The tool, with preventive and curative activity against influenza virus type b

 

(57) Abstract:

The invention relates to a new destination known compounds of a number of oxyindole, namely 1-methyl-2-phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate formula given in the text description, conventionally named Arbidol. The purpose of the invention is a tool that has activity against influenza virus type b and less toxicity in the treatment of people as compared with rimantadine and amantadine. This goal is achieved by the application of Arbidol in a new role, namely as a means for the treatment and prophylaxis of influenza type C.

The invention relates to known compounds of a number of oxyindole, namely 1-methyl-2-phenylthiomethyl-3 - carbethoxy-4 - dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate of formula 1.

HCl(I)

Mol. m 531,9

Mol. m 513 (anhydrous) conventionally named Arbidol.

Previously the connection I is known as a drug with pronounced chemotherapeutic action by influenza type A.

For the first time are encouraged to use the connection I as a drug for treatment and prophylaxis of influenza type Century.

In domestic and international medical practice today as anti-influenza drugs are used only two-Amand-tadin and close its structural analog-remantadin.

However, these drugs are inactive in the treatment of influenza type Century.

They are toxic. Their use in humans is accompanied by side effects of these drugs on the Central nervous system (insomnia), headache, loss of concentration, vomiting).

In addition, the widespread use of rimantadine and amantadine for the treatment of patients with influenza And led to the emergence of strains of influenza viruses that are resistant to these drugs.

The purpose of the invention is a tool that has activity against influenza virus type a and less toxicity in the treatment of people in comparison with known drugs rimantadine and amantadine.

This goal is achieved using the known compound 1-methyl-2-phenylthiomethyl-3-cubataxi-4-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride, ptx2">

1-methyl-2 - phenylthiomethyl-3-carbethoxy-4-dimethylaminomethyl - 5-hydroxy-6-bromoindole hydrochloride monohydrate is a crystalline powder white with white shade to svetlokremovogo color, slightly soluble in chloroform, it is difficult in alcohol, practically insoluble in water and ether. Stable when stored in a dark place for 2 years.

The biological part.

Virusinghviru action of Arbidol on the influenza virus In the studied model in ovo (in developing 9-day-old chick embryos). After a preliminary determination acceptability of Arbidol for chicken ambrinol the drug in the most intolerable (2 mg per embryo) and lower doses were introduced in allantoin cavity embryos for 1 h prior to their infection with the virus. After inoculation of the virus in a dose of 10 EI D50(embryonic infecting 50% of doses), embryos were incubated in an incubator at 36aboutC for 48 hours Indication of the virus was performed in the reaction of haemagglutination. The titer of the virus was expressed in Iodine2.

About the effectiveness of the drug was tried to reduce the number of infected embryos and to reduce the titre of virus in allantoine fluid treated by Arbidol chick embryos in comparison with contendah in table. 1, Arbidol has a strong virpiniemi effect on the reproduction of influenza virus type b (strain-Leningrad-369/75) in developing chicken embryos.

In doses of from 2 to 0.125 mg on embryo claimed the drug compared to control reduces the infection of embryos on 80-40% , and the titer of hematopoeisis virus - 7.8-3.6 Iodine2.

Chemotherapeutic activity of Arbidol was studied on the model of influenza pneumonia mice caused by influenza virus type b (Strain-Leningrad-369/75). In the study of influenza activity of Arbidol in doses of 60 and 30 mg/kg was administered to mice per os on oseltamivir treatment scheme (for 1 h before infection and then 1 time a day for 4 days). The General course of treatment was 5 days. Intranasal infection of mice was performed under light ether anesthesia using allantoin fluid of chicken embryos containing influenza virus (titer virus 5.5 lg EID50). Observation of the animals was carried out for 14 days.

The activity was judged to reduce the incidence of pneumonia and severity of lesion of lung tissue from patients with Arbidol mice in comparison with control (untreated mice).

The results are presented in table. 2

As can be seen from dannyjane lung tissue is 5 times lower than in the controls; at a dose of 30 mg/kg activity of Arbidol less pronounced.

