Compositions and methods of preventing and treating addictions

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented methods of treating or preventing an addiction or recurrent addictive behaviour, including: alcohol, nicotine, marijuana, marijuana derivative, opioid receptor antagonist, benzodiazepine, barbiturate and psychostimulant by administering the peroxisome proliferator-activated receptor gamma (PPARγ) agonist thiazolidinedione, alone or in a combination with another therapeutic agent - an opioid receptor agonist, a mixed partial opioid receptor agonist/antagonist, an anti-depressant, an antiepileptic agent, an antiemetic agent, a corticotrophin releasing factor 1 (CRF-1) receptor antagonist, a selective serotonin 5-HT3 receptor antagonist, a 5-HT2A/2C antagonist or a cannabinoid 1 (CB1) receptor antagonist (versions), related pharmaceutical compositions with the above combinations (versions), a standard dosage form (versions) and kits (versions).

EFFECT: it is shown that the PPARγ agonist pioglitazone had no effect on amphetamine sensitisation, however it reduced opiate consumption and opiate addiction, also reduced nicotine self-administration in rats, and reduced alcohol consumption if synergistically combined with topiramate Pioglitazone reduced ethanol self-administration in rats.

33 cl, 23 dwg, 27 ex

 

Cross-reference to related application

This application claims priority under 35 U.S.. $ 119(e) of provisional patent application U.S. No.60/911201, filed on April 11, 2007, and this provisional application is incorporated into this description in full by reference.

The prior art to which the invention relates.

The present invention is directed in General to the treatment or prevention of dependency with PPARγ agonists, alone or in combination with other therapeutic agents.

Description of the prior art

The world Health Organization (who) defines substance dependence as multiple re-use of the substance despite understanding and perception of harmful effects. The substance dependence is a chronic relapsing disease, characterized by loss of control over drug use, insurmountable search drug and craving for the drug substance, the use of which persistently continues despite negative consequences, and physical and/or psychological dependence on drugs. Dependence on drugs is usually accompanied by a period of tolerance, withdrawal, compulsive behavior with insurmountable use of a drug, what oodinium, characterized by the search of the drug, and relapse. Substance abuse and dependence are health issues with significant social and economic impact on the addict and on society due to the significant role in crimes involving violence against the person, and the spread of infectious diseases. Substances that cause addiction include alcohol, caffeine, nicotine, cannabinoids (marijuana) and derivatives of cannabinoids, opiates and other morphine-like agonists opioids, such as heroin, phencyclidine and phencyclidine connection, sedative hypnotics, such as benzodiazepines and barbiturates, and stimulants, such as cocaine, amphetamines and amphetamine-like drugs, such as dextroamphetamine and methylamphetamine.

Alcohol is the most common zloupotrebljeni narcotic drugs in the world. In addition, alcohol causes serious liver diseases and the cardiovascular system and causes dependence, leading to severe mental disorders, social problems and adverse consequences, including family breakdown, tragic accidents, and reduced efficiency. According to the who alcohol consumption leads to 20-30% of cases of esophageal cancer and liver cirrhosis pécs is no, murders, epilepsy and accidents around the world. Globally, alcohol abuse leads to approximately 1,8 million deaths per year. Compulsive behavior in relation to alcohol is a Central symptom of disturbance. In recent years investigated several approaches to care for patients with alcoholism not only in terms of control over alcohol consumption, but also in relation to craving for alcohol and relapse (Monti et al., 1993; Volpicelli et al. 1992; O'brien et al. 1997).

Medications, such as naltrexone, acamprosate, ondansetron, disulfiram, gamma-hydroxybutyrate (GHB) and topiramate tested for their potential therapeutic effect against alcohol abuse, belong to several classes (Volpicelli et al. 1992; O'brien et al. 1997). Some of these pharmacological agents, such as naltrexone, acamprosate, and disulfiram, proved to have a certain suitability and approved for the treatment of alcoholism. Among these drugs the non-selective opioid receptor antagonist naltrexone is currently considered as the gold standard of pharmacology. However, despite some promising results, none of these drugs, including naltrexone, are not sufficiently effective in alcoholism, and the prognosis remains poor is.

Nicotine is one of the most widely used drug, and nicotine abuse is the most common form of abuse of narcotic substance. The who estimates that in the world there is a 1.25 billion smokers aged over 15 years, representing one third of the world's population. Who further estimates that 5 million deaths occur each year as a direct result of tobacco use, which makes the abuse of nicotine, the most numerous separately preventable cause of death worldwide. In industrialized countries, 70-90% of cases of lung cancer, 56-80% of cases of chronic respiratory diseases and 22% of cases of cardiovascular disease are attributed to nicotine dependence. Smoking cigarettes is associated with to 430,000 deaths per year in the USA alone determines the price of 80 billion U.S. dollars annually as the cost of health care. Tobacco use is responsible for one third of all cases of cancer, including cancers of the lung, mouth, pharynx, larynx, esophagus, cervix, kidney, ureter and bladder. Total deaths from cancer two times higher in smokers compared with nonsmokers. Smoking is also a cause of lung diseases such as chronic bronchitis and emphysema; aggravates asthma symptoms; and increases the risk for which of olivani heart including stroke, heart attack, vascular disease, and aneurysm. As defined, 20% of deaths from heart disease is due to Smoking. Smokers, pregnant women have a higher risk compared with nonsmokers in relation to preterm birth, spontaneous abortion, and birth of children with low body weight.

The use of nicotine leads to increased levels of the neurotransmitter dopamine, which activates the path reinforcement in relation to the regulation of feelings of pleasure and mediates the desire to use nicotine symptoms associated with withdrawal of nicotine include cravings, irritability, anger, hostility, aggression, fatigue, depression and cognitive disorder, which lead the addict to seek more nicotine. Conditional reflex environmental factors and exposure to psychological stress are additional factors motivate the use of nicotine smokers. The recurrent use of nicotine leads to development of resistance, the need for consumption of higher doses of nicotine to get the same initial stimulation.

The most developed methods of treatment of nicotine addiction had only moderate success in the prevention of relapse, leading to a high failure rate when attempting to quit Smoking. Methods of treatment the Oia include the use of the products replacement nicotine, antidepressants, anti-hypersensitivity therapy for behaviour change.

National Institute on drug dependence was determined that 72 million Americans, approximately one third of the population has tried marijuana. Acute effects of the use of marijuana include problems with memory and learning, distorted perception, difficulty in making decisions, loss of coordination, and rapid heartbeat. Long-term abuse can cause the same respiratory problems as seen in tobacco smokers, such as daily cough, production of sputum, increased risk of lung infections and an increased risk of developing cancer of the head, neck and lungs. Depression, anxiety and problems, work-related, associated with marijuana use. Long-term use of marijuana can lead to addiction to compulsive use that interferes with daily activity. Symptoms of thrust and withdrawal, such as irritability, increased aggression, insomnia and anxiety, make it difficult for addicts in relation to stopping the use of marijuana. Does not exist pharmacological methods of treatment suitable for the treatment of addiction to marijuana and recurrence.

The who estimates that 13 million people abusing opiates around the world is, including 9 million drug addicts who use heroin. More than 25% of drug addicts, opiate users, dies from a suicide, murder or infectious diseases such as HIV and hepatitis, within 10-20 years from start of drug addiction. Tolerance and physical dependence can develop within two to three days.

The goal of treatment for opiate dependence, as in the case of other types of addictions from drugs are the cessation of opiate, while minimizing the painful withdrawal symptoms and preventing relapse. Currently, treatment options include the substitution of a drug that causes addiction, substitute opioid agonist or mixed agonist/antagonist. An alternative approach is to use an antagonist of opioid receptors blockade effect of the agonist. Antagonists do not provide pain relief or other withdrawal symptoms; rather, they can force the withdrawal, and their therapeutic use is associated with an increased accidental overdose of opioid agonists and increased mortality. The use of agonists with lower affinity to the receptor leads to the least severe withdrawal symptoms, but it can lead to dependence on opiate replacement. In addition, many variants of zamestitelnitsa take 3-6 months allowing the addicts to stop treatment halfway.

Psychostimulants, such as cocaine and amphetamines, cause people euphoria, heightened sense of energy and improved physical performance. These drugs first increase dopaminergic transmission, but long-term use of a drug leads to a decrease in dopaminergic activity, leading to dysregulation of system reinforcements brain and dysphoria. The who estimates that 33 million people around the world are abusing amphetamines.

Chronic abuse of cocaine can lead to over-stimulation, tachycardia, hypertension, dilated pupils, muscle spasms, insomnia, extreme anxiety, hallucinations, paranoia, aggressive behavior and depression. Overdose of cocaine can cause tremors, convulsions, delirium and death due to cardiac arrhythmia and heart failure. The desipramine, amantadine and parlodel, as shown, reduce the symptoms of cocaine withdrawal.

Symptoms of amphetamine withdrawal symptoms include changes in EEG, fatigue and mental depression. Over time develops tolerance and it may be associated with tachycardia, auditory and visual hallucinations, delusions, anxiety reactions, paranoid psychosis, exhaustion, satellite is the oneness of consciousness, memory loss and prolonged depression with suicidal tendencies. Currently, the treatment of amphetamine dependence include phenothiazines, haloperidol and chlorpromazine in relation to hallucinations, but the potential side effects of these drugs include postural hypotension and severe extrapyramidal movement disorders.

In the past, the treatment of dependency on drugs has focused on therapy for behaviour change but the dependence on many of these extremely strong narcotic substances difficult to overcome. In particular, dependence on alcohol, cocaine and heroin are considered as a chronic relapsing disorders. In addition, normal is a joint abuse of many drugs, such as nicotine, heroin, cocaine and alcohol.

Long-term, chronic nature of many addictions and a high rate of recurrence is a significant problem for the treatment of drug and alcohol dependency, so the understanding of the neurobiological basis of relapse is to the fore in the study of dependencies. Among the main causes of relapse are listed emotional factors and environmental factors (conditional reflex stimuli). For example, it is known that a particular state of stress, such as loss of work and economic difficulties, or predictable impact of the presence of alcohol, previously associated with its use, such as the preferred bottle of wine and a similar bar environment, can contribute significantly to relapse in treated drug treatment of former alcoholics.

There are two main theoretical explanations maintain propensity for drug use and vulnerability to relapse associated with drug and alcohol addiction, is a homeostatic hypothesis and reflex hypothesis.

Homeostatic hypothesis include the risk of relapse to neuroadaptive changes and disorders of the neuroendocrine homeostasis, which are believed to underlie anxiety disorders regulation of mood and physical symptoms that accompany acute withdrawal that can last for significant periods of time, during the so-called phase of protracted abstinence. This opinion, therefore, implies the relief of discomfort and negative effects as the motivational basis for relapse.

Reflex hypothesis is based on observations showing that relapse is often associated with exposure to environmental stimuli associated with the drug. In this view hold that specific environmental stimuli that have become associated is passed with the effects of drug reinforcement through classical conditioned reflex, can cause subjective conditions that trigger the resumption of drug use. Homeostatic and reflex hypotheses are not mutually exclusive. Indeed, homeostatic and reflex factors, obviously, additive effects, for example, that exposure is associated with drug by environmental stimuli may enhance susceptibility to relapse caused by homeostatic disorders.

Obviously, in the art there is a need for new methods of treatment and prevention of addiction and relapse of drug use. The present invention meets these needs by providing methods and pharmaceutical combinations suitable for the treatment and prevention of addiction and relapse.

Summary of the invention

The present invention is generally directed to the use of PPARγ agonists alone or in combination with one or more additional therapeutic means for the treatment and prevention of addictions and relapse of drug use or inclination to sensitive behavior. Accordingly, the present invention provides methods and related compositions, the standard dosage forms, and kits for the treatment and prevention of addictions and the treatment and prevention of relapse of drug use or implementation dependent or compulsive behavior.

In one embodiment, the present invention includes a method of treatment or prevention of dependency, including the definition of the individual availability of the development of dependence or risk of addiction, giving the individual number of agonist receptor gamma peroxisome proliferator-activated (PPARγ agonist), is effective for treatment or prevention of dependency.

In a related embodiment, the present invention proposes a method of treatment or prevention of addiction, including providing the individual with the addiction, the agonist receptor gamma peroxisome proliferator-activated (PPARγ agonist and the additional therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment or prevention of dependency.

In certain embodiments of the implementation of the methods of treatment or prevention According to the present invention, the PPARγ agonist isone of thiazolidinedione (TZD). In specific embodiments, the implementation of TZD is a pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone or darglitazone. In certain embodiments of the implementation of the additional therapeutic agent is an antagonist of opioid receptors, mixed frequent CNY agonist/antagonist opioid receptors, antidepressant, antiepileptic agent, an antiemetic, an antagonist of the receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), the antagonist of 5-HT2A/2Cor receptor antagonist 1 cannabinoids (SW). In specific embodiments, the implementation of the opioid receptor antagonist is a naltrexone or nalmefene. In specific embodiments, the implementation of an antidepressant is a fluoxetine, mirtazapine, or bupropion. In specific embodiments, the implementation of the antiepileptic agent represents topiramate, levetiracetam, or gabapentin. In one embodiment, the antagonist of CRF receptor-1 is antalarmin. In another embodiment, the selective receptor antagonist 3 serotonin (5-NT3) is ondansetron. In specific embodiments, the implementation receptor antagonist 1 cannabinoids (SW) represents rimonabant or canarabank. In one embodiment, a mixed opioid agonist/antagonist is a buprenorphine.

In certain embodiments of the implementation of the methods of the present invention the individual dependent on drugs or is at risk of recurrence of the use of narcotic drugs. In specific embodiments, the implementation is possible drugs include alcohol, nicotine, marijuana, a derivative of marijuana, agonist opioids, benzodiazepine, barbiturate, or psychostimulants. In certain embodiments of the implementation of the agonist opioid selected from the group consisting of: morphine, methadone, fentanyl, Sufentanil and heroin. In certain embodiments of the exercise is a psychostimulant cocaine, amphetamine, or a derivative of amphetamine. In addition, the individual may be depending on more than one drug, and a pharmaceutical composition, a standard dosage forms, and kits may be suitable for treatment or prevention of addiction or relapse use more than one drug.

In other embodiments, implementation of the present invention, the individual tends to be dependent or compulsive behavior, or is at risk of recurrence of the implementation dependent or compulsive behavior. In specific embodiments, implementation dependent or compulsive behavior is a pathological gambling, pathological overeating, pathological use of electronic devices, pathological use of electronic games, pathological use of electronic means of communication, pathological use of cell phones, the dependence on pornogr is the philosophy, sexual anxiety, obsessive compulsive violation, compulsive pastime, anorexia, bulimia, intermittent explosive breach, kleptomania, Pyromania, trichotillomania, compulsive overload training and compulsive overload. In addition, the individual may have a tendency to more than one dependent or compulsive behavior, and pharmaceutical compositions, the standard dosage forms, and kits may be suitable for treatment or prevention of addiction or relapse propensity to more than one dependent or compulsive behavior.

In specific embodiments, implementation of any of the methods of the present invention the drug is an alcohol and the additional therapeutic agent is an antagonist of opioid receptors or mixed antagonist/partial agonist opioids. In one embodiment, the opioid receptor antagonist is a naltrexone. In another embodiment, the mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In other specific embodiments, the implementation of any of the methods of the present invention a drug is the nicotine, and an additional therapeutic agent to depict is to place an antidepressant. In one embodiment, the antidepressant is an bupropion.

In additional specific embodiments, implementation of any of the methods of the present invention a drug is a psycho stimulant, and additional therapeutic agent is an antidepressant. In one embodiment, the antidepressant is an bupropion.

In other specific embodiments, the implementation of any of the methods of the present invention, the individual is dependent on two or more drugs, and the additional therapeutic agent is an antagonist of opioid receptors or mixed partial agonist/antagonist opioid receptors. In some embodiments, the implementation of the opioid receptor antagonist is a naltrexone or nalmefene. In other embodiments, the implementation of mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In additional related embodiments implementing the present invention proposes a method of preventing recurrent use of the drug or the implementation of propensity dependent or compulsive behaviour, comprising providing an effective amount of an agonist of the receptor gamma activators of cell proliferation p is roxicam (PPARγ agonist) to the individual, which is in the phase of abstinence in phase or in a limited or reduced use of drugs, or the implementation of propensity dependent or compulsive behavior. In certain embodiments of the implementation of the individual transfers physiological abolition of narcotic drugs during the phase of abstinence or limited or reduced use of drugs or stops the effect of the effective amount of drug taken against addiction. Treatment against addiction can be a remedy for addiction or can be a non-pharmacological therapy, such as counselling, psychotherapy or hypnosis treatment.

In a related embodiment, the present invention includes a method for preventing relapse use of drugs or the implementation of propensity dependent or compulsive behaviour, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist) to the individual who is in the phase of abstinence in phase or in a limited or reduced use of drugs or the implementation of propensity dependent or compulsive behavior, and also providing additional individual the aqueous therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective prevention of relapse or implementation of behavior. In certain embodiments of the implementation of the individual transfers physiological abolition of narcotic drugs during the period of abstinence or limited or reduced use of drugs or stops the effect of the effective amount of drug taken against dependency.

In another related embodiment, the present invention features a method of treating the recurrence of the use of drugs or the implementation of propensity dependent or compulsive behaviour, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist) to the individual who is in the phase of abstinence in phase or in a limited or reduced use of drugs or the implementation of propensity dependent or compulsive behavior. In certain embodiments of the implementation of the individual transfers physiological abolition of narcotic drugs during the period of abstinence or limited or reduced use of drugs or stops the effect of the effective number of drugs the frame of the substance, taken against dependency.

In an additional embodiment, the present invention includes a method of treating recurrent use of the drug or the implementation of propensity dependent or compulsive behaviour, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist) to the individual who is in the phase of abstinence in phase or in a limited or reduced use of drugs or the implementation of propensity dependent or compulsive behavior and also provide the individual an additional therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment of relapsed or implement the behavior. In certain embodiments of the implementation of the individual transfers physiological abolition of narcotic drugs during the period of abstinence or limited or reduced use of drugs or stops the effect of the effective amount of drug taken against dependency.

In another related embodiment, the present invention proposes a method of preventing recurrent use of the drug or the implementation of propensity is avisima. or compulsive behaviour, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist) to the individual, where the individual previously reduced or stopped use of drugs or the implementation of propensity dependent or compulsive behavior in response to treatment an effective amount of drug taken against addiction, and in which there is no impact on the individual an effective amount of drug taken against addiction. In certain embodiments of the exercise is terminated, the impact on the individual an effective amount taken against, because the individual has developed a conditioned reflex in relation to the tool taken against addiction. In certain embodiments of the exercise is terminated, the impact on the individual an effective amount of drug taken against dependency, as the individual is decreased or stopped the influence of drugs taken against dependency.

In a related embodiment, the present invention proposes a method of preventing recurrent use of the drug or the implementation of propensity dependent or compulsive behavior is Denia, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist) to the individual, where the individual previously reduced or stopped use of drugs or the implementation of propensity to dependent or compulsive behavior in response to treatment an effective amount of drug taken against addiction, and in which there is no impact on the individual an effective amount of drug taken against addiction, and also provide the individual an additional therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective prevention of the recurrence of the use or implementation of behavior. In certain embodiments of the exercise is terminated, the impact on the individual an effective amount taken against, because the individual has developed a conditioned reflex in relation to the tool taken against addiction. In certain embodiments of the exercise is terminated, the impact on the individual an effective amount of drug taken against dependency, as the individual is decreased or stopped the influence of drugs taken against dependency.

In an additional embodiment, the present invention includes a method of treating relapse drugs is the means or the implementation of propensity dependent or compulsive behavior, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist) to the individual, where the individual previously reduced or stopped use of drugs or the implementation of propensity dependent or compulsive behavior in response to treatment an effective amount of drug taken against addiction, and in which there is no impact on the individual an effective amount of drug taken against addiction, and also provide the individual an additional therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment of relapse use or implement the behavior. In certain embodiments of the exercise is terminated, the impact on the individual an effective amount taken against, because the individual has developed a conditioned reflex in relation to the tool taken against addiction. In certain embodiments of the exercise is terminated, the impact on the individual an effective amount of drug taken against dependency, as the individual is decreased or stopped the influence of drugs taken against dependency.

In late the specific embodiments implement any of the methods of treatment or prevention of relapse of drug use or implement the behavior of the present invention, the PPARγ agonist is a pioglitazone, and the additional therapeutic agent is a naltrexone.

In specific embodiments, the implementation of any of the methods of treatment or prevention of relapse of drug use or implement the behavior of the present invention relapse of drug use or relapse implement the behavior is induced by stress.

In another embodiment, the present invention proposes a method of reducing one or more symptoms associated with a physiological withdrawal syndrome narcotic drugs, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ) the individual experiencing physiological abstinence from drugs.

In a related embodiment, the present invention proposes a method of reducing one. or more symptoms associated with a physiological withdrawal syndrome narcotic drugs, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ) and an additional therapeutic agent to the individual experiencing physiological abstinence from drugs, where each of the PPARγ agonist and the additional therapeutic agent contribute to reducing one or more symptoms associated with fisiologicas is named the syndrome drugs.

In specific embodiments, the implementation of the methods of reducing one or more symptoms associated with a physiological withdrawal syndrome narcotic drugs, according to the present invention, the PPARγ agonist is thiazolidinedione (TZD). In certain embodiments of the implementation of the TZD is a pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone or darglitazone. In certain embodiments of the implementation of the additional therapeutic agent is an antagonist of opioid receptors, mixed partial agonist/antagonist opioid receptors, antidepressant, antiepileptic agent, an antiemetic, an antagonist of the receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), the antagonist of 5-HT2A/2Cor receptor antagonist 1 cannabinoids (SW).

In another embodiment, the present invention includes a pharmaceutical composition comprising the agonist receptor gamma peroxisome proliferator-activated (PPARγ) and an additional therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment or prevention of dependency. In certain embodiments of the implementation of the PPARγ agonist is thiazolidinedione (TZD). The op is edelenyi options exercise of TZD is a pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone or darglitazone.

In one embodiment, a pharmaceutical composition effective for treatment of addiction to narcotic drugs. In specific embodiments, the implementation of a drug is an alcohol, nicotine, marijuana, a derivative of marijuana, agonist opioids, benzodiazepine, barbiturate, or psychostimulants.

In another embodiment, the pharmaceutical composition is effective in the treatment propensity dependent or compulsive behavior. In specific embodiments, implementation dependent or compulsive behavior is a pathological addiction to gambling, pathological overeating, pathological use of electronic devices, pathological use of electronic games, pathological use of electronic means of communication, pathological use of cell phones, pornography, sexual anxiety, obsessive compulsive violation, compulsive pastime, anorexia, bulimia, intermittent explosive breach, kleptomania, Pyromania, trichotillomania, compulsive overload training and compulsive overload.

In certain embodiments of the implementation pharmaceutically the compositions of the present invention, the additional therapeutic agent is an antagonist of opioid receptors, mixed partial agonist/antagonist opioid receptors, antidepressant, antiepileptic agent, an antiemetic, an antagonist of the receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), the antagonist of 5-HT2A/2Cand receptor antagonist 1 cannabinoids (SW). In one embodiment, the opioid receptor antagonist is a naltrexone or nalmefene. In one embodiment, the antidepressant is a fluoxetine, mirtazapine, or bupropion. In one embodiment, the antiepileptic agent selected from the group consisting of topiramate, levetiracetam or gabapentin. In one embodiment, the antagonist of CRF receptor-1 is antalarmin. In one embodiment, the selective receptor antagonist 3 serotonin (5-NT3) is ondansetron. In one embodiment, the receptor antagonist 1 cannabinoids (SW) represents rimonabant or canarabank. In one embodiment, a mixed opioid agonist/antagonist is a buprenorphine.

In a specific embodiment, pharmaceutical compositions of the present invention the drug is an alcohol and an additional therapeutic means is about is the opioid receptor antagonist or a mixed antagonist/partial agonist opioids. In one embodiment, the opioid receptor antagonist is a naltrexone. In one embodiment, the mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In a specific embodiment, pharmaceutical compositions of the present invention a drug represents the nicotine and the additional therapeutic agent is an antidepressant. In one embodiment, the antidepressant is an bupropion.

In a specific embodiment, pharmaceutical compositions of the present invention a drug is a psycho stimulant, and additional therapeutic agent is an antidepressant. In one embodiment, the antidepressant is an bupropion.

