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Ivermectin: an award-winning drug with expected antiviral activity against COVID-19
伊维菌素：一种屡获殊荣的药物，具有预期的针对 COVID-19 的抗病毒活性

J Control Release. 2020 Oct 7;329:758–761. doi: 10.1016/j.jconrel.2020.10.009 J 控制释放。 2020 年 10 月 7 日；329:758–761。 doi：10.1016/j.jconrel.2020.10.009

https://pmc.ncbi.nlm.nih.gov/articles/PMC7539925/

1. Commentary
The 2015 Nobel Prize in Physiology and Medicine was awarded to William C. Campbell and Satoshi Ömura for their discoveries leading to ivermectin [1]. In addition to its extraordinary efficacy against parasitic diseases, ivermectin continues to offer new clinical applications due to its ability to be repurposed to treat new classes of diseases. Beyond its invaluable therapeutic role in onchocerciasis and strongyloidiasis, an increasing body of evidence points to the potential of ivermectin as an antiviral agent.
Ivermectin treatment was shown to increase survival in mice infected with the pseudorabies virus (PRV) [2] and reduced titers of porcine circovirus 2 (PCV2) in the tissues and sera of infected piglets [3]. In addition, Xu et al. reported the antiviral efficacy of ivermectin in dengue virus-infected Aedes albopictus mosquitoes [4]. Ivermectin was also identified as a promising agent against the alphaviruses chikungunya, Semliki Forest and Sindbis virus, as well as yellow fever, a flavivirus [5]. Moreover, a new study indicated that ivermectin presents strong antiviral activity against the West Nile virus, also a flavivirus, at low (μM) concentrations [6]. This drug has further been demonstrated to exert antiviral activity against Zika virus (ZIKV) in in vitro screening assays [7], but failed to offer protection in ZIKV-infected mice [8].
Recently, Caly et al. reported on the antiviral activity of ivermectin against SARS-CoV-2, the causative agent of COVID-19 [9]. These authors demonstrated that a single dose of ivermectin was able to reduce the replication of an Australian isolate of SARS-CoV-2 in Vero/hSLAM cells by 5000-fold. This finding has generated great interest and excitement among physicians, researchers and public health authorities around the world. However, these results should be interpreted with caution. Firstly, it is important to note that the drug was only tested in vitro using a single line of monkey kidney cells engineered to express human signaling lymphocytic activation molecule (SLAM), also known as CDw150, which is a receptor for the measles virus [10]. Also, ivermectin has not been tested in any pulmonary cell lines, which are critical for SARS-CoV-2 in humans [11]. Furthermore, these authors did not show whether the reduction seen in RNA levels of SARS-CoV-2 following treatment with ivermectin would indeed lead to decreased infectious virus titers. Importantly, the drug concentration used in the study (5 μM) to block SARS-CoV-2 was 35-fold higher than the one approved by the FDA for treatment of parasitic diseases, which raises concerns about its efficacy in humans using the FDA approved dose in clinical trials [12].
In light of the potential of ivermectin to prevent replication in a broad spectrum of viruses, the inhibition of importin α/β1-mediated nuclear import of viral proteins is suggested as the probable mechanism underlying its antiviral activity [6]. Since SARS-CoV-2 is an RNA virus, a similar mechanism of action may take place [9]. A possible ionophore role for ivermectin has also been reported [13]. Since ionophore molecules have been described as potential antiviral drugs [14], ivermectin could ultimately induce an ionic imbalance that disrupts the potential of the viral membrane, thereby threatening its integrity and functionality.
The pathology of COVID-19 is characterized by the rapid replication of SARS-CoV-2, triggering an amplified immune response that may lead to cytokine storm, which frequently induces a severe inflammatory pulmonary response [15]. Disease progression may result in progressive respiratory failure arising from alveolar damage, and can lead to death [16]. Moreover, the monitoring of SARS-CoV-2 viral load in the upper respiratory tract and bronchoalveolar lavage fluid (BALF) in patients with severe disease indicates higher loads, as well as greater viral persistence [[16], [17], [18], [19]].
In addition to the indication for antiviral therapy, anti-inflammatory intervention may also be necessary to prevent acute lung injury in SARS-CoV-2 infection. With regard to its anti-inflammatory properties, ivermectin have been shown to mitigate skin inflammation [20]. Importantly, ivermectin significantly diminished the recruitment of immune cells and cytokine production in BALF assessed in a murine model of asthma [21]. A study evaluating the ability of ivermectin to inhibit lipopolysaccharide (LPS)-induced inflammation revealed significantly decreased production of TNF-alpha, IL-1ss and IL-6 in vivo and in vitro [22]. Further studies may establish the role of ivermectin on inflammatory response caused by SARS-CoV-2, whether besides the antiviral activity ivermectin could play a supportive adjuvant role facing the hostile infection microenvironment.
