RU2306137C1 - Preparation for preventing and treating influenza - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying a preparation for preventing and treating influenza that contains methyl-1-adamantyl-methylamine hydrochloride, 2-ethylthiobenzimidazole hydrobromide and a pharmaceutically acceptable filler; moreover, it is of high curative effect and, also, increases protective body functions, endurance and recovery period by not deepening pathogenetic mechanisms caused by influenza virus at the following ratio of ingredients, weight%: methyl-1-adamantyl-methylamine hydrochloride 5-15; 2-ethylthiobenzimidazole hydrobromide 15-50; a filler- the rest.

EFFECT: higher efficiency of prophylaxis and therapy.

1 cl, 5 ex, 1 tbl

Description

The invention relates to medicine, namely to preparations for the prevention and treatment of influenza, i.e. to pharmaceutical compositions.

Influenza and other acute respiratory viral infections (SARS) are the most common diseases that occur throughout the year, but most often - in the fall and winter. According to the Ministry of Health of the Russian Federation, acute respiratory viral infections occupy the first place in the structure of infectious diseases and make up 80-90% of all cases of infectious diseases.

Influenza is an acute infectious disease of viral etiology, which is accompanied by damage to the upper respiratory tract. Influenza reduces the body's defenses, as a result of which it can cause various diseases of the upper and lower respiratory tract, central nervous system, heart, kidneys and other organs.

The economic damage from influenza is huge for every sick person and for society as a whole. The seasonal outbreak of influenza in Russia brings direct and indirect losses of about 40 billion rubles.

In addition to direct harm to human health, influenza can aggravate the course of other diseases, which is especially dangerous for people with chronic pathologies and a weakened immune system - elderly, newborns, patients with cardiovascular diseases, etc. Therefore, a new search is constantly underway for its prevention and treatment.

With influenza type A and type B, drugs are used in the treatment that facilitate the course of the disease, reducing muscle, joint, headaches, and lower the temperature. These drugs include acetylsallicylic acid, analgin, antigrippin (Influenza. Edited by G.I. Karpukhin, L .: Lenizdat, Medicine, 1986).

Currently, INN “Rimantadine” has gained wide popularity in the treatment and prevention of influenza (Kilburn ED In the book Influenza viruses and influenza, Moscow, 1978, 309-14, Mashkovsky MD Medicines, part 2, M .: Medicine, 1993, pp. 395-306, Kiselev O. I. et al. Antiviral drugs for the treatment of influenza and acute respiratory infections. Design of drugs based on polymer carriers. St., 2000, p. 33, Bogle et.al Biochem. Biophys. Res. Comm., 1991, v. 180, p. 926. Etc). INN "Rimantadine" - methyl-1-adamantylmethylamine hydrochloride is used in medical practice in the form of white tablets, bitter taste. Rimantadine is known to have antiviral activity against a wide range of strains of type A influenza virus, especially the H3N2 seroptype. INN "Rimantadine" is taken for early treatment (in adults and schoolchildren) and prevention (in adults) of influenza during epidemics. It should be noted that Rimantadine has a number of contraindications, namely for acute liver diseases, acute and chronic kidney diseases, thyrotoxicosis and pregnancy, and also causes the resistance of virus A.

Improving the pharmacokinetics of "Rimantadine" is observed with the addition of the drug no-shpa. This pharmaceutical composition is described in RF patent No. 2229877, priority date 02.25.2003, publication date 10.06.2004. The known pharmaceutical composition contains β-methyl-1-adamantylmethylamine hydrochloride and 1- (3,4-diethoxybenzylidene) -6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in the following ratio, wt.%:

-methyl-1-adamantylmethylamine hydrochloride 7-33 1- (3,4-diethoxybenzylidene) -6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride 13-53

This etiotropic complex for the treatment of the no-shpa-rimantadine flu virus has antiviral activity that is superior to the effectiveness of using each of its individual drugs. However, the following side effects of dizziness, fever, palpitations, as a result of antispasmodic action, are characteristic of No-shpa (INN Drotaverin). As you know, the influenza virus can cause precisely microcirculatory disorders, leading to atony of blood vessels - hypotension, and drotaverine, against the background of such complications, can aggravate the situation.

