RU2763024C1 - Mefloquine and combinations thereof for treating and preventing a coronavirus infection - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to the field of medicine and pharmaceuticals, namely, to an application of mefloquine as a medicinal agent against an infection caused by the SARS-CoV-2 virus, in the amount of 500 mg of mefloquine per day, for four days of treatment. Preferably, the agent is administered twice a day orally or gastroenterically.EFFECT: invention provides an acceleration of elimination of the viral RNA, a reduction in the duration of treatment, a lighter course of the disease, and a reduction in the severity of symptoms.3 cl, 3 tbl, 6 ex

Description

The invention relates to the field of pharmaceuticals and medicine and is intended for the treatment of infection caused by a virus from the coronavirus family. The present invention discloses a medicament and a method for the treatment and prevention of coronavirus infection using mefloquine and its combinations with other active substances, in particular with antibiotics.

Prior art

Currently, the viral disease caused by the coronavirus SARS-CoV-32 (corona virus disease 2019) is attracting everyone's attention, due to the severity of the course, the lack of etiotropic therapy and lightning-fast spread. Coronaviruses (lat.Coronaviridae) are a family of 40 types of RNA viruses that infect humans and animals as of January 2020. The name is associated with the structure of the virus, the spines of which resemble the sun's corona.

Over the past 20 years, at least 3 outbreaks of coronavirus infections have been observed (2002-2003, 2015, 2019-2020). Coronaviruses that infect humans, in particular, include: HCoV-229E virus, HCoV-NL63 virus, HCoV-OC43 virus, HCoV-HKU1 virus, SARS-CoV virus (the causative agent of SARS - SARS or severe acute respiratory syndrome, an outbreak was registered in 2002), MERS-CoV virus (causative agent of MERS - Middle East respiratory syndrome, outbreak occurred in 2015), SARS-CoV-2 virus (COVID-19, 2019-nCoV). The latter is the cause of the pandemic, which was announced by WHO in March 2020. An outbreak of this infection began in the Chinese city of Wuhan in December 2019, after which, in 2 months, this infection spread almost all over the world. As of April 13, 2020, more than 1.6 million people were infected in the world, while more than 100 thousand people died from coronavirus infection.

SARS-CoV-2 is characterized by high virulence, long incubation period and initiation of a powerful pathological pro-inflammatory response - "cytokine burst". The disease it causes, COVID-19, which in most cases proceeds as an acute respiratory viral infection (ARVI), is associated with the frequent development of severe respiratory complications (viral pneumonia, respiratory failure, acute respiratory distress syndrome in adults - ARDS) and delayed lung damage. Most often, a severe course of this infection is observed in people over 65 years old, as well as against the background of chronic diseases (bronchial asthma, diabetes mellitus, cardiovascular diseases, etc.).

Currently, effective treatment and prevention regimens for the new coronavirus infection caused by SARS-CoV-2 have not been developed, and therapy is often symptomatic and supportive. Neuraminidase inhibitors, effective against influenza viruses, did not demonstrate pronounced activity in coronavirus infection. Immunomodulators, traditionally prescribed in the development of ARVI, with COVID-19 can lead to an aggravation of the patient's condition, especially when prescribed in the later stages of the disease. Antibiotics can only be considered as a means of preventing and treating concomitant bacterial complications, since they do not affect the virus.

Attempts are being made to use drugs against HIV infection for the treatment and prevention of COVID-19, in particular, HIV protease inhibitors (lopinavir, darunavir). Earlier, in experiments in vitro (on cell culture) and in vivo (on laboratory animals), this group of drugs was found to have antiviral activity against SARS-CoV and MERS-CoV, the genetic material of which coincides by 80% with SARS-CoV-2. However, the results of clinical use of lopinavir / ritonavir did not allow to prove its effectiveness [Cao B., 2020]. Schemes have been developed that include lopinavir / ritonavir in combination with interferon beta-1b or interferon alpha and ribavirin [Bhatnagar T., 2020], however, the expediency of their use is controversial [Jin Y.H., 2020].

A clinical study of lopinavir / ritonavir, conducted in China with the participation of 199 patients, led to the following conclusions [Cao B., 2020]:

- no effect on the mortality rate after 28 days;

- no effect on the frequency of detection of viral RNA in patients at various times after the start of therapy;

- the average time to achieve clinical improvement in patients did not exceed 1 day.

