Patent 6,890,951

The present invention relates to the use of a composition that increases central nervous system GABA levels in a mammal, for the treatment of addiction to drugs of abuse and modification of behavior associated with addiction to drugs of abuse in said mammal.

Description of the Invention

BACKGROUND OF THE INVENTION

This invention relates to the use of an irreversible inhibitor of GABA-transaminase for the treatment of substance addiction and modification of behavior associated with substance addiction. Substance addiction, such as drug abuse, and the resulting addiction-related behaviors are enormous social and economic problems that continue to grow with devastating consequences.

The addictive liability of drugs of abuse, such as for example, cocaine, nicotine, methamphetamine, morphine, heroin, ethanol, phencyclidine, methylenedioxmethamphetamine or other drugs of abuse has been linked to their pharmacological actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-amino butyric acid (GABA).

Virtually all drugs of abuse, including nicotine, have been shown to acutely increase extracellular dopamine concentrations in the nucleus accumbens of mammals. This increase is clearly associated with the addictive liability of these compounds. Based on this unique biochemical fingerprint, drugs that attenuate or abolish this response may be quite effective for the treatment of substance abuse.

Substance addiction can occur by use of legal and illegal substances. Nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine (PCP), methylenedioxymethamphetamine (MDMA), and other addictive substances are readily available and routinely used by large segments of the United States population.

Many drugs of abuse are naturally occurring. For example, cocaine is a naturally occurring nonamphetamine stimulant derived from the leaves of the coca plant, Erythroylon coca. Coca leaves contain only about one-half of one percent pure cocaine alkaloid. When chewed, only relatively modest amounts of cocaine are liberated, and gastrointestinal absorption is slow. Certainly, this explains why the practice of chewing coca leaves has never been a public health problem in Latin America. The situation changes sharply with the abuse of the alkaloid itself.

It has been found that addicting drugs such as nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine and methylenedioxymethamphetamine enhance (in some cases directly, in other cases indirectly or even trans-synaptically) dopamine (DA) within the mesotelencephalic reward/reinforcement circuitry of the forebrain, presumably producing the enhanced brain reward that constitutes the drug user's "high."

Alterations in the function of these DA systems have also been implicated in drug craving and in relapse to the drug-taking habit in recovering addicts. For example, cocaine acts on these DA systems by binding to the dopamine transporter (DAT) and preventing DA reuptake into the presynaptic terminal.

There is considerable evidence that nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine, methylenedioxymethamphetamine and other abused drugs' addictive liability is linked to a re-uptake blockade in the central nervous systems' (CNS') reward/reinforcement pathways. For example, cocaine-induced increases in extracellular DA have been linked to its rewarding and craving effects in rodents.

In humans, the pharmacokinetics binding profile of ¹¹C-cocaine indicates that the uptake of labeled cocaine is directly correlated with the self-reported "high". In addition, human cocaine addicts exposed to cocaine-associated environmental cues experienced increased cocaine craving which is antagonized by the DA receptor antagonist haloperidol. Based upon the presumptive link between cocaine's addictive liability and the DA reward/reinforcement circuitry of the forebrain, many pharmacologic strategies for treating cocaine addiction have been proposed.

In the past, one treatment strategy was to target directly the DAT with a high-affinity cocaine analog, thereby blocking cocaine's binding. Another treatment strategy was to modulate synaptic DA directly by the use of DA agonists or antagonists. Yet another treatment strategy was to modulate synaptic DA, indirectly or trans-synaptically, by specifically targeting a functionally-linked but biochemically different neurotransmitter system.

A number of drugs have been suggested for use in weaning cocaine users from their dependency. Certain therapeutic agents were favored by the "dopamine depletion hypothesis." It is well established that cocaine blocks dopamine reuptake, acutely increasing synaptic dopamine concentrations. However, in the presence of cocaine, synaptic dopamine is metabolized as 3-methoxytyramine and excreted. The synaptic loss of dopamine places demands on the body for increased dopamine synthesis, as evidenced by the increase in tyrosine hydroxylase activity after cocaine administration. When the precursor supplies are exhausted, a dopamine deficiency develops.

