KR100745821B1 - Pharmaceutical composition for medical treatment and prevention of drug or alcohol addiction, or bipolar disorder using sodium phenylbutyrate - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention and treatment of drug or alcoholism, or manic depression, comprising a sodium phenylbutyrate (PBA) or a drug for the prevention and treatment of alcoholism or manic depression A composition is provided.

The pharmaceutical composition for preventing and treating drug or alcoholism or manic depression of the present invention is controlled by the expression of the neurotransmitter transporter to regulate the level of neurotransmitter, which is the behavioral indicator of drug or alcoholism, or mood swings There is an effect that can suppress the increase in the amount of activity.

Sodium Phenylbutyrate, Drug Addiction, Pharmaceutical Composition, Cocaine, Alcohol

Description

Pharmaceutical composition for medical treatment and prevention of drug or alcohol addiction, or bipolar disorder using sodium phenylbutyrate}

1 is a result showing the effect of sodium phenylbutyrate on the amount of cocaine-induced (acute) gait activity,

2 is a result showing the effect of sodium phenylbutyrate on cocaine-induced (acute) laering,

3 is a result showing the effect of sodium phenylbutyrate on the amount of amphetamine-induced (acute) gait activity,

4 is a result showing the effect of sodium phenylbutyrate on amphetamine-induced (acute) laering,

5 is a result showing the effect of sodium phenylbutyrate on the amount of amphetamine-induced (chronic) gait activity,

6 is a result showing the effect of sodium phenylbutyrate on amphetamine-induced (chronic) lairing, and

Figure 7 shows the effect of sodium phenylbutyrate on the amount of gait activity of the animal when the compound was intraperitoneally injected daily for 7 days.

The present invention relates to a pharmaceutical composition for the prevention and treatment of drug or alcoholism, or manic depression, and more particularly, for the prevention and treatment of drug or alcohol intoxication, or mood swings using sodium phenylbutyrate as a new medicinal use of sodium phenylbutyrate. It relates to a pharmaceutical composition.

Modern people who are exposed to various stresses in a complex modern society are at risk of drug addiction and drug or alcoholism is one of the most important social problems.

Addictive drugs include drugs such as morphine, cocaine and amphetamine, nicotine and alcohol. Among them, addictive drugs such as drugs are addictive and indulgent due to continuous use, and when they are stopped, they cause severe withdrawal symptoms, which prevents them from living a normal life without using drugs. It is a substance that makes it more dangerous.

Cocaine, for example, is an alkaloid derived from coca leaves from coca trees and is one of the most problematic drugs in the world. Cocaine is absorbed through the human mucosa and acts on the ends of the perceptual nerves, causing paralysis of pain and taste. Therefore, in 1862, he began to use local anesthetics for surgery or examination. However, absorption or repeated use of large amounts can lead to addiction and nutritional disorders, as well as mental disorders such as depression, anxiety, sleep disorders, chronic fatigue and mental confusion.

Cocaine poisoning is one of drug addictions caused by cocaine injection, ingestion, and nasal inhalation. In acute poisoning caused by mass use, it begins with dizziness, paleness, and pupil spawning, and falls into a clear state, and can cause mental confusion, hallucinations, hallucinations, fainting, and death due to difficulty breathing or collapse. The habitual addiction by continuous use is similar to the morphine addiction, but the physical consumption is prominent, such as loss of strength and dryness, and mental distress and deprivation of moral emotion. There are also unique cocaine hallucinations, such as hallucinations that make you feel like you are crawling over a body.

Addictive drugs, such as cocaine, increase the amount of gait activity associated with drug treatment due to repeated administration (Zavala AR, Nazarian A, Crawford CA, and Mcdougall SA, 2000). In addition, gait activity shows behavioral sensitization. Behavioral sensitization is a phenomenon in which locomotor activity and stereotype activity gradually increase when a small amount of addictive drug is repeatedly and intermittently administered. Behavioral sensitization is divided into a developmental phase with progressively increased activity and an expression phase with long-term sustained activity (Karler R, Chaudhry IA, Calder LD, and Turkanis SA, 1990). In addition, this behavioral sensitization is used as an indicator of drug addiction.

Cocaine induces addiction through strengthening effect. The factor affecting this behavioral sensitization is activation of dopamine (DA) neurotransmitter. In particular, the reward and strengthening effects of cocaine administration are known to play an important role in the midbrain limbic system where the A10 nerves directed in the ventral tegmental area (VTA) are projected to the nucleus accumbens (Einhorn LC, Johansen DA, and White FJ). , 1988). Cocaine pharmacologically causes cardiovascular diseases such as increasing cardiac output, raising blood pressure, and constricting peripheral blood vessels (Foltin RW, and Fischman MW, 1988). It also increases the release of dopamine, one of the neurotransmitters in the central nervous system, thus providing a pathogen for drug addiction (Dismukes K, and Mulder AH, 1977). This drug addiction is a mental problem and has been reported to be neurochemically caused by excessive release of dopamine in the nucleus and striatum (Kreek MJ, 1996).