In a specific embodiment, pharmaceutical compositions of the present invention a drug includes two or more drugs, and the additional therapeutic agent is an antagonist of opioid receptors or mixed partial agonist/antagonist opioid receptors. In one embodiment, the opioid receptor antagonist is a naltrexone or nalmefene. In one embodiment, to implement the Oia mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In a specific embodiment, pharmaceutical compositions of the present invention, the PPARγ agonist is a pioglitazone and the additional therapeutic agent is a naltrexone.

In additional related embodiments, the implementation of the present invention includes a standard dosage forms of the pharmaceutical composition adapted for the treatment of addiction, where the specified standard dosage form includes an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ) and an additional therapeutic agent, where the specified standard dosage form includes the PPARγ agonist and the additional therapeutic agent in the aggregate effective amount for the treatment of addiction, and where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment or prevention of dependency. In specific embodiments, the implementation of the PPARγ agonist is thiazolidinedione (TZD). In certain embodiments of the implementation of the TZD is a pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone or darglitazone. In certain embodiments of the implementation of the additional therapeutic agent is an antagonist of opioid receptors, mixed partial agonist/antagonist the opioid receptors, antidepressant, antiepileptic agent, an antiemetic, an antagonist of the receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), the antagonist of 5-HT2A/2Cor receptor antagonist 1 cannabinoids (CB1). In one embodiment, the opioid receptor antagonist is a naltrexone or nalmefene. In one embodiment, the antidepressant is a fluoxetine, mirtazapine, or bupropion. In one embodiment, the antiepileptic agent selected from the group consisting of topiramate, levetiracetam and gabapentin. In one embodiment, the antagonist of CRF receptor-1 is antalarmin. In one embodiment, the selective receptor antagonist 3 serotonin (5-NT3) is ondansetron. In one embodiment, the receptor antagonist 1 cannabinoids (CB1) is a rimonabant or canarabank. In one embodiment, a mixed opioid agonist/antagonist is a buprenorphine.

In one specific embodiment, a standard dosage forms of the present invention, the PPARγ agonist is a pioglitazone and the additional therapeutic agent is a naltrexone.

In another related Varian is the first implementation of the present invention includes a set, intended for the treatment and prevention of addiction, including: a first container comprising an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ); and a second container comprising an additional therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment or prevention of dependency. In specific embodiments, the implementation of the PPARγ agonist is thiazolidinedione (TZD). In certain embodiments of the implementation of the TZD is a pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone or darglitazone. In certain embodiments of the implementation of the additional therapeutic agent is an antagonist of opioid receptors, mixed partial agonist/antagonist opioid receptors, antidepressant, antiepileptic agent, an antiemetic, receptor antagonist 1 corticotropinreleasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), the antagonist of 5-HT2A/2Cor receptor antagonist 1 cannabinoids (SW). In one embodiment, the opioid receptor antagonist is a naltrexone or nalmefene. In one embodiment, osushestvlyaetsya is a fluoxetine, mirtazapine, or bupropion. In one var is ante implementation antiepileptic agent selected from the group consisting of: topiramate, levetiracetam and gabapentin. In one embodiment, the antagonist of CRF receptor-1 is antalarmin. In one embodiment, the selective receptor antagonist 3 serotonin (5-NT3) is ondansetron. In one embodiment, the receptor antagonist 1 cannabinoids (SW) represents rimonabant or canarabank. In one embodiment, a mixed opioid agonist/antagonist is a buprenorphine.

In one specific embodiment, the kit of the present invention, the PPARγ agonist is a pioglitazone and the additional therapeutic agent is a naltrexone.

In one specific embodiment, the kit of the present invention the drug is an alcohol and the additional therapeutic agent is an antagonist of opioid receptors or mixed opioid receptor antagonist/partial agonist. In one embodiment. implementation antagonisation receptors is the naltrexone. In one embodiment, the mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In one specific embodiment, the kit of the present invention narcotic with is adsto is the nicotine, and the additional therapeutic agent is an antidepressant. In one embodiment, the antidepressant is an bupropion.

In one specific embodiment, the kit of the present invention a drug is a psycho stimulant, and additional therapeutic agent is an antidepressant. In one embodiment, the antidepressant is an bupropion.

In one specific embodiment, the kit of the present invention a drug includes two or more drugs, and the additional therapeutic agent is an antagonist of opioid receptors or mixed partial agonist/antagonist opioid receptors. In one embodiment, the opioid receptor antagonist is a naltrexone or nalmefene. In one embodiment, the mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In an additional embodiment, the present invention includes a kit including one or more standard dosage forms agonist receptor gamma peroxisome proliferator-activated (PPARγ) and one or more standard dosage forms of nicotine. In one embodiment, one who does more than a standard dosage forms of nicotine includes two or more different variants of nicotine content. In one embodiment, the PPARγ agonist is thiazolidinedione (TZD). In one embodiment, TZD represents pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone or darglitazone.

In an additional embodiment, the present invention includes a method of preventing the development of dependence to the individual or to reduce the likelihood of development of an individual based on a therapeutic agent that causes addiction, including the provision of in need of this individual therapeutic tool, causing dependence, and an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist), where an effective amount of a PPARγ agonist is an amount effective to protect the individual from the development of dependence or to reduce the likelihood of development of an individual based on a therapeutic agent that causes the addiction. In a particular embodiment, this method further includes providing to the individual an additional therapeutic agent, where each of the PPARγ agonist and the additional therapeutic agent contribute to the protection of the individual from the development of dependence or decrease the likelihood of an individual based on terapeuticas the th means, calling dependence. In one embodiment, a therapeutic agent that causes the addiction, is an agonist opioids.

In certain embodiments of the implementation of the methods of the present invention, the individual is dependent on drugs or has a risk of recurrence of the use of narcotic drugs. In various embodiments, the implementation of the pharmaceutical composition, the standard dosage forms and kits of the present invention is suitable for treatment or prevention of dependency on drugs or recurrent use of the drug. In specific embodiments, the implementation of a drug is an alcohol, nicotine, marijuana, a derivative of marijuana, agonist opioids, benzodiazepine, barbiturate, or psychostimulants. In certain embodiments of the implementation of the agonist opioid selected from the group consisting of: morphine, methadone, fentanyl, Sufentanil and heroin. In certain embodiments of the exercise is a psychostimulant cocaine, amphetamine, or a derivative of amphetamine. In addition, the individual may be depending on more than one drug, and a pharmaceutical composition, a standard dosage forms, and kits may be suitable for treatment or prevention of a dependent is ti or recurrent use more than one drug.

In other embodiments, implementation of the present invention, the individual is characterized by a tendency to be dependent or compulsive behavior, or is at risk of recurrence of the implementation of propensity dependent or compulsive behavior. In various embodiments, the implementation of the pharmaceutical composition, the standard dosage forms and kits of the present invention is suitable for treatment or prevention propensity dependent or compulsive behavior or relapse implementation dependent or compulsive behavior. In specific embodiments, dependency or compulsive behavior is a pathological addiction to gambling, pathological overeating, pathological use of electronic devices, pathological use of electronic games, pathological use of electronic means of communication, pathological use of cell phones, pornography, sexual anxiety, obsessive compulsive violation, compulsive pastime, anorexia, bulimia, intermittent explosive breach, kleptomania, Pyromania, trichotillomania, compulsive overload training and compulsive overload. In addition, the individual may have a tendency to more than one dependent or compulsive is vedeniu, and pharmaceutical compositions, the standard dosage forms, and kits may be suitable for treatment or prevention of addiction or relapse implement more than one dependent or compulsive behavior.

A brief description of some of the images in figures

Figure 1 is a histogram showing the effect of acute injection of 10.0 or 30.0 mg/kg of pioglitazone (Pio 10 and Pio 30, respectively) on the use of alcohol Marchigian Sardinian prefer alcohol (msP) rats. Controls were injected only media (Veh). Values are presented as mean±standard error of the mean consumption of alcohol. Indicate the significance of differences relative to controls: *p<0,05.

Figure 2 is a histogram showing the effect of acute injection of 0.25 mg/kg naltrexone (Ntx), single or in combination with 10.0 or 30.0 mg/kg of pioglitazone (Pio 10 and Pio 30, respectively) on the use of alcohol msP rats. Controls were injected carriers drugs (Veh+Veh). Values are presented as mean±standard error of the mean consumption of alcohol. Indicate the significance of differences relative to controls: **p<0.001 and *p<0,05.

Figures 3A-3D are graphs showing the effect of sub-chronic introduction of 10.0 or 30.0 mg/kg of pioglitazone (Pio 10 and Pio 30, respectively) on the use of alcohol msP rats. Controls were injected carrier Lek is rstv (Veh). The values presented in figures 3A-3C represent mean±standard error of the mean daily consumption of alcohol, measured through: 2 hours (figure 3A); 8 hours (figure 3); and 24 hours (figure 3C) from the beginning phase of dark daily cycle of light/dark. Figure 3D presents daily food consumption, measured at intervals of 24 hours. Indicate the significance of differences relative to controls: *p<0,05.

Figures 4A-4D are graphs showing the effect of sub-chronic injection of 0.25 mg/kg naltrexone (Ntx), single or in combination with 10.0 or 30.0 mg/kg of pioglitazone (Pio 10 and Pio 30, respectively) on the use of alcohol msP rats. Controls were injected carrier medicines (Veh+Veh). The values presented in figures 4A-4C represent mean±standard error of the mean daily upotreblenyya measured through: 2 hours (figure 43A); 8 hours (figure 4B); and 24 hours (figure 4C) from the beginning phase of dark daily cycle of light/dark. Figure 4D presents the daily food consumption, measured at intervals of 24 hours. Indicate the significance of differences relative to controls: *p<0,05.

Figure 5 is a bar graph a bar graph showing the effect of pioglitazone on induced yohimbinum recovery search behavior of ethanol. Compared with extinction (Ext) yohimbin caused a significant recovery of the than, which was markedly decreased in the preliminary introduction of 10.0 or 30.0 mg/kg of pioglitazone (Pio 10 and Pio 30, respectively). Values are presented as mean (±standard error of the mean) of the number of presses on the active richguy significance of differences relative to controls (media pioglitazone; Veh): **P<0,05.

Figure 6 is a bar graph histogram showing the lack of effect of pioglitazone on induced conditioned stimulus recovery search behavior of ethanol. Presented values represent the mean (±standard error of the mean) of the number of presses on the active or passive lever. Conditioned reflexes: pressing in the last session discriminatory phase - 10% alcohol (filled circles) and water (unfilled circles). Extinction (EXT): clicking on the last day of this phase. Recovery: pressing in rats exposed to conditional stimuli that predict the availability of alcohol (SYCS*) or water (S-/CS-). Indicate the significance of differences relative to Ext: **P<0,01.

Figure 7 is a histogram showing effect of treatment with ciglitazone 5,0 (Cig 5) or 20.0 mg/kg (20 Cig) or its vehicle (Veh) on Samovodene ethanol in rats Wistar scheme FR1. Each press of the lever resulted in the delivery of 0.1 ml of 10% ethanol. Indicate the significance of differences relative to controls (Veh): *P<0,05.

Figure 8 is a graph showing the effect of introducing a 7.5 or 15.0 mg/kg rosiglitazone (Ros) on alcohol consumption by rats msP. Controls were injected carrier medications (Veh). Values are presented as mean±standard error of the mean alcohol consumption (g/kg) at the indicated time points. Indicate the significance of differences relative to controls: **p<0.01 and *p<0,05.

Figures 9A and 9B are graphs showing the effect of prior administration of the PPARγ antagonist GW9662 on pioglitazone-induced reduction in the consumption of alcohol. Figure 9A presents the effect of one GW9662 (GW) (1.0 and 5.0 mg/kg) on alcohol consumption by rats msP. The figure 9 presents the effect of GW9662 pretreatment of animals that were administered 30 mg/kg of pioglitazone (Pio) or the media. The control group received the carriers of both drugs (Veh+Veh). Values are presented as mean±standard error of the mean alcohol consumption (g/kg). Indicate the significance of differences relative to controls: **p<0,01.

Figure 10 is a graph showing the effect of prior administration of the PPARγ antagonist GW9662, administered ICV, on pioglitazone-induced reduction in the consumption of alcohol. Rat msP received 5,0 µg/rat one GW9662 (GW), 30 mg/kg of one of pioglitazone (Pio) or a combination thereof. The control group received media both Lek is rstv (Veh+Veh). Values are presented as mean±standard error of the mean alcohol consumption (g/kg). Indicate the significance of differences relative to controls: *p<0.05 and **p<0,01.

Figure 11 is a histogram showing the effect of naltrexone (Ntx) on induced yohimbinum recovery search behavior of ethanol. Compared with extinction (Ext) yohimbin caused a significant recovery of response that have not been modified during preview processing of 0.25 and 1.0 mg/kg naltrexone. Values are presented as mean (±standard error of the mean) of the number of presses on the active richest differences with respect to controls (0.0) was false.

Figure 12 is a histogram showing the effect of naltrexone (Ntx) on induced conditioned stimulus recovery search behavior of ethanol. Values represent the average (±standard error of the mean) of the number of clicks is not the active lever. Conditioned reflexes: pressing in the last session discriminatory phase - 10% alcohol (filled circles) and water (unfilled circles). Extinction (Ext): clicking on the last day of this phase. Recovery: pressing in rats exposed to conditional stimuli that predict the availability of alcohol (S-/CS-) or water (S-/CS-). Processing of 0.25 and 1.0 mg/kg of naltrexone is substantial reduced induced conditioned stimulus recovery search behavior of ethanol; **P<0,01.

Figures 13A and 13B represent a histogram showing the effect of the combination of naltrexone (ntx). plus pioglitazone (Pio) on: induced yohimbinum recovery search behavior of ethanol (figure 13A) or induced conditioned stimulus recovery search behavior of ethanol (figure 13B). Compared with extinction (Ext) yohimbin caused a significant recovery of response. The combination of naltrexone (1.0 mg/kg) plus pioglitazone (10 and 30 mg/kg) significantly inhibited induced yohimbinum recovery search behavior of ethanol (figure 13A). Introduction 1.0 mg/kg of naltrexone in combination with pioglitazone (10 and 30 mg/kg) also significantly reduced the induced conditioned stimulus recovery search behavior of ethanol. Conditioned reflexes: pressing in the last session discriminatory phase - 10% alcohol (filled circles) and water (unfilled circles). Extinction (Ext): clicking on the last day of this phase. Recovery: pressing in rats exposed to conditional stimuli that predict the availability of alcohol (S+/CS+) or water (S-/CS-). Values are presented as mean (±standard error of the mean) of the number of presses on the active lever. Indicate the significance of differences relative to Ext: *P<0,05, **p<0,01.

Figure 14 is a graph showing the effect is t introduction one of pioglitazone (Pio) 10 mg/kg or a single fluoxetine 3 mg/kg, or their combination on the consumption of alcohol msP rats. Controls were injected carriers drugs (Veh+Veh). Values are presented as mean±standard error of the mean alcohol consumption (g/kg) Indicated the significance of the differences with respect to controls: *p<0.05 and **p<0,01.

Figure 15 is a graph showing the effect of introducing one of pioglitazone (Pio) 10 mg/kg or one of mirtazapine 5 mg/kg, or their combination on the consumption of alcohol msP rats. Controls were injected carriers drugs (Veh+Veh). Values are presented. as mean±standard error of the mean alcohol consumption (g/kg). Indicate the significance of differences relative to controls: *p<0,05.

Figure 16 is a graph showing the effect of introducing one of pioglitazone (Pio) 10 mg/kg or a single topiramate 30 mg/kg, or their combination on the consumption of alcohol msP rats. Controls were injected carriers drugs (Veh+Veh). Values are presented as mean±standard error of the mean alcohol consumption (g/kg). Indicate the significance of differences relative to controls: *p<0,05.

Figure 17 is a graph showing the effect of introducing one of pioglitazone (Pio) 10 mg/kg or a single levetiracetam (Leve) 100 mg/kg, or their combination on the consumption of alcohol msP rats. Controls were injected only media (Veh+Veh). Values are presented as mean±standard error of the average the consumption of alcohol (g/kg). Indicate the significance of differences relative to controls: *p<0.05 and **p<0,01.

Figure 18 is a graph showing the effect of introducing one of pioglitazone (Pio). 10 mg/kg or one gabapentin 30 mg/kg, or their combination on the consumption of alcohol msP rats. Controls were injected carriers (Veh+Veh). Values are presented as mean±standard error of the mean alcohol consumption (g/kg). Indicate the significance of differences relative to controls: **p<0.01 and *p<0,05.

Figure 19 is a graph showing the effect of introducing one of pioglitazone (Pio) 10 mg/kg or a single ondansetron 1.0 mg/kg, or their combination on the consumption of alcohol msP rats. Controls were injected carriers drugs (Veh+Veh). Values are presented as mean±standard error of the mean alcohol consumption (g/kg). Indicate the significance of differences relative to controls: **p<0.01 and *p<0,05.

Figure 20 is a graph showing the effect of introducing one of pioglitazone (Pio) 10 mg/kg or one antalarmin 15 mg/kg, or their combination on the consumption of alcohol msP rats. Controls were injected carriers (Veh+Veh). Values are presented as mean standard error of the mean alcohol consumption (g/kg). Indicate the significance of differences relative to controls: *p<0.05 and **p<0,01.

Figure 21 is a histogram showing the impact of the introduction of 10 and 30 mgkg pioglitazone (Pio) on the indicator of the syndrome of alcohol in Wistar rats. Controls received oral administration of media alcohol. Values are presented as mean±standard error of the mean total rate of the syndrome. Indicate the significance of differences relative to controls: **p<0,01.

Figures 22A and 22B are histograms showing the impact of the introduction of 10.0 or 30.0 mg/kg of pioglitazone (10 or 30, respectively) or its vehicle (veh) on Samovodene cocaine under the scheme. FR5 Wistar rats. Figure 22A shows the number of reinforcements on the active lever, and every five presses of the lever resulted in the delivery of a single reinforcement (0.25 mg/0,1. ml cocaine). Figure 22B shows the number of clicks on left inactive richguy significance of differences relative to controls (Veh): **p<0,01.

Figures 23A and 23C are histograms showing the effect of pioglitazone (30 mg/kg) or its vehicle (veh) on Samovodene nicotine scheme FR5 Wistar rats. Figure 23A shows the number of reinforcements on the active lever, and every five presses of the lever resulted in the delivery of 0.25 mg/0.03 ml of nicotine. Figure 23C shows the number of clicks on left inactive lever. Indicate the significance of differences relative to controls (Veh): *p<0,05.

Detailed description

The present invention is based mostly on described in this document evidence that agonists R is Ceptor gamma peroxisome proliferator-activated (PPARγ) is suitable for the treatment and prevention of addictions and relapse use of drugs or dependent behavior. Accordingly, the present invention provides methods and related compositions, formulations, standard dosage forms, and kits for the treatment and prevention of addiction and relapse of drug abuse, which include one or more PPARγ agonists, alone or in combination with one or more additional therapeutic means, where each of the PPARγ agonist and the additional(different) therapeutic(fir) means(TV) contributes to the effective treatment or prevention of dependency.

As demonstrated in the accompanying examples, it was found that the number of different preparations of thiazolidinediones (TZDs) reduce the use of drugs in various models of addiction. For example, each of TZDs, pioglitazone, ciglitazone and rosiglitazone significantly reduced ethanol consumption in the rat models of alcohol dependence (examples 1, 3, 7 and 8). The effect is obvious for both acute and sub-chronic introduction of TZD (examples 1 and 2). In addition, it is shown that TZDs reduce the consumption of cocaine in the rat model of cocaine addiction (example 23) and a rat model of nicotine addiction (example 24). This effect of PPARγ agonists, as determined using two different PPARγ agonist, is mediated by the activation of PPARγ receptors (examples 9 and 10). In addition, the results of observations of sick people using PI is glitazone for diabetes, confirmed that the PPARγ agonist was effective in reducing the abuse of ethanol (example 22). These findings indicate that PPARγ agonists can be used for the treatment and prevention based on a number of different drugs.

In addition, in the accompanying examples demonstrate that PPARγ agonists used in conjunction with a number of different therapeutic agents significantly reduced the use of drugs. For example, it is shown that acute or sub-chronic treatment with TZD, pioglitazone, increased the inhibitory action of the opioid receptor antagonist naltrexone on ethanol consumption (examples 2 and 4). These data show that the use of a PPARγ agonist in combination with an antagonist of opioid receptors should increase, for example, additive or synergistic, the effectiveness of treatment or prevention of dependency.

In addition to reducing the use of drugs PPARγ agonists have also been able to reduce or prevent relapse or reinstatement of drug taking. As described in example 5, treatment with pioglitazone significantly reduced the induced stress recovery in consumption of alcohol. It is interesting, however, that it did not significantly reduce induced conditioned stimulus recovery of consumption of alcohol (example 6). On the contrary, the opioid receptor antagonist naltrexone reduces induced conditioned stimulus recovery of consumption of alcohol, but not induced stress recovery in consumption of alcohol (examples 12 and 11). These data support the concept that the combination of a PPARγ agonist and antagonist of opioid receptors must possess a high potential for preventing relapse use of narcotic drugs, as this combination should prevent as induced by stress and induced conditioned stimulus relapse drinking. Indeed, the combination of a PPARγ agonist pioglitazone and the opioid receptor antagonist naltrexone led to a significant reduction in recovery as induced by stress and induced conditioned stimulus drinking alcohol (example 13).

PPARγ agonists also work synergistically with other classes of therapeutic agents in the reduction or prevention of dependency and relapse drinking. For example, TZD, pioglitazone, used in conjunction with a number of different classes of antidepressants, including fluoxetine and mirtazapine, worked synergistically in reducing the consumption of ethanol in animal model based on ethanol (examples 14 and 15). Antiepileptic drugs, including topiramate, levetiracetam, and gabapentin, showed a synergistic effect in combination with TZD in reduction of ethanol consumption (examples 16-18) and anti-emetics, including the selective receptor antagonist 3 serotonin (5-NT3), ondansetron, a selective antagonist of the receptor 1 corticotropin-releasing factor, antalarmin, also showed a synergistic effect in combination with TZD in reduction of ethanol consumption (examples 19 and 20).

Interestingly, the experiments described in the accompanying examples, showed that PPARγ agonists significantly reduced the symptoms of the syndrome have a dependent spirit animals (example 21).

To sum up, the present invention demonstrated that treatment with PPARγ agonists represents a new pharmacological approach to the treatment and prevention of addiction, as it reduces the consumption of narcotic drugs and relapse associated with stress exposure.

In addition, given that the pathophysiology of addiction has the features (i.e. cravings for the drug, compulsive behavior, triggered by a thirst drug abstinence, the propensity to relapse, neurological disorders, depression, cognitive abilities)that are common to all drugs by their abuse, it is reasonable to assume that PPARγ agonists are suitable for treatment of addiction to other drugs or types of dependent behavior, including, for example, opiates (morphine, heroin, methadone), stimulants (cocaine, methamphetamine and related amphetamine compounds in General), nicotine, gamma-hydroxybutyrate (GHB), penticle the ins and derivatives of phencyclidine, etc.

PPARγ agonists have been effective in combination with antagonists of opioids; co-administration of the two drugs resulted in an additive effect on the effect on ethanol consumption and increased the effectiveness of the antagonist of opioid receptors on induced stress recovery. In the mode of joint introduction is particularly important to note neuroprotective anticonvulsants effect and the reduction effect of the syndrome under the action of TZDs, especially in the early phase of treatment. Indeed, opioid antagonists do not cause any attenuation of withdrawal symptoms and this can contribute to the early termination of treatment and low yielding, often observed when using these drugs.

The ability of TZDs to normalize liver function may also have positive implications in the study of the approach to the combined treatment. In fact, the clinical condition of patients alcoholics in General undermined, especially during the early phase of detoxification. Thus, rapid recovery and relief pathological conditions may favorably influence the maintenance of the course of treatment.

A. Methods of treatment and prevention of dependencies using the agonist(s) PPARγ

Thus, the present invention includes methods of treatment or prevention of dependency, vkluchaetsia one or more agonists of PPARγ individual, with addiction, or the risk of addiction. In various embodiments, the implementation of the individual is dependent on drugs or addictive behavior, including, but not limited to, any of those described herein in narcotic drugs and types of behavior. An individual may be physically or physiologically dependent on a substance or behavior; an individual may be psychologically dependent; or the individual may be both physically and psychologically dependent. An individual may depend on one or more than one drug or type of dependent behavior.

