Checked in the "red zone"

The St. Petersburg academician proposed a method of protection against coronavirus

Irina Baglikova, Alexander Gorshkov, Denis Lebedev, Fontanka

Since the spring, dozens of people in St. Petersburg have been using one of the freely available medicines in order not to get infected with coronavirus. They say they don't get sick. Even officials and deputies of the city parliament were among them. The drug is known by word of mouth, but its effectiveness is already being discussed at the level of city authorities.

Those for whom this is not news understand the strange dialogue that took place on November 11 at the Mariinsky Palace, where the report was held from the parliamentary rostrum by the "medical" vice-governor of St. Petersburg Oleg Ergashev. The uninitiated must have been left confused.

– How effective is the drug for the prevention of coronavirus (the name of the drug follows)? Have you heard of such a thing? Could you give an assessment? – one of the deputies of the vice-governor asks in the final question.

Oleg Ergashev showed awareness. We quote verbatim: "I know that the creators (the name of the drug) we are convinced of the effectiveness, many have experienced it for themselves. But until he has passed a randomized trial, I am wary of him, because there are not enough several dozen people who have tried him and are convinced of an absolute guarantee against infection. I find it difficult to give an estimate. Because there are tools to answer this question… But we still lack the confidence to recommend widely."

Then the chairman of the Legislative Assembly Vyacheslav Makarov joined the conversation:

– Academician Dubina predicted one to one how the epidemic will develop, what we will come to. Oleg Nikolaevich (Ergashev), please meet – his forecast is very accurate, and he spoke back in March.

It would seem, what does a Club have to do with it?

Mikhail Dubina is a graduate of the First Honey, one of the youngest member–cows, and then academicians of the Russian Academy of Sciences, in 2017-2019 - Chairman of the Health Committee of St. Petersburg. On the English-language website http://medrxiv.org On October 6, an article was published with the title "Pathogenetic drug prevention accompanied by a low risk of infection with SARS-CoV-2 in medical workers in a specialized hospital for the treatment of patients with COVID-19", which is difficult for the uninitiated reader.

From the editorial office:
Find the address of the article Dubina et al. Pathogenesis-based pre-exposure prophylaxis associated with low risk of SARS-CoV-2 infection in healthcare workers at a designated Covid-19 hospital on an "English-language website" is not difficult at all. It is more difficult to understand what is meant in the recipe described there:
"...participants received an aerosol combination of glutathione 21.3 mg/ml, inosine 8.7 mg/ml in 107 mM potassium solution for 14 days."
What is this "potassium solution" (probably some of its compounds) and at what concentration in g/l, and not in millimoles (and what is 107 – 10 ⁷? 10-7?⁾, as well as the exact dosage of the drug and the frequency of administration, the authors do not disclose – VM.

The co–authors are Dubina and four employees of the Northwestern Medical University. Mechnikov. (Medrxiv is a publicly available database of full–text preprints of medical articles awaiting publication in specialized journals. One of the creators is Yale University.) From this publication, we learned that back in June–July, a study was conducted at Peter the Great Hospital on the effectiveness and safety of the effect of certain drugs on infection with the virus among physicians. 100 people (the report included 99) who worked in the "red zone" received the medicine in aerosol form. The results of infection in this group were compared with a group of 268 doctors from the same clinic who did not receive the drug. In the first group, 2 people were infected with the virus, in the second – 24.

How the study was conducted, "Fontanka" was told by its head Veronika Gomonova, head of the Department of Cardiology at Mechnikov University, co-author of an article in Medrxiv:

– When we converted to covid, there was little information about the course of the disease and its treatment. We only understood that it was pneumonia, but not the one we were used to. The worst thing at that time was to lose staff: if our employees start getting sick, we will not be able to help those who are ill. And we began to cooperate with Mikhail Vladimirovich Dubina. He suggested that it is necessary to deal not with a cytokine storm (a complication in severe covid caused by an excessive immune response of the body to the virus) – when the patient is already in the most serious condition, but to act to prevent infection in general or to develop the disease in the first stages. That is, it is necessary to create such an environment in the respiratory system so that the innate and humoral immunity are activated and at the right moment they do not fail and resist the virus.

The combination of drugs that he suggested using is very simple. One of them is a potassium preparation, the other was previously used in the treatment of patients with chronic hepatitis to provide energy to liver cells. Mikhail Dubina hypothesized that he would be able to provide energy to the cells of the respiratory system, it is only necessary to deliver medicine to them. And he proposed a protocol for the prevention of coronavirus infection for health workers. They work for hours in SIZas, in which it is very difficult to breathe, which means they experience hypoxia – lack of oxygen. Hence the choice of the inhalation form of administration, it was assumed that the delivery of the drug directly to the lungs would be more effective than intravenous injection.

