President Donald Trump suggested doctors to consider using erythromycin for the COVID-19 patients during the White House News Conference on April 5th, 2020. He said: "Erythromycin, which will kill certain things that you don't want living within your body. It's a powerful drug". I don't know how he got this idea, but he is right!
Let me tell you why erythromycin could be very effective for COVID-19 patients.
When I was a PhD graduate student in Kumamoto University, Japan, my lab was a microbiology lab. Dr. Keizo Sato was graduate student three years senior than me in the lab. He was a physician. One day around midnight, I was going to go home, then he came in the lab. I asked him: why are you come in at midnight? He said he had some experiments to do. He was just back from hospital.
He published a paper "Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice" in American Journal of Critical Care Medicine in 1998. In this paper, he described a research of using erythromycin at 1 or 3.3 mg/kg per day from Day 1 to Day 6 by injection to the influenza virus infected lab mice. Erythromycin dose-dependently rescued mice life for more than 50% in survival rate (black circle in Fig. A below).
Dr. Sato further found that erythromycin suppressed the generation of nitric oxide in the infected lung (by using the supernatant from bronchoalveolar lavage stimulated macrophage cell line RAW264 in cell culture).
Let me tell you why erythromycin could be very effective for COVID-19 patients.
When I was a PhD graduate student in Kumamoto University, Japan, my lab was a microbiology lab. Dr. Keizo Sato was graduate student three years senior than me in the lab. He was a physician. One day around midnight, I was going to go home, then he came in the lab. I asked him: why are you come in at midnight? He said he had some experiments to do. He was just back from hospital.
He published a paper "Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice" in American Journal of Critical Care Medicine in 1998. In this paper, he described a research of using erythromycin at 1 or 3.3 mg/kg per day from Day 1 to Day 6 by injection to the influenza virus infected lab mice. Erythromycin dose-dependently rescued mice life for more than 50% in survival rate (black circle in Fig. A below).
Erythromycin is well-known as antibiotic and used for the treatment of bacterial infection. It was first discovered in 1952, and has been listed as essential medicine by WHO. Bacteria are different from virus, so as common sense, antibiotic won't work on inhibiting virus replication. So why erythromycin exhibited therapeutic benefit in respiratory virus infection and saved the life?
Actually, erythromycin has many function properties, especially the immune modulation property. It can suppress neutrophil migration, inhibit inflammatory cytokine IL-18 generation, chloride secretion by trachael epithelial cells, and suppress lymphocyte activities.
Our PhD mentors Dr. Takaaki Akaike and Dr. Hiroshi Maeda are famous in the field of pathogenic mechanism of free radicals in virus infection. They found that free radicals such as nitric oxide and superoxide are induced in a tremendous amount like storm after virus infection. It is because the immnue system is desperately trying to clear the infected virus thus over reacted. The lymphocytes, neutrophils and macrophages secret huge amount of free radicals as weapons to try to clear virus. Therefore the lung tissue got damage by indiscriminate destructive action of free radicals, and multiple organs consequently failed, which leading death of the infected host.
Dr. Sato supposed that erythromycin could rescue the infected mice by suppressing the generation of free radicals. He found that erythromycin can suppress the generation of interferon gamma in the virus infected mice. Interferon gamma is one of the most important inflammatory cytokines that can stimulate the generation of nitric oxide, a major free radical. Many inflammatory cytokines are generated during the virus infection, so people call it cytokine storm.
Erythromycin suppressed the neutrophils, lymphocytes and monocytes/macrophages in the lung of virus infected mice as shown below. This is important because these cells are responsible for secreting free radicals and proteases that damaging the lung.
Such inhibition could also be achieved by using antibody of interferon gamma (to neutralize interferon gamma), which means the suppression effect of erythromycin on nitric oxide production is via the suppression of interferon gamma secretion. It also tells us that cytokine storm can stimulate the free radical storm, and free radicals are the direct factors to cause DNA mutation, protein denaturation, cell membrane damage and cell death. We should focus on preventing the cytokine storm formation and the damage of free radical storm.
Interestingly, azithromycin, which is one of the so-called magic drugs to achieve 100% effect to COVID-19 patients when combined with hydroxychloroquine. Azithromycin is an macrolide antibiotic similar like erythromycin. However azithromycin can suppress the superoxide and other reactive oxygen species (ROS) generation by inhibiting the respiratory burst process in neutrophil (inflammation, 1998, 22(2): 191-201).
Erythromycin is about 0.03~0.06 USD per tablet in the developing world according to the Wikipedia. So it is very cost effective.
Precautions of erythromycin are allergic reaction and affect heart rhythm (QT prolongation) and gastrointestinal side effects similar like azithromycin. It is reported that erythromycin can reach higher plasma concentration (Cmax at 1.9~3.8 ug/L) with short half-life (1.5~3 hours) compared with azithromycin (Cmax 0.4 ug/L, half-life 11~14 hours) (Can J Infect Dis., 1993 4(3):148-152). The dose of erythromycin could be lower to achieve effect compared with azithromycin.
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