Recent studies have shown that neuronal activity is measured by cocaine administration, which is a direct indicator of neuronal activity in the projection of dopaminergic neurons such as the nucleus accumbens and striatum associated with drug addiction. There is a report of increased expression of the early gene c-fos (Robertson HA, Paul ML, Moratalla R, and Graybiel AM, 1991). In addition, when D1 receptor agonist (SKF-38393) was repeatedly administered to experimental animals, expression of c-fos, an indicator of gait activity and neuronal activity, was suppressed (Sally AF, Shawn AR, Mdgorzata). K, and David JK, 2000). In addition, experimental evidence has been shown to correlate with the biochemical side dopamine and the behavioral side gait activity (Kuczenski R, Segal DS, and Aizenstein ML, 1991), and in vivo microdialysis. ), The concentration of dopamine due to cocaine administration in the striatum and the nucleus, which are related to drug intoxication, was increased significantly (Pontieri FE, Tanda G, and Dichiara G, 1995). .

Manic depression is a major mental illness that is devastating associated with suicide and loss of work (Belmaker, 2004; Kupfer, 2005). Despite recent genetic, neurobiological and pharmacological developments, much remains unknown about the pathophysiology of manic depression. Benicio N. Frey et al. (2006. Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania.Life Sciences, LFS-11196) apply amphetamine in combination with lithium or valproate, one of the leading prescriptions for alcoholism. In addition, Roberto Arban et al. (2005, Evaluation of the effects of lamotrigine, valproate and carbazepine in a rodent model of mania.Behavioural Brain Research 158 (2005) 123-132) found that lamotrigine, valproate and carbamazepine reduce the amphetamine-induced behavioral activity by measuring the distance traveled by applying amphetamine in combination with lamotrigine, valproate and carbamazepine. I have reported.

Meanwhile, sodium phenylbutyrate (PBA) is a well-known compound, and the medicinal efficacy region reported to date is as follows.

Sodium phenylbutyrate (PBA) has been reported to play a role in reducing the amount of glutamine to reduce the production of harmful ammonia. Ammonaps® is currently marketed as a urea cycle disorder treatment based on sodium phenylbutyrate.

In addition, phenylbutyrate has been reported to be effective in treating autism by acting as a glutamine level reducing agent. That is, since glutamine and glycine are present at or above normal levels in autism patients, phenylbutyrate is administered to reduce the level of glutamine, a precursor of glutamine and a type of excitatory amino acid, thus reducing the level of glutamine, thereby treating autism. (US Pat. No. US 6,362,226).

In addition, phenylbutyrate is known to have a therapeutic effect on cystic fibrosis and tumor or cancer, but there are no reports on the therapeutic effect of drug or alcoholism or manic depression.

An object of the present invention is to control the expression of neurotransmitter transporter drug or alcohol poisoning using sodium phenylbutyrate (PBA) that can suppress the increase in the amount of walking activity by controlling the level of neurotransmitter, or It is to provide a pharmaceutical composition for the prevention and treatment of manic depression.

According to the present invention there is provided a pharmaceutical composition for the prevention and treatment of drugs or alcoholism, or manic depression, comprising sodium phenylbutyrate (PBA).

Hereinafter, the present invention will be described in more detail.

Sodium phenylbutyrate used as a main component in the pharmaceutical composition of the present invention has the following structural formula.

[Formula 1]

The present inventors completed the present invention by revealing that the sodium phenylbutyrate, which is currently mainly used as a therapeutic agent for urea cycle disorders, is effective in the treatment of drug or alcoholism or manic depression as a new therapeutic use.

Drug addiction treatable with the pharmaceutical composition of the present invention may be, but not limited to, amphetamine or cocaine. Repeated infusions of stimulants, such as amphetamines and cocaine, in animals tend to significantly increase their locomotor activity, which is called behavioral hypersensitivity, which is very important in neurobiological understanding of drug addiction. It is known to provide important clues.

In the present invention, the effect of sodium phenylbutyrate on the formation of behavioral hypersensitivity reactions by stimulants such as amphetamine or cocaine was investigated. As a result, sodium phenylbutyrate inhibited the increase in the amount of gait activity, a behavioral indicator of drug addiction. It was confirmed that there is an addiction treatment.

Although not intended to be limited by theory, the sodium phenylbutyrate, which is used as an active ingredient in the pharmaceutical composition of the present invention, regulates the expression of neurotransmitter transporters, thereby regulating the neurotransmitters such as glutamate, dopamine and GABA (γ-aminobutyric acid). It is believed to regulate the level. Sodium phenylbutyrate is believed to specifically regulate expression against Glu transporters.