When lopinavir / ritonavir was administered to patients with severe COVID-19, no advantages were found compared to standard treatment (standard care without the use of specific antiviral drugs) [Jin Y.H., 2020]. Low evidence of the effectiveness of the use of this combination in COVID-19. It should be noted that in 14-30% of cases, patients with coronavirus infection stopped taking lopinavir due to severe side effects [Cao B., 2020; Liu F., 2020].

Other drugs have been studied that have been shown to be effective for the treatment of coronavirus infection caused by SARS and MERS. The greatest activity against SARS-CoV-2 in in vitro experiments was found in remdizivir (an inhibitor of RNA-dependent RNA polymerase), chloroquine and hydroxychloroquine (antimalarial drugs)

Remdesivir is considered one of the most promising COVID-19 chemotherapy drugs. The minimum inhibitory concentration of the drug in the cell culture is 0.77 μM, and the EC ₉₀ (the concentration of the drug that causes a 90% decrease in virus copies) is 1.76 μM. However, at present, only one case of successful clinical use of the drug in a patient with coronavirus infection is known.

Another group of drugs that have antiviral activity against SARS-CoV2 are 4-aminoquinoline derivatives - chloroquine and hydroxychloroquine. In in vitro studies, chloroquine has shown itself as a versatile antiviral agent that has shown activity against RNA- (rabies virus; poliomyelitis virus; HIV; hepatitis A and C viruses; influenza A and B viruses, in particular, the H5N1 influenza virus; Chikungunya fever viruses, Dengue, Zika, Lassa, Ebola; Crimean-Congo haemorrhagic fever virus) and DNA viruses (hepatitis B virus; herpes simplex virus) [Devaux CA., 2020]. In a number of cases, the antiviral properties of chloroquine have been confirmed in studies on infected patients. As an alternative to chloroquine, hydroxychloroquine, which is a chloroquine derivative, is less toxic and is used to treat autoimmune diseases.

The ability of chloroquine and hydroxychloroquine to suppress the cytopathic effect of SARS-CoV in cell culture studies [Biot C., 2006], while the activity of chloroquine was about five times higher than that of hydroxychloroquine (EC ₅₀ in cell culture was 6.5 ± 3.2 μM and 34 ± 5 μM, and the selectivity index is> 15 and> 3, respectively). An even greater antiviral activity of chloroquine was established against the HCoV-OC43 strain (the causative agent of atypical pneumonia). The EC _{50 of} chloroquine to suppress viral replication in cell culture was 0.306 ± 0.091 μM, and the selectivity index was 1369. In experiments on mice, it was found that the drug at a dose of 15 mg / kg (about 80 mg per person) ensured the survival of mice upon infection HCoV-OC43 at a dose of 10 ³ copies [Keyaerts E., 2009]. The blocking effect of chloroquine on the replication of the MERS virus was manifested at drug concentrations of 3–8 μM [de Wilde AH., 2014].

In a comparative study of the antiviral activity of chloroquine and hydroxychloroquine in vitro [Liu J., 2020], it was shown that in the MOI range from 0.01 to 0.8 (MOI - multiplicities of infection, the ratio of the number of viral particles to the number of cells in culture) ED ₅₀ 48 h after infection for chloroquine was 2.71-7.36 μM, and for hydroxychloroquine - 4.51-12.96 μM. At the same time, the cytotoxic dose for both drugs was more than 100 times higher than the average effective dose.

In another study [Yao X., 2020] when using MOI = 0.01 and adding hydroxychloroquine to the experience medium 2 h after the start of incubation of the cell culture with viral particles, EC ₅₀ after 24 h was 6.14 μM (2060 μg / L) , and after 48 h - 0.72 μM (258 μg / L).

In preliminary clinical studies conducted in China involving 100 patients infected with SARS-CoV-2, it was noted that with the use of chloroquine, fever passes more quickly, the lung condition improves according to the results of computed tomography, and recovery occurs earlier than control group [Agrawal S., 2020]. In a pilot clinical study conducted in France with the participation of 20 patients, it was shown that the use of hydroxychloroquine in COVID-19 can reduce viral load and accelerate recovery [Gautret P, 2020]. Acceleration of viral RNA elimination, recorded according to the results of PCR analysis, can be achieved with the combined administration of hydroxychloroquine with azithromycin. At the same time, studies that will allow us to make a final conclusion about the antiviral activity of 4-aminoquinoline derivatives when used for the treatment of COVID-19 are not yet completed.