The above hypothesis led to the testing of bromocriptine, a dopamine receptor agonist. Another approach was the administration of amantadine, a dopamine releaser. Yet another approach, also based on the dopamine depletion hypothesis, was to provide a precursor for dopamine, such as L-dopa.

Agonists are not preferred therapeutic agents. A given agonist may act on several receptors, or similar receptors on different cells, not just on the particular receptor or cell one desires to stimulate. As tolerance to a drug develops (through changes in the number of receptors and their affinity for the drug), tolerance to the agonist may likewise develop. A particular problem with the agonist bromocriptine, for example, is that it may itself create a drug dependency. Thus, treatment strategies used in the past did not relieve the patient's craving for cocaine. Moreover, by using certain agonists such as bromocriptine, a patient was likely to replace one craving for another.

Another drug that is frequently abused is nicotine. The alkaloid (-)-nicotine is present in cigarettes and other tobacco products that are smoked or chewed. It has been found that nicotine contributes to various diseases, including cancer, heart disease, respiratory disease and other conditions, for which tobacco use is a risk factor, particularly heart disease.

Vigorous campaigns against the use of tobacco or nicotine have taken place, and it is now common knowledge that the cessation of tobacco use brings with it numerous unpleasant withdrawal symptoms, which include irritability, anxiety, restlessness, lack of concentration, lightheadedness, insomnia, tremor, increased hunger and weight gain, and, of course, an intense craving for tobacco.

The addictive liability of nicotine has been linked to the rewarding/reinforcing actions and its effects on DA neurons in the reward pathways of the brain (Nisell et al., 1995; Pontieri, et al., 1996). For example, the acute systemic administration of nicotine, as well as numerous other drugs of abuse, produces an increase in extracellular DA levels in the nucleus accumbens (NACC), an important component of the reward system (Damsma et al., 1989; Di Chiara and Imperato, 1988; Imperato et al., 1986; Nisell et al., 1994a, 1995; Pontieri et al., 1996). Similarly, the infusion of nicotine into the ventral segmental area (VTA) of the rodent produces a significant increase in DA levels in the NACC (Nisell et al., 1994b).

A few pharmaceutical agents have been reported as useful to treat nicotine dependence, including nicotine substitution therapy such as nicotine gum, transdermal nicotine patches, nasal sprays, nicotine inhalers and bupropion, the first nonnicotinic treatment for smoking cessation (Henningfield, 1995; Hurt, et al., 1997).

Unfortunately, nicotine substitution therapy involves the administration of the nicotine which frequently leads to nicotine withdrawal and subsequent relapse to use of tobacco products. Thus, there is a need for a therapy having a desirable side effect profile, to relieve nicotine withdrawal symptoms, including the long term cravings for nicotine.

Other known addictive substances are narcotic analgesics such as morphine, heroin and other opioids both natural and semisynthetic. Abuse of opioids induce tolerance and dependence. Withdrawal symptoms from the cessation of opioids use vary greatly in intensity depending on numerous factors including the dose of the opioid used, the degree to which the opioid effects on the CNS are continuously exerted, the duration of chronic use, and the rate at which the opioid is removed from the receptors.

These withdrawal symptoms include craving, anxiety, dysphoria, yawning, perspiration, lacrimation, rhinorrhoea, restless and broken sleep, irritability, dilated pupils, aching of bones, back and muscles, piloerection, hot and cold flashes, nausea, vomiting, diarrhea, weight loss, fever, increased blood pressure, pulse and respiratory rate, twitching of muscles and kicking movements of the lower extremities.

Medical complications associated with injection of opioids include a variety of pathological changes in the CNS including degenerative changes in globus pallidus, necrosis of spinal gray matter, transverse myelitis, amblyopia, plexitis, peripheral neuropathy, Parkinsonian syndromes, intellectual impairment, personality changes, and pathological changes in muscles and peripheral nerves. Infections of skin and systemic organs are also quite common including staphylococcal pneumonitis, tuberculosis, endocarditis, septicemia, viral hepatitis, human immunodeficiency virus (HIV), malaria, tetanus and osteomyelitis. The life expectancy of opioid addicts is markedly reduced, due to overdose, drug-related infections, suicide and homicide.