As used in this description, unless the context clearly indicates otherwise, the term treat, and a similar word, such as treatment, processing, etc. is an approach for obtaining beneficial or desired results, including the preferred clinical results. The treatment may not necessarily involve either the reduction or alleviation of a disease or condition (e.g., addiction, relapse drinking, abstinence), or delay progression of the disease or condition (e.g., addiction, relapse drinking, abstinence).

As used in this description, unless the context clearly indicates otherwise, the term to prevent and similar word, such as prevention, prevent the tion, etc., an approach to the prevention of occurrence or recurrence of the disease or condition (e.g., addiction, relapse drinking, abstinence), or to the prevention of occurrence or recurrence of symptoms of a disease or condition, or optional approach to delay the occurrence or recurrence of the disease or. condition, or delay the occurrence or recurrence of symptoms of a disease or condition.

Usually the individual is provided an effective amount of a PPARγ agonist. As used in this description, the effective amount or therapeutically effective amount of a substance, for example, PPARγ agonist, represents such an amount that is sufficient to affect the desired biological or psychological effect, such as, favorable results, including clinical results. For example, in the context of addiction treatment using the methods of the present invention an effective amount of a PPARγ agonist is a such amount that is sufficient to cause the individual reducing or stopping the use of drugs.

In accordance with certain variants of implementation of the present invention, the individual is provided with one PPARγ agonist while in other embodiments, implementation of the individual both is realised by the PPARγ agonist in combination with an additional therapeutic agent. It is clear that the effective amount of each or both of the PPARγ agonist and the additional therapeutic agent may vary when each offered individually or when they are offered in combination. For example, when the PPARγ agonist and the additional therapeutic agent act synergistically, the lower the amount of the PPARγ agonist, a lower amount of additional therapeutic agent or. a lower number of both agonist. PPARγ or additional therapeutic agent, may be required to achieve the same therapeutic effect than if the PPARγ agonist or an additional therapeutic agent offered separately. In other embodiments, the exercise of the same number of PPARy agonist and the additional therapeutic agent is used to provide an enhanced therapeutic effect in relation to therapeutic effect, or provide a PPARγ agonist, or an additional therapeutic tool separately. As another example, the data the following examples show that patients who are dependent on alcohol and treated with the PPARγ agonist. pioglitazone, are characterized by reduced depression, and the treatment of patients with addictive combination of a PPARγ agonist and antidepressant truly invented the Yu can provide increased antidepressant therapeutic effect as part of treatment violations, characterizing the dependency.

The individual can be any animal, including a mammal, and in particular people.

In one aspect of the invention the individual first identify or diagnose the existence of dependence or risk of addiction through diagnostic testing, observation or analysis with organizations that provide medical services. Then the individual an effective amount of a PPARγ agonist, or an effective amount of a PPARγ agonist and one additional therapeutic agent for the treatment or prevention of dependency. In another aspect of the invention the first individual identified or diagnosed with dependence or risk of dependency through diagnostic testing, observation or analysis with organizations that provide medical services, but the individual is not diagnosed or identified the presence of diabetes or other disturbance of the insulin axis. Then the individual an effective amount of a PPARγ agonist, or an effective amount of a PPARγ agonist and one additional therapeutic agent for the treatment or prevention of dependency. The dosage of the agonist PPARγ or PPARγ agonist and one additional therapeutic agent can be specifically determined by the attending physician for the treatment of the Oia or addiction prevention, and not any other disorders or diseases.

In specific aspects of the individual features PPARγ agonist alone or in combination with an additional therapeutic tool for the primary purpose of treatment or prevention of dependency. In related aspects, methods of the present invention the individual has not previously provided the PPARγ agonist for the treatment or prevention of any disease or impairment, other than addiction. In particular, in certain embodiments of the implementation of the individual has not previously provided the PPARγ agonist for the treatment of resistance to insulin or diabetes. In an additional related embodiment, the subject has not been diagnosed with insulin resistance or diabetes.

In various embodiments, implementation of the present invention the individual may be granted to any agonist PPARγ, including any of the specific PPARγ agonists are described below. In specific embodiments, the implementation of the PPARγ agonist is a TZD, including any of TZDs, described below. In certain embodiments of the implementation of the TZD is a pioglitazone, ciglitazone, rosiglitazone or troglitazone.

In specific embodiments, the implementation of the individual suffering from addiction or risk of dependence on any individual drugs or has a tendency to be dependent Il is compulsive behavior, including, for example, any of the following. In specific embodiments, the implementation of the individual suffering from dependence on alcohol, cocaine, nicotine, marijuana, opiate or other agonist opioids, or methamphetamine, or other stimulants, or derivatives of phencyclidine and phencyclidine.

In specific embodiments, the implementation of the individual is considered as having a risk of addiction or relapse use of drugs or implementation dependent behavior when the individual had previously been in a state of dependence from the same or different drugs, or in a state of inclination to a dependent or compulsive behavior. In a specific embodiment, the individual is considered as having a risk of addiction or relapse use of drugs or the implementation of propensity sensitive behavior when the individual is psychologically dependent on drugs or dependent or compulsive behavior, even if the individual is no longer in a state of physical dependence.

In certain embodiments of the implementation of the individual is in a state of dependence or risk depending on therapeutic agent provided to the patient for the treatment of diseases or disorders, for example, medicamentosa treatment of pain. In a related embodiment, the individual may be at risk of drug abuse therapeutic tool, such as used for treatment of pain. Abuse of narcotic therapeutic tool in a specific embodiment, it is understood as indicating the use of funds for purposes other than its intended use, or in addition to it. In this situation, the individual can be granted as a drug, therapeutic agent, and the PPARγ agonist, alone or in combination with an additional therapeutic agent. For example, the individual suffering from the pain or the risk of pain, can be provided opioid agonist and a PPARγ agonist or TZD, for example, pioglitazone, to provide both analgesia and prevention or treatment of addiction to opioid agonist receptors. As a PPARγ agonist, as shown, reduces neuropathic pain and inflammatory responses (see, for example, A. Oliveira et al., Antinociceptive and antiedematogenic activities of fenofibrate, an agonist of PPAR alpha, and pioglitazone, an agonist of PPAR gamma, Eur J Pharmacol. 561(1-3):194-201 (2007)), the PPARγ agonist can complement or increase the analgesic effect of the opioid agonist.

In various embodiments, the implementation of the individual is the PPARγ agonist at a time when the individual takes the drug is eticheskoe means, after the individual has stopped taking drugs or before the individual began to take a drug.

1. Drugs

The term addiction is used to describe repetitive compulsive urge of the individual to the passion for any specific activity, despite harmful consequences to the health of the individual, mental state or social life. The term is often use for drug addictions, but it is sometimes applied to other compulsive urges, such as problem gambling and compulsive overeating. Factors that are alleged causes of dependency, include genetic, biological/pharmacological and social factors.

The medical community is currently making a thorough theoretical distinction between physical or physiological dependence (characterized by withdrawal symptoms) and psychological dependence (sometimes referred to simply as a dependency). The dependence of the currently defined in the narrow sense as uncontrolled, compulsive use. If you do not experience harm from which the patient suffers, or another part of society, or they may not develop problems, clinically it can be regarded as compulsive, n is, by definition, some of it is not classified according. In practice, two types of dependencies (physiological dependence and psychological dependence) is not always easy to discern. Dependence often have both physical and psychological components.

Physical dependence (or drug dependence) refers to a state resulting from habitual use of a drug where negative physical symptoms cancellations occur because of a sudden interruption. Examples of drugs for which the consumer may develop physical dependence include nicotine, opioids, barbiturates, benzodiazepines, alcohol, i.e. ethyl alcohol, GHB and methaqualone.

Stimulants, which are usually abuse, such as cocaine or drug class amphetamine is not considered to cause significant physical dependence. However, their potential in relation to the ultimate psychological dependence may force the consumer to use the number that become physically damaging, but life-threatening effects withdrawal symptoms are not observed.

Used in the present description drugs include any and all funds from which the individual can develop dependence, either physical or psychological, or both. As noted above, the dependence includes the dependence on chemicals, so is x as drugs, for example, ethanol, nicotine or cocaine, and dependence on other types of behavior, for example, from a pathological passion for gambling, pathological overeating, pathological use of electronic devices, such as a BlackBerry®, pathological use of electronic games, pathological use of electronic communication, pathological use of cellular phones, pornography, sexual anxiety, obsessive compulsive violation, compulsive pastime, anorexia, bulimia, intermittent explosive breach, kleptomania, Pyromania, trichotillomania, compulsive overload training and compulsive overload.

Drugs include recreational drugs, and narcotic drugs. Examples of drugs include, but are not limited to, alcohol, e.g. ethanol, gamma-hydroxybutyrate (GHB), caffeine, nicotine, cannabinoids (marijuana) and derivatives of cannabinoids, opiates and other morphine-like agonists opioids, such as heroin, phencyclidine and phencyclidine connection, sedative hypnotics, such as benzodiazepines, methaqualone, mecloqualone, etaqualone and barbiturates, and stimulants, such as cocaine, amphetamines and ro is significantly amphetamine drugs, such as dextroamphetamine and methylamphetamine. Other examples include LSD, psilocybin, ecstasy and other hallucinogens. Examples of narcotic drugs include, for example, benzodiazepines, barbiturates, and analgesic medications, including Alfentanil, allylprodine, Alphaprodine, Anileridine, benzylmorphine, Bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, Dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, and dissapative, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, levallorphan, Levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, mirfin, nalbuphine, narceine, Nicomorphine, norlevorphanol, Normethadone, nalorfin, normorphine, norpipanone, opium, oxycodone, OXYCONTIN®, Oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, Phenoperidine, piminodine, Piritramide, proheptazine, promedol, properidine, propiram, propoxyethanol, tramadol, Tilidine, their salts, and mixtures of any of the above, mixed mu-agonists/antagonists and the like.

In certain embodiments implement an individual can have is dependent on the opioid agonist. The term opioid agonist, opioid and opiate use in the present description are interchangeable and are used to indicate the group of drugs that possess varying degrees of opium or morphine-like properties. They are used mainly for pain relief. These tools work as a result of binding with opioid receptors, which are found mainly in the Central nervous system and gastrointestinal tract. Opiates are narcotic drugs. Opiates include Alfentanil, allylprodine, Alphaprodine, Anileridine, apomorphine, benzylmorphine, beta-hydroxy-3-methylfentanyl, Bezitramide carpenter, clonitazene, codeine, desomorphine, dextromoramide, diacetylmorphine (heroin), diampromide, Dihydrocodeine, dihydromorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl, Dipipanone, eptazocine, ethoheptazine, timeintegrated, Ethylmorphine, etonitazene, Etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, LMM, Levorphanol, levophenacylmorphan, lofentanil, meperidine, metapan, metazocine, methadone, methdilazine, metopon, morphine, mirfin, Narain, Nicomorphine, norlevorphanol, Normethadone, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaverine, phenadoxone, phenomorphan, Phenoperidine, piminodine, Piritramide, profe the Tazin, promedol, properidine, propoksifen, Remifentanil, Sufentanil, thebaine, Tilden and tramadol.

Natural opiates include codeine, morphine, noscapine, papaverine, and thebaine. Semi-synthetic opioids include diacetylmorphine, hydrocodone, hydromorphone, Levorphanol, metapan, nalorfin, naloxone, naltrexone, oxycodone, Oxymorphone and tramadol. Synthetic opioids include ethoheptazine, fentanyl, Levorphanol, meperidine, methadone, phenazocine, propoksifen and Sufentanil.

Three broad classes of opiates are phenanthrenes, phenylephrine and phenylpiperidine. Examples phenanthrenes include codeine, Etorphine, hydrocodone, hydromorphone, morphine, oxycodone, and Oxymorphone. Examples of phenylheptane include dimepheptanol, dimenoxadol, Dipipanone, isomethadone, methadone, metagalactic and propoksifen. Examples of phenylpiperidines include Alfentanil, Alphaprodine, beta-promedol, carfentanil, fentanyl, lofentanil, meperidine, properdin and Sufentanil.

Specific psychostimulants include as an example, amphetamine, cocaine, dextroamphetamine, methamphetamine, pemoline and methylenedioxymethamphetamine.

Along with the fact that the individual may have a dependence on one drug or type of behavior, often the individual has a dependency on two or more drugs or types of behavior. Dependence on two or b is more drugs or types of dependent behavior is denoted as multiple dependency.

2. PPARγ agonists

Receptors of the peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors of the superfamily of nuclear hormone receptors. Currently identified three different PPAR isoforms, called PPARα, PPARβ/(and PPARγ (Breidert et al., 2002; Feinstain et al. 2003). Isoform receptor PPARγ in large quantities is expressed in the liver and kidney and it regulates the catabolism of fatty acids; PPARβ/(expressed everywhere and involved in the regulation of various cellular processes, including differentiation of adipocytes, keratinocytes and oligodendrocytes. Finally, the receptor PPARγ is expressed predominantly in adipose tissue and macrophages, where they are involved in the differentiation of adipocytes, the regulation of homeostasis of Sugars and lipid homeostasis and the control of inflammatory responses (Heneka et al. 1999; Landreth and Heneka 2001; Harris and Phipps 2002).

Endogenous ligands of PPAR receptors belong to different classes of compounds comprising unsaturated fatty acids, which include leukotrienes, a metabolite retinoic acid and prostaglandins. For example, the receptor PPARγ are mainly localized in the cytoplasmic fraction and activated 15-deoxy-Δ12-14-prostaglandin J2(Burstein 2005; Cernuda-Morollon, et al., 2002). Recent studies have also shown that in addition to the various peripheral is Canam receptor PPARβ/(and PPARγ are expressed in neurons and oligodendrocytes but not in astrocytes of the Central nervous system (CNS). The exact role of these receptors in the brain is still not clear how (Kainu et al. 1994).

It is known that activation of PPARγ mediates neuroprotective responses against toxic process of excitation and inflammatory lesions (Butcher et al. 2002). Activation of these receptors is also associated with improved cognitive abilities and with the presence of a protective capacity against epileptic strokes (Yu et al., 2008).

In 1997 in Japan have developed a new class of drugs, of preparations of thiazolidinediones (TZDs), originally as antioxidants. Some of these compounds were then approved for clinical treatment of resistance to insulin and type 2 diabetes.

At the molecular level TZDs bind with high affinity and activate PPARγ receptors; it has been suggested that this is the main mechanism by which these molecules exert their therapeutic effects. Currently, two connections TZD clinically used for the treatment of humans, pioglitazone (Actos®) and rosiglitazone (Avandia®). Pioglitazone and synthesis methods and compositions of pioglitazone, as well as the composition of pioglitazone additionally described in U.S. patent 4687777, 5965584 and 6150383, the disclosure of each of which is incorporated into this description by reference. Other compounds (i.e. ciglitazone, troglitazone, aleglitazar, muraglitazar, tesaglitazar and ragaglitazar etc) are the " go to bonus " development. Suitable PPARγ agonists for use in the present invention include selective PPARγ agonists, such as ciglitazone, troglitazone, pioglitazone, rosiglitazone, englitazone, rivoglitazone and darglitazone.

An additional class of PPARγ agonists are PPARγ agonists with double action. Dual active PPARγ agonists represent a new group of compounds that activate nuclear transcription factors. By activating receptors as PPARα and PPARγ, they simultaneously reduce atherogenic triglyceride, increase the levels of cardiotoxin HDI and develop resistance to insulin. Examples of dual active PPARγ agonists that may be suitable for use in the present invention include tesaglitazar, aleglitazar, muraglitazar and ragaglitazar.

Additional PPARγ agonists that can be used in the present invention include, but are not limited to, those described in the following patents and patent applications: U.S. patents№№6294580, 7067530, 6582738, 6794154, 4812570, 4775687, 4725610, 4582839 and 4572912; and in the publications of patent applications U.S. No. US2002/006942, US2007/0299047, US2004/0077525 and US 2008/0045580, disclosure of which is included in this description as a reference. Examples of dual PPARγ agonists which can be used in the present invention include, for example, described in patent bid, medium, small the x U.S. No. 2007/037882, US 2006/0270722, US 2006/0211749, US 2006/0167045 and US 2005/0014833, the disclosure of which is incorporated into this description as a reference.

C. Methods of treatment and prevention of addiction with the use of the agonist(s) PPARγ in combination with other therapies

As demonstrated in the accompanying examples, the PPARγ agonists can be used effectively in combination with one or more therapeutic means for the treatment and prevention of dependence, including dependence on one or more of the drugs described below, and compulsive or dependent behavior. Accordingly, in the present invention included are methods of treatment or prevention of dependency, including the provision of individual, dependent on drugs, one or more agonist(Tami) PPARγ and one or more additional therapeutic agents, where each of the agonist(s) PPARγ and more(ing) therapeutic(fir) means(TV) contribute to the effective treatment or prevention of dependency. In one embodiment, the individual is granted or entered one PPARγ agonist and one additional therapeutic agent. In another embodiment, the individual has a dependency on two or more drugs. As shown in the examples below, the combination of agonist. PPARγ and another terapeutiche what someone means may have a beneficial additive or synergistic efficacy in the treatment or prevention of addiction or relapse use of narcotic drugs. In some embodiments, the implementation of the additional tool is a other drug drug.

The PPARγ agonist and the additional therapeutic agent can be entered at the same time (i.e. simultaneously) or you can enter them one over the other (i.e. sequentially). In General, the PPARγ agonist and the additional therapeutic agent are present in an individual at the same time within the time and at levels sufficient to provide a therapeutic effect in an individual, i.e. during the treatment or prevention of dependency or prevention of relapse of drug use (or recovery) of drugs or compulsive or dependent behavior. The PPARγ agonist and the additional therapeutic agent can be entered using the same or different routes of administration. Typically, the PPARγ agonist and the additional therapeutic agent is given to each individual in accordance with the standard scheme the introduction of commercially available or other pharmaceutical compositions. In one embodiment, the PPARγ agonist and the additional therapeutic agent are administered together with the composition, including both tools.

Additional therapeutic tool, offered in combination with a PPARγ agonist, can represent any therapist who ical means, which contributes to the effective treatment or prevention of dependency. For example, the additional therapeutic agent can be a drug used to treat addiction, or drug used to alleviate the side effects associated with the physiological cancellation drugs. In addition, the additional therapeutic agent may be any drug that affects serotonergic neurotransmission in the brain, such as selective inhibitors of serotonin reuptake (SSRIs) and tricyclic and tetracyclic inhibitors of reuptake of serotonin and norepinephrine (SNRIs), as described below, and serotonin agonists, such as sumatriptan, ergonovine, digidroergotamin and buspirone. In certain embodiments of the implementation of the additional therapeutic agent is an antagonist of opioid receptors, including mixed partial agonist/antagonist opioid, antidepressant, antiepileptic agent, an antiemetic, an antagonist of the receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), the antagonist of 5-HT2A/2Csuch as mianserin, mirtazapine and ketanserin, or antagonist of the receptor 1 cannabinoids (SW), including, but not limited to,those therapeutic means, specifically described below.

In one embodiment, a drug is an alcohol and the additional therapeutic agent is an antagonist of opioid receptors or mixed opioid receptor antagonist/partial agonist. In a specific embodiment, the antagonist of opioid receptors is the naltrexone. In another embodiment, the mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In one embodiment, a drug is an alcohol and the additional therapeutic agent is a topiramate or levetiracetam.

In one embodiment, a drug is the nicotine, and an additional therapeutic agent is an antidepressant. In a specific embodiment, the antidepressant is an bupropion.

In one embodiment, a drug is a cocaine and the additional therapeutic agent is a buprenorphine.

In one embodiment, a drug is a psycho stimulant, and additional therapeutic agent is an antidepressant. In a specific embodiment, Khujand the exercise of antidepressant is an bupropion.

In one embodiment, the individual is dependent on two or more drugs, and the additional therapeutic agent is an antagonist of opioid receptors or mixed partial agonist/antagonist opioid receptors. In a particular embodiment, the mixed partial agonist/antagonist opioid receptor is a buprenorphine.

In specific embodiments, the implementation of the individual is provided by the combination of pioglitazone and naltrexone; ciglitazone and naltrexone; rosiglitazone and naltrexone; englitazone and naltrexone; rivoglitazone and naltrexone; darglitazone and naltrexone; pioglitazone and fluoxetine; ciglitazone and fluoxetine; rosiglitazone and fluoxetine; englitazone and fluoxetine; rivoglitazone and fluoxetine; darglitazone and fluoxetine; pioglitazone and mirtazapine; ciglitazone and mirtazapine; rosiglitazone and mirtazapine; englitazone and mirtazapine; rivoglitazone and mirtazapine; darglitazone and mirtazapine; pioglitazone and topiramate; ciglitazone and topiramate; rosiglitazone and topiramate; englitazone and topiramate; rivoglitazone and topiramate; darglitazone and topiramate; pioglitazone and levetiracetam; ciglitazone and levetiracetam; rosiglitazone and levetiracetam; englitazone and levetiracetam; rivoglitazone is levetiracetam; darglitazone and levetiracetam; pioglitazone and gabapentin; ciglitazone and gabapentin; rosiglitazone and gabapentin; englitazone and gabapentin; rivoglitazone and gabapentin; darglitazone and gabapentin; pioglitazone and ondansetron; ciglitazone and ondansetron; rosiglitazone and ondansetron; englitazone and ondansetron; rivoglitazone and ondansetron; darglitazone and ondansetron; pioglitazone and antalarmin; ciglitazone and antalarmin; rosiglitazone and antalarmin; englitazone and antalarmin; rivoglitazone and antalarmin of darglitazone and antalarmin.

For the treatment of alcohol dependence combinations for injection of the present invention include the PPARγ agonist and the opioid agonist or mixed opioid receptor antagonist/partial antagonist, a PPARγ agonist and an antidepressant, the PPARγ agonist and antagonist/inverse agonist of the receptor SW, the PPARγ agonist and varenicline, the PPARγ agonist and acamprosate and the PPARγ agonist and disulfiram.

For treatment of addiction to stimulant combinations for injection of the present invention include, for example, a PPARγ agonist and an antidepressant or a PPARγ agonist and a partial opioid agonist/antagonist, for example, buprenorphine.

For the treatment of nicotine addiction combinations for injection of the present invention include, for example, the PPARγ agonist and antidepres the ant, the PPARγ agonist and nicotine (as a substitute composition for oral, percutaneous injection or other conventional structure), a PPARγ agonist and antagonist of opioid receptors, PPARγ agonist and antagonist/inverse agonist of the receptor SW and the PPARγ agonist and varenicline.

For treatment of addiction to many drug compounds combinations for injection of the present invention include, for example, the PPARγ agonist and the opioid agonist or mixed opioid receptor antagonist/partial antagonist.

For treatment of addiction to gambling combinations for injection of the present invention include, for example, a PPARγ agonist and an antidepressant or a PPARγ agonist and a means of affecting dopaminergic neurotransmission, for example, a direct or indirect dopamine antagonist.

The effective amount of each or both of the PPARγ agonist and the additional therapeutic agent, can be reduced with the introduction of the combination compared with the introduction of each of them separately. For example, when the PPARγ agonist and the additional therapeutic agent are additive or synergistic, fewer PPARγ agonist, fewer additional therapeutic agent or fewer as of the PPARγ agonist and the additional therapeutic agent may be required to achieve the E. therapeutic effect, than those offered to or for the PPARγ agonist, or an additional therapeutic agent separately.

A. Antagonists of opioids

The opioid receptor antagonist acts on one or more opioid receptors. Describe at least three types of opioid receptors, mu, Kappa and Delta opioid receptors, and opioid antagonists are usually classified according to their effects on opioid receptors. Opioid antagonists can be the Central antagonists of receptors, peripheral receptors or both. Naloxone and naltrexone are commonly used opioid drug antagonists, which are competitive bind with opioid receptors with a higher affinity than agonists, but it does not activate the receptors. This effectively blocks the receptor, protecting the body from the response to opiates and endorphins.

Many opioid antagonists are not pure antagonists, but also have some weak partial agonistic effects of opioids and can cause analgesic effects with the introduction of high doses to individuals not exposed to opioids. Examples of such compounds include nalorfin and levallorphan. However, the analgesic effects of these drugs are limited and have a tendency to develop related dysphoria, most likely obukov the authorized action on Kappa-opioid receptors. Because they induce the effects of opioid withdrawal symptoms in people who may be taking a full opioid agonists, these drugs are considered as being antagonists.

Naloxone is an example of an antagonist of opioid receptors, which did not have the effects of a partial agonist. Instead, it is a weak inverse agonist at the level of mu-opioid receptors and is used to treat overdoses of opioids.

