": "Chin. J. Comp. Med.", "key": "74084_CR19", "unstructured": "Lei, J. I. et al. Study on the subacute inhalation toxicity of Ivermectin TC in rats. Chin. J. Comp. Med. 26, 70–74 (2016).", "volume": "26", "year": "2016" }, { "DOI": "10.1016/j.actatropica.2013.03.019", "author": "MM Homeida", "doi-asserted-by": "publisher", "first-page": "97", "journal-title": "Acta Trop.", "key": "74084_CR20", "unstructured": "Homeida, M. M. et al. The lack of influence of food and local alcoholic brew on the blood level of Mectizan((R)) (ivermectin). Acta Trop. 127, 97–100. https://doi.org/10.1016/j.actatropica.2013.03.019 (2013).", "volume": "127", "year": "2013" }, { "key": "74084_CR21", "unstructured": "FDA. Center for drug evaluation and research. Approval package for Mectizan. https://www.accessdata.fda.gov/drugsatfda_docs/nda/96/050742ap.pdf. Accessed July 2016." }, { "DOI": "10.1002/cpph.43", "author": "JR Mathiasen", "doi-asserted-by": "publisher", "first-page": "e43", "journal-title": "Curr. Protoc. Pharmacol.", "key": "74084_CR22", "unstructured": "Mathiasen, J. R. & Moser, V. C. The Irwin test and functional observational battery (FOB) for assessing the effects of compounds on behavior, physiology, and safety pharmacology in rodents. Curr. Protoc. Pharmacol. 83, e43. https://doi.org/10.1002/cpph.43 (2018).", "volume": "83", "year": "2018" }, { "DOI": "10.1016/j.fct.2010.05.043", "author": "G Eraslan", "doi-asserted-by": "publisher", "first-page": "2181", "journal-title": "Food Chem. Toxicol.", "key": "74084_CR23", "unstructured": "Eraslan, G. et al. Comparative pharmacokinetics of some injectable preparations containing ivermectin in dogs. Food Chem. Toxicol. 48, 2181–2185. https://doi.org/10.1016/j.fct.2010.05.043 (2010).", "volume": "48", "year": "2010" }, { "DOI": "10.1016/s0304-4017(99)00175-2", "author": "A Lifschitz", "doi-asserted-by": "publisher", "first-page": "327", "journal-title": "Vet. Parasitol.", "key": "74084_CR24", "unstructured": "Lifschitz, A. et al. Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle. Vet. Parasitol. 87, 327–338. https://doi.org/10.1016/s0304-4017(99)00175-2 (2000).", "volume": "87", "year": "2000" }, { "DOI": "10.1007/s002280050131", "author": "OZ Baraka", "doi-asserted-by": "publisher", "first-page": "407", "journal-title": "Eur. J. Clin. Pharmacol.", "key": "74084_CR25", "unstructured": "Baraka, O. Z. et al. Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus. Eur. J. Clin. Pharmacol. 50, 407–410 (1996).", "volume": "50", "year": "1996" }, { "DOI": "10.1093/cid/ciu797", "author": "AL Ouedraogo", "doi-asserted-by": "publisher", "first-page": "357", "journal-title": "Clin. Infect. Dis.", "key": "74084_CR26", "unstructured": "Ouedraogo, A. L. et al. Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial. Clin. Infect. Dis. 60, 357–365. https://doi.org/10.1093/cid/ciu797 (2015).", "volume": "60", "year": "2015" }, { "DOI": "10.1093/jn/116.12.2525", "author": "CL Ferrell", "doi-asserted-by": "publisher", "first-page": "2525", "journal-title": "J. Nutr.", "key": "74084_CR27", "unstructured": "Ferrell, C. L. & Koong, K. J. Influence of plane of nutrition on body composition, organ size and energy utilization of Sprague-Dawley rats. J. Nutr. 116, 2525–2535. https://doi.org/10.1093/jn/116.12.2525 (1986).", "volume": "116", "year": "1986" }, { "DOI": "10.1016/0360-3016(89)90494-x", "author": "E El-Khatib", "doi-asserted-by": "publisher", "first-page": "745", "journal-title": "Int. J. Radiat. Oncol. Biol. Phys.", "key": "74084_CR28", "unstructured": "El-Khatib, E. & Lehnert, S. Lung density changes observed in vivo in rat lungs after irradiation: variations among and within individual lungs. Int. J. Radiat. Oncol. Biol. Phys. 16, 745–754. https://doi.org/10.1016/0360-3016(89)90494-x (1989).", "volume": "16", "year": "1989" }, { "DOI": "10.1016/0041-008x(70)90077-3", "author": "GS Wiberg", "doi-asserted-by": "publisher", "first-page": "718", "journal-title": "Toxicol. Appl. Pharmacol.", "key": "74084_CR29", "unstructured": "Wiberg, G. S., Trenholm, H. L. & Coldwell, B. B. Increased ethanol toxicity in old rats: changes in LD50, in vivo and in vitro metabolism, and liver alcohol dehydrogenase activity. Toxicol. Appl. Pharmacol. 16, 718–727. https://doi.org/10.1016/0041-008x(70)90077-3 (1970).", "volume": "16", "year": "1970" }, { "DOI": "10.1016/S0009-9236(03)90702-8", "author": "SR Vanapalli", "doi-asserted-by": "publisher", "first-page": "P94", "journal-title": "Clin. Pharmacol. Ther.", "key": "74084_CR30", "unstructured": "Vanapalli, S. R. et al. Orange juice decreases the oral bioavailability of ivermectin in healthy volunteers. Clin. Pharmacol. Ther. 73, P94–P94. https://doi.org/10.1016/S0009-9236(03)90702-8 (2003).", "volume": "73", "year": "2003" }, { "DOI": "10.1002/ccr3.326", "author": "SS Papadatos", "doi-asserted-by": "publisher", "first-page": "769", "journal-title": "Clin. Case Rep.", "key": "74084_CR31", "unstructured": "Papadatos, S. S. et al. Nontraumatic rhabdomyolysis with short-term alcohol intoxication—a case report. Clin. Case Rep. 3, 769–772. https://doi.org/10.1002/ccr3.326 (2015).", "volume": "3", "year": "2015" }, { "DOI": "10.1007/BF03012146", "author": "T Nishiyama", "doi-asserted-by": "publisher", "first-page": "753", "journal-title": "Can. J. Anaesth.", "key": "74084_CR32", "unstructured": "Nishiyama, T., Yokoyama, T. & Hanaoka, K. Liver function after sevoflurane or isoflurane anaesthesia in neurosurgical patients. Can. J. Anaesth. 45, 753–756. https://doi.org/10.1007/BF03012146 (1998).", "volume": "45", "year": "1998" }, { "author": "AG Gil", "first-page": "25", "journal-title": "Contemp. Top. Lab. Anim. Sci.", "key": "74084_CR33", "unstructured": "Gil, A. G., Silvan, G., Illera, M. & Illera, J. C. The effects of anesthesia on the clinical chemistry of New Zealand White rabbits. Contemp. Top. Lab. Anim. Sci. 43, 25–29 (2004).", "volume": "43", "year": "2004" }, { "DOI": "10.1111/acer.13291", "author": "RR MacLean", "doi-asserted-by": "publisher", "first-page": "238", "journal-title": "Alcohol Clin. Exp. Res.", "key": "74084_CR34", "unstructured": "MacLean, R. R., Valentine, G. W., Jatlow, P. I. & Sofuoglu, M. Inhalation of alcohol vapor: measurement and implications. Alcohol Clin. Exp. Res. 41, 238–250. https://doi.org/10.1111/acer.13291 (2017).", "volume": "41", "year": "2017" }, { "DOI": "10.1016/j.pt.2017.12.007", "author": "C Schwartz", "doi-asserted-by": "publisher", "first-page": "388", "journal-title": "Trends Parasitol.", "key": "74084_CR35", "unstructured": "Schwartz, C., Hams, E. & Fallon, P. G. Helminth modulation of lung inflammation. Trends Parasitol. 