RU2404976C1 - Agent to reduce alcohol addiction, pharmaceutical composition, method for making thereof, medicinal agent and method of treating - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to a new agent to reduce alcohol addiction, representing hydroxy-substituted flavonoids of general formula 1,

1

1.1

1.1 (1), where: R1, R2, R3, and R5 independently represent hydrogen atom or optionally substituted hydroxyl; R4 represents hydrogen atom, hydroxyl, optionally substituted monosaccharide, with the exception of β-D-glucopyranosyl and α-L-rhamnopyranosyl (6-deoxy- α-L-mannopyranosyl), optionally substituted disaccharide; R6 represents hydrogen atom or methyl. Preferentially, the agent represents flavonoid of general formula 1.1 where R1, R2 and R4 have the above-stated value, e.g., such as apigenin - 5,7-dihydroxy-2-(4-hydroxyphenyl)-chromene-4 of formula 1.1(1). Also the agent can represent mixed effective amount of flavonoid of general formula 1, preferentially of formula 1.1, such as apigenin of general formula 1.1(1) and thianine of formula 2

or its pharmaceutically acceptable salt.

EFFECT: improved clinical effectiveness.

9 cl, 2 dwg, 2 ex

Description

Technical field

The invention relates to a means of reducing the craving for alcohol, and can be used to obtain a pharmaceutical composition, drug and treatment.

Alcoholism affects approximately 10% of the population, and the consequence of this disease is the occurrence of social problems, poor health, increased mortality and a significant financial burden on the health care system [McGinnis J.M., Foege W.H. Actual causes of death in the United States. JAMA 1993,270: 2207-12. Rice D.P. Economic cost of substance abuse: 1995. Proc Assoc Am Physicians. 1999, 111 (2): 119-25]. Most people who abuse products that contain ethyl alcohol, during the period of abstinence from the use of these products, experience an insurmountable attraction (“craving”) to alcohol. The consequence of this alcohol motivation is recurring episodes of alcohol abuse.

Despite the fact that to date, many drugs have been proposed to treat addiction to alcohol, the most famous of which include, for example, naltrexone, acamprosate and sodium oxyburate, the search for effective and safe treatments for alcoholism continues to be an urgent problem in modern medicine.

State of the art

Known drug naltrexone, belonging to the group of opiate receptor antagonists, which, when used in combination with alcohol, can weaken the alcohol motivation, which is expressed in a decrease in the amount of alcohol consumed [RU 2090190]. It is known that contraindications that limit the use of naltrexone include liver failure [Krystal J.H., Cramer J.A., Krol W.F., Kirk G.F., Rosenheck R.A .; Veterans Affairs Naltrexone Cooperative Study 425 Group. Naltrexone in the treatment of alcohol dependence. N. Engl. J. Med. 2001, 345 (24): 1734-9].

There is a known drug acamprosate, which, when used during sobriety, can weaken alcohol motivation, which is expressed in a moderate decrease in the amount of alcohol consumed in the future [Moncrieff J., Drummond D.C. New drug treatments for alcohol problems: a critical appraisal. Addiction. 1997, vol. 92, pp. 939-47; discussion on pages 949-964]. It is also known that contraindications that limit the use of acaprosate include impaired liver function [Williams S.H. Medications for treating alcohol dependence. Am. Fam. Physician. 2005, 72 (9): 1775-80].

A means is known containing gamma-hydroxybutyric acid or its salts as active components, which, when used during the period of sobriety, can weaken alcohol motivation, which is reflected in a further reduction in the number of relapses of drunkenness [Nava F., Premi S., Manzato E., Campagnola W., Lucchini A., Gessa GL Gamma-hydroxybutyrate reduces both withdrawal syndrome and hypercortisolism in severe abstinent alcoholics: an open study vs. diazepam. Am. J. Drug Alcohol Abuse. 2007, 33: 379-392; 2007]. It is also known that the use of gamma-hydroxybutyric acid or its salts can cause addiction symptoms [Sumnall H.R., Woolfall K., Edwards S., Cole J.C., Beynon C.M. Use, function, and subjective experiences of gamma-hydroxybutyrate (GHB). Drug Alcohol Depend. 2008, 92 (1-3): 286-90], which complicates its safe use in patients with alcoholism. In this regard, gamma-hydroxybutyric acid or its salts are mainly used in preclinical studies as reference drugs.