Specific examples of opioid antagonists that can be used in the present invention include alvimopan, binaltorphimine, buprenorphine, cyclazocine, cyclorphan, ziprider, dinicotinate, beta-funaltrexamine, levallorphan, methylnaltrexone, nalbuphine, naled, nalmefene, naloxone, nalorfin, alertindication, naloxone, naloxonazine, naltrindole, naltrexone, naltrindole, oxilorphan and pentazocine.

b. Antidepressants

Antidepressants are medicines used to treat depression. It is believed that three neurotransmitter involved in the development of depression are serotonin, dopamine and norepinephrine. Certain types of antidepressants increase the levels of one or more of these neurotransmitters in the brain by blocking their reuptake.

Identified several different classes of antidepressants, including the Aya selective inhibitors of serotonin reuptake (SSRIs), tricyclic and tetracyclic inhibitors of reuptake of serotonin and norepinephrine (SNRIs), reuptake inhibitors of norepinephrine (NRIs), inhibitors of reuptake of norepinephrine and dopamine (NDRIs), azaperone, monoamine oxidase inhibitors (MAOIs), and atypical antidepressants.

SSRIs include, for example, cericlamine, citalopram, clomipramine, cyanidation, priligy generic, DULOXETINE, ESCITALOPRAM, femoxetine, fluoxetine, fluvoxamine, ifoxetine, imipramine, indalpine, indeloxazine, litoxetine, lofepramine, mianserin, milnacipran, mirtazapine, nefazodone, nortriptyline, paroxetine, sertraline, sibutramine, tomoxetin, trazodone, venlafaxine and zimeldine.

Amitriptyline, amoxapine, butriptyline, clomipramine, deoxidation, desipramine, dibenzepin, timetaken, dothiepin, doxepin, imipramine, iprindole, lofepramine, maprotiline, melitracen, metabromine, mianserin, mirtazapine, nortriptyline, proposedin, protriptyline, quinupristin, setiptiline, tianeptine and trimipramine are tricyclic and tetracyclic antidepressants.

SNRIs include, for example, amoxapine, Atomoxetine, bicifadine, desipramine, desvenlafaxine, DULOXETINE, maprotiline, milnacipran, nefazodone, reboxetine, sibutramine and venlafaxine.

Nisoxetine, nortriptyline, reboxetine, talsupram, and tomoxetin, all are examples of NRIs.

NDRIs in luchot, for example, bupropion, hydroxybupropion and tesofensine.

Azapirone include, for example, buspirone, gepirone, ipsapirone, tandospirone and diaspirin. Buspirone is an anxiolytic (a partial agonist at 5-NT of autoreceptors), which may be offered with an antidepressant such as an SSRI.

Specific MAOIs include, for example, amiflamine, brofaromine, clorgyline, alpha ethyltryptamine, preclosed, iproniazid, isocarboxazid, maransin, moclobemide, nialamide, pargyline, phenelzine, fenyprazin, pirlindola, sarazin, selegiline, toloxatone and tranylcypromine.

Atypical antidepressants include, for example, emteryd, amineptine, benactyzine, bupropion, clozapine, Ptolemy, lipoprotein, lithium, modificatin, mianserin, minupren, olanzapine, oxaprozin, oxitriptan, rolipram, danilochkin, ciencin, trazodone, tryptophan and viloxazine.

C. Antiepileptic drugs

The anticonvulsants, also called antiepileptic drugs (AEDs)are a diverse group of drugs used to prevent epileptic seizures and bipolar disorder. AEDs suppress the rapid and excessive excitation of neurons, which leads to the seizure and/or prevent the spread of seizure in the brain and provide protection against possible toxic excitatory effects which can lead to brain damage. Many antiepileptic drugs block sodium channels, calcium channels, receptors, AMPA or NMDA receptors.

Antiepileptic drugs include, but are not limited to, benzodiazepines, barbiturates, valproate, GABA, iminostilbene, hydantoins, NMDA antagonists, blockers of sodium channels and succinamide.

Benzodiazepines include alprazolam, chlordiazepoxide, halazepam, clobazam, clonazepam, diazepam, halazepam, lorazepam, oxazepam and prazepam.

Barbiturates used as anti-epileptics include, for example, amobarbital, mephobarbital, methylphenobarbital, pentobarbital, phenobarbital and primidone.

Valproate used as anti-epileptics include, for example, sodium valproate, valproate acid, valproate of volunatry and valpromide.

Antiepileptic GABA tools include, for example, gabapentin, losigamone, pregabalin, retigabine, rufinamide and vigabatrin.

Carbamazepine and oxcarbazepine are examples of iminostilbene.

The hydantoins include, for example, fosphenytoin sodium, mephenytoin and phenytoin sodium.

The NMDA antagonists, such as sarcosine, are used as anti-epileptics.

Blockers of sodium channels, such as lamotrigine, are also protevoepilepticeski the means.

Suktinimida include, for example, ethosuximide, methsuximide and phensuximide.

Other antiepileptic drugs include acetazolamide, brivaracetam, CBD derived cannabinoids, camtasyagirl, divalproex sodium, felbamate, isovaleramide, lacosamide, lamotrigine, levetiracetam, methanesulfonamide, talampanel, tiagabine, topiramate, safinamide, seletracetam, foretold, stiripentol, Altium, valrocemide and zonisamide.

d. Antiemetic

Antiemetics are drugs that are effective against nausea and vomiting. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, General anesthetics, and chemotherapy.

Classes of antiemetics include, for example, antagonists of the receptor 5-hydroxytryptamine 3 (5-NT3), antagonists of histamine receptors, antagonists of dopamine receptors, antagonists of muscarinic receptors, antagonists of acetylcholine receptors, antagonists of cannabinoid receptors, inhibitors of the limbic system, antagonists of NK-1 receptors, corticosteroids, antagonists tachykinin, GABA agonists, cannabinoids, benzodiazepines, anticholinergics and inhibitors of substance P.

Antagonists of the receptor 5-NT3 include, for example, alosetron, azasetron, Betaseron, cilansetron, dola is etron, granisetron, indication, fusetron, ondansetron, palonosetron, tropisetron, ramosetron, renzapride, tropisetron and zatosetron.

Corticosteroid anti-emetics include dexamethasone and methylprednisolone.

Inhibitors of the limbic system include alprazolam, lorazepam and midazolam.

Antagonists of dopamine receptors include diphenhydramine, dronabinol, haloperidol, metoclopramide and prochlorperazine.

Antagonists of NK-1 receptor, used as antiemetics include either aprepitant and morpholine, and an example of the GABA agonist is propofol.

Tietilperazin is a type of antagonist histamine receptors.

Antagonists of cannabinoid receptors used as antiemetics include dronabinol, nabilone, rimonabant, talkabout and tetrahydrocannabinol.

Examples of other antiemetics include acetylation, monoethanolamine, alizapride, benchenane, beatnuts, bromopride, buclizine, chlorpromazine, clebopride, cyclizine, dimenhydrinate, difenidol, domperidone, granisetron, meclizine, metallca, metopimazine, oxybenzyl, pipamazine, piperidine, scopolamine, thioproperazine and trimethobenzamide.

that is, the Antagonists of cannabinoid receptors

The cannabinoid receptors are a class of receptor superfamily, SOP is agennix with G-proteins. Their ligands are known as cannabinoids. Currently, there are two subtypes, SW, which is expressed mainly in the brain, but also in lung, liver and kidney, and SV, which is expressed mainly in the immune system and in haematopoietic cells. It is also believed that there are new cannabinoid receptors, which do not belong to SV nor SW, and which is expressed in endothelial cells and Cnsentint cannabinoid receptors can be selective for either SW or SW receptor. The present invention encompasses the use of antagonists of each or both receptors SW and SW.

Drugs (such as alcohol, opiates, Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and psychostimulants, including nicotine) causes a variety of chronic relapsing disorders as a result of interaction with endogenous neural pathways in the brain. In particular, they exhibit a common property of the activation of the mesolimbic dopamine system reinforcements in the brain, and virtually all drug abusers increased levels of dopamine in the adjacent core. Receptors 1 cannabinoids (SW) expressed in the Central reinforcement of the brain and modulate the effects of Delta(9)-THC and nicotine stimulates dopamine.

Rimonabant (SR141716), receptor antagonist SB blocks at the front of the animal effects of Delta(9)-THC, as releasing dopamine and discriminatory and supportive. Although receptor blockade SW usually ineffective in reducing Samovodene of cocaine in rodents and primates, it reduces the recovery Parenago search behavior of cocaine caused associated with cocaine conditional reflex stimuli and primarysite injections of cocaine. Similar receptor blockade SW effective in reducing the search behavior of nicotine induced by repeated exposure associated with nicotine stimulus. In clinical trials in humans it was shown that rimonabant blocks the subjective effects of Delta(9)-THC in humans and prevents relapse to Smoking among former smokers.

Other examples of receptor antagonists SW cannabinoids include SR141716A (rimonabant), rosenband, taranabant and CP-945598.

C. Methods of treatment and prevention of relapse

Relapse use or recovery refers to the process of returning to alcohol or other drugs or implementation dependent behavior after a period of abstinence from, or limited or reduced use of drugs or implementation dependent behavior. In certain situations, the recurrent use of drugs refers to the return of the use of narcotic medium spans the VA is an individual, who have suffered physical cancellation drugs. It is usually assumed that the individual suffered physical cancellation drugs for a period of no use or limited or reduced use of drugs. In one embodiment, the recurrent use arises from the individual who had previously undergone a treatment effective amount against drug addiction for reducing or stopping the use of drugs, but which no longer uses effective amount against drug addiction. Anti-drug dependence include any and all funds used for the treatment or prevention of addiction or withdrawal symptoms.

Alcoholism, like many other dependence is a chronic relapsing disorder characterized by a high degree of recurrence. The two main factors triggering recurrent behavior, are stress and conditional reflex influence of the environment (O'brien et al. 1997; Monti et al. 1993; Shaham et al. 1995), which, obviously, contribute to the recurrence of the behavior of search alcohol by certain mechanisms in the brain. For example, activation of the mesolimbic dopamine system through a mechanism dependent on opioids (or through direct measurement is possible dopamine transmission in basolateral the nucleus of the amygdala), obviously, mediates the effect of conditional stimuli associated with the drug (Liu and Wiess 2002; Ciccocioppo et al. 2001), and negiotiations CRF in the bed nucleus of the terminal strips and median nucleus seam, probably mediates induced stress recovery behavior with a tendency to drug search (Erb et al 1998; Shaham et al. 1995; Le et al. 2000).

Several lines of evidence suggest that the molecular mechanisms underlying relapse dependencies that are common to different classes of drugs. Craving for drugs and the loss of control over behavior, characterized by the tendency to use drugs associated with relapse, are under the direct influence of stress and conditional reflex of environmental stimuli; the two main factors affecting the resumption of drug use.

Chronic drug abuse induces neuroadaptive changes not only in the systems involved in the acute reinforcing effects of ethanol, but also in other motivational systems, particularly in the regulatory mechanisms of stress in the brain. Stress is characterized by a set role in the initiation and maintenance of drug abuse and is a major determinant of relapse in individuals with abstinence (Brown et al. 1995; Marlatt et al. 1985; McKay et al. 1995; Wallace 198.9). The value of stress in behavior with a tendency to the SKU drug also has been well-documented in the literature on animal models. Physical, social and emotional stress can facilitate the susceptibility or increase Samovodene cocaine (Goeders et al. 1995; Haney et al. 1995; Ramsey and VanRee 1993; Ahmed and Koob 1997), heroin (Shaham and Stewart 2004) and ethanol (Nash et al. 1998; Mollenauer et al. 1993; Blanchard et al. 1987; Higley et al. 1991) in rodents and not non-human primates. Stress stimuli, as was also shown, cause the recovery behavior with a tendency to search for cocaine, heroin and ethanol in animals, free from the drug, after the extinction of the reflex (Ahmed and Koob 1997; Shaham 1993; Shaham and Stewart 1995; Ie et al. 1998), and these data provide experimental validation of the role of stress in relapse.

Traditionally associated with stress behavior with a tendency to seek the drug, believed to be mediated by activation of the hypothalamic-pituitary-adrenal (hPa) axis. However, there is growing evidence suggesting that the system corticotropin-releasing factor (CRF) in the Central nucleus of the amygdala (CEA), not related to the neuroendocrine regulation may play asistenciasocial role in the regulation of stress-related dependent behavior. CEA richly bodies and terminalname cells, immunoreactive against CRF, and receptors to him and this neuronal system CRF is involved in mediating behavioral and emotional responses to stress stimuli (Dunn and Berridge 1990; Koob et al. 1994). For example, the IMM is bilization stress increases extracellular levels of CRF in the CEA (Merlo Pich et al. 1995; Merali et al. 1998), whereas the introduction of CEA CRF receptor antagonist α-helical CRF9-41, reduces behavioral signs of anxiety caused by social stress factors and stress impacts the environment (Heinrichs et al. 1992; Swiergiel et al. 1993). Anxiety and similar stress symptoms are Central to the syndrome of abstinence from drugs and alcohol. Reviewing evidence of the role of CRF neurons in the CEA in the regulation of emotional and entries of the effects of stress suggests that entries and the like to stress the consequences of the abolition of drug abuse may be mediated by a system of CRF in the CEA.

Changes in regulation of the activity system of CRF in the CEA may be the key neuroadaptive mechanism responsible for the development of addiction and compulsive. search behavior of the drug.

As discussed above, the data identify neuroadaptive changes in the brain structures and abnormalities in stress systems as important elements of the compulsive behavior of search of drugs and addiction. Another important factor in the long-term potential dependence drug abuse is a conditional reflex reinforcement of their use by specific environmental stimuli. Conditional stimuli of the environment, netnorth what about the associated with the subjective effects of drug abuse, including alcohol, can trigger cravings for the drug (Childress et al. 1988; Ehrman et al. 1992; Monti et al. 1993; Pomerleau et al. 1983; Stormark et al. 1995) or to cause automatic behavioral responses (Miller and Gold 1994; Tiffany and Carter 1998), which ultimately can lead to relapse. Acquired answers related to drug stimuli can therefore make a decisive contribution to a high degree of relapse associated with addiction to cocaine and other drugs.

Data on mouse models with specific response-recovery by conditioned reflexes developed to study the behavior with a tendency to search for a drug that is associated with exposure to contingent environmental stimuli associated with drug search, show that the discriminative stimuli that predict the availability of cocaine (Weiss et al. 2000), ethanol (Katner et al. 1999; Katner and Weiss 1999) or heroin (Gracy et al. 2000), to reliably detect a strong recovery paid search behavior of the drug in the absence of additional availability of the drug. Reducing response effects of these stimuli show a marked resistance to extinction after repeated exposure, and in the case of cocaine can still be observed after several months of forced abstinence. In addition, in the case of ethanol, the search behavior of drug induced pre is marked ethanol discriminatory incentives as detected, amplified genetically prefer alcohol P rats compared with not prefer alcohol (NP). and not selected on this basis Wistar rats:(Weiss and Ciccocioppo 1999). This observation suggests that genetic predisposition to increased alcohol consumption is also reflected in a higher susceptibility to the motivational effects of conditional stimuli consumption of ethanol (i.e. to increase search drug in conditions when the behavior is not directly supported by the ethanol). Together, these data significantly. support the hypothesis that the acquired responses associated with drug incentives are a significant factor in long-term susceptibility to relapse.

In humans, the risk of recurrence includes multiple determinants that are likely to interact. For example, exposure to conditional stimuli for drugs may increase susceptibility to relapse associated with protracted withdrawal symptoms in the neuroadaptive changes in dependent individuals In recent work on these problems, it is confirmed that an additional interaction between restorative response effects associated with ethanol conditional stimuli and stress effects can actually be demonstrated, and that these effects is velicious in rats with a history of ethanol dependence (Liu and Weiss 2000).

In the experimental laboratories of the recovery behavior of search drug get at introduction of the antagonist α-2-adrenergic receptors of yohimbine that increasing the excitation of noradrenergic cells in the brain and the release of norepinephrine, acts as a pharmacological stressor funds. Stress with electrical stimulation of the paws and induced yohimbinum recovery types of behavior with a tendency to seek the drug, both are an effective experimental model for studies of induced stress relapse of alcoholism (Lee et al. 2004; Le et al. 2000).

As shown in the attached examples, the PPARγ agonists significantly reduce the induced stress relapse use of drugs (example 5). In addition, sick people pioglitazone, a TZD, significantly reduces the rate OCDS (example 22). Obsessive dependence on alcohol and the urge to binge (which are measured using the indicator OCDS) are the main factors predicting relapse. These data show, therefore, that pioglitazone has properties that prevent relapse.

Interestingly, the results showed that pioglitazone is not significantly prevents recurrence, called conditional reflex factors. Interestingly, various studies have shown that deselect wny the opioid receptor antagonist naltrexone reduces the craving to drink, the callee. demonstration of alcohol-related contingent stimuli people-alcoholics (Monti et al. 1993) and reduces the effectiveness of alcohol-related conditional stimulus in relation to recovery Parenago earlier answer by clicking on the associated with drug arm in rats (Katner et al. 1999). However, naltrexone does not reduce relapse behavior caused by stress (Le A.D. Psychopharmacology 1998).

These data suggest that the combination of pioglitazone and naltrexone should lead to a synergistic effect in reducing relapse behavior, whether caused by stress and conditional reflex factors.

Accordingly, the present invention provides methods of treatment and combinations of drugs that protect individuals from the effects of more than one risk factor environment (i.e. from stress and conditional reflex environmental factors).

In one embodiment, the present invention proposes a method of treatment or prevention of induced stress recurrence of the use of drugs, including the provision of a PPARγ agonist to the individual who is experiencing physiological abstinence from drugs.

In a related embodiment, the invention includes a method of treatment or prevention of relapse drugs environments is tion or implementation dependent or compulsive behavior, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ agonist) an individual who previously reduced or stopped use of drugs or implementation dependent or compulsive behavior in response to exposure to an effective amount of another therapy against drug addiction, where the individual is no longer under the influence of an effective amount of therapy against drug addiction. Therapy against drug addiction can be a remedy for drug addiction or may be non-pharmacological. therapy such as counselling, psychotherapy or hypnosis therapy. Relapse eating can be triggered by stress.

In certain embodiments of the implementation of the individual is no longer under the influence of an effective amount of anti-drug dependence, since the individual became tolerant K. means, so that the concentration in plasma tools against drug addiction, which had previously been effective for treatment is no longer effective. In other embodiments, implementation of the individual is no longer under the influence of an effective amount of anti-drug dependence, as is individuum is currently under the influence of a low concentration of anti-drug funds in the blood plasma, and this lower concentration in the blood plasma ineffective.

In certain embodiments of the implementation of the methods of the present invention, the individual is in the phase of abstinence in phase or in a limited or reduced use. drugs or implementation dependent or compulsive behavior. This phase of abstinence or limited or reduced use may continue, for example, at least 24 hours, at least 48 hours, at least 3 days, at least 5 days, at least one week, at least 2 weeks, at least 1 month, at least 2 months, at least 4 months, at least 6 months, at least 9 months, at least, one year at least 2 years or at least 5 years.

In another embodiment, the present invention includes a method of treating or preventing relapse use of drugs, including the provision of a PPARγ agonist and antagonist of opioid receptors with the individual who is experiencing physiological abstinence from drugs.

In an additional embodiment, the present. the invention includes a method of treating or preventing relapse use of drugs, including the provision of a PPARγ agonist and antagonist SW, for example, is isulfiram, topiramate, levetiracetam, SSRIs or ondansetron, an individual who is experiencing physiological abstinence from drugs.

In specific embodiments, the implementation of relapse drinking provoked by stress, conditional reflex environmental factor, or both. Examples of suitable PPARγ agonists are TDZs, such as pioglitazone, etc. One example of a suitable opioid receptor antagonist is naltrexone.

Along with the fact that the methods of the present invention can be implemented in practice for individuals that are dependent on one drug, they can also be used in individuals dependent on two or more drugs.

Similar, along with the fact that these methods can be used to prevent recurrence of the use of narcotic drugs, in a state of abstinence from whom is an individual, they may be also adapted to prevent relapse use or first use of a drug other than the one in a state of physiological withdrawal from the individual.

D. Methods of reducing withdrawal symptoms and treatment of depression/anxiety

Cancel, also known as withdrawal/abstinence refers to the characteristic signs and symptoms, which is Vlada when a drug or narcotic drug, which causes physical dependence is regularly used for a long time and then suddenly stop drinking or reduce the dosage. Withdrawal symptoms can vary greatly among individuals, but there are some common symptoms. Dysfunction of the brain, associated with abstinence, often characterized by depression, anxiety and overwhelming thrust, and in extreme cases can contribute to the desire of the individual to the continued use of substance despite significant harm, by definition, addiction or even suicide.

Increased heart rate and/or high blood pressure, sweating, and tremor are common signs of abstinence. More serious symptoms such as confusion, seizures and visual hallucinations indicate the seriousness of the situation and the need for emergency medical care. Alcohol, opiates, benzodiazepines and barbiturates are in most cases only zloupotreblenie substances that can be detrimental when abstinence. Sudden removal of other drugs, such as nicotine or stimulants may increase from weak to moderate. neurotoxic side effects caused by hyperthermia and production of free radicals, but threatening the life and complications are very rare.

As shown in the attached examples, the PPARγ agonists reduce withdrawal symptoms (example 21). In addition, they reduce anxiety and depression, which are also associated with abstinence (example 22). These data indicate that PPARγ agonists can successfully be used to reduce withdrawal symptoms, including depression and anxiety, thereby making abstinence easier for individuals and helping them process the complete abolition.

The present invention includes a method of reducing one or more symptoms of withdrawal associated with the reduction or cessation of a drug, comprising providing an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ) an individual who is experiencing physiological abstinence from drugs.

The PPARγ agonist may be provided to the individual before the individual will cancel and/or during the process of withdrawal. In a related method, the individual is provided a PPARγ agonist in the period of time during which the individual uses a reduced number of drugs. In one embodiment, the individual uses to gradually reduce the number of drugs at the same time as the PPARγ agonist, up until physiological cancellation will be the head of the Shen. The individual can then stop using the PPARγ agonist or continue to use the PPARγ agonist for the prevention of relapse. In one specific embodiment, a drug is the nicotine, and an individual reduce the use of nicotine in the period of time during which the individual is offered a PPARγ agonist, such as TZD, for example, pioglitazone, alone or in combination with another therapeutic agent.

E. Pharmaceutical compositions, routes of administration, standard dosage forms, kits

In the present invention the effectiveness of the use of combinations of PPARγ agonist, for example, TZD, such as pioglitazone in combination with one or more additional therapeutic means, such as antagonists of opioids, antidepressants, ANTIEPILEPTICS, anti-emetics and antagonists of the receptor SW. Thus, the present invention further includes compositions comprising one or more agonists of PPARγ and one or more additional therapeutic agents, such as opioid antagonists, mixed antagonists/partial agonists opioideven antidepressants, antiepileptic drugs, anti-emetics, CRF1 receptor antagonists and receptor antagonists SW.

In some cases, the implementation of whom azizia includes one PPARγ agonist and one additional therapeutic agent. In a separate embodiment, the composition includes TDZ and one additional therapeutic agent. In certain embodiments of the implementation of the additional therapeutic agent is an antagonist of opioid receptors or mixed antagonist/partial agonist opioids. In one embodiment, the implementation of the opioid receptor antagonist is a naltrexone. In another embodiment, the mixed partial agonist/antagonist opioid receptor is a buprenorphine. In some embodiments, the implementation of the additional therapeutic agent is an antidepressant. In a separate embodiment, the antidepressant is an bupropion. In some embodiments, the implementation of the additional therapeutic agent is an antiepileptic agent, an antiemetic or the opioid receptor antagonist or a mixed partial agonist/antagonist opioid receptors.