Thus, Arbidol has a strong virpiniemi effect on the reproduction of influenza virus In developing chicken embryos and on the model of influenza pneumonia in mice.

Tolerability and safety of Arbidol for people.

The study of the tolerability and safety of Arbidol (compared to placebo) were conducted in a group of 22 people (11 men and 11 women) aged from 18 to 25 years with a clinical diagnosis of acute respiratory disease, mild (stage of convalescence). All taken in the study had a normal body temperature, the absence of signs of intoxication and in 7 out of 22 people - residual catarrhal symptoms in the form of weak rhinitis and slight hyperemia of mucous pharynx. Body weight observed ranged from 58 to 72 kg (medium - to 66.4 kg).

The scheme of the drug.

Subjects received Arbidol at a dose of 0.2 g 3 times a day for 3 days.

Tolerability and safety of Arbidol was determined on the basis of these clinical observations, clinical, instrumental, clinical, laboratory and biochemical studies.

Along with the General about the clinical analysis of blood, General analysis of urine, determination of the levels in the blood of bilirubin and cholesterol, and the activity of alanine aminotransferase. During the whole period of the clinical study (5 days) were carried out daily thermometry (2 times daily) and measurement of blood pressure.

In the course of studies no adverse reactions (insomnia, headache, poor concentration, vomiting, dyspepsia) and subjective complaints (poor health) associated with the medication were noted.

The rise in body temperature was not observed. Objective clinical data and indicators hemogram corresponded to the age norm. Urine analysis revealed no pathology none of the test.

The average values of the investigated biochemical parameters were also within normal limits (table. 3).

Studies have shown that Arbidol when receiving this scheme is well tolerated and virtually harmless to the human body.

therapeutic activity of Arbidol.

Clinical testing of Arbidol conducted on patients with clinical diagnosis of "flu", are in outpatient treatment, the Total num is the Diagnosis was confirmed by serological reactions. Patients received Arbidol 200 mg 3 times daily for 3 days.

Therapeutic efficacy was assessed (compared to placebo) duration of major symptoms of the flu-fever, intoxication and catarrhal syndrome, as well as the duration of the disease, the frequency and the form of arising complications.

The results of the study of clinical effectiveness of Arbidol in ambulatory patients (see table. 4) indicate the presence of therapeutic effect, expressed in significantly shortening the number of indicators:

- the duration of fever and such clinical symptoms as headache, chills, etc;

- the total duration of the disease;

and the prevention of complications compared with patients who received symptomatic therapy.

Data serological surveys confirm therapeutic activity of Arbidol.

A study of the effectiveness of Arbidol as a means of emergency prevention in family outbreaks of influenza Century Arbidol got 48 people who had contact with patients with influenza Century To prevent the drug was administered orally in a dose of 200 mg 1 time a day for 5 days.

The control group SL ሺ/P> Analysis of the material on the application of Arbidol as a means of emergency prevention in family outbreaks of influenza (see tab. 5) indicate a high prophylactic efficacy of the drug.

Epidemiological data are confirmed by the results of immunological tests.

The coefficient of effectiveness of Arbidol was 86.3% compared with the placebo group, and the rate of growth of antibodies to influenza virus In was equal to 4, while in control group it was 9.7.

Thus, the positive effect of the invention is as follows: found tool-Arbidol, which has a strong virpiniemi effect against influenza virus type b, medical and profilakticheski efficiency when influenza In humans, as well as having anti-influenza drugs amantadine and rimantadine, due to better tolerability and safety to human body, in comparison with these drugs, and effectiveness in the treatment and prevention of influenza In where these drugs are ineffective. (56) Romanov, Y. A. and other Chemoprophylaxis of influenza amantadine. L, 1971, S. 220-230.

The TOOL, WITH PREVENTIVE AND CURATIVE is Tyl-3-carbethoxy-dimethylaminomethyl-5-hydroxy-6-bromoindole hydrochloride monohydrate.

 

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