The aim of this invention is to provide a means for the treatment of influenza based on the INN "Rimantadine", which would have a high therapeutic effect and at the same time increase the protective functions of the body, endurance and the period of convalescence, without aggravating the pathogenetic mechanisms caused by the influenza virus.

To this end, the authors of this invention propose to use the composition for the treatment of influenza INN "Rimantadine" in combination with INN 2-ethylthiobenzimidazole hydrobromide in the following ratio, wt.%:

-methyl-1-adamantylmethylamine hydrochloride 5-15 2-ethylthiobenzimidazole hydrobromide 15-50

The optimal ratio of the components is the following, in wt.%:

-methyl-1-adamantylmethylamine hydrochloride 10 2-ethylthiobenzimidazole hydrobromide 25

filler to form a tablet or capsule.

As fillers in the proposed tool for the prevention and treatment of influenza can be used:

microcrystalline cellulose, starch, Mg / Ca stearate, lactose, polyvinylpyrrolidone, etc.

Below are examples of the proposed funds with various fillers, the ratio of the components is given in wt.%.

Example 1

-Metyl-1-adamantylmethylamine hydrochloride 5-15 2-Ethylthiobenzimidazole hydrobromide 15-50 Microcrystalline cellulose 25-80

Example 2

-Metyl-1-adamantylmethylamine hydrochloride 5-15 2-Ethylthiobenzimidazole hydrobromide 15-50 Starch rest

Example 3

-Metyl-1-adamantylmethylamine hydrochloride 5-15 2-Ethylthiobenzimidazole hydrobromide 15-50 Mg / Ca Stearate rest

Example 4

-Metyl-1-adamantylmethylamine hydrochloride 5-15 2-Ethylthiobenzimidazole hydrobromide 15-50 Lactose rest

Example 5

-Metyl-1-adamantylmethylamine hydrochloride 5-15 2-Ethylthiobenzimidazole hydrobromide 15-50 Polyvinylpyrrolidone rest

2-Ethylthiobenzimidazole hydrobromide (better known as "Bemethyl") is a crystalline powder, white or white with a creamy tint, soluble in water with the formation of turbid solutions. It has a psychostimulating effect, has antihypoxic activity, increases the body's resistance to hypoxia and increases performance during physical exertion. It is considered as a representative of a new group - actoprotective drugs. Slowly absorbed by ingestion.

So 2-ethylthiobenzimidazole hydrobromide in various experiments shows the following results:

1. When studying the protective activity of the plague vaccine, this drug increased the survival of animals infected with 1-10 Dcl of the highly virulent strain of plague by 20-30%. Russia, Research Anti-Plague Institute, Volgograd (National Conf. Russian Association of Allergists and Clinical Immunologists "Modern. Probl. Allergol., Clinical Immunol. And Immunofarmakol.", Moscow, January 28-31. 1997 )

2. We studied the effectiveness of 2-ethylthiobenzimidazole hydrobromide (bemethyl) in the treatment of pyoderma in 51 patients compared with conventional therapy in 58 patients (control group). It was found that in the treatment of 2-ethylthiobenzimidazole with hydrobromide, clinical recovery occurred in 44 (86, 34, 8%) patients; significant improvement - in 6 (11, 84, 5%) patients; slight improvement - in 1 (2, 02, 0%) patients. (Samtsov A.V., Tarasenko G.N., Smirnov A.V. A new approach to the treatment of pyoderma in military personnel: the use of bemetil actoprotector, Military Medical University, issue No. 5, 1998, pp. 50-54 , 96).

3. There is also work in which it is recommended to use it in an unstable epidemiological situation. The reliability and validity of such a long use of 2-ethylthiobenzimidazole hydrobromide is controversial, but shows the effectiveness of its use in such socially and economically significant diseases as influenza and SARS (Bortnovsky V.N., Epidemiological efficacy of bemethyl for the prevention of acute respiratory infections, Gomel State Medical Institute, Gomel, 1996).