With regard to investigations into potential drug treatments against COVID-19, ivermectin has received particular attention. Indeed, a number of clinical studies have been conducted in various countries such as USA, India and Egypt, as registered on the repository of data ClinicalTrials.gov. Table 1 shows a compilation of these studies, with patients receiving monotherapy or combination therapy, using different approaches of ivermectin dosing. In Spain, the SAINT clinical trial is currently underway and aims to determine the efficacy of a single dose of ivermectin, administered to low risk, non-severe COVID-19 patients [23]. Despite the fact that ivermectin has been shown to be effective in vitro against Sars-Cov-2, it is possible that the necessary inhibitory concentration may only be achieved via high dosage regimes in humans. The enthusiasm surrounding ivermectin use is restrained by a lack of appropriate formulations capable of providing improved pharmacokinetics and drug delivery targeting mechanisms. Although patients could be treated using systemic therapy, high-dose antiviral therapy could lead to severe adverse effects. Regardless, no commercially available injectable forms of ivermectin are available for human use. In COVID-19 patients, the rapid evolution of disease requires prompt treatment, as therapeutic intervention must be introduced within a narrow window of time. Considering that the respiratory tract has been shown to be a primary site of infection, the delivery of ivermectin by pulmonary route would provide high drug deposition in the airways and lungs to mitigate the high viral loads seen in these sites. It is worth noting that inhalation therapy has been reported to be the most effective treatment for respiratory infections due to increased drug bioavailability [24,25]. Indeed, pulmonary and nasal administration bypasses the first-pass metabolism observed in oral administration and the lungs and nasal cavity are known to be low drug-metabolizing environments [26]. In severe cases of SARS-CoV-2-induced pneumonia, antiviral aerosol formulations could be delivered by inhalation to patients on mechanical ventilation. In addition, patients presenting mild symptoms of COVID-19 could benefit from being treated with antiviral aerosol formulations at earlier stages of disease. Importantly, Gilead Sciences recently announced human trials of an inhaled version of its antiviral drug remdesivir for non-hospitalized patients [27].
Table 1.
Ongoing clinical trials evaluating potential treatments for COVID-19 using ivermectin with patients receiving either monotherapy or drug combinations. Studies in very early stages (“not yet recruiting”) or with missing information have not been included.
Intervention/treatment Study design Phase Enrollment Status Sponsor/location Identifiera
Ivermectin, days 1–2: 12 mg total daily dose (weight < 75 kg); days 1–2: 15 mg total daily dose (weight > 75 kg:) Single-center, randomized, parallel assignment, open label II 240 Recruiting University of Kentucky, Markey Cancer Center, United States NCT04374019
Ivermectin,3 mg capsules, 12–15 mg/day for 3 days Single-center, randomized, parallel assignment, double-blind, placebo-controlled NA 100 Recruiting Sheba Medical Center, Israel NCT04429711