In the present invention, a drug addiction test for cocaine and amphetamine was conducted, but the pharmaceutical composition of the present invention is considered to be effective in the treatment of alcoholism and manic depression.

It is known that addiction mechanisms such as alcohol and cocaine are influenced by neurotransmitters such as dopamine and glutamate in the nucleus accumbens (Charles A. Dackis, 2005). It is known that the regulation of sodium phenylbutyrate, which is claimed in the present invention, means that the level of neurotransmitters in the nucleus can be regulated by modulating (or increasing) the expression of the transporter to such neurotransmitters. It is considered to be. It has been reported in recent papers that the expression of these transporters is associated with addiction. Specifically, glutamate and dopamine transporters have been described as alcoholism (Spanagel R et al., Nat Med. 2005 Jan; 11 (1): 35- 42) and cocaine addiction (Colleen A. McClung, PNAS. 2005 June; 28 (102): 9377-9381). In addition, in connection with most drug addiction research, the clinical and experimental studies are proceeding to bind alcohol addiction. For example, Drug Discovery Today: Therapeutic Strategies Vol. 2. No. 1 2005, p71-78 (George A. Kenna, "Pharmacotherapy of alcohol dependence: Targeting a complex disoder") and Drug Discovery Today: Therapeutic Strategies Vol. 2. Refer to No. 1 2005, p87-92 (Barbara H. Herman et al., "Medication for the treatment of cocaine addiction: Emerging candidates"). It can be seen that drugs already used for alcoholism are effective in drug addiction such as cocaine. That is, to some extent, drugs and alcohols such as cocaine have been found to share similar mechanisms with their addictions, and for that reason, it can be seen that medicines are being developed. In addition, Benicio N. Frey et al. (2006. Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania.Life Sciences, LFS-11196) have identified amphetamines as lithium or valproate, one of the leading prescriptions for alcoholism. In addition, the emotional stability effects of lithium and valproate were measured by checking the amount of gait activity. Therefore, although the drug addiction test for cocaine and amphetamine was mainly investigated in the present invention, the pharmaceutical composition of the present invention is considered to be effective in the treatment of alcoholism and manic depression.

The pharmaceutical composition containing sodium phenylbutyrate according to the present invention may be used for the treatment of drug or alcoholism, or mood swings, and may also be used for the purpose of preventing drug or alcoholism, or mood swings. In addition, the pharmaceutical composition according to the present invention may be administered by a method such as oral, intraperitoneal, subcutaneous administration during clinical administration. In addition, the dosage of the pharmaceutical composition according to the present invention can be variously adjusted according to the age, symptoms, dosage form or type of drug of the patient.

The pharmaceutical composition of the present invention may be prepared by adding a pharmaceutically acceptable carrier, for example, a diluent such as lactose, a lubricant such as magnesium stearate, a binder such as polyvinylpyrrolidone, and a disintegrant such as calcium carboxymethylcellulose. Tablets, capsules, soft capsules, liquids, and the like.

The unit dose of the pharmaceutical composition according to the present invention depends on various factors such as the poisoning state, age, etc. of the subject to be administered, but is generally 5-2000 mg, preferably 10-1000 mg. In this case, the unit dose means a dose that can be administered once or divided into several times as a daily dose of the preparation for adults, and the pharmaceutical composition of the present invention divides the unit dose once to three times a day. It is preferred to be administered orally.

Hereinafter, the present invention will be described through specific examples, and the present invention is not limited to the following examples.

<Example>

To investigate the effect of a drug containing sodium phenylbutyrate (PBA) according to the present invention or a pharmaceutical composition for the prevention and treatment of alcoholism or bipolar disorder (Spraugue-Dawley rat, 250-275g (on arrival), 쌤) Taco) was used to perform the following animal experiments.

Locomotor activity was measured using a bank of 12 activity measurement boxes (Kim & Vezina, 1998). Each box (22 × 43 × 33 cm) measured gait activity from photo beam interruption. Rats were placed in the activity measurement box for a one hour habituation period, administered each dose to them and immediately placed back into the box, and their walking activity and lairing measured for an additional two hours. That is, the rat is moved through the photo beams installed on the top, bottom, left and right, and counted in a computer, and this was confirmed for two hours. Rare measurement was also performed by counting up and down movements through the photo beam in the activity measurement box. For reference, in the case of lairing, unlike a measure of gait activity to check movement, rats stand up with their paws up (which usually does not happen except for standing up to eat food on the cage). It is known that such doses increase with ambulatory activity when administered). For reference, the present embodiment is also an experiment confirming the effect on drug or alcohol addiction as well as on manic depression. For example, Benicio N. Frey et al. (2006. Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania.Life Sciences, LFS-11196) used amphetamine in a similar manner to the one used in this example. In addition, experiments were conducted to measure the effect of emotional stability on the drug by identifying the behavior (walking activity).