Along with the fact that at present the activity of chloroquine and hydroxychloroquine against the SARS-CoV-2 coronavirus has been noted only in pilot studies, these drugs are characterized by pronounced side effects. The most serious negative effects were noted on the part of the organ of vision (corneal opacity, damage to the retina, visual impairment), the central nervous system (dizziness, loss of consciousness, sleep disturbances, hallucinations, mental disorders, polyneuropathy) and the cardiovascular system (rhythm disturbances, increased blood pressure). Common side effects include vomiting, diarrhea, abdominal pain, and increased transaminase activity.

Thus, there are currently no registered drugs intended for the etiotropic therapy of COVID-19, although the need for effective treatment and prevention of infection caused by a virus from the coronavirus family is constantly increasing against the background of the development of a pandemic.

The present invention provides an effective regimen for the treatment and prevention of COVID-19 with the following benefits:

- efficacy for therapeutic use in the form of monotherapy and in combination with antibiotics, while the following is observed:

a) acceleration of viral RNA elimination by PCR analysis;

b) reduction of treatment time (duration of fever, rate of decrease in the concentration of C-reactive protein, and others);

c) a decrease in the number of complications (the development of pneumonia in patients with a mild form of the disease; the development of respiratory failure and ARDS).

- effectiveness in prophylactic use by persons in contact with the sick, both once and repeatedly, while it is observed:

a) a decrease in the incidence of COVID-19 disease;

b) a decrease in the incidence of complications in COVID-19 disease.

Description of the invention

The present invention provides the use of mefloquine as a medicament for the prevention and treatment of an infection caused by a virus from the coronavirus family. In this case, the causative agent of a viral infection can be a virus of the SARS-CoV-2 type (Severe acute respiratory syndrome coronavirus 2).

According to the invention, there is provided the use of mefloquine for the treatment of infection in a dose ranging from 250 mg to 1500 mg per day. Mefloquine can be taken orally or administered to the patient by gastroenterology, at a time or in divided doses, for example, dividing the daily dose into 2 to 3 times 250 mg - 750 mg each. The course of treatment for an infection caused by a virus from the coronavirus family is from 3 to 14 days. During the course of treatment, mefloquine may be given in combination with an additional drug. This additional drug can be an agent selected from the group consisting of antibiotics, antiviral agents, interferon preparations, antibodies. For example, clarithromycin, azithromycin, amoxicillin, clavunic acid can be used as antibiotics. According to the invention, when used for the treatment of coronavirus infection, mefloquine is administered in combination with clarithromycin, the dose of which is from 500 to 1000 mg per day, possibly in divided doses 2 times a day. The introduction can be carried out orally or intravenously. Also, azithromycin can be used as an additional agent, as well as amoxicillin with clavulanic acid. Azithromycin in combination with mefloquine can be administered in an amount from 500 mg to 1000 mg of azithromycin per day, 500-1000 mg orally 1 time per day, or intravenous drip of 500 mg 1 time per day.

Antiviral drugs may include drugs against HIV infection, such as lopinavir, ritonavir and combinations thereof, darunavir, remdesivir, penciclovir, favipiravir. Interferon preparations include interferon alpha and beta groups, for example, interferon beta-1b, interferon alpha, and others. Antibodies can include antibodies to the proteins of the coronavirus that caused the infection, as well as other antibodies, for example, antibodies to interleukin-6 - tocilizumab, sarilumab.

In addition, according to the present invention, the use of mefloquine for the prevention of infection caused by a virus from the group of the coronavirus family is provided, in particular for the prevention of infection caused by SARS-CoV, SARS-CoV-2. For the prevention of infection, mefloquine is administered at a dose of 250 to 750 mg per day. Mefloquine can be administered orally in 1-3 doses, for example 1-3 times a day, dividing the total by the appropriate number of doses. The course of prophylaxis can be up to 3 days, when taken 1-2 times a day. Further, according to the invention, it is possible to reduce the total amount of mefloquine taken for prophylaxis, before taking once a week in an amount of 250 to 500 mg, while the course of weekly intake can be from 2 to 8 weeks.