Pharmaceutical agents used in treating opioid dependence include methadone, which is an opioid, and opioid antagonists, primarily naloxone and naltrexone. Clonidine has been shown to suppress some elements of opioid withdrawal but suffers from the side effects of hypotension and sedation, which can be quite extreme. Behavior-modifying psychological treatment and training are frequently adjunctive therapy used in association with pharmaceutical agents. There is a need for a therapy having a more desirable side effect profile, to relieve opioid addiction and withdrawal symptoms.

Ethanol is probably the most frequently used and abused depressant in most cultures and a major cause of morbidity and mortality. Repeated intake of large amounts of ethanol can affect nearly every organ system in the body, particularly the gastrointestinal tract, cardiovascular system, and the central and peripheral nervous systems. Gastrointestinal effects include gastritis, stomach ulcers, duodenal ulcers, liver cirrhosis, and pancreatitis.

Further, there is an increased rate of cancer of the esophagus, stomach and other parts of the gastrointestinal tract with ethanol abuse. Cardiovascular effects include hypertension, cardiomyopathy and other myopathies, significantly elevated levels of triglycerides and low-density lipoprotein cholesterol. These cardiovascular effects contribute to a marked increase risk of heart disease.

Ethanol abuse can manifest in peripheral neuropathy as evidenced by muscular weakness, parathesias, and decreased peripheral sensation. Central nervous system effects include cognitive deficits, severe memory impairment degenerative changes in the cerebellum, and ethanol-induced persisting amnesiac disorder in which the ability to encode new memory is severely impaired. Generally, these effects are related to vitamin deficiencies, particularly the B vitamins.

Individuals with ethanol dependence or addiction exhibit symptoms and physical changes including dyspepsia, nausea, bloating, esophageal varices, hemorrhoids, tremor, unsteady gait, insomnia, erectile dysfunction, decreased testicular size, feminizing effects associated with reduced testosterone levels, spontaneous abortion, and fetal alcohol syndrome. Symptoms associated with ethanol cessation or withdrawal include nausea, vomiting, gastritis, hematemises, dry mouth, puffy blotchy complexion, and peripheral edema.

The generally accepted treatment of ethanol addiction and withdrawal is accomplished by administering a mild tranquilizer such a chlordiazepoxide. Typically, vitamins, particularly the B vitamins, are also administered. Optionally, magnesium sulfate and/or glucose are also administered. Nausea, vomiting and diarrhea are treated symptomatically at the discretion of the attending physician. Disulfiram may also be administered for help in maintaining abstinence. If ethanol is consumed while on disulfiram, acetaldehyde accumulates producing nausea and hypotension. There is a need for a therapy having a more desirable side effect profile, to relieve ethanol addiction and withdrawal symptoms.

Recently, it has been reported that polydrug or combination drug abuse has been increasing at an alarming rate. For example, cocaine and heroin are often abused together in a drug combination known as a "speedballing." Such reported increase is believed to be a result of a synergistic effect that increases the euphoria of the user.

In many instances, drug dealers combine various drugs of abuse to increase the intensity of the "high." This is especially prevalent where the drug user is a regular customer and has built up a tolerance to the drug alone. Most times the drug user is unaware of this dangerous combining.

Phencyclidine, commonly known as PCP, is described as dissociative in action. This means that the mind feels separated from the body. PCP was first used as an anesthetic for surgery in the 1950's. Due to the highly undesirable side effects, such as convulsions and hallucinations, its use was discontinued.

The first reports of the illicit use of PCP originated in late 1960's. However, due to numerous reports of bad experiences, PCP lost popularity. In the 1970's PCP use re-emerged by itself and in combination with other illicit drugs such as marijuana and cocaine. PCP continues to be an abused substance. Many people after using it once, will not choose to use it again. Others use it consistently and regularly. A numbing effect on pain, both emotional and physical is one reason why others say they use PCP.