In various embodiments, the implementation of the composition includes: pioglitazone and naltrexone; ciglitazone and naltrexone; rosiglitazone and naltrexone; englitazone and naltrexone; rivoglitazone and naltrexone; darglitazone and naltrexone; pioglitazone and fluoxetin; ciglitazone fluoxetin; rosiglitazone and fluoxetin; englitazone and fluoxetin; rivoglitazone and fluoxetin; darglitazone and fluoxetin; pioglitazone and mirtazapine; ciglitazone and mirtazapine; rosiglitazone and mirtazapine; englitazone and mirtazapine; rivoglitazone and mirtazapine; darglitazone and mirtazapine; pioglitazone and topiramate; ciglitazone and topiramate; rosiglitazone and topiramate; englitazone and topiramate; rivoglitazone and topiramate; darglitazone and topiramate; pioglitazone and levetiracetam; ciglitazone and levetiracetam; rosiglitazone and levetiracetam; englitazone and levetiracetam; rivoglitazone and levetiracetam; darglitazone and levetiracetam; pioglitazone and gabapentin; ciglitazone and gabapentin rosiglitazone and gabapentin; englitazone and gabapentin; rivoglitazone and gabapentin; darglitazone and gabapentin; pioglitazone and ondansetron; ciglitazone and ondansetron; rosiglitazone and ondansetron; englitazone and ondansetron; rivoglitazone and ondansetron; darglitazone and ondansetron; pioglitazone and antalarmin; ciglitazone and antalarmin; rosiglitazone and antalarmin; englitazone and antalarmin; rivoglitazone and antalarmin; darglitazone and antalarmin.

Compositions of the present invention can be supplied by the individual in the form of a pharmaceutical composition or drug. In some cases, the implementation of the pharmaceutical compositions of the present invention can have any shape that allows the introduction of the composition to the individual. For example, the composition can find is about being in the form of solids, liquid or gas (aerosol). The usual routes of administration include, without limitation, oral, local, parenteral, sublingual, rectal, vaginal, and intranasal administration. Used in the present description, the term includes parenteral methods, subcutaneous injections, intravenous, intramuscular, epidural, vnutrigrudne injections or infusions.

The pharmaceutical composition used in the present invention include the PPARγ agonist, the other therapeutic agent and a pharmaceutically acceptable diluent, excipient or media. Pharmaceutically acceptable carriers for therapeutic use are well known in the pharmaceutical field techniques and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985). For example, can be used with a sterile saline solution or phosphate buffered saline at physiological pH. In the pharmaceutical composition may be added as preservatives, stabilizing tools, dyes and even fragrances. For example, as preservatives may be added sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. There, at 1449. In addition, you can use antioxidants and suspendresume funds. Ibid.

The pharmaceutical compositions of the invention typically comprise so, the button after administration of the composition to the individual provided the bioavailability of the contained active ingredients. Due to the introduction of individual compositions can be in the form of one or more standard dosage form such as tablet, capsule or sachet can be a standard dosage form, and the container comprising the combination of means according to the present invention in the form of an aerosol spray can contain many standard dosage forms.

In some cases, the implementation of a composition comprising a PPARγ agonist and the other therapeutic agent is administered in one or more doses of the composition of the tablets, usually for oral administration. The tablet can be, for example, the immediate-release formulation, the composition of the controlled release or composition with prolonged release. In one embodiment, the tablet includes an effective amount of a composition comprising a PPARγ agonist and another therapeutic agent. In some cases, the implementation tablet contains approximately 1, 5, 10, 20, 30, 50 100, 150, 200, 250 or 300 mg of a PPARγ agonist, such as pioglitazone, and approximately 1, 5, 10, 20, 30, 50, 100, 150, 200, 250 or 300 mg of another therapeutic agent.

The present invention additionally includes a standard dosage forms of pharmaceutical compositions comprising a PPARγ agonist and another therapeutic agent. Each standard dosage form includes therapeutically effective amount of the pharmaceutical compositions of the present. the invention when used in the recommended quantity. For example, a standard dosage form may include a therapeutically effective amount in a single tablet or a standard dosage form may include a therapeutically effective amount of two or more pills, so that the prescribed amount comprises a therapeutically effective amount.

A number of PPARγ agonists and other therapeutic agents described in the present description, approved for use in humans in specific doses. The present invention involves the use of these funds in the approved doses or other effective doses. Since it has been shown that the combination of a PPARγ agonist and the other therapeutic agent exerts a synergistic effect, it is clear that an effective amount of one or both means can be reduced when the joint introduction compared with an effective amount of each of them with a separate introduction. In some cases, the implementation of the PPARγ agonist is administered to the individual in an amount in the range of 0.1-1000 mg/day, 1-1000 mg/day, 10-100 mg/day or 25-50 mg/day. In one embodiment, the pioglitazone is administered to the patient in the amount of about 30 mg/day.

Table 1 lists the typical media used in the present invention, and presents daily dose of cat is where these funds are traditionally administered to adult humans for other indications, moreover, it is expected that these doses suitable for administration in accordance with the methods of the present invention for the treatment or prevention of addiction and relapse consumption or sale. These doses are oral, unless specified otherwise. It is assumed that the doses of these funds can be reduced with the introduction of combinations of the PPARγ agonist and the additional therapeutic agent of the present invention for the treatment or prevention of dependency or for the treatment or prevention of relapse of consumption. This reduction can reach up to 10% of the conventional dose or up to 20% of the conventional dose, or up to one-third from the traditional doses, or up to half of the traditional doses, or two-thirds of the traditional doses. For example, pioglitazone is most often administered in a dose of 30 mg a day for diabetes, and it was found that this dose is effective for treatment of alcoholism (example 22). It is assumed that in combination with 50 mg/day of naltrexone in the present invention for treatment based therapeutic effect can be observed when the dose of pioglitazone 10-15 mg per day.

Table 1
Therapeutic agentThe typical dose when used as the only means what
pioglitazone15-45 mg
rosiglitazone2-8 mg
troglitazone200-600 mg
rimonabant10-20 mg
buprenorphine0.3 mg (in/in or/m) 12-16 mg (sublingual)
naltrexone25-50 mg
fluoxetine20-80 mg
mirtazapin15-45 mg
topiramate400 mg
levetiracetam1000-6000 mm. mg
gabapentin900-1800 mg
ondansetron8-24 mg
bupropion200-400 mg

In a separate embodiment, a standard dosage form of the pharmaceutical composition of the present invention includes about 30 mg pioglitazone and about 50 mg of naltrexone. This standard medicinal Faure is and may consist of one or more tablets.

Some combination of PPARγ agonists and other therapeutic agents cannot be easily adapted to co-locating in the same composition. For example, one of the funds may be more suitable for intravenous, while other means may be more adapted for oral administration. Or the half-life in serum of two means may be such that one of them must be administered more often than the other. Accordingly, the present invention provides kits comprising one or more standard dosage form of the PPARγ agonist and one or more standard dosage form of another therapeutic agent, so that two standard dosage forms you can enter the individual a therapeutically effective manner. In some cases, the implementation of the set includes a standard dosage forms of pioglitazone and naltrexone; ciglitazone and naltrexone;, rosiglitazone and naltrexone; englitazone and naltrexone; rivoglitazone and naltrexone; darglitazone and naltrexone;, pioglitazone and fluoxetine; ciglitazone and fluoxetine; rosiglitazone and fluoxetine; englitazone and fluoxetine; rivoglitazone and fluoxetine; darglitazone and fluoxetine; pioglitazone and mirtazapine; ciglitazone and mirtazapine; rosiglitazone and mirtazapine; englitazone and Myrtle is APIN; rivoglitazone and mirtazapine; darglitazone and mirtazapine; pioglitazone and topiramate; ciglitazone and topiramate; rosiglitazone and topiramate; englitazone and topiramate; rivoglitazone and topiramate; darglitazone and topiramate; pioglitazone and levetiracetam; ciglitazone and levetiracetam; rosiglitazone and levetiracetam; englitazone and levetiracetam; rivoglitazone and levetiracetam; darglitazone and levetiracetam; pioglitazone and gabapentin; ciglitazone and gabapentin; rosiglitazone and gabapentin; englitazone and gabapentin; rivoglitazone and gabapentin; darglitazone and gabapentin; pioglitazone and ondansetron; ciglitazone and ondansetron; rosiglitazone and ondansetron; englitazone and ondansetron; rivoglitazone and ondansetron; darglitazone and ondansetron; pioglitazone and antalarmin; ciglitazone and antalarmin; rosiglitazone and antalarmin; englitazone and antalarmin; rivoglitazone and antalarmin; darglitazone and antalarmin.

In one embodiment, the present invention includes a kit comprising a standard dosage forms of the PPARγ agonist and a standard dosage forms of nicotine. In one embodiment, a standard dosage forms of nicotine include many different standard dosage forms of nicotine, where different standard dosage forms of nicotine represent the keys of a declining number, which can be used one after the other in time, in order to overcome addiction and to ensure the withdrawal from nicotine. Standard dosage forms of nicotine can be, for example, in the form of a skin patch, gum or lozenges.

EXAMPLES

The following examples describe a number of studies carried out to demonstrate the various actions of PPARγ agonists in the treatment of addiction and the prevention of relapse for many drugs. In some examples, the described studies showing the effect of PPARγ agonists used in combination with other therapeutic means for the treatment of alcohol dependence. These studies were conducted using proven models of alcohol abuse and cocaine abuse on laboratory animals.

Most of the studies described in examples 1-21 were performed using male genetically selected rats with a preference for alcohol, referred to as the Marchigian Sardinian prefer alcohol (msP) rats. These animals were bred at the Department of pharmacological Sciences and experimental medicine, University of Camerino (Marche, Italy) for 60 generations of Sardinian prefer alcohol rats 13th generation, proposed by the Department of neurology of the University of Cagliari, Italy. During the experiment, the x body weight was in the range of from 300 to 350, They were kept indoors with a reversed 12-hour cycle of light/dark (the light turns off at 9:00 a.m.) when the temperature of 20-22°C and relative humidity of 45-55%. Rats had free access to tap water and food pellets (4RF18, Mucedola, Settimo Milanese, Italy). In operant experiments with Samovodene used males heterogeneous Wistar rats (Charles River, Germany).

The experiments were conducted at 9:30 a.m., which corresponds to the beginning of the dark phase of the cycle of light/dark. In each experiment used a separate group of animals. All procedures were performed vsootvetstvie with the Directive Committee of the European community for the care of laboratory animals and their use and rules for the care of laboratory animals and their use of the National institutes of health.

Pioglitazone, rosiglitazone, fluoxetine, mirtazapine, topiramate, gabapentin, ondansetron and levetiracetam were obtained from commercial sources. Yohimbin and ciglitazone were obtained from SIGMA SRL (Mi, Italy). Naltrexone and GW9662 were obtained from TOCRIS. (U.).

Before the introduction of pioglitazone suspended in distilled water, and the resulting suspension was maintained at a constant shaking until the introduction. The drug is administered orally (OS) using a gastric probe in a volume of 1.0 ml/kg

Yohimbin was dissolved in distilled water and was administered within brusina (br) in a volume of 1.0 ml/kg Naltrexone hydrochloride was dissolved in distilled water and was administered/br in a volume of 1.0 ml/kg of Rosiglitazone, fluoxetine, mirtazapine, topiramate, gabapentin and levetiracetam suspended in distilled water, and the resulting suspension was maintained at a constant shaking until the introduction. These drugs were administered orally (OS) using a gastric probe in a volume of 1.0 ml/kg. Yohimbin was dissolved in distilled water and injected intraperitoneally (br) in a volume of 1.0 ml/.GW9662 was prepared in 5% DMSO and 5% tween 80 and were introduced either/br (1 ml/kg), or in the ventricle of the brain (ICV, 1 ál/rat). Antalarmin was prepared in 10% tween 80 and introduced into/br (1 ml/kg). Ondansetron was prepared in aqueous solution and was injected into/br (1 ml/kg).

At the beginning of the experiments, rats msP provided a free choice between water and 10% (vol./about.) alcohol a 24 hour/day for at least 15 days. The liquid was offered in graduated test tubes for drinking, with metal spouts for drinking. The position (left or right) tubes for drinking alcohol and water was changed daily to avoid the development of hand preference. Water and food were provided for the needs of, and access to alcohol was either limited to 2 hours/day (examples 1 and 2), or was open 24 hours/day (examples 3 and 4). Measured consumption of alcohol, water and food.

Training and testing were manufactured in standard the x operant chambers (Med associates), located in noise-ventilated areas. Each camera was supplied with the tank for drinking (length: 0,30 ml), located at a distance of 4 cm above the mesh floor in the center front of the camera, and two receding levers located 3 cm to the right or to the left of capacity for drinking. Audio and visual stimuli were presented through a loudspeaker, and a lamp located on the front panel. Using a microcomputer controlled delivery of liquids, the presentation of audio and visual stimulation, and produced the record data relating to the behavior.

Rats were trained to Samovodene 10% alcohol (V/V) in 30-min daily sessions of the program is fleshed out with a constant factor of 1, in which each response has led to the introduction of 0.1 ml of fluid, as described previously (Economidou et al. 2006). In the first 3 days of a rat pressing the lever was injected with 0.2% (wt./about.) saccharine, and then they were taught Samovodene 10% alcohol content decreased saccharin (Weiss et al. 1993). During the first 6 days of training a rat pressing the lever was introduced in 5.0% (vol./about.) a solution of alcohol containing 0.2% (wt./about.) saccharin. Starting from the 7th day the alcohol concentration is gradually increased from 5.0% to 8.0% and, finally, to 10.0%, while the concentration of saccharin respectively reduced to 0%.

Experimental procedures caused by signal recovery behavior is the CECC alcohol consisted of three phases: (1) phase of a conditioned reflex; (2) phase damping; and (3) the recovery phase, as described below.

Phase of a conditioned reflex after completion of the extinction (see above) in 30-min daily sessions, animals were trained to discriminate between 10% alcohol and water. Starting with learning Samovodene alcohol at a concentration of 10%, during the sessions Samovodene alcohol and water were brought differencirovanie stimuli (SD), predicting the availability of alcohol or water, respectively. Differencirovany stimulus for alcohol consisted of smell extract of oranges (S+), and signal the availability of water (i.e. without remuneration) served anise extract (S-). Olfactory stimuli were created by applying six to eight drops of the appropriate extract bedding operant chamber. In addition, each press of the lever, resulting in the introduction of alcohol, accompanied by the lighting of the camera for 5 seconds (CS+). The corresponding conditional signal when water sessions served as the sound within 5 seconds (70 dB) (CS-). Simultaneously with the presentation of these stimuli was actually a 5-sec pause, during which responses were recorded but not reinforced. Olfactory stimuli,which served as S+and S-for availability of alcohol, was applied for one minute before the extension levers and remained so for 30-min sessions. M is waiting for sessions litter camera replaced, and trays for litter washed. During the first three days of the phase of a conditioned reflex in rats were sessions only with the introduction of alcohol. Then in the days of training sessions have been conducted with alcohol and water in a random order with the restriction that all rats had a total of 10 alcohol and 10 water sessions.

For phase damping after the last day of a conditioned reflex in rats were subjected to 30-min sessions of extinction throughout the following 15 days. During this phase, the session began with the nomination of levers without SD. Impacts on the lever activated the mechanism, but did not lead to the introduction of liquids or submission of appropriate response conditional signal (light or sound).

Testing phase recovery began the day after the last session of extinction. This test was continued for 30 min under conditions identical to that used during the phases of a conditioned reflex, except that the alcohol and water were not available. The session began with the nomination of both levers and the presentation of paired signals or alcohol S+or water S-. The corresponding SD remained throughout the session, and answers to previously aktivirovaniya lever tracked by the activation mechanism for the injection and 5-sec presentation of CS+in the condition S+or CS-/sup> (sound) in state S-. Rats were tested in the condition S+/CS+on day 1 and S+/CS+on day 2.

Experimental procedure-induced stress recovery search of alcohol consisted of three phases: (1) the learning phase; (2) phase damping; and (3) the recovery phase, as described below.

For the learning phase after completion of the fading rats msP taught Samovodene 10% (vol./about.) alcohol for 15 days in a 30-min daily sessions of the program FR1 reinforcement. During the infusion were included signal lighting for 5 seconds (break;). Pressing the lever at the time IT was recorded, but was not accompanied by additional infusions.

For phase damping after the last session Samovodene alcohol animals were subjected to 30-min sessions of extinction throughout the subsequent 15 days. Impacts on the lever activated the mechanism, but did not lead to the introduction of alcohol.

For phase recovery the next day after a phase damping rats were injected with yohimbine (1.25 mg/kg), and after 30 minutes they were placed in the operant chamber and tracked pressing the lever within 30 minutes it is Known that the introduction of the antagonist α-2 adrenergic receptors of yohimbine, amplifying the excitation of noradrenergic cells of the brain and its release, acts as a pharmacological stressor means and legcay relapse search of alcohol (Le et al. 2005).

Results used analysis of variance (ANOVA). data. Possible after ANOVA produced secondary tests. In particular, the effect of acute injection of pioglitazone, naltrexone, or a combination of consumption of alcohol (examples 1 and 2) was evaluated by means of two-way ANOVA with two internal factors (time and treatment). The influence of chronic administration of pioglitazone, naltrexone, or a combination of consumption of alcohol (examples 3 and 4) was estimated using the tripartite ANOVA with one factor (treatment) and two common factors (days and hours). Effect of pioglitazone on the restoration of search alcohol (examples 5 and 6) were evaluated using one-way ANOVA with repeated measurements using the medication as internal personal factor. Samovodene alcohol (example 7) in Wistar rats was studied using one-way ANOVA with one internal factor (dose). Secondary analysis was made using the test of Newman-Keuls.

EXAMPLE 1

Effect of acute injection of pioglitazone on voluntary alcohol consumption

Effect of acute injection of pioglitazone on voluntary alcohol consumption was demonstrated at the first training rats to take 10% (vol./about.) alcohol for 24 hours a day. (free choice between water and ethanol). After reaching stabil the aqueous background consumption of ethanol (6-8 g/kg body weight daily) access to ethanol was limited to 2 hours per day at the beginning of the dark phase. Food and water were freely available.

After reaching a stable baseline consumption of ethanol (and ri conditions of limited access) rats (n=7) tested the effect of pioglitazone (0,0, 10,0, 30.0 mg/kg) using a balanced Latin square plan with one individual, when each animal received all doses of medication. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water).

The treatment was performed with intervals, comprising at least three days. Before each experiment with the consumption of ethanol msP rats received two doses of pioglitazone or media for 12 hours and 1 hour before access to ethanol. Experiments with consumption conducted immediately after the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 30, 60, 90 and 120 minutes after ensuring access to ethanol.

Analysis of variance showed no significant effect of treatment on ethanol consumption [F(2,6)=1.22v NS]. However, we found a statistically significant relationship with the time of treatment [F(6,18)=6,87 p<0,01]. As shown in figure 1, the secondary tests showed that acute treatment with 30 mg/kg of pioglitazone significantly reduces the consumption of ethanol in 2 hours, but not after 30, 60 or 90 minutes. The effect of selectivity was trademonster the Rowan lack of significant influence, consumption of food and water (data not shown).

EXAMPLE 2

Effect of acute injection of pioglitazone plus naltrexone on voluntary alcohol consumption

In this experiment assessed the effect of joint administration of pioglitazone and naltrexone on alcohol consumption to demonstrate that PPARγ agonists can potentiate the inhibitory effect of opioid antagonists on ethanol consumption. Previously it was shown that used in these trials the dose of naltrexone (0.25 mg/kg) minimally effective in reducing the consumption of ethanol in rats msP in the same experimental conditions (Ciccocioppo et al. 2007).

The msP rats (n=8) was prepared for testing as described in example 1. After achieving a stable basal consumption of ethanol access to alcohol was limited to 2 hours per day at the beginning of the dark phase. Food and water were freely available. Animal examined the influence of the combination of pioglitazone (0,0, 10,0, 30 mg/kg), administered 12 hours and 1 hour before access to ethanol, and naltrexone (0.0 and 0.25 mg/kg), injectable after 2 minutes after the second injection of pioglitazone. The experiment was performed using a balanced Latin square plan with one individual, when each animal received all doses of the medication.

These experiments were conducted at the beginning of the dark cycle, and consumption of alcohol, water and food is dleivery 30, 60, 90 and 120 minutes after the opening of access to ethanol. Consumption of food and water did not change significantly when different modes of treatment.

Analysis of variance showed a significant overall effect of treatment [F(3,7)=5,95 p<0,01] consumption of alcohol. As shown in figure 2, the secondary tests showed that one naltrexone and naltrexone+pioglitazone significantly reduce the consumption of ethanol in 30, 60 and 90 minutes. After 120 minutes the one treatment with naltrexone and naltrexone+pioglitazone (10 mg/kg) had no significant effect. On the contrary, compared with the control joint introduction of naltrexone+pioglitazone (30 mg/kg) had a significant effect also after 120 minutes (p<0,05). These data suggest that co-administration of the two drugs increases their actions or may lead to increased duration of effect of naltrexone.

EXAMPLE 3

The effect of sub-chronic administration of pioglitazone on voluntary alcohol consumption

The effect of sub-chronic administration of pioglitazone has been demonstrated using rats trained to consume 10% (vol./about.) alcohol for 24 hours a day (free choice between water and ethanol) to achieve a stable background level of consumption of ethanol. At this point in msP rats (N=9/group) examined the influence of pioglitazone (0,0, 10.0 or 30.0 mg/kg) on ethanol consumption with ISOE what Itanium schema comparison individuals, in which each group of animals received a different dose of medication. Before treatment the rats were habituated to the procedure for insertion through the gastric tube for three days, during which they received the vehicle (distilled water).

Pioglitazone lasted continuously for; seven days, and the drug (or the media)was administered twice daily for 12 and 1 hour before the start of the dark period of the cycle of light/dark. The consumption of alcohol, food and water was monitored after 2, 8 and 24 hours. The consumption of liquids and food tracked within three days after the end of treatment medication.

Sub-chronic (7 days) administration of pioglitazone significantly reduced voluntary ethanol consumption by rats msP. Analysis of variance showed a significant overall effect of treatment [F(2,33)=9,51; p<0,01]. As shown with the secondary tests, the effect arose from the first day of treatment with the highest dose of the drug (figures 3A, 3B and 3C). The effect was progressively increased during treatment, and starting from the 4th day of treatment, both doses of medication (10 and 30 mg/kg) significantly reduced the consumption of ethanol.

During treatment, the water consumption was relatively low and did not change significantly under the influence of drugs. In contrast, food consumption (figure 3D) was significantly increased by pioglitazone [F (2,33)=7,34 p<0,01]. The effect was higher after administration of the lower dose (10 mg/kg) is carsta. At the end of treatment the rats were gradually receding from the action of drugs and the consumption of ethanol was gradually returned to the level before treatment (data not shown).

EXAMPLE 4

The effect of sub-chronic administration of pioglitazone plus naltrexone on voluntary alcohol consumption

The effect of chronic joint administration of pioglitazone and naltrexone on alcohol consumption was investigated to assess whether PPARγ agonists can potentiate the inhibitory effect of opioid antagonists on ethanol consumption after repeated treatment. As in the studies described in example 2 was used, the dose of naltrexone (0.25 mg/kg), which was previously shown to be minimally effective in reducing the consumption of ethanol in rats msP (Ciccocioppo et al. 2007). In accordance with the plan comparison individuals were prepared by the four groups of rats tosr (N=9/group)as described in example 3. Specifically, after reaching a stable baseline of daily consumption of ethanol in different groups of rats msP examined the effect of pioglitazone in combination with naltrexone. Continuously for seven days msP rats were treated by injection of pioglitazone (0,0, 10.0 or 30.0 mg/kg) for 12 hours and 1 hour before the start of the dark period of the cycle of light/dark, and naltrexone (0.0 and 0.25 mg/kg) were injected with 2 min after the second injection of pioglitazone. The consumption of alcohol, water and food tracked is via 2, 8 and 24 hours. The consumption of liquids and food tracked within three days after the end of the period of drug treatment.

Sub-chronic (7 days) administration of naltrexone or naltrexone+pioglitazone significantly reduced voluntary ethanol consumption by rats msP. Analysis of variance showed a significant overall effect of treatment [F(3,32)=9,59 p<0,01]. As shown by secondary tests (figures 4A, 4B and 4C), naltrexone significantly reduced ethanol intake after 2 hours (p<0,05), but not after 8 and 24 hours. In addition, the effect gradually decreased with increasing duration of treatment. At the same time in animals treated with pioglitazone plus naltrexone, alcohol consumption decreased significantly in all tested time points (2, 8 and 24 hours). This effect remained significant throughout the period of treatment. These results indicate that co-administration of pioglitazone and naltrexone may cause additive. or synergistic effects.

During treatment, the water consumption was quite low and did not change significantly with the introduction of drugs. In contrast, food consumption was significantly increased under the action of pioglitazone [F(3,32)=5,34 p<0,05] (figure 4D). The effect was higher after administration of the lowest dose (10 mg/kg) drugs. By the end of the treatment the rats gradually escaped from the action of drugs and the consumption of ethanol was gradually returned to the level before treatment.