Detailed description of the invention

Mefloquine is a 4-methanzinoline derivative,
(R *, S *) - (±) -alpha-2-Piperidinyl-2,8-bis- (trifluoromethyl) -4-quinoline-methanol, of the following formula

.

...

Meflokhin (in Russia known by the trade name "Meflokhin", abroad - under the trade name "Lariam"), is known as an antimalarial, antiprotozoal drug. It has a high hematoschizontic activity against Plasmodium falciparum and P. vivax, is not effective against P. falciparum gamonts and P. vivax hepatic histochizonts, and may act on circulating P. ovale and P. malariae schizonts.

According to the present invention, mefloquine in an amount of 200 to 1500 mg of mefloquine per day can be administered to treat or prevent an infection caused by a virus from the coronovirus family. Coronaviruses include, in particular, the following types of viruses: HCoV-229E, HCoV-NL63 virus, HCoV-OC43 virus, HCoV-HKU1 virus, SARS-CoV virus (the causative agent of SARS or severe acute respiratory syndrome), MERS-CoV virus ( the causative agent of the Middle East respiratory syndrome), the SARS-CoV-2 virus (COVID-19, 2019-nCoV). In particular, according to the present invention, mefloquine is used as a drug against SARS-CoV, MERS-CoV, SARS-CoV-2 viruses (COVID-19, 2019-nCoV), particularly preferably against SARS-CoV-2 virus (COVID- 19, 2019-nCoV). This virus is characterized by high virulence and an incubation period of up to 14 days. With a mild course, it has similar symptoms to an acute respiratory viral infection that develops under the influence of the influenza virus. When proceeding in a moderate form, the disease is characterized by the development of viral pneumonia and a high frequency of complications (severe course), which include acute respiratory failure, ARDS, sepsis. The diagnosis is confirmed by detecting the RNA of the virus by PCR or by detecting antibodies to virus proteins by ELISA.

Thus, the diagnosis of coronavirus infection can only be made after performing a series of tests, for example, taking a swab from the throat or nose or blood for analysis, and determining the presence of the nucleic acid of the virus, or nucleotide sequences characteristic of the virus, or antibodies against the virus based on the results PCR or ELISA.

According to the invention, for treatment, mefloquine is administered in a single dose of 250 to 750 mg. The total total daily dose can range from 250 to 1500 mg. In this case, the total total dose of mefloquine can be divided into 2-3 doses per day, in an amount of 250 to 750 mg. Mefloquine can be administered to a patient orally, for example, in the form of a tablet, capsule, suspension, solution, syrup, with the addition of excipients necessary to obtain a stable dosage form, or gastroenterically, for example, nasogastric, through a tube, in the form of a suspension. Preferably, mefloquine is administered in tablet form, 250 mg every 8 hours, 2-3 times a day. Additionally, mefloquine should be taken with plenty of water or after meals.

Treatment with mefloquine is carried out in a course of 3-14 days. The total dose when administered to a patient may vary, depending on the day of treatment, the severity of the disease, and other parameters determined by the attending physician. In particular, mefloquine can be taken as follows:

1st day: 750 mg of mefloquine per day, by mouth, in tablets of 250 mg 3 times a day - 1 tablet every 8 hours.

2nd day: 500 mg of mefloquine, by mouth, in tablets of 250 mg 2 times a day - 1 tablet every 12 hours.

3rd - 7th day: 250 mg of mefloquine, by mouth, in tablets of 250 mg 1 time per day at the same time.

Mefloquine can be used in combination with additional drugs, for example, antibiotics, other antiviral agents, interferon drugs, antibodies. For example, mefloquine can be administered in combination with clarithromycin, azithromycin, amoxicillin, and clavulanic acid. Doses of clarithromycin, azithromycin may vary depending on the severity of the disease, the weight of the patient, concomitant diseases and other parameters that, in the opinion of the attending physician, affect the course of treatment and the amount of the drug used. For example, for the treatment of COVID-19, mefloquine can be administered to a patient in combination with clarithromycin, the dose of which ranges from 500 to 1000 mg per day, possibly in divided doses 2 times a day. The introduction can be carried out orally or intravenously. Also, mefloquine can be administered in combination with azithromycin, while azithromycin can be administered in a dose of 500 mg to 1000 mg of azithromycin per day, 500-1000 mg orally once a day, or intravenously 500 mg once a day.

