Evaluation of the effectiveness and safety of adding ivermectin to treatment in severe COVID-19 patients
Nurullah Okumuş, Neşe Demirtürk, Rıza Aytaç Çetinkaya, Rahmet Güner, İsmail Yaşar Avcı, Semiha Orhan, Petek Konya, Bengü Şaylan, Ayşegül Karalezli, Levent Yamanel, Bircan Kayaaslan, Gülden Yılmaz, Ümit Savaşçı, Fatma Eser, Gürhan Taşkın
BMC Infectious Diseases, doi:10.1186/s12879-021-06104-9
Background and objectives: An effective treatment option is not yet available for SARS-CoV2, which causes the COVID-19 pandemic and whose effects are felt more and more every day. Ivermectin is among the drugs whose effectiveness in treatment has been investigated. In this study; it was aimed to investigate the presence of gene mutations that alter ivermectin metabolism and cause toxic effects in patients with severe COVID-19 pneumonia, and to evaluate the effectiveness and safety of ivermectin use in the treatment of patients without mutation. Materials and methods: Patients with severe COVID19 pneumonia were included in the study, which was planned as a prospective, randomized, controlled, single-blind phase 3 study. Two groups, the study group and the control group, took part in the study. Ivermectin 200 mcg/kg/day for 5 days in the form of a solution prepared for enteral use added to the reference treatment protocol -hydroxychloroquine + favipiravir + azithromycin-of patients included in the study group. Patients in the control group were given only reference treatment with 3 other drugs without ivermectin. The presence of mutations was investigated by performing sequence analysis in the mdr1/ abcab1 gene with the Sanger method in patients included in the study group according to randomization. Patients with mutations were excluded from the study and ivermectin treatment was not continued. Patients were followed for 5 days after treatment. At the end of the treatment and follow-up period, clinical response and changes in laboratory parameters were evaluated.
Supplementary Information The online version contains supplementary material available at https://doi. org/10.1186/s12879-021-06104-9. Additional file 1: Supplementary Table 1 . Laboratory parameter changes.
Declarations Ethics approval and consent to participate Ethics board approval (Afyonkarahisar Health Science University, Local Ethical Commitee 03.04.2020/139). All participants provided informed consent prior to study enrollment.
Consent for publication Not applicable.
Competing interests The authors declare that they have neither financial nor non-financial competing interests.
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Beigel, Tomashek, Dodd, Mehta, Zingman et al., Remdesivir for the treatment of Covid-19. Final report, N Engl J Med,
doi:10.1056/NEJMoa2007764Bhatraju, Ghassemieh, Nichols, Covid-19 in critically ill patients in the Seattle Region-Case Series, NEJM
Cao, Wang, Wen, Liu, Wang et al., A trial of lopinavirritonavir in adults in hospitalized with severe Covid-19, NEJM,
doi:10.1056/NEJMoa2001282Capra, Rossi, Mattioli, Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia, Eur J Intern Med,
doi:10.1016/j.ejim.2020.05.009Chandler, Serious neurological adverse events after Ivermectin-do they occur beyond the indication of Onchocerciasis?, Am J Trop Med Hyg,
doi:10.4269/ajtmh.17-0042Choudhary, Sharma, Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance, New Microbes New Infect,
doi:10.1016/j.nmni.2020.100684Croci, Bottaro, Chan, Watanabe, Pezzullo et al., Liposomal systems as Nanocarriers for the antiviral agent Ivermectin, Int J Biomater,
doi:10.1155/2016/8043983Fei, Tong, Tao, Wang, Zhonghua et al., Value of neutrophil-to-lymphocyte ratio in the classification diagnosis of coronavirus disease, Bing Ji Jiu Xue
Gall, Klafke, Torres, Detoxification mechanisms involved in ivermectin resistance in the cattle tick , Rhipicephalus (Boophilus) microplus, Sci Rep,
doi:10.1038/s41598-018-30907-7Heidary, Gharebaghi, Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen, J Antibiot,
doi:10.1038/s41429-020-0336-zHenry, De Oliveira, Benoit, Plebani, Lippi, Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a metaanalysis, Clin Chem Lab Med,
doi:10.1515/cclm-2020-0369Ivashchenko, Dimitriev, Vostokova, AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial, Clin Infect Dis,
doi:10.1093/cid/ciaa1176Liu, Liu, Wang, Du, Ma et al., Clinical course and characteristics of patients with coronavirus disease 2019 in Wuhan, China: a single-centered, retrospective, observational study, Aging,
doi:10.18632/aging.103745Liu, Liu, Xiang, Pu, Xiong et al., Neutrophil to lymphocyte ratio predicts critical illnes patients with 2019 coronavirus disease in the early stage, J Transl Med,
doi:10.1186/s12967-020-02374-0Mastrangelo, Pezzullo, Burghgraeve, Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase aactivity: new prospects for an old drug, J Antimicrob Chemother,
doi:10.1093/jac/dks147Meo, Alhowikan, Al-Khlaiwi, Novel coronavirus 2019-nCoV: prevalence, biological and clinical characteristics comparison with SARS-CoV and MERS-CoV, Eur Rev Med Pharmacol Sci,
doi:10.26355/eurrev_202002_20379Mishra, Sahu, Lal, Reporting of all cardiac medications and their outcome in COVID-19, J Med Virol,
doi:10.1002/jmv.25843Rajter, Sherman, Fatteh, Vogel, Sacks et al., ICON (ivermectin in COvid nineteen) study: use of ivermectin is associated with lower mortality in hospitalized patients with COVID19, medRxiv,
doi:10.1101/2020.06.06.20124461Sun, Qie, Liu, Ren, Li et al., Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: a single arm meta-analysis, J MedVirol
Wenjing, Chen, Li, Dynamic changes of D-dimer and neutrophillymphocyte countr atio as prognostic biomarkers in COVID-19, Respir Res
Winck, Ambrosino, COVID-19 pandemic and noninvasive respiratory management: every goliath needs a David: an evidence based evaluation of problems, Pulmonology,
doi:10.1016/j.pulmoe.2020.04.013Xu, Yang, Yang, Zou, Wang et al., Clinical course and predictors of 60-day mortality in 239 critically ill patients with COVID-19: a multicenter retrospective study from Wuhan, China, Crit Care,
doi:10.1186/s13054-020-03098-9Yang, Yu, Xu, Shu, Xia et al., Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study, Lancet Respir Med,
doi:10.1016/S2213-2600(20)30079-5Yang, Zheng, Gou, Pu, Chen et al., Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis, Int J Infect Dis,
doi:10.1016/j.ijid.2020.03.017Zhang, Li, Zhou, The analysis of clinical characteristics of 34 novel coronovirus pneumonia cases in Ningxia Huiautonomous region, ZhonghuaLie He He Hu XizaZhi