34, 388–403. https://doi.org/10.1016/j.pt.2017.12.007 (2018).", "volume": "34", "year": "2018" }, { "DOI": "10.1016/j.pt.2010.11.008", "author": "IA Sutherland", "doi-asserted-by": "publisher", "first-page": "176", "journal-title": "Trends Parasitol", "key": "74084_CR36", "unstructured": "Sutherland, I. A. & Leathwick, D. M. Anthelmintic resistance in nematode parasites of cattle: a global issue?. Trends Parasitol 27, 176–181. https://doi.org/10.1016/j.pt.2010.11.008 (2011).", "volume": "27", "year": "2011" }, { "DOI": "10.1056/NEJMc1210168#SA2", "author": "CJ Chaccour", "doi-asserted-by": "publisher", "first-page": "1670", "journal-title": "N. Engl. J. Med.", "key": "74084_CR37", "unstructured": "Chaccour, C. J. & Del Pozo, J. L. Case 23–2012: a man with abdominal pain and weight loss. N. Engl. J. Med. 367, 1670–1671. https://doi.org/10.1056/NEJMc1210168#SA2 (2012).", "volume": "367", "year": "2012" }, { "DOI": "10.1007/s00134-005-2725-y", "author": "JI Salluh", "doi-asserted-by": "publisher", "first-page": "1292", "journal-title": "Intensive Care Med.", "key": "74084_CR38", "unstructured": "Salluh, J. I. et al. Successful use of parenteral ivermectin in an immunosuppressed patient with disseminated strongyloidiasis and septic shock. Intensive Care Med. 31, 1292 (2005).", "volume": "31", "year": "2005" }, { "DOI": "10.4269/ajtmh.2005.73.122", "author": "J Pacanowski", "doi-asserted-by": "publisher", "first-page": "122", "journal-title": "Am. J. Trop. Med. Hyg.", "key": "74084_CR39", "unstructured": "Pacanowski, J. et al. Subcutaneous ivermectin as a safe salvage therapy in Strongyloides stercoralis hyperinfection syndrome: a case report. Am. J. Trop. Med. Hyg. 73, 122–124 (2005).", "volume": "73", "year": "2005" }, { "DOI": "10.1111/j.1472-8206.2010.00896.x", "author": "X Zhang", "doi-asserted-by": "publisher", "first-page": "700", "journal-title": "Fundam. Clin. Pharmacol.", "key": "74084_CR40", "unstructured": "Zhang, X. et al. Protective effect of abamectin on acute lung injury induced by lipopolysaccharide in mice. Fundam. Clin. Pharmacol. 25, 700–707. https://doi.org/10.1111/j.1472-8206.2010.00896.x (2011).", "volume": "25", "year": "2011" }, { "DOI": "10.15252/emmm.201404084", "author": "A Melotti", "doi-asserted-by": "publisher", "first-page": "1263", "journal-title": "EMBO Mol. Med.", "key": "74084_CR41", "unstructured": "Melotti, A. et al. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol. Med. 6, 1263–1278. https://doi.org/10.15252/emmm.201404084 (2014).", "volume": "6", "year": "2014" } ], "reference-count": 41, "references-count": 41, "relation": { "has-preprint": [ { "asserted-by": "object", "id": "10.21203/rs.3.rs-64501/v2", "id-type": "doi" }, { "asserted-by": "object", "id": "10.21203/rs.3.rs-64501/v1", "id-type": "doi" } ] }, "resource": { "primary": { "URL": "https://www.nature.com/articles/s41598-020-74084-y" } }, "score": 1, "short-title": [], "source": "Crossref", "subject": [], "subtitle": [], "title": "Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats", "type": "journal-article", "update-policy": "http://dx.doi.org/10.1007/springer_crossmark_policy", "volume": "10" }