The combinations of mefloquine and clarithromycin, or mefloquine and azithromycin, can be presented in a single dosage form containing mefloquine and clarithromycin or mefloquine and azithromycin, or a kit with separate dosage forms of mefloquine and clarithromycin or mefloquine and azithromycin.

The present invention, with the introduction of mefloquine in the indicated amounts in combination with antibiotics, makes it possible to increase the effectiveness of mefloquine when administered as monotherapy. At the same time, there is an acceleration of the elimination of viral RNA during PCR analysis, a reduction in the treatment time for infection, and a decrease in the frequency of complications.

Also, according to the invention, mefloquine can be used for emergency or planned prevention of infection with viruses from the coronavirus family, in particular, the types SARS-nCoV, SARS-CoV-2. This prophylaxis is especially important for persons who have one or more contact with infected patients, for example: medical personnel; from persons conducting an examination at the entrance to the institution; from persons engaged in particularly important work. For the prevention of infection, mefloquine is administered at a dose of 250 to 750 mg per day. Mefloquine can be administered orally in 1-3 doses, for example 1-3 times a day, dividing the total by the appropriate number of doses. The course of prophylaxis can be up to 3 days, when taken 1-2 times a day. Further, according to the invention, it is possible to reduce the total amount of mefloquine taken for prophylaxis before taking once a week in an amount of 250 to 500 mg, while the course of weekly intake can be from 2 to 8 weeks. In this case, it is desirable that the weekly doses of the drug are administered on the same day of the week, preferably with plenty of water or after meals. Mefloquine can be administered orally, for example, in the form of tablets, capsules, suspension, solution or syrup, with the addition of excipients necessary to obtain a stable dosage form, or gastroenterically.

In the prevention of mefloquine, efficacy was noted in the form of a decrease in the number of cases, as well as the incidence of complications in COVID-19 (development of pneumonia, development of respiratory failure and ARDS) (acute respiratory failure)).

In the following, the invention will be illustrated by examples which are not intended to limit the scope of the invention.

Examples of

Example 1

Evaluation of the effectiveness of mefloquine against coronavirus
SARS-CoV-2 in cell culture

The study of the antiviral activity of mefloquine was carried out in in vitro systems on green monkey kidney cell cultures of the Vero E6 line. When studying the antiviral activity, a SARS virus strain of the SARS-CoV-2 type was used, isolated from patients diagnosed with COVID-19 and clinical signs of the disease, in whom the diagnosis was confirmed by detecting the RNA of the virus in swabs from the nasopharynx by PCR.

To determine the antiviral efficacy of mefloquine, the decrease in the level of virus accumulation under the action of the drug was assessed, and the inhibition coefficient was also calculated. The study drug was introduced 2 hours after infection, the infectious dose was 0.01 CPP / cell. The concentration of mefloquine was noted, which completely prevented the cytotoxic activity of the virus against the cultures.

In a series of preliminary experiments, the cytotoxic effect of mefloquine on the Vero E6 cell line was evaluated. It was shown that at concentrations from 0.5 μM to 18.0 μM mefloquine did not cause visually observed changes in cells. Higher concentrations of the drug were found to be cytotoxic.

When studying the effect of mefloquine on the cytotoxic activity of the virus, it was found that the drug at a concentration of 4.7 μM completely suppressed the ability of the SARS-CoV-2 virus to induce a cytopathic effect in the monolayer of cell cultures 48 h after infection, and at a concentration of 3.0 μM, the suppressive ability amounted to about 60%.

When studying the suppression of the reproduction of the SARS-CoV-2 virus in a Vero E6 cell culture under the influence of mefloquine, it was shown that the drug effectively prevented viral replication 72 hours after infection at concentrations of more than 3.0 μM. The level of suppression of virus accumulation at this concentration was 1.4 ± 0.2 lg CPP ₅₀ / ml, while the inhibition coefficient was more than 92.5%. Considering the results of studying the cytotoxicity and antiviral efficacy of mefloquine, the value of the chemotherapeutic index for this drug was 6.0.