Example 1

Rats were intraperitoneally injected at different concentrations (0.1, 1.0, 5.0, 10.0 mg / kg) of sodium phenylbutyrate alone or together with cocaine (15 mg / kg), for 2 hours of walking activity and rare The ring was measured. The results are shown in FIGS. 1 and 2. In FIG. 1 and FIG. 2, the white bar shows the case of saline + sodium phenylbutyrate and the black bar shows the case of cocaine + sodium phenylbutyrate. A represents the entire 2 hours and B represents the 20 minute time course. The minus on the x-axis at B indicates habituation before drug delivery and drug injection at point 0 (n = 8-17).

As can be seen from FIGS. 1 and 2, sodium phenylbutyrate has been shown to dose-dependently reduce the amount of gait activity and lairing caused by cocaine, and this effect is 1.0 mg / kg. It was found to be the largest at the dose of.

Example 2

As in Example 1, sodium phenylbutyrate at different concentrations (0.1, 1.0, 10.0 mg / kg) was intraperitoneally injected alone or in combination with amphetamine (1.5 mg / kg) and gait activity was measured for 2 hours. . The results are shown in FIGS. 3 and 4. In Figures 3 and 4, A represents the entire two hours and B represents the time course at 20 minute intervals. The minus on the x-axis at B indicates habituation prior to drug delivery and drug injection at point 0 (n = 7-8).

As can be seen from Figures 3 and 4, sodium phenylbutyrate has been shown to have an effect of reducing the amount of gait activity by amphetamine, and this effect was similar at doses of 0.1-10.0 mg / kg. .

Example 3

Behavioral sensitization with different concentrations (0.1, 1.0, 10.0 mg / kg) of sodium phenylbutyrate in combination with amphetamine (1.5 mg / kg) four times every 2-3 days The effect of sodium phenylbutyrate on the formation was investigated. Behavioral sensitization was followed by a 1-week withdrawal period after amphetamine pre-exposure followed by a 2 hour intraperitoneal injection of the same dose of amphetamine (1.5 mg / kg) to all groups of rats. It was confirmed by measuring the amount of gait activity during. The results are shown in FIGS. 5 and 6. In Figures 5 and 6, A represents the entire two hours and B represents the time course at 20 minute intervals. The minus on the x-axis at B indicates habituation prior to drug delivery and drug injection at point 0 (n = 7-8).

As can be seen from FIGS. 5 and 6, it was observed that sodium phenylbutyrate had a significant blocking effect on the behavioral sensitization induced by amphetamine, and this effect was particularly strong at doses of 0.1-1.0 mg / kg. .

Example 4

Two different concentrations (0.1, 1.0 mg / kg) of sodium phenylbutyrate were measured intraperitoneally every day for 7 days to determine how the animal's ambulatory activity response to this compound changed. The amount of gait activity on the first and seventh days was measured. The results are shown in FIG. In FIG. 7, A represents the entire 2 hours for the amount of walking activity on the first day and the 7th day, and B represents the result of rarering measurement (n = 6-7).

As can be seen from FIG. 7, when sodium phenylbutyrate (0.1, 1.0 mg / kg) was repeatedly administered once a day for a total of 7 days, it did not show any change in walking activity by itself.

According to the present invention, sodium phenylbutyrate (PBA), which controls the expression of neurotransmitter transporter and regulates the level of neurotransmitter, can inhibit the increase in the amount of gait activity, a behavioral indicator of drug addiction. Provided is a pharmaceutical composition for preventing and treating used drug or alcoholism or manic depression.

Claims (9)

Pharmaceutical composition for the prevention and treatment of drugs or alcoholism, or mood swings, comprising sodium phenylbutyrate (PBA). The pharmaceutical composition according to claim 1, wherein the drug poisoning is amphetamine or cocaine poisoning. The method of claim 1, wherein the sodium phenylbutyrate increases the expression of neurotransmitter transporter to reduce the level of neurotransmitter, wherein the neurotransmitter is composed of glutamate, dopamine and GABA (γ-aminobutyric acid) Pharmaceutical composition, characterized in that it is selected from the group. delete The pharmaceutical composition according to claim 1, which is formulated as a unit preparation for oral administration. The pharmaceutical composition according to claim 5, wherein the preparation is a tablet, a capsule, a soft capsule, or a liquid. The pharmaceutical composition according to claim 5, which contains 5-2000 mg of sodium phenylbutyrate per unit formulation. The pharmaceutical composition according to any one of claims 1 to 3 or 5 to 7, further containing at least one pharmaceutically acceptable carrier. 9. A pharmaceutical composition according to claim 8, wherein the carrier is at least one component selected from the group consisting of diluents, lubricants, binders, disintegrants and stabilizers.

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