Known flavonoid apigenin, which has the ability to reduce the symptoms of osteoarthritis [US 2007154540 (A1)], liver cirrhosis [KR 20040013919 (A)] bladder fibrosis [US 6329422], and also have an antidepressant effect, confirmed in animal experiments [Nakazawa T. , Yasuda T., Ueda J., Ohsawa K. Antidepressant-like effects of apigenin and 2,4,5-trimethoxycinnamic acid from Perilla frutescens in the forced swimming test. Biol. Pharm. Bull. 2003, 26 (4): 474-480]. However, the ability to reduce the symptoms of alcohol motivation has not been shown for apigenin.

Known amino acid tianin, which has the ability to reduce the symptoms of premenstrual syndrome [US 6831103], the negative effects of cerebral ischemia [Egashira N., Ishigami N., Pu F., Mishima K., Iwasaki K., Orito K., Oishi R., Fujiwara M. Theanine prevents memory impairment induced by repeated cerebral ischemia in rats. Phytother Res. 2008, 22 (1): 65-68], improve sleep [US 7273621], reduce nicotine addiction in tobacco smokers [US 7094787], and in combination with caffeine and arginine can stimulate mental performance [US 6462051]. However, the ability to influence alcohol motivation is not known for tianin.

Disclosure of invention

The aim of this invention is to provide a means of causing a pronounced decrease in craving for alcohol, for pharmaceutical compositions and medicines.

This goal is achieved by a means of hydroxy-substituted flavonoids of the general formula 1,

where R1, R2, R3 and R5 independently from each other represent a hydrogen atom or an optionally substituted hydroxyl; R4 represents a hydrogen atom, hydroxyl, an optionally substituted monosaccharide, with the exception of β-D-glucopyranosyl and α-L-rhamnopyranosyl (6-deoxy-α-L-mannopyranosyl), an optionally substituted disaccharide; R6 represents a hydrogen atom or methyl.

As hydroxy-substituted flavonoids of the general formula 1, flavonoids 1 (1-14) can be used, which are presented below:

Preferred hydroxy-substituted flavonoids are flavonoids of general formula 1.1.

where R1, R2 and R4 have the above meaning.

A more preferred hydroxy-substituted flavonoid is 5,7-dihydroxy-2 (4-hydroxyphenyl) -chromen-4-one apigenin of formula 1.1 (1).

This goal is achieved by a means of tianin of formula 2 or a pharmaceutically acceptable salt thereof.

It was found that the thianine of formula 2 or its pharmaceutically acceptable salt also causes a pronounced decrease in alcohol cravings and can be used as a tool for pharmaceutical compositions and medicines.

The goal is achieved by means of a mixture, in an effective amount, of a hydroxy-substituted flavonoid of general formula 1 and tianin of formula 2 or a pharmaceutically acceptable salt thereof.

The specified mixture cause a synergistic decrease in the craving for alcohol and can be used as a means of reducing the craving for alcohol for pharmaceutical compositions and medicines.

The subject of this invention is a pharmaceutical composition that reduces the attraction to alcohol, containing as a means a pharmaceutically effective amount of a hydroxy-substituted flavonoid of general formula 1 or simultaneously a flavonoid of general formula 1 and tianin of general formula 2 or a pharmaceutically acceptable salt of tianine.

A more preferred alcohol-lowering pharmaceutical composition is a composition comprising, as an agent, an effective amount of apigenin of formula 1 (1) and tianin of formula 2 or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions may include pharmaceutically acceptable excipients. By pharmaceutically acceptable excipients are meant diluents, excipients and / or carriers used in the pharmaceutical field. The pharmaceutical composition along with the agent of general formula 1 of the present invention may include other active ingredients, provided that they do not cause undesirable effects, for example, allergic reactions.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, and they may include traditional pharmaceutical carriers, for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as solutions or suspensions for injection, or dry powder for injection, which only requires the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

A subject of the present invention is also a method for preparing pharmaceutical compositions, which consists in mixing with an inert excipient and / or solvent of at least one agent of the general formula 1 or an agent of the general formula 1 and a tianine of the formula 2 or a pharmaceutically acceptable salt thereof.

A subject of the present invention is also a medicament in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, comprising the agent of the present invention or a pharmaceutical composition intended to reduce the craving for alcohol.

The subject of the invention is also a therapeutic cocktail comprising an agent or a pharmaceutical composition or a medicine according to the invention.

The subject of the present invention is also a method of treating and preventing alcoholism by administering to a human or warm-blooded animal a pharmacologically effective amount of an agent, or a pharmaceutical composition, or a medicine according to this invention, or a therapeutic cocktail according to this invention.