Thus, mefloquine completely prevented the cytopathic effect of the SARS-CoV-2 virus in cell culture at a concentration of 4.7 μM, which is 2.0 μg / ml.

Example 2

Determination of plasma concentration of mefloquine after a single oral dose of 750-1500 mg

In a study conducted with healthy male volunteers aged 18-45 years, a comparative study of the pharmacokinetic parameters of mefloquine after a single oral administration in doses of 750 mg and 1500 mg was carried out. The number of volunteers in each group was 6 people. In addition, the dynamics of the concentration of mefloquine in the blood plasma was assessed on the 2nd and 3rd days after the course of administration of the drug according to the following scheme: 1st day - 750 mg, 2nd day - 500 mg, 3rd day 250 mg ... The results are shown in Table 1.

Table 1. - Plasma concentration of mefloquine in healthy volunteers after administration in doses of 750 mg and 1500 mg.

Indicator Meaning 1st day (750 mg) 2nd day (+500 mg) 3rd day (+250 mg) 1500 mg once С _max, μg / ml 0.65
(0.4-1.5) 1.28
(0.9-3.4) 2.2
(1.4-3.8) 1,3
(0.7-2.8)

The time to reach the maximum concentration of mefloquine in the blood plasma after taking the drug at a dose of 750 mg was 15.4 hours, and the half-life was 17.6 ± 3.4 days. Given the long half-life, repeated administration of mefloquine on days 2 and 3 was accompanied by a non-linear increase in the drug concentration in blood plasma by 1.97 times and 1.71 times, respectively. This effect could be associated with a slowdown in the metabolism of mefloquine in the liver or a redistribution of its bound and free fraction.

Thus, with the course of administration of mefloquine according to the scheme described above, the concentration of the drug, providing its antiviral effect (~ 2 μg / ml), is achieved on the 2nd - 3rd day.

Example 3

Effect of clarithromycin on plasma mefloquine concentration after a single dose

In a comparative study conducted with healthy male volunteers aged 18-45 years, the effect of clarithromycin on the pharmacokinetic parameters of mefloquine after a single oral administration was evaluated.

Volunteers in group 1 (6 people) took mefloquine at a dose of 750 mg.

Group 2 volunteers received mefloquine 750 mg in combination with clarithromycin 500 mg.

Comparison of the main pharmacokinetic parameters showed that the maximum concentration of mefloquine in the blood plasma was 0.65 ± 0.21 μg / ml and 0.89 ± 0.29 μg / ml in the volunteers of group 1 and group 2, respectively (the differences between the groups were significant for p <0.05), while the time to reach the maximum concentration of mefloquine in the blood plasma while taking clarithromycin increased from 15.4 hours to 16.8 hours. mefloquine was 18.2 ± 5.3 μg / ml * day, and after the administration of mefloquine in combination with clarithromycin it increased to 21.9 ± 9.6 μg / ml * day. The half-life of mefloquine was 17.6 ± 3.4 days and 15.0 ± 3.5 days, and the apparent volume of distribution was 19.6 ± 2.9 L / kg and 14.7 ± 5.9 L / kg in groups 1 and 2, respectively (for both indicators, the differences between the groups are significant at p <0.05).

Thus, the combined administration of mefloquine with clarithromycin allows a higher concentration of mefloquine in the blood plasma to be achieved, which contributes to a more rapid achievement of a concentration that prevents the spread and replication of the virus. At the same time, the apparent volume of distribution of the drug is reduced and its excretion from the body is accelerated, which can help to reduce the incidence of side effects.

Example 4

The use of mefloquine for the treatment of patients with an infection caused by a virus from the coronavirus family.

Patients were selected who, on the basis of clinical and laboratory data, were diagnosed with "New coronavirus infection COVID-19 (confirmed), mild form." The criteria for making a diagnosis in accordance with the guidelines of the Ministry of Health of the Russian Federation “Temporary guidelines. Prevention, diagnosis and treatment of new coronavirus infection (COVID-19) ", Version 5 (04/02/2020) were:

- a positive result of the analysis of a swab from the nasopharynx for the presence of SARS-CoV-2 RNA by PCR;

- ARVI symptoms (dry cough, sore throat, weakness, symptoms of intoxication);

- body temperature less than 38.5 ° С;

- RR ≤ 22 / min, SpO2 ≥93%;

- concentration of C-reactive protein in blood plasma ≤10 mg / l;

- absence of signs of pneumonia according to the results of computed tomography of the chest organs.