An elegant, simple theory, pathophysiologically savvy, formed the basis of the protocol of our study. Of course, it is difficult for the first to decide on this step – we did not know how the drug would act on a person with inhalation use. But, considering that (the name of the drug) after all, minimal side effects, and potassium is already used in inhalations, it was considered that the risks are small. It was possible to include 100 people in the group. They breathed this aerosol combination for two weeks, another two weeks – an observation period to detect possible delayed side effects.

The participation of those who were not ill before and at the time of the study was crucial. One of the included volunteers raised doubts – before the start of the study, PCR was negative, but immunoglobulins were found in small quantities.

During the inhalation procedure, 5 out of 99 people complained of headaches, cough, sore throat, appearing during inhalation. When it was over, these side effects passed by themselves in just a couple of minutes, we considered them insignificant. We didn't see any allergic reactions on our pool of volunteers.

The percentage of cases among those who used "respiratory" prevention was significantly lower than among those who entered the "red zone" without prior drug protection.

We really wanted to try the drug on patients as well. But we were taken out of covid, and we had to stop the study. And the plans were as follows: to prove the effectiveness and safety of the method and implement it further, at the next stage – to include patients, including those with pneumonia, in the study.

How it works

"How it works" – Fontanka asked Mikhail Dubin. With his consent, we tried to convey the words of the scientist in the most accessible language for a wide range of readers.

– The most important thing to understand about the effect of the SARS-CoV-2 virus and the complications it causes is that it initially initiates a functional, not an immunological defect of the body, – says the academician. – The pulmonary and vascular systems are directly connected. Our lungs can be represented in the form of a tree with branches – bronchi, where the leaves are 500 million balloons-alveoli with a size of 0.3–0.5 mm. The outer side of each alveolus is in contact with a blood vessel through the basement membrane. This interface is an aerogematic barrier between air and blood up to 200 nm thick. On inhalation, air enters the alveoli, oxygen passes through the barrier to the erythrocyte, and the erythrocyte gives off carbon dioxide, which leaves on exhalation. From the trachea with a diameter of 1.5–2 cm, the air path at the periphery passes through the terminal bronchi, whose diameter is comparable to the alveoli, followed by clusters of alveoli. If you spread all the alveoli on the surface, you will get an area of about 100 sq. m. With each inhalation, of which there are about 20 thousand per day, up to 500 ml of air should be distributed on the alveoli with a total area of about a hundred square meters.

So the fundamental thing for this coronavirus is the peripheral part of the lungs. There, smooth muscle cells are located in the walls of the terminal bronchi, which constrict or relax the bronchi. In other words, these are muscle sphincters that control the uniformity of oxygen supply. Physiologically, excess oxygen is just as harmful to cells as its lack. The areas of the bronchi and alveoli behind these sphincters are inflated only by the flow of air. We have about 15,000 terminal bronchi in each lung. On inhalation, air passes through them, as through a siphon, to the alveoli and on exhalation returns with carbon dioxide.

The virus we are dealing with has several features. It is distinguished by its large size and extremely high affinity – affinity to its receptor-enzyme (APF2), which is abundant in the cells of the nasal mucosa and alveoli. Here, the virus is populated and multiplies. But this enzyme in the human body is primarily responsible for vasodilation. Its blocking leads to a contraction of vascular muscle cells, and activation leads to relaxation. The enzyme is also present in the smooth muscle cells of the bronchi. Therefore, getting on its receptors, the virus not only uses them to penetrate into cells, but also blocks the activity of the enzyme itself, causing compression of the bronchi and blood vessels.

Now imagine what's going on. First, the virus infects the upper and lower respiratory tract. Further, with each inhalation and exhalation, it circulates and continuously accumulates in the air volume of the lungs. At some point, it begins to compress thousands of terminal bronchi. The person is breathing, but the oxygen to the alveoli is getting worse and worse. Gradually, the valve intake of air begins, which cannot escape. Imagine a ball with compressed air, where pumping continues – it enters through a valve, but cannot exit. The bronchi contract unevenly, so part of the clusters of alveoli begins to inflate with air, and the other collapses – this is what makes the X-ray image of the lungs of a patient with COVID-19 look like frosted glass or marble. Lack of oxygen – hypoxia – leads to damage to alveolar cells, activating immune processes.

Mikhail Dubina draws attention to the fact that this "medical history" at the first stages is a functional disorder in the lungs, and not an immunological defect.

– This is a different mechanism of disease development. Even if it was an immunity problem, then immune cells or antibodies should come to the affected area from the blood. But the blood flow in the peripheral vessels of the lungs slows down and stops, since the viral blocking of the enzyme compresses not only the bronchi, but also the vessels. As a result, neither blood comes to the peripheral parts of the lungs, nor oxygen reaches.

