From the paper I posted in a prior post
6. Conclusion
The effective concentration of ivermectin against SARS-CoV-2 in an in vitro experiment72) by Caly et al. is as high as 2 μM; in clinical practice, it is necessary to administer tens of times the normal dose in order to obtain such a blood concentration. Therefore, there are opinions from the IDSA98) and others that the therapeutic effect of COVID-19 cannot be expected by the adminis- 82 （ 82 ） THE JAPANESE JOURNAL OF ANTIBIOTICS 74―1 Mar. 2021 tration of the normal dose of ivermectin. However, in actual medical practice, there are many study reports demonstrating that the administration of a normal dose does indeed show a clinical response. As of the 27th of February 2021, the results of 42 clinical studies worldwide have undergone meta-analysis and concluded101) that ivermectin is effective in the treatment and prevention of COVID-19. In the UK, a consensus-based recommendation by 75 healthcare professionals from 17 countries around the world has been carried out and submitted to the WHO to further encourage the issuance of guidelines for the use of ivermectin in the treatment and prevention of COVID-19. We must consider why such a discrepancy is occurring. The first consideration should be focused on the setting of the sensitivity of the SARSCoV-2 infection for experimental systems in vitro. By use of Vero/hSLAM cells, the antiviral activity of the test drug is reliably measured. The sensitivity setting is set to be as low as possible, because it is necessary to eliminate false-positive samples. If the sensitivity is set high, the number of test drugs (noise) that give a positive reaction increases. Furthermore, if the setting is high, it becomes necessary to set secondary and tertiary tests to exclude false-positive samples. It seems that the sensitivity of the IC50＝2 μM set by Caly et al. was appropriate because neither false positives nor false negatives occurred. If the sensitivity of this test is set to 10 or 50 times higher, then changes in the IC50 (IC50＝0.2 μM, IC50＝0.04 μM, respectively) might be expected. Depending on the test cells, viral load, medium composition, and culture conditions, the experimental system in vitro can be set in different ways. Therefore, the paper by Caly et al. merely indicated that ivermectin was found to have anti-SARS-CoV-2 activity in vitro—no more, no less. Extrapolating the results to evaluate clinical effects is too much of a leap. There are in vivo infection experiments that can be used to connect in vitro experiments to clinical studies. In an in vivo infection experiment158) conducted at the Pasteur Institute in France, they employed the olfactory abnormality in hamsters as an index, along with dosage, in order to determine the equivalent dose that would be needed in humans. It was confirmed that the amount of SARS-CoV-2 virus did not change between groups administered ivermectin and the control. However, a significant decrease in the ratio of IL-6/IL-10 in the lung was observed in the ivermectin group. It has been suggested that ivermectin might be effective on COVID-19 by acting to regulate host inflammatory reactions. As shown in Fig. 1, ivermectin has a macrolide structure. Like other macrolide compounds, it is known to exhibit extremely wide diverse actions159). Regulation of the hostʼs inflammatory response is one of those diverse effects. In Japan, in 1994, ahead of the rest of the world, a “Research Group on Novel Action of Macrolides” was established. It was done for the purpose of clarifying actions160) other than the antibacterial activity of macrolide compounds, such as clarithromycin. The clinical use of several effective macrolide antibiotics for the management and treatment of patients with diffuse lung disease (previously designated as refractory diseases) was established. One such disease is diffuse panbronchiolitis (DPB). DPB causes an obstructive respiratory dysfunction similar to cystic fi- Mar. 2021 THE JAPANESE JOURNAL OF ANTIBIOTICS 74―1 83 （ 83 ） brosis (CF) (which occurs frequently in Westerners) and has been observed in Japan and East Asia. Although it is a fatal and intractable disease, the long-term administration of low-dose macrolides161) has made it possible to treat and reduced the mortality rate. In elucidating the mechanism of action of macrolides on DPB, novel actions such as chlorine ion channel regulation162) and anti-inflammatory actions163,164) were confirmed one after another. Following the elucidation of erythromycinʼs suppressive actions on the infiltration of macrophages into the endothelium, there were studies that investigated the prevention and treatment of diabetic nephropathy, as well as the treatment of active stage Crohnʼs disease. Several studies have also been conducted investigating the inhibitory effects of clarithromycin on the production of cytokines. One such study involves the suppression of excessive inflammatory reactions caused by influenza and other chronic otolaryngology diseases. Prior to this, effects such as these that go beyond the antibacterial activity of the macrolide antibiotics could never have been imagined. Additionally, for example, it has been found that erythromycin exhibits prokinetic effects for gastroparesis in diabetic patients. This was discovered to be due to the motilin-like action of a metabolite. A metabolite derivative165) (which exerted no antibacterial activity) was found to enhance motilin-like activity. By taking advantage of such derivative165) side effects, a new treatment for constipation in patients with severe diabetes was discovered. The biological reactions of macrolide compounds have been shown to be extremely diverse. Even though some have been elucidated, it is difficult to estimate how many other actions may have not yet been elucidated. Although clinical trial results have been and continue to be accumulated showing that ivermectin is effective in the treatment and prevention of COVID-19, basic in vitro findings that can reasonably explain its effectiveness have not yet been obtained. It is considered that a wide variety of biological activities exhibited by macrolide compounds, such as the above-mentioned actions, at multiple stages could possibly serve to exert an overall and more comprehensive action/ effect. Although it must be further elucidated by future studies, clinical efficacy can be determined by investigation of any of the following parameters: (1) antiviral activity, (2) inhibition of the relationship between the virus and the host cell, and (3) actions related to the regulation of host reactions. It is necessary to prove that other effects are being exerted, and it seems that such investigations could be suitable research topics for basic researchers, pharmacological researchers, and clinical researchers to collaborate and elucidate on.
When the effectiveness of ivermectin for the COVID-19 pandemic is confirmed with the cooperation of researchers around the world and its clinical use is achieved on a global scale, it could prove to be of great benefit to humanity. It may even turn out to be comparable to the benefits achieved from the discovery of penicillin—said to be one of the greatest discoveries of the twentieth century. Here, one more use for ivermectin, which has been described as “miracle” or “wonder”166) drug, is being added. History has demonstrated that the existence of such natural product-derived compounds with such diverse effects is exceedingly rare. 84 （ 84 ） THE JAPANESE JOURNAL OF ANTIBIOTICS 74―1 Mar. 2021 However, in order to pass on to posterity the fact that ivermectin has become widely used to control the world-shattering COVID-19 pandemic, only one simple action is required: the addition of only one word, “COVID-19”, to the 9th item (of the 11 listed) under the “Antiviral” category in the “Ivermectin: The Future” section of the Nobel Lectureʼs record167) entitled “Splendid Gift from the Earth”.
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