Depending on the therapy, the patients were divided into two groups:

1) Group 1: patients who received symptomatic treatment (without prescribing drugs with antiviral activity).

2) Group 2 - patients who took mefloquine according to the following scheme:

• 1st day: 750 mg of mefloquine per day, by mouth, in tablets of 250 mg 3 times a day - 1 tablet every 8 hours.

• 2nd day: 500 mg of mefloquine, by mouth, in tablets of 250 mg 2 times a day - 1 tablet every 12 hours.

• 3rd - 7th day: 250 mg of mefloquine, orally, in tablets of 250 mg 1 time per day at the same time.

The drug was taken with plenty of water, if possible after a meal.

The results of PCR analysis 5 days and 11 days after the start of treatment are presented in Table 2.

Group Detection rate of SARS-CoV-2 RNA
in PCR analysis for 5 days for 11 days n % Significance level n % Significance level Symptomatic therapy (n = 20) 3/20 15 0.031 4/20 twenty 0.023 Mefloquine (n = 20) 12/18 66.7 15/18 83.3

5 days after the start of treatment, in 66.7% of patients who took mefloquine, PCR analysis did not reveal viral RNA in nasopharyngeal swabs, while in patients with symptomatic therapy, the absence of viral RNA according to the results of PCR analysis was observed in only 15 % of patients, the differences between the groups were significant at p <0.05. 11 days after the start of treatment, in 83.3% of patients who took mefloquine, PCR analysis did not reveal viral RNA in nasopharyngeal swabs, while in patients with symptomatic therapy, the absence of viral RNA according to the results of PCR analysis was observed in 20% patients, the differences between the groups are not significant.

Thus, mefloquine promoted more rapid elimination of viral RNA in patients infected with SARS-CoV-2.

Example 5

Use of mefloquine in combination with azithromycin and clarithromycin for the treatment of patients with coronavirus infection

Patients were selected who, on the basis of clinical and laboratory data, were diagnosed with “New coronavirus infection COVID-19 (confirmed), mild form” or “New coronavirus infection COVID-19 (confirmed), severe form, community-acquired bilateral pneumonia. Criteria for diagnosing a mild form of the disease are presented in Example 4. Criteria for diagnosing a moderate form in accordance with the guidelines of the Ministry of Health of the Russian Federation “Temporary guidelines. Prevention, diagnosis and treatment of new coronavirus infection (COVID-19) ", Version 5 (08.04.2020) were:

- a positive result of the analysis of a swab from the nasopharynx for the presence of SARS-CoV-2 RNA by PCR;

- signs of pneumonia based on the results of computed tomography of the chest organs;

- body temperature over 38.5 ° С;

- dry cough, pronounced signs of intoxication (complaints of malaise, weakness and fatigue; headache, muscle pain), a feeling of congestion in the chest;

- shortness of breath, RR> 22 / min, SpO2 <93%, plasma C-reactive protein concentration> 10 mg / L.

- no indications for mechanical ventilation, no ARDS, sepsis, multiple organ failure.

Three groups of patients were identified:

- group 1: patients with mild COVID-19 (n = 20) who received symptomatic treatment without prescribing drugs with antiviral activity. This group did not include patients with a moderate form of the disease, since such patients were necessarily prescribed antiviral therapy;

- group 2 - patients with moderate COVID-19 who were prescribed mefloquine and azithromycin according to the following scheme:

• 1st day: 750 mg of mefloquine per day, by mouth, in tablets of 250 mg 3 times a day - 1 tablet every 8 hours.

2nd day: 500 mg of mefloquine, by mouth, in tablets of 250 mg 2 times a day - 1 tablet every 12 hours.

3rd - 7th day: 250 mg of mefloquine, by mouth, in tablets of 250 mg 1 time per day at the same time.