PCP is a synthetic substance that can be in the form of a pill, powder or liquid suspension. It can be smoked, snorted, orally ingested or intravenously administered. The short-term effects can last for hours or days and include rapid breathing, increased blood pressure and heart rate, increased temperature, profuse sweating, bizarre postures and muscle jerking. Higher doses can cause vomiting, blurred vision, convulsions and coma.

The long-term effects of PCP include flashbacks, speech problems, loss of memory, anxiety, depression and social withdrawal. Frequent users report the need to increase intake to maintain a ‘high’. There is no known accepted treatment for PCP abuse.

Methylenedioxymethamphetamine (MDMA), commonly known as "ecstacy," is a synthetic psychoactive drug possessing stimulant and hallucinogenic properties. MDMA was first synthesized in 1912 as a possible appetite suppressant. Illicit use of MDMA did not become popular until the late 1980's.

MDMA is usually taken orally and its effects can last from four to six hours. Users say that it produces profoundly positive feelings and extreme relaxation. MDMA is also said to suppress the need to eat, drink or sleep. Consequently, MDMA use sometimes results in severe dehydration or exhaustion.

MDMA users may encounter problems similar to those of amphetamine and cocaine users, which includes addiction. In addition, MDMA can cause confusion, depression, sleep problems, anxiety, and paranoia. Physical effects of MDMA use include muscle tension, involuntary teeth clenching, nausea, blurred vision, faintness and chills or sweating.

The effects of long term MDMA use are just beginning to undergo scientific analysis. The National Institute of Mental Health conducted a study of habitual MDMA users in 1998 that revealed damage to the neurons of the brain that transmit serotonin. Serotonin is an important biochemical involved in a variety of critical functions including learning, sleep and integration of emotion. The results of the study indicate that MDMA users are at risk of developing permanent brain damage that may manifest itself in depression, anxiety, memory loss and other neuropsychotic disorders. There is no known and accepted treatment for MDMA abuse.

Accordingly, there is a need in the treatment of addiction to drugs of abuse to provide new methods which can relieve a patient's craving by changing the pharmacological actions of drugs of abuse in the central nervous system. There is also a need to provide new methods to treat combination drug abuse.

SUMMARY OF THE PRESENT INVENTION

The present invention, which addresses the needs of the prior art, provides methods for treating addiction to drugs of abuse. Also provided are methods for diminishing, inhibiting or eliminating addiction-related behavior of a mammal, for example a primate, suffering from addiction to drugs of abuse by administering to the mammal an effective amount of a pharmaceutical composition or medicament that increases central nervous system GABA levels.

The addictive liability of drugs of abuse, such as for example, cocaine, nicotine, methamphetamine, morphine, heroin, ethanol, phencyclidine, methylenedioxmethamphetamine or other drugs of abuse has been linked to their pharmacological actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-amino butyric acid (GABA).

Virtually all drugs of abuse, including nicotine, have been shown to acutely increase extracellular dopamine concentrations in the nucleus accumbens of mammals. This increase is clearly associated with the addictive liability of these compounds. Based on this unique biochemical fingerprint, drugs that attenuate or abolish this response may be quite effective for the treatment of substance abuse.

In a preferred embodiment, the present invention provides a method for diminishing, inhibiting or eliminating addiction-related behavior of a mammal suffering from addiction to drugs of abuse which comprises administering to the mammal an effective amount of topiramate (available as Topomax®) or a pharmaceutically acceptable salt thereof or an enantiomer or racemic mixture thereof, to diminish, inhibit or eliminate said addiction-related behavior.

In another embodiment, the present invention provides a method for diminishing, inhibiting or eliminating the rewarding/incentive effects of drugs of abuse in a mammal suffering from addiction to drugs which comprises administering to the mammal an effective amount of topiramate or a pharmaceutically acceptable salt thereof or enantiomer or racemic mixture thereof, to diminish, inhibit or eliminate said rewarding/incentive effects.

