Actual aspects of ARVI and COVID-19 immunoprophylaxis in difficult epidemiological conditions

The treatment of coronavirus infections is a rather complex clinical task. It is known that in the process of biological evolution, nature has endowed the human body with an excellent mechanism to resist viral attacks, which is implemented in the system of cytokine proteins — interferons (IFN).

The history of interefron polypeptides began more than 60 years ago, when Alik Isaacs and Jean Lindemann discovered the phenomenon of viral interference: cells infected with viruses produced a protein that inhibited the growth of these viruses. Interferon provides both innate and systemic reactions of the body in response to a viral attack [1].

Type I interferons (IFN-α, IFN-β provide the expression of interferon-stimulated genes (ISG), stimulate antigen-presenting functions of macrophages, increase the synthesis of cytokines, enhance the activity of natural killers (NK cells) and dendritic cells. Through protein kinase, oligoadenylate synthetase accumulates, leading to to the formation of 2,5-oligoadenylic acid — it activates cellular endonuclease, which destroys viral RNA molecules.

Figure 1. Scheme of the antiviral action of interferon

Studies have shown that an increase in the production of type I IFN is observed 30–40 minutes after viral entry into the cell [2,3].

In 1981, S. Levin et al. for the first time revealed congenital and acquired disorders in the interferon defense system associated with a low level of endogenous interferon synthesis. French researchers C. Le Page et al. proved that an acute viral infection is characterized by an increased level of IFN, more than 70% of the cells of the body are in the status of an antiviral regime, but in severe forms of viral diseases, the interferon system of the body experiences functional depression and interferon deficiency. There is no interferon depot in the body. VV Malinovskaya et al. (2005) clarified that acute viral infection also leads to transient immunosuppression and depletion of the interferon pool in the body [4,5,6].

In the process of evolution, coronaviruses, like other viruses, have developed a molecular biological mechanism for inhibiting IFN in cells. The NS1 influenza virus protein can block the expression of type I and III IFN genes, and the PA-X protein suppresses the expression of cellular immune response genes — it inhibits the synthesis of protein kinase R, an important factor in antiviral protection, IFN types I and III are responsible for the synthesis of this enzyme [ 7,8].

The new coronavirus SARS-CoV-2 at the initial stage of infection also blocks the synthesis of IFN through the ORF9b protein [9, 10]. In addition, coronaviruses have the enzyme endoribonuclease, with the help of which they suppress the early activation of IFN both in epithelial cells and in macrophages. The S-protein of the virus binds to the lectins of immune cells, inhibits the function of macrophages and T-lymphocytes [11,12,13].

Thus, the mechanism of blocking the synthesis of endogenous IFN by coronaviruses, the damage of both epithelial cells and macrophages by the SARS-CoV-2 virus, the absence of a “depot” of IFN are sufficient grounds for introducing exogenous interferon into the body as a means of preventing and treating ARVI and COVID- 19. Interferons (IFN) have demonstrated clinical efficacy in the treatment of various viral infections and are widely used to treat patients with COVID-19 [14,15,16]

To date, there are many drugs on the pharmaceutical market, both native recombinant IFN and its inducers. The most popular among clinicians are preparations of recombinant interferon — α2b with antioxidants (tocopherol acetate — vitamin E and ascorbic acid — vitamin C), gel, ointment, rectal suppositories produced in dosage forms [17,18,19].

Antioxidants successfully fight oxidative stress, destroy free radical molecules by transferring free electrons to them, and therefore, free radicals lose their aggressive oxidative properties.

Ascorbic acid (vitamin C) performs the biological functions of a reducing agent and coenzyme of some metabolic processes; has strong antioxidant properties. Tocopherol acetate (vitamin E) belongs to the group of fat-soluble substances. Its main function is to neutralize free radicals that cause damage to human cells and tissues. In addition, tocopherol is an excellent chemical conductor. Due to its small molecular size and lipophilicity, it easily crosses transepidermal barriers and can help other active substances, such as interferon, to penetrate into the body.

Antioxidants increase the antiviral activity of recombinant human IFN-α-2b by 10–14 times, which makes it possible to obtain a high therapeutic effect even at the minimum dose.

However, the use of small doses of exogenous interferon does not always clinically justified, especially with intranasal dosage forms, which in most cases contain a low dose of 3000 IU/ml.

When administered intranasally, an aqueous solution of IFN collides with the hydrophobic mucinous mucus of the nasal cavity. In this case, droplets of the solution are formed, which weakly interact with the non-wettable surface of the mucinous mucus and under the action of gravity, with the patient in the vertical position, these drops roll off the nasal cavity.

Figure 2. Interaction of the drug solution with hydrophobic nasal mucus

The use of the IFN dosage form in the form of a gel allows dosed administration of the drug, overcoming the hydrophobic mucus of the nasal cavity, with In this case, according to studies, the active substance is released from the gel evenly over 5 hours [20].

Figure 3. Kinetic curves for the release of the active substance from gel compositions

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The dosage form of IFN in the form of rectal suppositories allows you to enter the active substance directly into the systemic circulation, bypassing the enzymatic function of the liver, since lipophilic non-ionized molecules freely penetrate the muco-epithelial barrier of the ampoule directly to the lymphatic and blood vessels, then to the systemic circulation.

Important!

Absorption from the rectum is faster than than when taken orally, thereby increasing the bioavailability of the drug substance. Another plus of suppositories is that the rectal route of administration does not cause side effects.

The bioavailability of drugs in the «rectal suppository» dosage form in a volume of 80% occurs at 20 minutes and is comparable to injectable forms.

Figure 4. Bioavailability of various dosage forms

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Source http://900igr.net/up/datas/207727/015.jpg

The results of the studies indicate that the combined use of rectal and topical forms of IFN α-2b (suppositories + gel) allows obtaining positive results that can be seen in assessing the clinical efficacy of ARVI treatment:

• the duration of the febrile period, intoxication syndrome and asthenia is reduced,

• the number of bacterial complications is reduced,

• accelerates the achievement of clinical remission.

Positive clinical effects are usually accompanied by positive dynamics on the part of the immune system.

Tab. Comparative characteristics of relief of clinical symptoms of influenza when using recombinant interferon α2b with antioxidants (suppositories) and umifenovir (M±m)

Figure 5. Decrease in temperature by the end of the first day in patients taking recombinant interferon α2b with antioxidants — suppositories and umifenovir -capsules (%)

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The combination of rectal and topical forms of IFN α-2b (suppositories + gel) provides positive clinical dynamics and is an effective and safe therapy for patients with acute respiratory viral infections and influenza [21,22].< /span>

Figure 6. Experience with the use of recombinant IFN-α-2b with antioxidants in suppositories + gel lekforms

< spanstyle="font-size:10pt;">*Main group — people who used INF α-2b with antioxidants;

Comparison group — people who used standard therapy

To date, several principle schemes for the treatment of COVID-19 using recombinant interferon-α2b have been proposed. Thus, Chinese authors suggest dosages for different age groups from 1,200,000 IU to 10,000,000 IU/day. Smaller doses will not be sufficient to suppress the development of a viral infection, but will only slow down the spread of the virus in the body [23].

Russian researchers are also conducting scientific research on the development of methods using high doses of recombinant IFN-α2b with antioxidants at a dose of 1 million IU to 3 million IU 2 times a day in the form of rectal suppositories, with parallel administration of the gel at a dose of 4000 IU 5 times a day. day.

Thus, from the presented data, it can be concluded that recombinant IFN-α2b with antioxidants has proven antiviral activity against ARVI and the new coronavirus infection COVID-19.

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