The epidemiological effectiveness of the use of 2-ethylthiobenzimidazole hydrobromide in an organized team with an unstable epidemic situation in relation to influenza and acute respiratory viral infections in the autumn-winter period was studied. 2-ethylthiobenzimidazole hydrobromide was used for 4 weeks in five-day courses of 0.25 g / day with two-day breaks between courses, starting from the first decade of November. The pronounced prophylactic efficacy of 2-ethylthiobenzimidazole hydrobromide in relation to acute respiratory infections in the first month of observation was established. As a result, the number of cases among those taking 2-ethylthiobenzimidazole hydrobromide decreased by 1.7 times, and the duration of inpatient treatment - by 1.4 times. The reduction in the incidence in the group protected by the immunomodulator allows us to talk about the economic effectiveness of the studied drug and the feasibility of its use before the flu epidemic and in organized groups with an unstable epidemic situation.

In addition to the indicated properties of the effect on the protective functions of 2-ethylthiobenzimidazole, hydrobromide has a pronounced positive effect on redox metabolism.

4. The effect of AH and AP is due to the normalization of energy metabolism and lipid peroxidation processes of 2-ethylthiobenzimidazole hydrobromide (Russian National Congress "Man and Medicine", Moscow, April 8-12, 1997, Antihypoxants and actoprotectors in prevention and treatment cardiovascular pathologies).

... The inclusion of 2-ethylthiobenzimidazole hydrobromide in the complex of preoperative preparation reduces the severity of oxidative stress in the postoperative period ... (Lakhin R.E., Polushin Yu.S., Smirnov A.V., Belozerova L.A., Romanov D. M., Ketskalo M.V., Russia, VMA, St. Petersburg, Bibl. 9).

5. The mechanism of action of 2-ethylthiobenzimidazole hydrobromide is associated with rapidly developing activation of RNA and protein synthesis in various organs. As a result, the formation of enzymes of energy metabolism, antioxidant protection, and structural proteins is enhanced (Smirnov A.V., Ganchgo V.Yu. et al., Bemethyl regulation of adaptive processes in humans and animals, Materials of the 8th Int. Symposium "Ecological Physiol. Problems of adaptation ", M., January 27-30, 1998).

The authors suggested that the use of INN "Rimantadine" and INN 2-ethylthiobenzimidazole hydrobromide preparations at the same time will lead to an increase in the body's protective functions, reduction of complications and a reduction in the incidence of disease. However, the result exceeded all expectations. During the experiments, significant advantages were noted in comparison with: rimantadine, and rimantadine with the addition of succinic acid. A control group was also present.

It is impossible to achieve such a result using Rimantadine or 2-ethylthiobenzimidazole hydrobromide preparations separately.

Obviously, at the stage of exposure to the virus of the rimantadine molecule 2-ethylthiobenzimidazole, the hydrobromide has a potentiating effect on the interferonogenic activity of rimantadine and increases the resistance of cells to the ability of the influenza virus to penetrate through the cell membrane. But in addition to the etiotropic effectiveness of this combination, the addition of 2-ethylthiobenzimidazole hydrobromide helps, with an already developed infectious process, reduce the destruction of ciliated epithelial cells, as well as microcirculatory disorders, and also reduce the period of the disease and the severity of the disease. And as a result, reduce the number of complications.

To prove this, we give experimental data obtained as a result of studies conducted in accordance with the GLP rules and the “Methodological guidelines for the study of the antiviral activity of pharmacological substances (in the book“ Manual on the experimental (preclinical) study of new pharmacological substances ”, Ministry of Health of the Russian Federation, Remedium, M ., 2000. The experiments were performed on non-linear white male mice weighing 16-18 g, age 3.5-4 months, Rats came from the nursery Rappolovo, St. Petersburg.