The drug was taken with plenty of water, if possible after a meal. In some patients who could not administer the drug orally, it was administered through a nasogastric tube, after preparing a suspension, finely grinding mefloquine and adding distilled water to it at the rate of 10 ml of water per 1 tablet of 250 mg.

• 500 mg of azithromycin per day, by mouth, 500 mg once a day, during the entire period of taking mefloquine.

- group 3 - patients with moderate COVID-19 who were prescribed mefloquine and clarithromycin according to the following scheme:

• 1st day: 750 mg of mefloquine per day, by mouth, in tablets of 250 mg 3 times a day - 1 tablet every 8 hours.

2nd day: 500 mg of mefloquine, by mouth, in tablets of 250 mg 2 times a day - 1 tablet every 12 hours.

3rd - 7th day: 250 mg of mefloquine, by mouth, in tablets of 250 mg 1 time per day at the same time.

The drug was taken with plenty of water, if possible after a meal. In some patients who could not administer the drug orally, it was administered through a nasogastric tube, after preparing a suspension, finely grinding mefloquine and adding distilled water to it at the rate of 10 ml of water per 1 tablet of 250 mg.

• 1000 mg of clarithromycin per day, by mouth, 500 mg 2 times a day, throughout the period of administration of mefloquine.

The results of PCR analysis 5 days and 11 days after the start of treatment are presented in Table 3.

Group Detection rate of SARS-CoV-2 RNA
in PCR analysis for 5 days for 11 days n % Significance level n % Significance level Group 1
(symptomatic therapy, n = 20) 3/20 15 - 4/20 35 - Group 2
Mefloquine + azithromycin (n = 10) 9/10 90 0.015 9/10 90 0.03 Group 3
Mefloquine + azithromycin (n = 16) 14/16 87.5 0.014 16/16 one hundred 0.01

When patients with a moderate course of COVID-19 were prescribed mefloquine in combination with azithromycin or mefloquine in combination with clarithromycin, in most cases (80-90%), the elimination of viral RNA was noted already on the 5th day after the start of treatment. After 11 days, a negative PCR analysis for viral RNA was recorded in all patients taking mefloquine and clarithromycin, and in 90% of patients taking mefloquine and azithromycin.

Thus, both azithromycin and clarithromycin enhanced the effect of mefloquine on SARS-CoV-2. The drugs provided faster elimination of viral RNA based on the results of PCR analysis of nasopharyngeal swabs obtained from patients with COVID-19.

Example 6

The use of mefloquine for the prevention of coronavirus infection in people who have come into contact with people who have been diagnosed with a new coronavirus infection COVID-19 based on PCR results

We established “contact” medical personnel with an increased risk of infection with SARS-CoV-2 - doctors and nurses who directly worked in the “infectious zone with patients who, based on the results of PCR analysis, were diagnosed with“ New coronavirus infection (COVID-19) ”.

They were divided into 2 groups of 40 people:

1) group 1 - the medical staff took mefloquine according to the following scheme:

1st and 2nd days: at a dose of 500 mg per day, by mouth, in tablets of 250 mg 2 times a day - 1 tablet every 12 hours.

3rd day: mefloquine at a dose of 250 mg per day, by mouth, in tablets of 250 mg once a day.

Further, mefloquine is taken at 250 mg (1 tablet) once a week for 6 weeks. The drug was taken on the same day of the week at the same time with plenty of water.

2) group 2 - the medical staff took a placebo in the same dose and according to the same scheme.

7-8 weeks after starting mefloquine or placebo, it was determined how many people at increased risk of COVID-19 infection developed signs of the disease, confirmed by PCR results.

It was found that while taking placebo COVID-19 developed in 35% of cases, while while taking mefloquine, the disease developed only in 10% of cases (differences between groups are statistically significant at p <0.05).

Thus, according to the present invention, mefloquine can be successfully used for the treatment and prevention of new coronavirus infection caused by SARS-CoV-2.

Claims (3)

1. The use of mefloquine as a drug against infection caused by the SARS-CoV-2 virus, in an amount of 500 mg of mefloquine per day, for four days of treatment. 2. Application according to claim 1, characterized in that mefloquine is administered in an amount of 250 mg 2 times a day, at a daily dose of 500 mg, for four days of treatment. 3. Use according to claim 1, characterized in that the mefloquine is administered orally or gastroenterically.