EXAMPLE 5

Effect of acute administration of troglitazone on induced yohimbinum recovery search alcohol

To demonstrate the effect of TZDs on induced stress relapse search of alcohol after reaching a stable baseline consumption of 10% ethanol reacting msP rats (n=10) were subjected to blanking period (14 days), during which the response to ethanol was gradually decreased. The next day after the last session of extinction, rats were subjected to a test restore. Animals were injected OS pioglitazone (0,0, 10.0 or 30.0 mg/kg) for 12 hours and 1 hour before the test recovery. Yohimbin (1.25 mg/kg/br) was administered 30 min after the last injection of pioglitazone.

Animals received all the medicines according to a balanced Latin square plan. Between tests left 3-day interval, during which the animals were exposed to the sessions of extinction. In the test recovery was recorded by clicking on the active and inactive levers.

Stable baseline consumption of 10% (vol./about.) alcohol was done for 15 days. After this phase Samovodene alcohol began extinguishing training. During phase damping consumption gradually decreased, and on the last day of clearing the values 16,1±3,9. Intraperitoneal administration of an antagonist of alpha-2 adrenergic receptors of yohimbine at a dose of 1.25 mg/kg significantly restored the operant response to JV the RT [F(1,18)=22,78 p< of 0.01]. As shown by variance analysis, pre-treatment with pioglitazone significantly reduced the effect of yohimbine [F(2,9)=12,21, p<0,01] (figure 5). Secondary analysis showed a significant inhibition of recovery after administration of 30 mg/kg of pioglitazone (p<0,01).

At the lowest dose (10 mg/kg) showed a clear trend (p=0.07) to inhibition by pioglitazone actions yohimbine. Analysis of presses on the inactive lever showed no effect of treatment on clicking on this Richet shows the selective action of yohimbine on the induction of recovery search of alcohol.

EXAMPLE 6

Effect of acute administration of pioglitazone on the induced conditional signal recovery search alcohol

In this experiment to demonstrate the effect of TZDs on the induced conditional signal a relapse consumption of alcohol msP rats (n=14) were trained in the operant Samovodene 10% ethanol or water in 30-min daily sessions FR-1 scheme reinforcement when every answer led to the introduction of 0.1 ml of liquid. Signal availability of ethanol was the smell of orange extract, which served as differentsirovanogo stimulus. In addition, each press of the lever, resulting in release of ethanol, combined with the inclusion of light in a room for 5 s (S+/CS+). Water as differentsirovanno is about and concurrent conditional signal (S -/CS-used, respectively, anise odor and 5-s white noise. Then the animals were subjected to daily sessions of extinction, during which pressing the lever gradually decreased.

Recovery test was performed by re-presenting them conditional stimuli that predict the availability of ethanol or water, but in the absence of liquids. Pioglitazone (0,0, 10.0 or 30.0 mg/kg) was administered 12 hours and 1 hour before the start of the test recovery. The experiments were conducted at the beginning of the dark phase of the cycle of light/dark. Animals received all the medicines according to a balanced Latin square plan, and between sessions recover left 3-day interval. C. test recovery was recorded by clicking on the active and inactive levers.

During the phase formation of the conditioned reflex, in which animals are perceived availability of alcohol and water, rats responded more on the alcohol. ANOVA showed a significant overall effect of the formation of the conditioned reflex [F(1,28)=41,89, p<0,01]. On the Last day of discriminatory period the animals had reached a response by pressing a lever approximately 120 times for 30 min, while the response of the water was 20. During blanking pressing the lever gradually decreased to 5.87±1.07 in the last day of clearing. In the test recovery ANOVA showed that the conditional signals okazyvaetsya the overall impact on the search alcohol [F(1,28)=30,4, p<0,01]. More detailed analysis showed a marked recovery response when S+/CS+(p<0,01), but not when S-/CS-compared to the last day of clearing. As shown in figure 6, the conditioned-reflex recovery search of alcohol did not change significantly prior to the introduction of pioglitazone. Treatment had no effect on clicking on the inactive lever (data not shown).

EXAMPLE 7

The impact of the introduction of ciglitazone on Samovodene ethanol rats Wistra

This study was performed to demonstrate that the effect of pioglitazone on ethanol consumption extends to other PPARγ agonists. Determined the impact of ciglitazone structurally different TDZ, Samovodene ethanol. In addition, to test the applicability of the observed actions of pioglitazone. in other experimental models of consumption of alcohol, these studies were performed on heterogeneous Wistar rats in conditions of operant Samovodene.

Rats Wistra (n=7) were trained Samovodene ethanol for 30 min/day according to the scheme FR1 reinforcement. After reaching a stable level of response of rats in a balanced order (Latin square) in one individual was treated with ciglitazone (0,0, 5.0 or 20.0 mg/kg), administered 30 minutes before the start of the session Samovodene. Recorded the number of reactions in the active and inactive is on levers. Between seansmithsucks left a 3-day interval.

During Samovodene ethanol Wistar rats were purchased expressed operant response to alcohol. At the end of this phase, the rats pressed the alcohol lever 30-35 times for 30 minutes At this point, animals were injected with ciglitazone/br. The results showed that treatment with ciglitazone significantly reduces Samovodene ethanol [F(2,6)=by 5.87, p<0,05]. The reaction on the inactive lever was very low and did not depend on the introduction of drug [F(2,6)=1,52 NS]. Secondary tests showed that Samovodene ethanol significantly decreased after administration of the highest dose (figure 7).

EXAMPLE 8

Effect of acute injection of rosiglitazone on voluntary ethanol consumption

Was demonstrated by the ability of the other TZD, rosiglitazone, to reduce the consumption of ethanol. First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After achieving a stable consumption of ethanol (6-8 g/kg/day) in rats tested the effect of rosiglitazone (0,0, 7.5 and 15 mg/kg) using the plan comparison individuals. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Rosiglitazone was administered twice, 12 hours and 1. h to open the ing access to ethanol. Experiments on the reception started at the beginning of the dark cycle. The consumption of alcohol, water and food tracked. after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance showed a significant effect of treatment on ethanol consumption [F(2,18)=0,4 p<0,05]. As shown in figure 8, with the secondary tests Nyoman-Keuls it was found that acute introduction 15 mg/kg rosiglitazone significantly reduces ethanol intake after 2 hours (p<0,05). Inhibition of ethanol consumption was very significant after 24 hours (p<0,01). The selectivity of action was demonstrated by the absence of any significant effect on the consumption of food and water (data not shown).

EXAMPLE 9

Impact/br introduction of the PPARγ antagonist GW9662 on pioglitazone-induced reduction of ethanol consumption

This experiment showed that the effect of pioglitazone on the consumption of ethanol is mediated by the activation of PPARγ receptors. After achieving a stable basal consumption of ethanol in msP rats (n=22) tested the effect of GW9662 on pioglitazone-induced reduction of ethanol consumption. Rats were treated with 30 mg/kg of pioglitazone entered OS for 1 hour before access to ethanol. GW9662 was introduced/br 30 min after administration of pioglitazone, and within 30 min the rats were expecting the opening of access to ethanol. Before treatment the rats were accustomed to the% is the stupid feeding through a stomach tube and/br injection for three days. The experiment was carried out according to plan matching individuals (n=22). Another group of msP rats (n=22) received only GW9662. to demonstrate the effect of the blockade of PPARγ on ethanol consumption. Experiments on consumption started in the beginning of the dark cycle. Monitor the consumption of alcohol, water and food after 2, 8 and 24 hours after ensuring access to ethanol.

As shown in figure 9A, analysis of variance showed that blockade of PPARγ receptors under the effect of GW9662 does not affect ethanol consumption by rats msP [F(2,18)=0,40 NS]. However, analysis of variance revealed a significant effect of the introduction on ethanol consumption F(3,24)=18,64 p<0,01] after administration of pioglitazone (figure 9B). Tests Nyoman-Keuls showed that treatment with 30 mg/kg of pioglitazone significantly reduces ethanol consumption after 8 and 24 hours (p<0,01). Pre-treatment with GW9662 blocked the effect of pioglitazone dependent on dose. Doing drugs is not influenced by the consumption of food and water (data not shown).

EXAMPLE 10

The effect of ICV injection of the PPARγ antagonist GW9662 on pioglitazone-induced reduction of ethanol consumption

This experiment showed that the effect of pioglitazone on the consumption of ethanol is mediated by activation of PPAR (brain to this end, the msP rats (n=6) was administered GW9662 (5 μg/rat) ICV for selective blockade of PPARγ receptors of the brain, and pioglitazone (30 mg/is d) was introduced OS. The experiment was performed using a balanced Latin square plan with one individual, when each animal received all doses of the medication.

Experiments on consumption conducted at the beginning of the dark cycle, and tracked the consumption of alcohol, water and food after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance indicated a significant effect of the introduction of the consumption of ethanol [F(3,5)=12,93 p<0,001]. As shown in figure 10, the secondary tests Nyoman-Keuls revealed that the treatment with 30 mg/kg of pioglitazone significantly reduces ethanol intake after 2 hours (p<0.05)and 8 hours (p<0.05) and 24 hours (p<0,01). ICV introduction GW9662 does not by itself had no significant effect on ethanol consumption. However, it completely prevented the effect of pioglitazone. Doing drugs is not influenced by the consumption of food and water (data not shown).

EXAMPLE 11

Effect of acute injection of naltrexone on induced yohimbinum recovery search alcohol

Was demonstrated by the inability of naltrexone to suppress induced yohimbinum recovery of consumption of alcohol. After reaching a stable background consumption of 10% ethanol reacting msP rats (n=10) were exposed to the effect of the blanking period (14 days), during which the response to ethanol was gradually decreased. Through the day poslepoletnogo session damping rats were subjected to testing for recovery.

To determine the ability of naltrexone to prevent the action of the pharmacological stressor of yohimbine animals (n=7) was injected into/br antagonist of opioid receptors (0,0, 0.25 and 1.0 mg/kg) 1 hour before the test recovery. Yohimbin (1.25 mg/kg/br) was administered 30 min after the injection of naltrexone. Drug administration the animals were made in accordance with the balanced Latin square plan. Between testing drugs left 3-day interval, during which the animals were exposed to the sessions of extinction. In the test recovery was recorded by clicking on the active and inactive levers.

Stable background reaction in 10% (vol./about.) alcohol was done for 15 days. After this phase Samovodene alcohol began extinguishing training. During phase damping consumption gradually decreased. Intraperitoneal administration of an antagonist of alpha-2 adrenergic receptors of yohimbine at a dose of 1.25 mg/kg was significantly restored the operant response to alcohol [F(1,8)=19,99 p<0,01]. As shown by variance analysis, pre-treatment with naltrexone did not reduce significantly the effect of yohimbine [F(2,8)=0,46, NS] (figure 11). Analysis of presses on the inactive lever showed no effect of treatment on pressing this lever (data not shown). This indicates that the selective action of yohimbine in the induction restore search of alcohol.

EXAMPLE 12

The influence of the OS is cerned the introduction of naltrexone on the induced conditional signal recovery search alcohol

Was demonstrated by the ability of naltrexone to suppress the induced conditional signal recovery search of alcohol. In this experiment, msP rats (n=9) were trained in the operant Samovodene 10% ethanol or water in 30-min daily sessions under the scheme FR-1 reinforcement, in which each response has led to the introduction of 0.1 ml of liquid. Signal availability of ethanol was the smell of orange extract, which served as differentsirovanogo stimulus. In addition, each press of the lever, resulting in release of ethanol, combined with the inclusion of light in a room for 5 s (S+/CS+). Water as differentsirovanogo and concurrent conditional signal (S-/CS-used, respectively, anise odor and 5-s white noise. Then the animals were subjected to daily sessions of extinction, during which pressing the lever gradually decreased.

Recovery test was performed by re-presenting them conditional stimuli that predict the availability of ethanol or water, but in the absence of liquids. Naltrexone (0,0, 0.25 and 1.0 mg/kg) was administered one hour before the start of the test recovery. The experiments were conducted at the beginning of the dark phase of the cycle of light/dark. Animals received all the medicines according to a balanced Latin square plan, and between sessions of no the of left 3-day interval. In the test recovery was recorded by clicking on the active and inactive levers.

During the phase formation of the conditioned reflex, in which animals are perceived availability of alcohol and water, rats responded more on the alcohol. During blanking pressing the lever gradually decreased. In the test recovery ANOVA showed a significant overall effect of conditional stimuli in search of alcohol [F(1,8)=36,31, p<0,01]. A more detailed analysis showed a marked recovery response when S-/CS-1(p<0,01), but not when S-/CS-compared to the last day of clearing.

As shown in figure 12, the conditioned-reflex recovery search of alcohol decreased significantly with naltrexone [F(2,8)=15,90; p<0,01]. Secondary analysis showed that both tested doses (0.25 and 1.0 mg/kg) antagonist of opioid receptors significantly reduce recovery search of ethanol (p<0,01). Treatment had no effect on clicking on the inactive lever (data not shown).

EXAMPLE 13

The effect of joint administration of pioglitazone and naltrexone on induced yohimbinum and conditional signals the restoration of search alcohol

Was determined by the combined effect of the PPARγ agonist pioglitazone and the opioid receptor antagonist naltrexone on the effect of different inducers restore search of alcohol.

For induzione the nogo-yohimbinum restore search of ethanol after reaching a stable baseline consumption of 10% ethanol msP rats (n=9) were subjected to blanking period (14 days) during which the response to ethanol was gradually decreased. The next day after the last session of extinction, rats were subjected to a test restore.

To assess the ability of the combination of naltrexone plus pioglitazone to prevent the action of the pharmacological stressor of yohimbine animals were injected/br antagonist of opioid receptors (1.0 mg/kg) and OS TDZ (30 mg/kg) 1 hour before the test recovery. Animals received all medications in accordance with a balanced ladiescom square plan. Between sessions, drug testing left a 3-day interval during which the animals were exposed to the sessions of extinction. In the test recovery was recorded by clicking on the active and inactive levers.

For induced conditioned stimulus search of alcohol Another group of msP rats (n=10) were trained in the operant Samovodene 10% ethanol or water in 30-min daily sessions under the scheme FR-1 reinforcement, in which each response has led to the introduction of 0.1 ml of liquid. Signal availability of ethanol was the smell of orange extract, which served as differentsirovanogo stimulus. In addition, each press of the lever, resulting in release of ethanol, combined with the inclusion of light in a room for 5 s (S-/CS-). Water as differentsirovanogo and concurrent conditional signal (S-/CS- used, respectively, anise odor and 5-s white noise. Then rats were subjected to daily sessions of extinction, during which pressing the lever gradually decreased.

Recovery test was performed by re-presenting them conditional stimuli that predict the availability of ethanol or water, but in the absence of liquids. Naltrexone (1.0 mg/kg) and pioglitazone were co-injected 1 hour before the test recovery. The experiments were conducted at the beginning of the dark phase of the cycle of light/dark. Animals received all the medicines according to a balanced Latin square plan, and between sessions recover left 3-day interval. In the test recovery was recorded by clicking on the active and inactive levers.

When induced by yohimbine recovery search of stable baseline ethanol consumption 10% (vol./about.) alcohol was achieved after 15 days. After this period began the training phase damping of Samovodene alcohol. In phase damping response gradually decreased. Intraperitoneal administration of an antagonist of alpha-2 adrenergic receptors of yohimbine at a dose of 1.25 mg/kg significantly restored the operant response to alcohol [F(1,8)=12,86 p<0,01]. As shown by analysis of variance,preliminary treatment with naltrexone plus pioglitazone significantly reduces the effect of yohimbine [F(2,8)=5,71, p<0,01] (figure 13A). Analysis Nagatino inactive lever showed no effect of treatment on clicking on this link.

When induced conditioned stimulus recovery search of alcohol msP rats quickly learned to distinguish between the availability of alcohol and water; rats responded more on the alcohol. During blanking pressing the lever gradually decreased. In the test recovery ANOVA showed a significant overall effect of conditional stimuli in search of alcohol [F(1,9)=31,83, p<0,01]. A more detailed analysis showed a marked recovery response when S+/CS+(p<0,01), but not when S-/CS-compared to the last day of clearing. As shown in figure 13, the conditioned-reflex recovery search of alcohol significantly decreased joint introduction of naltrexone and pioglitazone [P(2,9)=16,58; p<0,01]. Treatment had no effect on clicking on the inactive lever (data not shown).

EXAMPLE 14

Effect of acute injection of pioglitazone plus fluoxetine on voluntary ethanol consumption

In this experiment investigated the effect of joint administration of pioglitazone and fluoxetine on alcohol consumption to demonstrate that the joint treatment with PPARγ agonists, for example, TZDs, and antidepressants, such as selective inhibitors of serotonin uptake, has a synergistic inhibitory effect on ethanol consumption. With this purpose used a low dose of fluoxetine (3.0 mg/kg OS), which in the pilot and the following did not reduce ethanol consumption by rats msP. Was also selected dose of pioglitazone (10 mg/kg OS), which by itself had no significant effect on alcohol consumption.

First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After achieving a stable consumption of ethanol (6-8 g/kg/day) on the msP rats (n=34) tested the effect of pioglitazone, fluoxetine, or their combinations using the plan comparison individuals. As control served rats treated with the native drug. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Pioglitazon and fluoxetine was administered twice, 12 hours and 1 hour prior to the opening of access to ethanol. Experiments on the reception started at the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance showed a significant overall effect of treatment on ethanol consumption [F(3,30)=lower than the 5.37 p<0,01]. As shown in figure 14, the secondary tests revealed that the low dose of one of pioglitazone or a single fluoxetine no significant impact on ethanol consumption by rats msP. However, co-administration of the two funds prevodilac significant inhibition of ethanol consumption after 2 and 8 cha is s (p< 0.01)and also after 24 hours (p<0,05). These data suggest that co-administration of the two drugs has a synergistic inhibitory effect on ethanol consumption.

After drug treatment were observed moderate, inaccurate tendency to increase food intake (data not shown). Water consumption was very low and did not change with the introduction of drugs (data not shown).

EXAMPLE 15

Effect of acute injection of pioglitazone plus mirtazapine on voluntary ethanol consumption

Investigated the effect of joint administration of pioglitazone and mirtazapine on alcohol consumption to demonstrate that the joint treatment with PPARγ agonists and this antidepressant has a synergistic inhibitory effect on ethanol consumption. With this purpose used a low dose of mirtazapine (5.0 mg/kg OS), which in the pilot study did not reduce ethanol consumption by rats msP. Was also selected dose of pioglitazone (10 mg/kg OS), which in itself neoclasical significant impact on the consumption of alcohol.

First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After reaching a stable baseline consumption of ethanol (6-8 g/kg/day) on the msP rats (n=34) tested the effect of pioglitazone, mirtazapine or used in combination with the drug plan comparison individuals. As control served rats treated with the native drug. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Pioglitazone and mirtazapine was administered twice, 12 hours and 1 hour prior to the opening of access to ethanol. Experiments on the reception started at the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance showed a significant overall effect of treatment on ethanol consumption [F(3,30)=12,50 p<0,01]. As shown in figure 15, the secondary tests revealed that the low dose of one of pioglitazone or one of mirtazapine has no significant impact on ethanol consumption by rats msP. However, co-administration of the two funds has led to a marked inhibition of ethanol consumption after 2 and 8 hours (p<0,05); a significant decrease in the consumption of ethanol after 2 hours it was also noted for one of pioglitazone (p<0,05). These data suggest that co-administration of the two drugs has a synergistic inhibitory effect on ethanol consumption.

After drug treatment was observed misleading tendency to increase food intake (data not shown). Water consumption was very low and did not change with the introduction of the learning about your medicine (data not shown).

EXAMPLE 16

Influence ocrporo introduction of pioglitazone plus topiramate on voluntary ethanol consumption

In this experiment investigated the effect of joint administration of pioglitazone and topiramate for alcohol consumption to demonstrate that the joint treatment with PPARγ agonists and this protevoepilepticeski means exerts a synergistic inhibitory effect on ethanol consumption. With this purpose used a low dose of topiramate (30.0 mg/kg OS), which in the pilot study did not reduce ethanol consumption by rats msP. Was also selected dose of pioglitazone (10 mg/kg OS), which by itself had no significant effect on alcohol consumption.

First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After reaching a stable baseline consumption of ethanol (6-8 g/kg/day) on the msP rats (n=34) tested the effect of pioglitazone, topiramate, or combinations thereof using the plan comparison individuals. As control served rats treated with the native drug. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Pioglitazone and topiramate was administered twice, 12 hours and 1 hour prior to the opening of access to ethanol. Experiments n the reception started at the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance showed a significant overall effect of treatment on ethanol consumption [F(3,30)=4,35 p<0,01]. As shown in figure 16, the secondary tests revealed that the low dose of one of pioglitazone or a single topiramate no significant impact upotreblenie ethanol msP rats. However, co-administration of the two funds has led to a marked inhibition of ethanol consumption after 2, 8 and 24 hours (p<0,05); a significant decrease in the consumption of ethanol. after 2 hours it was also noted for one of topiramate (p<0,05). These data suggest that co-administration of the two drugs has a synergistic inhibitory effect on ethanol consumption.

After drug treatment was observed misleading tendency to increase food intake (data not shown). Water consumption was very low and did not change with the introduction of drugs (data not shown).

EXAMPLE 17

Effect of acute injection of pioglitazone plus levetiracetam on voluntary ethanol consumption

Investigated the effect of joint administration of pioglitazone and levetiracetam on the consumption of alcohol is to demonstrate that the joint treatment with PPARγ agonists and these antiepileptic provides synergistic ingibiruet is its effect on ethanol consumption. With this purpose used a low dose of levetiracetam (100.0 mg/kg OS), which in the pilot study did not reduce ethanol consumption by rats msP. Was also selected dose of pioglitazone (10 mg/kg OS), which by itself had no significant effect on alcohol consumption.

First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After reaching a stable baseline consumption of ethanol (6-8 g/kg/day) on the msP rats (n=33) tested the effect of pioglitazone, levetiracetam or combinations thereof using the plan comparison individuals. As control served crise treated carriers of drugs. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Pioglitazone and levetiracetam was administered twice, 12 hours and 1 hour prior to the opening of access to ethanol. Experiments on the reception started at the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance showed a significant overall effect of treatment on ethanol consumption [F(3,29)=3,76 p<0,05]. As shown in figure 17, the secondary tests revealed that the low dose of one of pioglitazone or a single levetiracetam does not provide for is to maintain the impact on ethanol consumption by rats msP. In contrast, co-administration of the two funds has led to a marked inhibition of ethanol consumption after 2 hours (p<0,01), and after 8 and 24 hours (p<0,05). These data suggest that co-administration of the two drugs has a synergistic inhibitory effect on ethanol consumption.

Consumption of food and water did not change with the introduction of drugs (data not shown).

EXAMPLE 18

Effect of acute injection of pioglitazone plus gabapentin on voluntary ethanol consumption

Investigated the effect of joint administration of pioglitazone and gabapentin on the consumption of alcohol is to demonstrate that the joint treatment with PPARγ agonists and these antiepileptic agent has a synergistic inhibitory effect on ethanol consumption. With this purpose used a low dose gabapentin (60,0 mg/kg OS), which in the pilot study did not reduce ethanol consumption by rats msP. Was also selected dose of pioglitazone (10 mg/kg OS), which by itself had no significant effect on alcohol consumption.

First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After reaching a stable baseline consumption of ethanol (6-8 g/kg/day) on the msP rats (n=36) tested the effect of pioglitazone, gabapentin or their combinations used with the eating plan comparison individuals. As control served rats treated with the native drug. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Pioglitazone and topiramat was administered twice, 12 hours and 1 hour prior to the opening of access to ethanol. Experiments on the reception started at the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance showed a significant overall effect of treatment on ethanol consumption [F(3,7)=3.31, p<0,05]. As shown in figure 18, the secondary tests revealed that the low dose of one of pioglitazone or one gabapentine no significant impact on ethanol consumption by rats msP. In contrast, co-administration of the two funds has led to a marked inhibition of ethanol consumption after 2 and 8 hours (p<0,05). These data suggest that co-administration of the two drugs has a synergistic inhibitory effect on ethanol consumption.

After drug treatment was observed misleading tendency to increase food intake (data not shown). Water consumption was very low and did not change with the introduction of drugs (data not shown).