The clinical dosage of a pharmaceutical composition or medicine containing, as an agent, a compound of general formula 1 or a compound of general formula 1 and formula 2 in patients can be adjusted depending on: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion, and also depending on the age, gender and stage of the patient’s disease, the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. Therefore, during the preparation of the pharmaceutical compositions of the present invention as dosage units, the above effective dosage should be taken into account, with each dosage unit of the preparation containing 10 ~ 500 mg of an agent of general formula 1 or an agent of general formula 1 and formula 2, preferably 50 ~ 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times).

The pharmacological properties of the agent of the general formula 1, tianin of the formula 2 and mixtures of the compounds of the general formula 1 and the formula 2 were compared with the reference drug sodium hydroxybutyrate (GHB) in experiments on male SHK mice.

In accordance with the current recommendations of the Federal Service for Supervision of Healthcare and Social Development of the Russian Federation, the criterion for alcohol motivation was the increase in alcohol solution consumption caused by short-term alcohol deprivation, which is a model of loss of self-control during binge [Maisky AI, Salimov P.M. Guidelines for the study of drugs for the treatment of alcoholism. Guidance on the experimental (preclinical) study of new pharmacological substances, ed. Khabriev R.U., Moscow, ed. “Medicine”, 2005, p.342-356].

To overcome the possible initial refusal to take an alcohol solution during the first 6 days of the experiment, male SHK mice did not receive water, but only had access to an alcohol solution of increasing concentration (3% on day 1 and 2, 6% on day 3 and 4 and 10 % on day 5 and 6) [McKinzie et al., Alcohol Clin Exp Res. 1998, 22 (7): 1584-90]. Moreover, they had free access to food. Over the next 2 months, the mice had free access to clean water, food, and a 10% alcohol solution.

To assess alcohol motivation, we calculated the degree of increase in voluntary consumption of a 10% alcohol solution during a 90-minute test after 4-day alcohol deprivation compared with the same test performed before 4-day alcohol deprivation (alcohol deprivation effect, ADE). The ADE index was calculated as the ratio of alcohol consumption after its cancellation (in terms of grams of pure alcohol per kilogram of body weight) to its total consumption before and after cancellation of access to alcohol. If the ADE index was more than or less than 0.5, then this meant the presence or absence of alcohol motivation, respectively.

At the end of the 2-month period of free access of mice to water and alcohol, the ADE assessment described above was performed and mice were selected for further experiments with an ADE index greater than 0.5. These mice were divided into groups of 9-12 individuals that did not differ from each other in ADE.

The invention is illustrated, but not limited to the following examples and diagrams.

Figure 1 shows the effect of 4-day deprivation of access to a 10% solution of ethyl alcohol on its voluntary consumption by male SHK mice. On the abscissa axis is the consumed dose of alcohol in terms of pure alcohol. A statistically significant difference from consumption before deprivation of alcohol # is the alcohol deprivation effect (ADE), Fisher's LS test (ANOVA).

Figure 2 shows the effect of the studied substances on the consumption of a 10% solution of ethyl alcohol by male SHK mice in the first 30 minutes of the test, carried out before and after 4 days of alcohol deprivation. On the abscissa axis is the consumed dose of alcohol in terms of pure alcohol. A statistically significant difference from the placebo group: * - Fisher LS-test (ANOVA), & - Chi-square test.

Example 1. In this example, the reaction of mice is presented, which during the period of deprivation of alcohol using sterile probe was injected into the esophagus sterile water.

As can be seen from figure 1, the dose of alcohol consumed by mice in the first 30-60 minutes of the test after alcohol deprivation is approximately 2 times greater than before deprivation of alcohol. In accordance with existing ideas, this indicates the presence of alcoholic motivation in these mice, which is enhanced after a period of forced sobriety [Maisky AI, Salimov P.M. Guidelines for the study of drugs for the treatment of alcoholism. Guidance on the experimental (preclinical) study of new pharmacological substances, ed. Khabriev R.U., Moscow, ed. “Medicine”, 2005, p.342-356].

Example 2. This example presents the voluntary consumption of alcohol (figure 2) in mice with formed alcohol motivation, which during the period of deprivation of alcohol was administered a placebo (sterile water), apigenin of formula 1 (1), and tianine of formula 2 into the esophagus or apigenin in combination with tianin in subeffective doses. The introduction was made 1 time per day for 4 consecutive days during the period of deprivation of alcohol. Sodium oxybutyrate (GHB) at a dose of 150 mg / kg was used as a comparison drug.