The duration of the quarantine (acclimatization period) for all animals was 14 days. During quarantine, each animal was inspected daily. Before the start of the study, animals meeting the criteria for inclusion in the experiment were divided into groups using the randomization method.

The room is a standard virological unit with lock chambers, vestibule rooms, forced draft and filters on the exhaust system.

Cages with animals were placed in separate rooms. Light mode: 12 hours - light, 12 hours - darkness. The air temperature was maintained within 19-25 ° C, relative humidity - 50-70%. Temperature and humidity were recorded daily. When weather conditions changed, the air exchange in the room was monitored using an anemometer and by measuring the content of carbon dioxide and ammonia in the air. The ventilation mode was established, providing about 15 room volumes per hour, the concentration of СО _{2 was} not more than 0.15 volume%, ammonia - not more than 0.001 mg / l.

During the study, each animal was examined daily. The examination included an assessment of the behavior and general condition of the animals. Inspection was carried out approximately 1 hour after administration of the pharmaceutical composition.

In total, 4 experimental groups were formed (each experimental group included 10 animals).

1. Animals treated with rimantadine.

2. Animals treated with rimantadine + succinic acid.

3. Animals treated with rimantadine + 2-ethylthiobenzimidazole hydrobromide.

4. Control.

RESEARCH MEDICINES

Rimantadine is a substance.

2-ethylthiobenzimidazole hydrobromide - substance,

Succinic acid is a substance.

The drugs were administered intraperitoneally in physiological saline. The comparative effectiveness of the drugs was evaluated by several groups of indicators.

The results of the study are presented in the table.

Group number Injected drug Heads The dynamics of the death of mice after infection with HAV during the observation period (10 days) Total fell Veego survived % survival one 2 3 four 5 6 7 8 9 10 one Drug No. 1 (rimantadine) 10 5 one 2 8 2 twenty 2 The drug No. 2 * (rimantad in + X) 7 ** one 2 2 one 6 one 14.3 3 Drug No. 3
(rimantad in + Y) 10 2 one four one 8 2 twenty four virus control 10 one 3 3 3 10 0 0 * - the drug showed toxicity: 3 mice fell before infection, the rest were in poor condition ** - 3 mice died before infection.

The drugs were administered 24 hours before infection intraperitoneally in a volume of 0.5 ml. Infection was carried out intranasally with influenza A virus, Aichi (H3N2), at an infectious dose of 8.4 LD ₅₀ .

Amount of rimantadine in each dose of 1 mg, drug X - succinic acid in a quantity of 6 mg. The drug Y - 2-ethylthiobenzimidazole hydrobromide 1 mg.

The average life time of animals for the preparation No. 1 is 6.5 days, No. 2 - 3.7 days, No. 3 - 7.3 days, No. 4 - 5.8 days. The increase in the average life time in relation to control is 0.7 days for the preparation No. 1, 1.5 days for the preparation No. 2 (- 2, 1), and 1.5 days for No. 3.

The obtained experimental data showed that:

1. The combination of rimantadine + succinic acid has a pronounced toxicity and is not of interest for further research.

2. The combination of rimantadine + 2-ethylthiobenzimidazole hydrobromide is not inferior to rimantadine in the percentage of survival and significantly exceeds it in increasing the average life expectancy. It should be borne in mind that the study was conducted on a model of a hard virus that causes 100% mortality among this line of mice.

Claims (2)

1. An agent for the prevention and treatment of influenza containing β-methyl-1-adamantyl-methylamine hydrochloride and a pharmaceutically acceptable excipient, characterized in that it additionally contains 2-ethylthiobenzimidazole hydrobromide in the following ratio, wt.%: methyl 1-adamantyl methylamine hydrochloride 5-15 2-ethylthiobenzimidazole hydrobromide 15-50 filler rest 2. The tool according to claim 1, characterized in that it contains components in the following ratio, wt.%: methyl 1-adamantyl methylamine hydrochloride 10 2-ethylthiobenzimidazole hydrobromide 25 filler rest