EXAMPLE 19

Effect of acute injection of pioglitazone plus ondansetron is on voluntary ethanol consumption

Investigated the effect of joint administration of pioglitazone and ondansetron on alcohol consumption to demonstrate that the joint treatment with PPARγ agonists and selective antagonist of the receptor 3 serotonin (5-NT3) has a synergistic inhibitory effect on ethanol consumption. With this purpose used a low dose of ondansetron (1.0 mg/kg/BD), which in the pilot study did not reduce ethanol consumption by rats msP. Was also selected dose of pioglitazone (10 mg/kg OS), which by itself had no significant effect on alcohol consumption.

First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After reaching a stable baseline consumption of ethanol (6-8 g/kg/day) on the msP rats (n=36) tested the effect of pioglitazone, ondansetron, or combinations thereof using the plan comparison individuals. As control served rats treated with the native drug. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Pioglitazone and ondansetron was administered twice, 12 hours and 1 hour prior to the opening of access to ethanol. Experiments on the reception started at the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 2, 8 and 24 h the sa after ensuring access to ethanol.

Analysis of variance showed insignificant overall effect of treatment [F(3,32)=2,73 p<0,05], but there was a significant effect of time of treatment on alcohol consumption [F(6,64)=2,29, p<0,05]. As shown in figure 19, the secondary tests revealed that the low dose of one of pioglitazone or a single ondansetron no significant impact on ethanol consumption by rats msP. However, co-administration of the two funds has led to a marked inhibition of ethanol consumption after 24 hours (p<0,05). Consumption of food and water was very low and did not change with the introduction of drugs (data not shown). These data suggest that co-administration of the two drugs has a synergistic inhibitory effect on ethanol consumption.

EXAMPLE 20

Effect of acute injection of pioglitazone plus antalarmin on voluntary ethanol consumption

Investigated the effect of joint administration of pioglitazone and antalarmin on the consumption of alcohol is to demonstrate that the joint treatment with PPARγ agonists, and this selective CRF1 receptor antagonist of the corticotropin-releasing factor has a synergistic inhibitory effect on ethanol consumption. With this purpose used a low dose antalarmin (15,0 mg/kg/BD), which in the pilot study weakly reduced the consumption of ethanol by rats msP, was Also selected dose of pioglitazone is (10 mg/kg, OS), which by itself had no significant effect on alcohol consumption.

First, msP rats were trained to consume 10% (wt./about.) alcohol for 24 hours a day (free choice between water and ethanol). After reaching a stable baseline consumption of ethanol (6-8 g/kg/day) on the msP rats (n=32) tested the effect of pioglitazone, antalarmin or combinations thereof using the plan comparison individuals. As control served rats treated with the native drug. Before treatment the rats were accustomed to feeding through a stomach tube for three days, during which they received the vehicle (distilled water). Pioglitazone and antalarmin was administered twice, 12 hours and 1 hour prior to the opening of access to ethanol. Experiments on the reception started at the beginning of the dark cycle. The consumption of alcohol, food and water was monitored after 2, 8 and 24 hours after ensuring access to ethanol.

Analysis of variance showed a significant overall effect of treatment on ethanol consumption [F(3,28)=3,29 p<0,05]. As shown in figure 20, the secondary tests revealed that the low dose of one of pioglitazone or one antalarmin no significant impact on ethanol consumption by rats msP. However, co-administration of the two funds has led to a marked inhibition of ethanol consumption through 8 (p<0.01) and 24 hours (p<0,05); significant decrease in p the consumption of ethanol was also observed for one antalarmin (p< 0,05). These data suggest that co-administration of the two drugs has a synergistic inhibitory effect on ethanol consumption.

Consumption of food and water did not change with the introduction of drugs (data not shown).

EXAMPLE 21

The impact of the introduction of pioglitazone on the abolition of alcohol

The impact of the introduction of pioglitazone on the abolition of the alcohol was determined in rats. Male Wistar rats were subjected to a six-day periodic alcoholic intoxication. During the dark phase rats 4 times orally injected 2.5-3.0 g/kg of 20% ethanol. The first dose of ethanol was introduced at the beginning of the dark phase. The remaining 3 daily doses were injected with 3-hour intervals. During the light phase of the cycle of light/dark injections to rats did not produce. The desired level of alcohol in blood was 250-300 mg/DL. After 6 days of this treatment the rats were subjected to spontaneous withdrawal, which is usually manifested between 8 and 14 hours after the last injection of ethanol. Pioglitazone (0,0, 10 and 30 mg/kg) was administered twice, 12 hours and 1 hour prior to the assessment of withdrawal symptoms. Behavioral signs of withdrawal were: (1) answer ventromedial distal bending; (2) the stiffness/rigidity of the tail; and (3) tremor (Schulteis et al. 1995). Each trait ranged during 3-5 min observation on a scale of 0-2 (Museu et al., 1996; Schulteis et al., 1995). All the signs are summed to obtain the total is the service provider severity of withdrawal symptoms.

Twelve hours after the last injection of ethanol in animals treated with the carrier for pioglitazone, manifested symptoms of abstinence. Analysis of variance showed an overall effect of treatment with pioglitazone, which reduces the rigidity of the tail [F(4,25)=11,98 p<0,001] (figure 21). Secondary tests showed that the signs of alcohol withdrawal significantly reduced after the introduction and 10 mg/kg, and 30 mg/kg of pioglitazone with highly significant influence on the rigidity of the tail (p<0.01), and tremor (p<0.01) and depression ventromedial segment (p<0,01). Interestingly,during the measurement of symptoms in two out of 7 animals of the group treated with the carrier, convulsions were observed. In contrast, none of the 12 rats treated with pioglitazone, seizures were observed. These data suggest that pioglitazone not only reduces the consumption of alcohol (see the previous experiments), but also has the ability to suppress or control the alcohol abstinence syndrome and associated symptoms, including seizures.

EXAMPLE 22

Effect of pioglitazone on the abuse of alcohol in humans

A study was conducted according to the observation of patients taking pioglitazone (Actos®) for the treatment of diabetes, to demonstrate that PPARγ agonists alone or in combination with antagonists of opioiddependent in reducing the abuse of ethanol.

The study included a total of 12 patients. 4 patients (2 men and 2 women) had received only psychotherapy (control; CRT); 4 patients (men) received naltrexone 50 mg/day (NTX)+psychotherapy; and 4 patients (3 men and 1 woman) received pioglitazone 30 mg/day (Actos®, ACT)+psychotherapy. The age of patients ranged from 25 to 45 years; All patients had a previous bad experience detoxification from alcohol. Found no severe concomitant psychiatric morbidity. All patients treated with Actos®, was diagnosed with diabetes.

Patients were evaluated at time 0 (immediately before treatment) for various psychological indicators. Anxiety was determined using the questionnaire S.T.A.I. Y-1; craving for alcohol was determined using a questionnaire with a scale of manic-compulsive alcohol; and depression were determined using questionnaires M.A.D.R.S 10 ibid. Estimated daily and weekly consumption of ethanol. Patients also tested once a week on anxiety, depression and cravings for alcohol.

In addition, patients took blood samples at the time Of and after four weeks (T1) and 12 weeks (T2) of treatment. Measured hematological parameters included: the average volume of erythrocytes (MCV), gamma GT; aspartataminotransferaza (AST); alanineaminotransferase (ALT); and lack of transport of carbohydrates (CDT). MCV and CDT are the two who are biological markers of ethanol consumption, a GGT, ALT and AST are the biological markers of the functional activity of the liver.

Data were analyzed using analysis of variance and, if necessary, with subsequent secondary tests Newman-Keuls.

The results showed rapid normalization of all parameters of blood in patients treated with pioglitazone (ACT), as shown in table 2.

The decrease in MCV and CDT pointed to a gradual reduction in the consumption of ethanol sick for two months of treatment with medication. Reduction of GGT, ALT and AST reflect normalization of liver function. Patients treated with naltrexone (NTX), we also observed a decrease in MCV and CDT, but weaker compared to the group of pioglitazone. The parameters of the liver was also improved with naltrexone, but again the effect of pioglitazone was more pronounced. In the control group who received only psychotherapy, was not observed any improvement over the 2-month treatment.

Statistical analysis revealed an overall effect of treatment on all measured blood parameters (MCV, [F(2,9)=89,7 P<0,0001]; GGT; [F(2,9)=5328 P<0,0001]; ALT [F(2,9)=52,57 P<0,0001]; AST [F(2,9)=771 P<0,0001]; CDT [F(2,9)=26,54 P<0,0001]). Secondary tests showed that for all five of biological markers there is a statistical difference between the control (only psychotherapy) and patients treated with naltrexone (P<0,0001) or pioglitazone P< 0,0001). Pioglitazone bis more effective than naltrexone in reducing the values of MCV (P<0,001), GGT (P<0.001) and ALT (p<0,001). Was not identified znachenii in action naltrexone and pioglitazone on CST and AST.

The results also showed a gradual decrease in anxiety during treatment. Pioglitazone showed the greatest effect, as shown in table 3. The control patients (only psychotherapy) anxiety did not decrease during treatment.

Table 3
The rate of anxiety, obtained using the scale STAY-Y-1 (average value)
ACTNTXCTR
T=0596163
T=1.1586164
T=1.2555962
T=1.3545369
T=1.4565265
ACTNTXCTR
T=2.1495161
T=2.2475363
T=2.3435267
T=2.4405164
T=0 corresponds to the beginning of treatment;
T=1.1 corresponds to 1 week to 1 month;
T=1.2 corresponds to 2 week, 1 month, etc

Analysis of variance revealed an overall effect of treatment[F(2,9)=142,86 P<0,0001]). Secondary tests showed a statistically significant difference between. control patients and patients treated with naltrexone (P<0,001) or pioglitazone is ω (P< 0,001). Pioglitazone was more effective than naltrexone, and there was also a statistically significant difference between pioglitazone and naltrexone (P<0,001).

The results also showed a gradual decrease in manic-compulsive alcohol. The effect was much pronounced in the case of pioglitazone. As shown in table 4, OCDS control patients remained at the level before the treatment.

Table 4
The scale of manic-compulsive alcohol (OCDS) (average value)
ACTNTXCTR
T=0504952
T=1.1454749
T=1.2374548
T=1.3364149
T=1.434 4047
ACTNTXCTR
T=2.1314147
T=2.2294349
T=2.3284250
T=2.4284451
T=0 corresponds to the beginning of treatment;
T=1.1 corresponds to 1 week to 1 month;
T=1.2 corresponds to 2 week, 1 month, etc

Analysis of variance revealed an overall effect of treatment[F(2,9)=329,27 P<0,0001]). Secondary tests showed a statistically significant difference between control patients and patients treated with naltrexone (P<0,001) or pioglitazone (P<0,001). Pioglitazone was more effective than naltrexone, and there was also a statistically significant difference between pioglitazone and naltrexone (P<0,001).

Baseline on the MADRS scale showed that this population of patients is e is related disease severe depression. During treatment with pioglitazone indicator of depression decreased since the second week of treatment, as shown in table 5. On week 3, he had reached a plateau. However, in the rapid establishment of the plateau could make the effect of low level value.

Table 5
Depression scale .A.D.R.S.(average value)
ACTNTXCTR
T=0211920
T=1.1151618
T=1.2131819
T=1.3101617
T=1.4111719
.ACTNTXCTR
T=2.1121721
T=2.2131519
T=2.3101819
T=2.41219
T=0 corresponds to the beginning of treatment;
T=1.1 corresponds to 1 week to 1 month;
T=1.2 corresponds to 2 week, 1 month etc

Analysis of variance revealed an overall effect of treatment[F(2,9)=42,12 P<0,0001]). Secondary tests showed a statistically significant difference between control patients and patients treated with pioglitazone (P<0,001), but not naltrexone. Pioglitazone also differed significantly from naltrexone (p<0,001).

In General, certain in the course of this study the blood parameters showed different normalization associated with the consumption of alcohol markers in patients treated with pioglitazone or naltrexone. The effect was more pronounced in the case of pioglitazone. In patients who were treated only with psychotherapy, improvement during treatment were not found. Uh what about the indicates, what is the difference between control patients and patients treated with the drug depended on pharmacological interventions.

There is a strong link between alcohol abuse, anxiety and depression. The symptoms of these are associated with mood disorders have a tendency to aggravate during the early phase of alcohol detoxification, contributing to the low compliance of patients to treatment. In this regard, it is very important that pioglitazone reduces symptoms of anxiety and depression in patients with alcoholism. This could also explain why, after two months of drug administration all 4 patients receiving pioglitazone, still continued treatment, while 2 patients from the control group and 1 patient from group treated with naltrexone, refused treatment. It is also very important that pioglitazone has steadily reduced rate OCDS. Craving for alcohol and the urge to binge (which are measured on a scale OCDS) are the main predictors of relapse. These data thus show that pioglitazone has the ability to prevent a relapse.

No treatment placebo control (only psychotherapy) the group may have been influenced by the high efficiency of drug treatment, as the effect of naltrexone was higher effect usually observed in controlled randomized clinical trials and the test. However, the placebo effect cannot be the cause of the difference between the effectiveness of pioglitazone and naltrexone. Indeed, in this case, both groups of patients received pharmacological medication in conjunction with psychotherapy. On this basis, although we cannot exclude that the effect of pioglitazone in these studies was somewhat exaggerated, it is clear that this medicine is highly effective in the control of alcohol abuse, and its effects can exceed the effect of naltrexone.

EXAMPLE 23

Influence pioglitazone on Samovodene cocaine

The ability of pioglitazone to reduce the consumption of cocaine has been demonstrated in a rat model of addiction to cocaine. Cocaine hydrochloride (obtained from the National Institute of drug abuse, Bethesda, MD) was dissolved in sterile saline at a concentration of 0.25 mg/0.1 ml of drug Solution or the media was injected in a volume of 0.1 ml for 4 sec. Pioglitazone obtained from a commercial source, suspended in distilled water, and the resulting suspension was maintained at a constant shaking until the introduction. Pioglitazone is administered orally (OS) via a stomach tube for 12 hours and 1 hour before Samovodene cocaine.

Used male Wistar rats weighing 180 to 200 g at the time postplan the I in the laboratory. Animals were placed in groups of three in vivarium with controlled humidity and temperature (22°C) when directed cycle of light/dark 12 h: 12 h (on 17:00, off 05:00) with free access to food and water. One week after arrival, rats were subjected to surgical implantation selectimage catheter in the right jugular vein.

Rats (n=6) were trained to Samovodene cocaine in 2-hour daily sessions under the scheme with a constant factor of 5, in which each response has led to the introduction of 0.25 mg/0.1 ml liquid solution of cocaine. Training Samovodene cocaine continued to achieve stable baseline level of response (deviation less than 10% continuously for 3 days, calculated for each rat) At this point started testing drugs.

Animals were treated with pioglitazone (0,0, 10.0 or 30.0 mg/kg), injected OS for 12 hours and 1 hour before the start of the session Samovodene in accordance with a balanced order (Latin square plan) for the individual. Recorded the number of presses on the active and inactive levers. Between sessions of the test drugs was left a 3-day interval. During these intervals continued Samovodene cocaine to restore the background level of pressing the lever.

The impact of the introduction of pioglitazone on Samovodene cocaine was evaluated using one-way EXT is refactoring ANOVA with subsequent secondary test of Newman-Keuls.

Treatment with pioglitazone significantly reduced Samovodene of cocaine [F(2,5)=13,189 p<0,01]. Secondary tests showed significant (p<0.01) decrease in Samovodene cocaine and of 10.0, and 30.0 mg/kg of pioglitazone (figure 22A). Pressing left inactive lever were very rare and were not affected by treatment with pioglitazone (figure 22).

EXAMPLE 24

Effect of pioglitazone on the consumption of nicotine

The ability of PPARγ agonists and antidepressant to reduce the consumption of nicotine has been demonstrated in animal models of addiction to nicotine.

Bupropion hydrochloride (Sigma, Milan, Italy) was dissolved in physiological solution. Nicotine tartrate (Sigma, Milan, Italy) was dissolved in isotonic saline solution at a concentration of 0.03 mg/0.1 ml free base. the pH of the nicotine solution was brought to 7 with diluted NaOH. The drug solution or the media was injected in a volume of 0.1 ml for 4 sec. Pioglitazone was obtained from a commercial source; it suspended in distilled water, and the resulting suspension was maintained, with constant shaking until the introduction. Pioglitazone is administered orally (OS) via a stomach tube for 12 hours and 1 hour before Samovodene nicotine.

Used male Wistar rats weighing 180 to 200 g at the time of receipt in the laboratory. Animals were placed in groups of three. in vivarium with controlling what my humidity and temperature (22°C) when directed cycle of light/dark 12 h: 12 h (on 17:00, off 05:00) with free access to food and water. One week after arrival, rats were subjected to surgical implantation selectimage catheter in the right jugular vein.

Rats (n=9) were trained for one week Samovodene cocaine in 2-hour daily sessions under the scheme with a constant factor of 5, in which every fifth response has led to the introduction of 0.25 mg/0.1 ml liquid solution of cocaine. After successful completion of training Samovodene cocaine rats were given the opportunity to enter a nicotine at a dose of 0.03 mg/kg/introduction by switching the injection of cocaine on the introduction of nicotine. Training Samovodene nicotine continued to achieve stable baseline level of response (deviation less than 20% continuously for 3 days, calculated for each rat). At this point, started testing drugs.

Animals were treated with pioglitazone (0.0 and 30.0 mg/kg), injected OS for 12 hours and 1 hour before the start of the session Samovodene in accordance with counterbalanced order (Latin square plan) for the individual. Recorded the number of presses on the active and inactive levers. Between sessions of the test drugs was left a 3-day interval. During these intervals continued Samovodene nicotine to restore the background level of pressing the lever.

The impact of the introduction of pioglitazone is and Samovodene nicotine was evaluated using a paired t-test. Statistical significance was set a P<0,05.

After a few days of training Wistar rats were purchased pronounced operant response to nicotine. As shown in figa, treatment with 30 mg/kg of pioglitazone significantly reduced Samovodene nicotine [tdf8=-2,70 p<0,05]. Pressing left inactive lever were very rare and were not affected by treatment with pioglitazone (Fig). These results suggest that PPARγ agonists are effective in reducing the intake of nicotine.

EXAMPLE 25

Effect of pioglitazone and individual therapeutic agents in the consumption of nicotine

The ability of PPARγ agonists in combination with other therapeutic means, such as bupropion, nicotine replacement composition, naltrexone, varenicline and antagonists/inverse agonists of the receptor SW, for example, rimonabant, resonant, taranabant and CP-945598, synergistically to reduce the consumption of nicotine determined on rat model of addiction to nicotine.

The experiments are performed using operant paradigms Samovodene as described in example 23 (see also Bruijnzeel and Markou, 2003; Rauhut et al 2003). Briefly, male Wistar rats implanted permanent elasticity catheter in the right jugular vein for intravenous Samovodene nicotine (0.03 mg/introduction). Using operant. cameras Samovodene rats trained to Samovodene nicotine scheme with the post is permanent factor 5 reinforcements (five presses of the lever for receiving infusions of nicotine). Training Samovodene nicotine continue to establish a stable baseline level of response. At this point, start testing drugs.

In accordance with a balanced order (Latin square plan) for individual rats treated with pioglitazone (predicted dose range 5-30,0 mg/kg) or other PPARγ agonists in combination with bupropion, nicotine (surrogate compounds; i.e., nicotine patches), naltrexone, varenicline or rimonabant. To assess the synergies between PPARγ agonists and those of the listed drug test lowest effective dose of each of the compounds together with a PPARγ agonist. The dose range for bupropion is 10-100 mg, enter OS; dose range for naltrexone 0.25-2.5 mg/kg, administered at/br; dose range for varenicline is 0.25-2.5 mg/kg, administered at/br, and the range of doses of rimonabant (0.1 to 3.0 mg/kg, administered at/br) (Bruijnzeel and Markou, 2003; Rauhut et al. 2003; Steensland P, et al. 2007; Cohen et al. 2005). Count the number of presses on the active and inactive levers. Between sessions, drug testing is leave a 3-day interval. During these intervals continue Samovodene nicotine to restore the background level of pressing the lever.

Data analyzed by ANOVA with subsequent appropriate secondary tests (Nyoman-Keuls or is UNDESA). Statistical significance was set at the level of P<0,05. It is expected that these experiments must demonstrate that the combination of a PPARγ agonist and any of the following medicines should act synergistically in reducing Samovodene nicotine, thereby demonstrating the effectiveness of the use of PPARγ and any of these medications to treat addiction.

EXAMPLE 26

Effect of pioglitazone and antidepressants or partial agonists/antagonists of opioids to cocaine use

The ability of PPARγ agonists in combination with antidepressants, bupropion, fluoxetine, or partial agonist/antagonist opioid receptors, buprenorphine, synergistically to reduce cocaine use is determined on a rat model of dependence on cocaine.

The experiments are performed using operant paradigms Samovodene as described in example 23 (see also Glatz et al, 2002; Peltier et al. 1993). Briefly, male Wistar rats implanted permanent elasticity catheter in the right jugular vein for intravenous Samovodene of cocaine (0.25 mg/introduction). Using operant chambers Samovodene rats trained to Samovodene cocaine scheme with constant coefficient 5 reinforcements (five presses of the lever to receive a single infusion of cocaine). Training Samovodene nicotine continue to establish stable phonolog the level of response. At this point, start testing drugs.

In accordance with a balanced order (Latin square plan) for individual rats treated with pioglitazone (predicted dose range 5-30,0 mg/kg) or other PPARγ agonist in combination with bupropion, fluoxetine, or buprenorphine. To assess the synergies between PPARγ agonists and those of the listed drug test lowest effective dose of each of the compounds together with a PPARγ agonist. The dose range for bupropion is 10.0-100.0 mg/kg, administered OS; dose range for fluoxetine is 3.0 to 15.0 mg/kg, administered OS; and a range of doses of buprenorphine is 0.1-5.0 mg/kg, administered at/br (Glatz et al. 2002; Peltier et al. 1993; Sorge et al. 2005). Count the number of presses on the active and inactive levers. Between sessions, drug testing is leave a 3-day interval. During these intervals continue Samovodene nicotine to restore the background level of pressing the lever.

Data analyzed by ANOVA with subsequent appropriate secondary tests (Nyoman-Keuls or Dunnets). Statistical significance was set at the level of P<0,05. It is expected that these experiments must demonstrate that the combination of a PPARγ agonist and any of the following medicines should act synergistically in reducing Samovodene cocaine is, thereby demonstrating the effectiveness of the use of PPARγ and any of these drugs for the treatment of dependencies.

EXAMPLE 27

Effect of pioglitazone on the development of opiate addiction

The ability of PPARγ agonists to reduce the consumption of opiate and prevent opiate dependence is determined on rat model of opiate dependence.

Experiments carried out using the apparatus of preferences conditional places, and also adopted procedures for studying induced by morphine preferences conditional places (Ciccocioppo et al. 2000). In short, by using two conventional apparatus designated male Wistar rats trained to associate the action of morphine on one side of the house, and saline on the other side. Use many groups of rats, and the experiment is carried out in terms of a comparison between individuals. Animals pre-injected carrier pioglitazone before the injection of the carrier morphine. The control group receives the media morphine and pioglitazone in both compartments.

In rats produce a conditioned reflex during the phase of a conditioned reflex in six days. After a day or three times the rats receiving subcutaneous injections of 3 mg/kg morphine or its carrier. Pioglitazone (5,0-30,0 mg/kg) was injected one hour prior to morphine. During the production of the conditioned reflex lift door remains closed, and the rats kept EOI is in Perth for 1 hour in one compartment of the house. The day after the last session of a conditioned reflex in rats allowed to explore the entire house for 15 min, and measure the time spent in each compartment.

The measure of preference space (denoted as Δ time) for each rat is obtained by subtracting the time spent in the compartment associated with the media morphine, from time spent in the compartment associated with the injection of morphine. The value of Δ time subjected to statistical analysis. Data analyzed by. analysis of variance with subsequent appropriate secondary tests (Newman-Keuls or Dunnets). Statistical tracemastervue at the level of P<0,05.

Predicted that morphine should call expressed conditioned reflex preference and pioglitazone should reduce production induced by morphine conditioned reflex places (see as an overview Sanchis-Segura and Spanagel 2006). These results should demonstrate the ability of PPARγ agonists to prevent the development of opioid dependence and, more specifically, from morphine.

Different ways of implementation described above, can be combined with additional embodiments. All U.S. patents, published patent applications U.S. patent application U.S., foreign patents, foreign patent applications and non-patent is ublications, related to this description and/or listed in the bid data sheet, included in the present description by reference in their entirety. Aspects of the embodiments can be modified, if it is necessary to use concepts from different patients, applications and publications to obtain additional embodiments.