The results presented in figure 2 show that the alcohol deprivation effect (ADE) in the form of an increase in alcohol consumption after its 4-day deprivation is observed only in groups of mice that were given placebo, apigenin at a dose of 2 mg / kg and tianine at a dose 4 mg / kg. In the remaining groups, which were administered apigenin (5-20 mg / kg) or tianine (10 mg / kg), as well as apigenin (2 mg / kg) in combination with tianine (4 mg / kg), a weakening of the alcohol deprivation effect was observed (ADE).

Thus, as can be seen from figure 2, the comparison drug sodium oxybutyrate (GHB) in a dose of 150 mg / kg causes a pronounced decrease in the alcohol-deprivation effect, which indicates a weakening of alcohol motivation. The tianin of formula 2 has the same effect at a dose of 10 mg / kg. Apigenin of formula 1 (1) has a stronger effect, the effect of which appears already at a dose of 5 mg / kg and is enhanced at doses of 10 and 20 mg / kg. These results indicate that apigenin 1 (1) in doses of 5-20 mg / kg, as well as tianin 2 in a dose of 10 mg / kg weaken the formed alcoholic motivation and reduce the risk of an uncontrolled increase in alcohol consumption. The ability of apigenin 1 (1) and tianin 2 mutually reinforce each other's ability to weaken the formed alcoholic motivation seems to be very useful. With the simultaneous use of subthreshold doses of apigenin 1 (1) and tianin 2 (apigenin 2 mg / kg and tianin 4 mg / kg), a pronounced synergistic decrease in the alcohol deprivation effect (ADE) was observed by almost two times with a decrease in the dose of the drug that reduces the craving for alcohol mg / kg, almost four times, which may allow us to expect a more sustainable effect on alcohol consumption.

The data presented indicate the ability of the pharmaceutical composition, including hydroxy-substituted flavonoids of the general formula 1, tianin of the formula 2 or its pharmaceutically acceptable salts in an effective amount alone or in combination with each other, to weaken the objectively recorded symptoms of alcoholic motivation (ADE) - an increase in the dose used alcohol after a period of sobriety.

A pharmaceutical composition in the form of a combination of apigenin with tianin is comparable in effectiveness with sodium hydroxybutyrate (GHB), but does not have such a detrimental effect on liver function and appears to be more preferable in comparison with other known drugs, since it consists of safe components that exhibit synergism in ability to reduce alcohol motivation (ADE).

Claims (9)

1. An agent that reduces the craving for alcohol, which is a hydroxy-substituted flavanoid of the general formula 1,

where R1, R2, R3 and R5 independently from each other represent a hydrogen atom or an optionally substituted hydroxyl; R4 represents a hydrogen atom, hydroxyl, an optionally substituted monosaccharide, with the exception of β-D-glucopyranosyl and α-L-rhamnopyranosyl (6-deoxy-α-L-mannopyranosyl), an optionally substituted disaccharide; R6 represents a hydrogen atom or methyl. 2. The tool according to claim 1, which is a flavanoid of General formula 1.1

where Rl, R2 and R4 have the above meaning. 3. The tool according to claim 2, which is apigenin-5,7-dihydroxy-2- (4-hydroxyphenyl) -chromen-4-one of the formula 1.1 (1)

4. A means of reducing the craving for alcohol, which is a mixture, in an effective amount, of a flavanoid of general formula 1 and tianine of formula 2

or a pharmaceutically acceptable salt thereof. 5. The tool according to claim 4, which is a mixture, in an effective amount, of apigenin-5,7-dihydroxy-2 (4-hydroxyphenyl) -chromen-4-one of formula 1.1 (1) and thianine of formula 2 or a pharmaceutically acceptable salt thereof . 6. A pharmaceutical composition that reduces the craving for alcohol, containing a pharmaceutically effective amount of an agent according to any one of claims 1 to 5. 7. The method of obtaining the pharmaceutical composition according to claim 6, mixing the agent according to any one of claims 1 to 5 with an inert filler and / or solvent. 8. A drug that reduces the craving for alcohol, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package, comprising the composition according to any one of claims 1 to 5 or the pharmaceutical composition according to claim 6. 9. A method of reducing the craving for alcohol by administering a pharmacologically effective amount of an agent according to any one of claims 1-5, or a pharmaceutical composition according to claim 6, or a drug according to claim 8.

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