If so, then we need something that will unclench and keep the bronchi dilated until the virus leaves the body. There is another feature that you also need to know from physiology. At first glance, energy is spent on muscle compression, but in fact it is spent on relaxation. It's like a compressed spring. That is, to unclench, expand the bronchi, you need energy. In other words, in order to prevent damage caused by the SARS-CoV-2 virus, medicines are needed that relax smooth muscles, give energy for this and remove what has already formed or could potentially form – an oxygen imbalance. At the same time, the delivery of drugs should be only directly – in the inhaled air to reach the terminal bronchi. This was my hypothesis, which formed the basis of the study.

Study

It should be noted that the study initiated by the university was conducted in accordance with all legal requirements for clinical trials of registered drugs under the decree of the Government of the Russian Federation 441 of 03.04.2020.

In April, in accordance with this decree, the effectiveness of the drug in question was investigated at the Moscow NMIC of Cardiology of the Ministry of Health as part of the complex therapy of patients with coronavirus infection (COVID-19) of moderate and severe forms. There the drug was administered intravenously. The result was the fixation of the absence of progression of the severity of the disease. None of the patients needed to be transferred to the intensive care unit (ICU), whereas in the comparison group receiving therapy according to clinical recommendations, treatment in the ICU was required in 35% of cases.

Veronika Gomonova evaluates the results of summer research in this way:

– It seems to me that we have coped with the security evidence. The drug is not dangerous, does not cause serious side effects, is well tolerated. As for the effectiveness, we saw a small percentage and sent the reports to the Ministry of Health.

As a university, we understand how important sampling is for an objective assessment of the result. And we understand that it is very important not to be deceived. There are skeptics who say that perhaps our volunteers felt better due to the fact that inhalation itself is a humidification of the upper and lower respiratory tract. There are a lot of assumptions and assumptions "maybe". In order to definitively declare the effectiveness of this prevention, larger-scale studies with a large number of volunteers are needed. If we had at least 1000 people, but on such a small sample we have nothing to prove yet. It would be nice if the research could be continued. There are already colleagues who have tried it, they would support this idea. But this is my personal opinion.

I think that while no means of protection against coronavirus infection has been found, such an absolutely safe means that allows a person to breathe easier is still a way out for employees of the "red zones", they cannot wait for the vaccine, they need to work now. And for the purpose of prevention, such a method of prevention can be recommended to people working in SIZas who have breathing disorders.

Vaccination will win

At the same time, Gomonova does not believe that this method is able to replace vaccination.

– No, they are aimed at different things. Vaccination will definitely win: compare Sputnik-V, which promises immunity for two years after two vaccinations – and you are spared the hassle, or constant attachment to the device and inhalation 4 times a day? Such prevention is not viable in ordinary life. That is, she will not be able to replace vaccination, and this method will be very useful to help: for example, there are people to whom it is contraindicated. Besides, when else will the vaccination appear? When will people decide to get vaccinated – is there a lot of wariness? And we live today, and we need to defend ourselves somehow. I came from a store where someone sneezed on you- I breathed. Just to recommend it, we need more information – more research, calculations. But all this can be considered, implemented, such prevention will be in demand for a long time.

This method of protection could be recommended not only to those working in the "red zone", but also to district doctors who walk around the apartments – they breathed, put on SIZAS and went to the apartments. Employees of CT and ambulance centers. But use only with personal protective equipment. Although here, again, we must understand that our doctors did not wear shields, but full-fledged SIZAS with hermetic glasses. But all the same, the percentage of their degree of protection will be higher, it will develop.

Biologist Aron Chehnaver, winner of the Nobel Prize in Chemistry, professor at the Israel Technion Institute of Technology and a member of several academies of sciences, including in the USA, Germany, China and Russia, after reviewing the publication in Medrhiv, appreciated it in the Fontanka commentary:

– Mikhail Dubina's theory is a really good idea. But his hypothesis requires confirmation. After all, we are not researching some section of literature. This is biology, we are fighting a virus, and we need some essential data.

Now the question is whether his theory works. It is necessary to conduct more in-depth clinical trials, test this model on animals and carry out the following stages to prove its validity.

So far, none of the drugs that people have tried to fight the coronavirus have shown their 100% effectiveness. Steroids and other anti-inflammatory medications may help a little. But even the largest studies under the auspices of WHO have not yet yielded any positive, encouraging results.

If you ask me, I will say that in the end only vaccination can defeat the coronavirus. I don't see any other options. More than 200 companies around the world are currently developing a coronavirus vaccination. So it will definitely end with the creation of a vaccine that will have enough power to eradicate this disease and convince people of its effectiveness.

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