Ivermectin,200 to 400 μg per kg body weight Single-center, non-randomized, crossover assignment, open-label NA 50 Recruiting Max Healthcare Insititute Limited, India NCT04373824
Ivermectin,6 mg and doxycycline 100 mg twice daily for 5 days Single-center, randomized, parallel assignment, double-blind, placebo-controlled III 400 Completed Dhaka Medical College, Bangladesh NCT04523831
Ivermectin,200 μg/kg single dose and 200 mg doxycycline day-1 followed by 100 mg doxycycline 12 hourly for 4 days Single-center, randomized, parallel assignment, double-blind, placebo-controlled II 72 Enrolling by invitation International Centre for Diarrhoeal Disease Research, Bangladesh NCT04407130
Ivermectin,sub-cutaneous injection 200 μg/kg body weight once every 48 hourly with 80 mg/kg/day Nigella sativa;Sub-cutaneous injection ivermectin 200 μg/kg body weight once every 48 hourly with 20 mg zinc sulphate 8 hourly Single-center, randomized, parallel assignment, open-label, placebo-controlled I, II 40 Recruiting Sohaib Ashraf, Sheikh Zayed Federal Postgraduate Medical Institute, Pakistan NCT04472585
Ivermectin,12 mg weekly + hydroxychloroquine 400 mg/daily + azithromycin 500 mg daily Single-center, randomized, parallel assignment, I 100 Completed University of Baghdad, Iraq NCT04343092
Ivermectin,two doses 72 h apart: 40–60 kg (15 mg/day) 60–80 kg (18 mg/day) >80 kg (24 mg/day) Single-center, randomized, sequential assignment, open label II, III 340 Completed Zagazig University, Egypt NCT04422561
Ivermectin,single dose tablets at 400 μg/kg Single-center, randomized, parallel assignment, double-blind, placebo-controlled II 24 Recruiting Clinica Universidad de Navarra, Universidad de Navarra, Spain NCT04390022
Ivermectin,single oral dose 600 μg/kg or 1200 μg/kg, for 5 days Multi-center, randomized, sequential assignment, double-blind, placebo-controlled II 102 Recruiting IRCCS Sacro Cuore Don Calabria di Negrar, Italy NCT04438850
Ivermectin,at the time of inclusion and the same dose at 24 h, depending on the body weight, from 12 mg to 24 mg in tablets Single-center, randomized, parallel assignment, double-blind, placebo-controlled II, III 500 Recruiting Instituto de Cardiología de Corrientes, Argentina NCT04529525
Ivermectin,600 μg/kg/once daily Multi-center, randomized, parallel assignment, open label II 45 Recruiting Laboratorio Elea Phoenix S.A., Argentina NCT04381884
Ivermectin,300 μg/kg, once daily for 5 days Single-center, randomized, parallel assignment, double-blind, placebo-controlled II, III 400 Recruiting Centro de Estudios en Infectogía Pediatrica, Colombia NCT04405843
Ivermectin,6 mg once daily in day 0,1,7 and 8 plus azithromycin 500 mg once daily for 4 days, plus cholecalciferol, 400 IU twice daily for 30 days) Single-center, non-randomized, parallel assignment, open-label NA 30 Recruiting Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico NCT04399746
Ivermectin,12 mg every 24 h for one day (weight < 80 kg) or 18 mg every 24 h for one day (weight > 80 kg) Single-center, randomized, parallel assignment, placebo-controlled III 108 Active, not recruiting Centenario Hospital Miguel Hidalgo, Mexico NCT04391127