These and other changes can be made in the variants of implementation in the light of the above detailed description. In General, the following claims the terms used should not be construed as limiting the invention to specific variants of the implementation disclosed in the description and the claims, but should be interpreted as including all possible variants of implementation, together with the full scope of equivalents of the claims that are devoted to them. Accordingly, the claims are not limited by the disclosure.

1. Method for the treatment or prevention of addiction, including: determining whether a dependency or a risk of drug dependence environments is TBA at the individual, selected from the group consisting of: alcohol, nicotine, marijuana, a derivative of marijuana, opioid agonist, a benzodiazepine, barbiturate, and stimulant; and the introduction of individual agonist receptor gamma peroxisome proliferator-activated (PPARγ agonist) in an amount effective for treatment or prevention of dependency, where the PPARγ agonist is thiazolidinedione (TZD).

2. The method according to claim 1, where the individual must narcotic therapeutic agent selected from the group consisting of: alcohol, nicotine, marijuana, a derivative of marijuana, opioid agonist, a benzodiazepine, barbiturate, and stimulant, optionally including the introduction of individual drug therapeutic agent, where the effective amount of the PPARγ agonist is an amount effective to prevent the onset of dependence to the individual or to reduce the likelihood of dependence of the individual from the drug therapeutic agent.

3. Method for the treatment or prevention of relapse of consumption of narcotic drugs selected from the group consisting of: alcohol, nicotine, marijuana, a derivative of marijuana, opioid agonist, a benzodiazepine, barbiturate, and stimulant, including the introduction of an effective amount of the agonist is of receptor gamma peroxisome proliferator-activated (PPARγ agonist), represented by thiazolidinediones (TZD), the individual that is in phase abstinence or limited or reduced by taking drugs.

4. The method according to claim 3, where the individual previously reduced or stopped taking drugs as a result of treatment an effective amount of the drug against addiction and where the individual is no longer receiving treatment an effective amount of the drug against dependency.

5. A method of reducing one or more symptoms associated with physiological withdrawal syndrome taking drugs selected from the group consisting of: alcohol, nicotine, marijuana, a derivative of marijuana, opioid agonist, a benzodiazepine, barbiturate, and stimulant; including the introduction of an effective amount of an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ), which is thiazolidinedione (TZD), the individual physiological withdrawal syndrome taking drugs.

6. The method according to claim 1, further comprising an introduction to the individual an additional therapeutic agent selected from the group consisting of: opioid agonist, mixed partial agonist/antagonist opioid receptors, antidepressant, antiepileptic drugs, anti-emetics, the antagonist of the receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), an antagonist of 5-HT2A/2Cand antagonist receptor 1 cannabinoids (SV), where the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment or prevention of addiction or relapse consumption or reducing one or more symptoms associated with physiological withdrawal syndrome taking drugs.

7. The method according to claim 1, where the individual has a dependency or risk of addiction from drugs.

8. The method according to claim 1, where the drug is an alcohol.

9. The method according to claim 1, where the drug is a nicotine.

10. The method according to claim 1, where a drug is: opioid agonist selected from the group consisting of: morphine, methadone, fentanyl, Sufentanil and heroin; or psychostimulant selected from the group consisting of cocaine, amphetamine and a derivative of amphetamine.

11. The method according to any one of claims 1 to 10, where TZD selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglitazone.

12. The method according to claim 11, where TZD represents pioglitazone.

13. The method according to claim 2, where drug therapeutic agent is an opioid agonist.

14. With the persons indicated in paragraph 13 where the PPARγ agonist is a pioglitazone and opioid agonist selected from the group consisting of: morphine, methadone, fentanyl, Sufentanil, diacetylmorphine (heroin), Alfentanil, allylprodine, Alphaprodine, Anileridine, apomorphine, benzylmorphine, beta-hydroxy-3-methylfentanyl, Bezitramide, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, diampromide, Dihydrocodeine, dihydromorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioksifenilalanina, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, Etorphine, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, LMM, Levorphanol, levophenacylmorphan, lofentanil, meperidine, metopon, metazocine, methdilazine, metaphone, myrophine, narceine, Nicomorphine, norlevorphanol, Normethadone, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaverine, phenadoxone, phenomorphan, Phenoperidine, piminodine, Piritramide, proheptazine, promedol, properidine, propoxyphene, Remifentanil, Sufentanil, thebaine, Tilden, tramadol, noscapine, nalorfina, naloxone, naltrexone, phenazocine and propoxyphene.

15. A pharmaceutical composition comprising the agonist receptor gamma peroxisome proliferator-activated (PPARγ), which is a t solidilin (TZD), and an additional therapeutic agent selected from the group consisting of: opioid agonist, mixed partial agonist/antagonist opioid receptors, antidepressant, antiepileptic drugs, anti-emetics, antagonist receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), an antagonist of 5-HT2A/2Cand antagonist receptor 1 cannabinoids (SV), where each of the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment and prevention of addiction.

16. Pharmaceutical composition comprising the agonist receptor gamma peroxisome proliferator-activated (PPARγ), which is thiazolidinedione (TZD), and drug therapeutic agent selected from the group consisting of: alcohol, nicotine, marijuana, a derivative of marijuana, opioid agonist, a benzodiazepine, barbiturate, and stimulant, to prevent the onset of dependence of the individual or decrease the probability of an individual based on drug therapeutic agent, where the individual is administered this drug therapeutic agent.

17. The composition according to item 16, where TZD selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglita is on, englitazone, rivoglitazone and darglitazone.

18. The composition according to 17, where TZD represents pioglitazone.

19. The composition according to item 16, where drug therapeutic agent is an opioid agonist.

20. The composition according to claim 19, where the PPARγ agonist is a pioglitazone and opioid agonist selected from the group consisting of morphine, methadone, fentanyl, Sufentanil, diacetylmorphine (heroin), Alfentanil, allylprodine, Alphaprodine, Anileridine, apomorphine, benzylmorphine, beta-hydroxy-3-methylfentanyl, Bezitramide, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, diampromide, Dihydrocodeine, dihydromorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioksifenilalanina, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, Etorphine, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, LMM, Levorphanol, levophenacylmorphan, lofentanil, meperidine, metopon, metazocine, methdilazine, metaphone, myrophine, narceine, Nicomorphine, norlevorphanol, Normethadone, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaverine, phenadoxone, phenomorphan, Phenoperidine, piminodine, Piritramide, proheptazine, promedol, properidine, propoxyphene, Remifentanil, sufenta the sludge, thebaine, Tilden, tramadol, noscapine, nalorfina, naloxone, naltrexone, phenazocine and propoxyphene.

21. Standard dosage form pharmaceutical composition adapted for the treatment of addiction, where the specified standard dosage form contains agonist receptor gamma peroxisome proliferator-activated (PPARγ), which is thiazolidinedione (TZD), and an additional therapeutic agent selected from the group consisting of: opioid agonist, mixed partial agonist/antagonist opioid receptors, antidepressant, antiepileptic drugs, anti-emetics, receptor antagonist 1 corticotropinreleasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), an antagonist of 5-HT2A/2Cand antagonist receptor 1 cannabinoids (SW)where the specified standard dosage form includes the PPARγ agonist and the additional therapeutic agent in a combined amount effective for the treatment of addiction, and the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment or prevention of dependency.

22. Standard dosage form of a pharmaceutical composition where the specified standard dosage form contains agonist receptor gamma activator by proliferationresistant (PPARγ), which is thiazolidinedione (TZD), and drug therapeutic agent selected from the group consisting of: alcohol, nicotine, marijuana, a derivative of marijuana, opioid agonist, a benzodiazepine, barbiturate, and stimulant where the specified standard dosage form includes a PPARγ agonist in an amount effective to prevent the onset of dependence of the individual or decrease the probability of an individual based on drug therapeutic agent, where the individual is administered this drug therapeutic agent.

23. Standard dosage form according to item 22, where TZD selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglitazone.

24. Standard dosage form according to item 23, where TZD represents pioglitazone.

25. Standard dosage form according to item 22, where drug therapeutic agent is an opioid agonist.

26. Standard dosage form according A.25, where the PPARγ agonist is a pioglitazone and opioid agonist selected from the groups consisting of morphine, methadone, fentanyl, Sufentanil, diacetylmorphine (heroin), Alfentanil, allylprodine, Alphaprodine, Anileridine, apomorphine, benzylmorphine is a, beta-hydroxy-3-methylfentanyl, Bezitramide, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, diampromide, Dihydrocodeine, dihydromorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioksifenilalanina, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, Etorphine, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, LMM, Levorphanol, levophenacylmorphan, lofentanil, meperidine, metopon, metazocine, methdilazine, metaphone, myrophine, narceine, Nicomorphine, norlevorphanol, Normethadone, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaverine, phenadoxone, phenomorphan, Phenoperidine, piminodine, Piritramide, proheptazine, promedol, properidine, propoxyphene, Remifentanil, Sufentanil, thebaine, Tilden, tramadol, noscapine, nalorfina, naloxone, naltrexone, phenazocine and propoxyphene.

27. The set, designed for the treatment or prevention of dependency, comprising: a first container containing an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ), which is thiazolidinedione (TZD); and a second container comprising an additional therapeutic agent selected from the group consisting of: opioid agonist, mixed partial agonist/antagonist is East of opioid receptors antidepressant, antiepileptic drugs, anti-emetics, antagonist receptor 1 corticotropin-releasing factor (CRF-1), selective receptor antagonist 3 serotonin (5-NT3), an antagonist of 5-HT2A/2Cand antagonist receptor 1 cannabinoids (SV), where the PPARγ agonist and the additional therapeutic agent contribute to the effective treatment or prevention of dependency.

28. The set, designed for the prevention of drug dependence therapeutic agent, comprising: a first container comprising an agonist of the receptor gamma peroxisome proliferator-activated (PPARγ), which is thiazolidinedione (TZD); and a second container containing a drug, a therapeutic agent selected from the group consisting of: alcohol, nicotine, marijuana, a derivative of marijuana, opioid agonist, a benzodiazepine, barbiturate, and stimulant.

29. Set containing one or more standard dosage forms agonist receptor gamma peroxisome proliferator-activated (PPARγ), which is thiazolidinedione (TZD), and one or more standard dosage forms of nicotine, to prevent the occurrence of addiction in the individual or to reduce the probability of occurrence according to the individual from nicotine, where the individual is administered nicotine.

30. The set is on clause 29, where TZD selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglitazone.

31. Set in item 30, where TZD represents pioglitazone.

32. Set p, where drug therapeutic agent is an opioid agonist.

33. Set p, where the PPARγ agonist is a pioglitazone and opioid agonist selected from the group consisting of morphine, methadone, fentanyl, Sufentanil, diacetylmorphine (heroin), Alfentanil, allylprodine, Alphaprodine, Anileridine, apomorphine, benzylmorphine, beta-hydroxy-3-methylfentanyl, Bezitramide, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, diampromide, Dihydrocodeine, dihydromorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioksifenilalanina, Dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, Ethylmorphine, etonitazene, Etorphine, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, Ketobemidone, LMM, Levorphanol, levophenacylmorphan, lofentanil, meperidine, metopon, metazocine, methdilazine, metaphone, myrophine, narceine, Nicomorphine, norlevorphanol, Normethadone, normorphine, norpipanone, opium, oxycodone, Oxymorphone, papaverine, phenadoxone, phenomorphan, Phenoperidine, piminodine, Piritramide is, proheptazine, promedol, properidine, propoxyphene, Remifentanil, Sufentanil, thebaine, Tilden, tramadol, noscapine, nalorfina, naloxone, naltrexone, phenazocine and propoxyphene.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology, and concerns the new application of 5-ethoxy-2-[2-(morpholino)ethylthio]-benzimidazole dihydrochloride (the anxiolytic Afobazole) as a medication for withdrawal syndrome management in opiate dependence. It is shown that Afobazole administered in a single or sub-chronic dose decreases the manifestations of 'spontaneous' or naloxone-caused morphine withdrawal syndrome, i.e. decreases physical morphine dependence.

EFFECT: anxiolytic Afobazole represents an effective medication for correcting the clinical manifestations of opiate withdrawal syndrome.

3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine, namely to pharmaceutical industry and deals with disulfiram-based medication, which additionally contains corticosteroid. Medicine contains 59.5-97.0 wt % of disulfiram base, 0.5-3.0 wt % of corticosteroid, 2.0-37.0 wt % of nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. Composition of nitrogen-containing polymers includes copolymer of N-vinylpyrrolidone and 2-methyl-5-vinylpyridine or salts of dissolved oligomers of hexamethylenediamine and guanidine and polyvinylpyrrolidone.

EFFECT: medication can be applied in addictology for treatment of alcohol or opiate-dependent patient.

2 cl, 4 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine and represents a method for detoxification infusion therapy of drug-impaired patients involving the introduction of an infusion preparation and preparations enhancing the somatic state, differing by the fact that the therapy is prescribed once admitted to hospital and starts with measuring the extent of the infusion therapy by determining a degree of narcotisation manifestation, namely the presence of changed response syndrome, psychological dependence syndrome (obsession), physical dependence syndrome (compulsion) and withdrawal syndrome, body weight and daily physiological requirements that is followed by calculating the extent of the infusion therapy by formula: U=Kn×(Ks×MT)+PR; the infusion preparations are presented by electrolyte/glucose/colloid solutions in the ratio 3:3:1; it is added with psychopharmacotherapy; the therapeutic course makes 5-7 days in case of observing changed response, 10-14 days in case of psychological dependence, 15-21 days in case of physical dependence, 22-30 days in withdrawal syndrome with the extent of the infusion therapy calculated by formula is divided on 3 portions and administered in the patient at regular intervals within one day; if the patient is unassisted to compensate physiological requirements, the amount of parenteral solutions is reduced respectively.

EFFECT: invention provides adequate detoxification infusion therapy of patients in desomorphine consumption, higher effectiveness and reduced length of the therapy.

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for pain management, as well as to application of said composition for making a drug for pain management. The declared composition contains a number of multilayer pills containing a water-soluble core, an antagonist layer containing HCI naltrexone and coating the core, an isolating polymer layer coating the antagonist layer, an agonist layer coating the isolating polymer layer, a delayed-release shell coating the agonist layer, an agent layer regulating osmotic pressure and containing sodium chloride immediately under the agonist layer. The isolating polymer layer contains acrylic-methacrylic ester polymers with quaternary ammonium groups, sodium lauryl sulphate in the amount of 1.6 wt % to 6.3 wt % and talc in the amount of 75 wt % to 125 wt % in relation to acrylic-methacrylic ester polymers with quaternary ammonium groups. The agonist layer contains morphine sulphate and hydroxypropyl cellulose, while sodium lauryl sulphate is found in the multilayer pills only in the isolating polymer layer.

EFFECT: invention provides preparing the pharmaceutical composition wherein the antagonist and agonist are isolated from each other, and the antagonist does not release from the composition due to osmotic pressure.

9 cl, 1 tbl, 23 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula in which R1 represents C1-C10-alkyl with a straight or branched chain, optionally substituted by an aromatic ring, or -(CH2)nX(CH2)n- in which each n is equal to an integer from 0 to 2, X represents O, S, NH and where R2 represents H or C1-C6-alkyl with the straight or branched chain. Also, the invention refers to application of buprenophine derivative esters on a hydroxyl group of phenol for treating opiate dependences and/or moderate to strong pain, and to application as an agent releasing a therapeutic amount of buprenophine into a human body.

EFFECT: preparation of new buprenophine derivatives a hydroxyl group of phenol for treating opiate dependences and/or moderate to strong pain.

20 cl, 7 dwg, 1 tbl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are dosed forms of guanfacine for per oral application, suitable for single intake per day, which has acceptable general size of pills.

EFFECT: dosed form by invention ensures satisfactory pharmacological profile for prolonged delivery of guanfacine during period of time up to 24 hours with regulated total weight of dosed form.

79 cl, 1 dwg, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and its application for prevention and treatment of abuse with psychoactive substances and dependence on psychoactive substances, which contains compound of formula (R)-2-{3-[1-(acenaphthene-1-yl)pyperidin-4-yl]-2,3-dihydro-2-oxo-benzimidazol-1-yl} -N-methyl acetamide or its pharmaceutically acceptable salt as active ingredient.

EFFECT: compound, which is agonist and has highly selective affinity to ORL-1 receptors, possesses effects of reduction of intensity of alcohol abstinence symptoms and suppression of surplus intake of alcohol and other psychoactive substances.

18 cl, 1 tbl, 8 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: compounds are suitable for use as kinase 1β-adrenergic receptor (βARK-1) inhibitors. The invention also relates to compositions containing such compounds and to use of compounds of formula to treat and prevent chronic heart failure, hypertension myocardial ischemia and hepatitis C viral infections (HCV) and for preventing opiate addiction. The invention also pertains to methods of producing formula (I) compounds.

EFFECT: more effective use of the compounds.

11 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, namely consisting of many portions of an oral dosage form containing at least two portions; each of the above two portions comprises at least one pharmaceutically active agent or an agent specified from a teeth whitening agent, an oral health agent, an oral anti-caries agent, a saliva-enhancing agent and/or herbal extracts wherein at least one of the above two portions comprises a pharmaceutically active agent selected from a group consisting of nicotine compounds, wherein the above at least two portions comprise a different flavour to notice the user that the above on the pharmaceutically active agent or the agents selected from the teeth whitening agent, the breath agent, the oral health agent, the anti-caries agent, the saliva-enhancing agent, and herbal extract, got to release from the above portion; and the above dosage form is other than a chewing gum.

EFFECT: invention provides creating the organoleptic feeling when digesting nicotine.

14 cl, 19 ex, 31 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a composition for nicotinic immunonanotherapy containing synthetic nanocarriers having a polymeric surface conjugated with a variety of nicotine residues with the variety of the nicotinic residues on the nanocarrier form an immunogenic surface providing a low affinity, a high-avidity binding of the nicotinic residues to the surfaces of an antigen presenting cell (APC) compared with an antibody binding, and a pharmaceutically acceptable excipient. The invention provides the nanocarriers capable to stimulate an immune response in T-cells and/or B cells and to produce the antinicotin antibodies with the humoral and cellular response to be achieved in the absence of an exogenous adjuvant.

EFFECT: invention provides the absence of the non-specific response on an inflammation caused by an adjuvant.

17 cl, 37 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to bupropion hydrobromide and formulations thereof, and applications thereof. The pharmaceutical composition contains an effective amount of bupropion hydrobromide, and at least one pharmaceutically acceptable adjuvant. The composition is applicable as a drug for preventing and/or decreasing a rate of convulsions and/or attacks associated with the administration of bupropion, in treating major depressive disorder, bipolar affective disorder, other affective disorders, anxiety disorder, general neurotic syndrome, panic disorder, posttraumatic stress disorder, nicotine addiction, obesity, attention deficit/hyperactivity disorder, restless legs syndrome (Ekbom syndrome), sexual dysfunctions and seasonal mood disorders.

EFFECT: invention provides reducing serious side-effects associated with the administration of bupropion.

9 cl, 54 dwg, 42 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: modified release pharmaceutical composition of bupropion hydrobromide contains a core with a therapeutically effective amount of bupropion hydrobromide and a controlled release polymeric coating. The coating contains a water-insoluble polymer in an amount of 1 wt % to 12 wt % of tablet weight and a water-soluble polymer in an amount of 1.5 wt % to 10 wt % of weight tablet. The above coating surrounds the core at least partially. The composition releases bupropion hydrobromide in a dissolution medium containing 0.1N HCl and 5%-40 vol % of ethanol at a rate of approximately 1.1 or less than a release rate of bupropion hydrobromide from a modified-release similar pharmaceutical composition in a dissolution medium containing 0,1N HCl, measured over the range of time at least from 0 to 2 hours by means of type I USP apparatus at 75 rpm and at 37 ±5°C.

EFFECT: invention provides a reduction in the alcohol-caused dose fall (drop) of bupropion hydrobromide.

9 cl, 55 dwg, 46 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a controlled release drug exceeding an active ingredient in stability. The drug may show pharmacological effects stably and immediately after the introduction, and provides a prolonged pharmacological effect for a long period of time.

EFFECT: controlled release solid drug contains a combination of (1) antacid, (2) an immediate release portion containing an acid and base unstable compound, and (3) a prolonged release portion containing an acid and base unstable compound, and having a film which is dissolved at pH 6,5 and higher.

14 cl, 12 ex, 8 tbl

FIELD: chemistry.

SUBSTANCE: compound, selected from compound given in Table 1 or in Table A correspond to general formulae: or . In Table 1 compounds are selected from compounds, where Y corresponds to NH or O; R2 is selected from H, 2-fluorophenyl, furan-2-yl; group R4-R3- is selected from group =-CH2-, tetrahydrofuran-3-yl, cyclopentyl, group -(CH2)qZ is selected from phenyl, substituted with CH3, CF3, Cl. In compounds, selected from Table A, R is selected from probably substituted phenyl, CH2CH2OBn, where Bn stands for benzyl; X represents O; R9 is selected from propargyl and cyclopentyl.

EFFECT: compounds are selective antagonists of adenosine A2a receptors and are suitable for manufacturing medication, useful in treatment of diseases, which require antagonistic action with respect to activity of said receptors.

6 cl, 2 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry and represents liquid composition for treatment of tobacco or nicotine addiction or for weight control after giving up smoking, characterised by the fact that it represents medicinal body lotion, which contains nicotine in any form in amount 0.5-15 mg, calculated relative to form of free base of nicotine per strandardised dose, and solvent, where composition is intended for transdermal delivery of nicotine to patient and does not contain tobacco, composition does not contain any uncrosslinked water-insoluble vinylpyrrolidone copolymer, copolymerised with hydrophobic comonomer.

EFFECT: invention ensures regulation of rate of nicotine absorption, and eliminated negative impact of vinylpyrrolidone copolymers on skin.

26 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaadamantane derivatives of formula (I), to their pharmaceutically acceptable salts possessing the properties of nAChR ligands, their application, a method of treating and based pharmaceutical compositions, and also to intermediate compounds of formula (VI) and (VII) and to application of the compound of formula (V) for preparing the compound (I). In general formulas

L1 represents -O- or -NRa-; A represents -Ar1 or -Ar2-L2- Ar3; Ar1 represents 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxyalkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2, (NH2)carbonyl and oxido; Ar2 represents 5-6-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxy alkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2 and (NH2) carbonyl; Ar3 represents aryl, optionally substituted alkoxy, alkoxyhalogenalkyl, alkyl, aryl, halogenalkoxy, halogen, hydroxy and -NH2; or Ar3 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, carboxy, carboxyalkyl, halogenalkyl, heterocyclyl and tritylaryl; L2 represents a bond, -O- or -C(O)NRa-; and Ra represents hydrogen.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of nAChR ligands.

41 cl, 11 dwg, 162 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a film containing as a film-forming agent an alginic acid salt with monovalent cation or mixed alginic acid salts containing at least one alginic acid salt with monovalent cation with 10% aqueous solution of the film-forming agent at temperature 20°C characterised by the viscosity of 100-1000 mPa-sec in accordance with the values measured at shear velocity 20 rpm with using a Brookfield viscometre equipped with a spindle No.2, as well as a method for making such film.

EFFECT: film is applicable for active ingredient delivery in a mammal's body and fast soluble while contacting with a wet surface.

18 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly using an aqueous extract of tobacco leaves for preparing an agent for treating tobacco dependence. Using an aqueous solution of the aqueous extract of tobacco leaves or a lyophilizate of the aqueous extract of tobacco leaves in sterile water for preparing the agent in the form of injections for treating tobacco dependence wherein said solution have the certain content of a dry substance. A kit for treating tobacco dependence comprising a syringe, a sterile water bottle and the lyophilizate of the aqueous extract of tobacco leaves.

EFFECT: aqueous extract of tobacco leaves and kit are effective for treating tobacco dependence.

8 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a drug preparation containing 97.0-59.5 wt % of naltrexone base, 0.5-3.0 wt % of corticosteroid specified in triamcinolone, betamethasone or dexamethasone, 2.0-37.0 wt % of a nitrogen-containing polymer composition and 0.2-0.5 wt % of stearic acid or magnesium stearate. The nitrogen-containing polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or a salt of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone. The drug preparation may be used in addictology for treating the alcohol- or opioid-dependent patients.

EFFECT: invention provides prolonged and uniform naltrexone release with a lower probability of the implant rejection caused by an inflammatory response.

2 cl, 3 ex, 2 tbl

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