Ivermectin,12 mg followed by losartan 50 mg orally once daily for 15 consecutive days Single-center, randomized, parallel assignment, double-blind, placebo-controlled II 176 Recruiting Instituto do Cancer do Estado de São Paulo, Brazil NCT04447235
Ivermectin, oral dosage based on body weight, once on day for 2 days. This dose schedule should be repeated every 14 days for 45 days associated with 20 mg twice on day of active zinc Single-center, randomized, parallel assignment, open-label, placebo-controlled NA 400 Recruiting Núcleo de Pesquisa eDesenvolvimento de Medicamentos (NPDM), Universidade Federal do Ceará, Brazil NCT04384458
Ivermectin, oral dosing schedules: 100 μg/kg single dose; 100 μg/kg on the first day, followed by 100 μg/kg after 72 h; 200 μg/kg single dose; and 200 μg/kg on the first day, followed by 200 μg/kg after Single-center, randomized, parallel assignment, open-label 1.评论2015年诺贝尔生理学和医学奖被授予William C. Campbell和SatoshiÖmura，用于他们的发现导致Ivermectin [1]。 除了对寄生虫病的非凡疗效外，Ivermectin还在继续提供新的临床应用，因为它是为了治疗新的疾病而被重新培训。 除了在onchocerciagisis和抗肌腱肌腱中的其无价值的治疗作用，越来越多的证据表明伊维菌素作为抗病毒药剂的潜力。 显示伊维菌素治疗在感染伪论病毒（PRV）[2]中的小鼠中增加，并在感染仔猪的组织和血清中降低猪胃肠病毒2（PCV2）的滴度[3]。 此外，Xu等人。 据报道，Ivermectin在登革热病毒感染的AEDES Albopictus蚊子中的抗病毒疗效[4]。 Ivermectin还被鉴定为对甲基颈春宫，Semliki森林和Sindbis病毒的有前景的剂，以及黄热病，一种黄病毒[5]。 此外，一项新的研究表明，Ivermectin在低（μm）浓度下对西尼罗病毒的强烈抗病毒活性提出了强烈的抗病毒活性[6]。 进一步证明该药物在体外筛查测定中对Zika病毒（ZIKV）施加抗病毒活性[7]，但未能在ZIKV感染的小鼠中提供保护[8]。 最近，Caly等人。 关于伊维菌素对SARS-COV-2的抗病毒活性，Covid-19的致病剂[9]。 这些作者证明，单一剂量的伊维菌素能够减少澳大利亚SARS-COV-2在Vero / Hsllam细胞中的复制5000倍。 这一发现在世界各地的医生，研究人员和公共卫生当局产生了极大的兴趣和兴奋。 但是，这些结果应谨慎解释。 首先，重要的是要注意，该药物仅在体外使用工程化的单线进行测试以表达人信令淋巴细胞活化分子（SLAM），也称为CDW150，其是麻疹病毒的受体[10 此外，伊维菌素尚未在任何肺细胞系中进行测试，这对于人类中的SARS-COV-2至关重要[11]。 此外，这些作者并未显示在用伊维菌素治疗后的SARS-COV-2中的RNA水平降低，确实导致感染性病毒滴度降低。 重要的是，研究中使用的药物浓度（5μm）嵌段SARS-COV-2高于FDA批准的用于治疗寄生虫疾病的35倍，这促进了使用FDA批准的剂量对人类疗效的担忧 鉴于Ivermectin的潜力来防止在广谱的病毒中的复制，抑制Importinα/β1介导的病毒蛋白核导入是其抗病毒活性的可能机制[6]。 由于SARS-COV-2是RNA病毒，因此可能发生类似的作用机制[9]。 据报道，伊维菌素的可能的离子素作用[13]。 由于离子载体分子被描述为潜在的抗病毒药物[14]，伊维菌素最终可能诱导破坏病毒膜的电位的离子不平衡，从而威胁其完整性和功能。 Covid-19的病理学的特征在于SARS-COV-2的快速复制，引发可能导致细胞因子风暴的扩增的免疫应答，这通常会诱导严重的炎症性肺反应[15]。 疾病进展可能导致肺泡损伤引起的渐进呼吸衰竭，并导致死亡[16]。 此外，在严重疾病患者的上呼吸道和支气管肺泡灌洗液（BALF）中的SARS-COV-2病毒载体的监测表明载荷较高，以及更高的病毒持久性[[16]，[17]，[18 除了抗病毒治疗的指示外，还可能需要抗炎干预以防止SARS-COV-2感染中的急性肺损伤。 关于其抗炎性质，已显示伊维菌素削弱皮肤炎症[20]。 重要的是，伊维菌素显着减少了在哮喘的小鼠模型中评估的BALF中的免疫细胞和细胞因子产生的募集。 评估伊维菌素抑制脂多糖（LPS）诱导的炎症的能力的研究显示，在体内和体内的TNF-α，IL-1S和IL-6的产生显着降低了[22]。 进一步的研究可以建立伊维菌素对SARS-COV-2引起的炎症反应的作用，除了抗病毒活性Ivermectin是否可以发挥面临敌对感染微环境的支持性佐剂作用。 关于调查对Covid-19的潜在药物治疗，Ivermectin已特别注意。 实际上，在美国，印度和埃及等各个国家进行了许多临床研究，如数据诊所诊所的存储库。 表1显示了使用伊维菌素给药的不同方法，接受单药治疗或联合治疗的患者的汇编。 在西班牙，目前的圣临床试验目前正在进行中，旨在确定单剂量伊维菌素的疗效，施用于低风险，非严重的Covid-19患者[23]。 尽管伊维菌素已被证明在体外对SARS-COV-2有效，但可能只能通过人体的高剂量制度实现必要的抑制浓度。 伊维菌素使用的热情通过缺乏能够提供改善的药代动力学和药物递送靶向机制的适当配方抑制。 虽然患者可以使用全身治疗治疗，但高剂量的抗病毒治疗可能导致严重的不良反应。 无论如何，没有商业上可用的Ivermect素可用于人类使用。 在Covid-19患者中，疾病的快速进化需要及时处理，因为必须在狭窄的时间窗口内引入治疗干预。 考虑到呼吸道已被证明是一种感染的主要部位，肺途径递送Ivermectin将在气道和肺中提供高药物沉积，以减轻这些位点中所见的高病毒载量。 值得注意的是，由于药物生物利用度增加，据报道，吸入治疗是呼吸道感染最有效的治疗方法[24,25]。 实际上，肺和鼻给药绕过口服给药和肺和鼻腔中观察到的一级代谢，已知是低药物代谢环境[26]。 在严重的SARS-COV-2诱导的肺炎中，抗病毒气溶胶配方可以通过吸入对机械通气患者进行递送。 此外，呈现Covid-19轻度症状的患者可以受益于在疾病早期阶段的抗病毒气溶胶配方治疗。 重要的是，Gilead Sciences最近宣布为非住院患者的抗病毒药物RemdesiviR的吸入版的人类试验[27]。 表1.在接受单疗法或药物组合的患者使用伊维菌素评估Covid-19的潜在治疗的持续临床试验。 在非常早期的阶段（“尚未招聘”）或缺失的信息尚未被列入。 介入/治疗 天1-2：15 mg总日剂量（重量> 75千克：），随机，并行分配，Open Label。
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