In a preferred embodiment, the present invention provides a method for diminishing, inhibiting or eliminating addiction-related behavior of a mammal suffering from addiction to drugs of abuse which comprises administering to the mammal an effective amount of GVG or a pharmaceutically acceptable salt thereof to diminish, inhibit or eliminate said addiction-related behavior.

In another embodiment, the present invention provides a method for diminishing, inhibiting or eliminating the rewarding/incentive effects of drugs of abuse in a mammal suffering from addiction to drugs which comprises administering to the mammal an effective amount of GVG or a pharmaceutically acceptable salt thereof to diminish, inhibit or eliminate said rewarding/incentive effects.

Drugs of abuse are selected from the group consisting of nicotine, cocaine, amphetamine, methamphetamine, ethanol, heroin, morphine, phencyclidine (PCP), methylenedioxymethamphetamine (MDMA), and other addictive substances.

The amount of GVG varies from about 15 mg/kg to about 2 gm/kg, preferably from about 15 mg/kg to about 600 mg/kg, and most preferably from about 150 mg to about 600 mg/kg .

The preferred amount of Topiramate varies from about 25 mg/kg to about 50 mg/kg.

As a result of the present invention, methods of diminishing, inhibiting or eliminating addiction to drugs of abuse and diminishing, inhibiting or eliminating addiction-related behavior are provided which are based on a pharmaceutical composition or medicament which is not itself addictive, yet is highly effective in diminishing, inhibiting or eliminating addiction and addiction-related behavior of addicted mammals.

The pharmaceutical composition or medicament useful for the methods of the present invention diminishes, inhibits, or eliminates the cravings for drugs of abuse that are experienced by mammal suffering from addiction to drugs of abuse.

Moreover, the methods provided by the present invention diminish, inhibit or eliminate addiction-related behavior associated with drugs of abuse in the absence of an aversive or appetitive response to the composition administered.

In addition, the methods provided by the present invention diminish, inhibit or eliminate addiction-related behavior associated with drugs of abuse in the absence of an alteration in the locomotor function of the mammal.

In yet another embodiment, the present invention includes a method for diminishing, inhibiting or eliminating cravings associated with addiction to drugs of abuse, which comprises administering to a mammal suffering from addiction to drugs of abuse, an amount of GVG or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof, effectively diminishes, inhibits or eliminates said cravings associated with addiction to drugs of abuse.

In yet another embodiment, the present invention includes a method for diminishing, inhibiting or eliminating cravings associated with addiction to drugs of abuse, which comprises administering to a mammal suffering from addiction to drugs of abuse, an amount of Topiramate or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof, effectively diminishes, inhibits or eliminates said cravings associated with addiction to drugs of abuse.

In another exemplary embodiment of the present invention, the method includes diminishing, inhibiting or eliminating addiction-related behavior of a mammal suffering from addiction to drugs of abuse which comprises administering to the mammal an effective amount of a composition or medicament that increases central nervous system GABA levels wherein the effective amount is sufficient to diminish, inhibit or eliminate said addiction-related behavior.

In another exemplary embodiment of the present invention, the method includes diminishing, inhibiting or eliminating cravings associated with use of drugs of abuse in a mammal suffering from addiction to drugs of abuse which comprises administering to the mammal an effective amount of a composition or medicament that increases central nervous system GABA levels wherein the effective amount is sufficient to diminish, inhibit or eliminate said eliminating cravings associated with use of drugs of abuse.

In yet another exemplary embodiment, the present invention provides a method for diminishing, inhibiting or eliminating addiction-related behavior of a mammal suffering from addiction to a combination of abused drugs which comprises administering to the mammal an effective amount of GVG or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof, wherein the effective amount is sufficient to diminish, inhibit or eliminate said addiction-related behavior.

In yet another exemplary embodiment, the present invention provides a method for diminishing, inhibiting or eliminating addiction-related behavior of a mammal suffering from addiction to a combination of abused drugs which comprises administering to the mammal an effective amount of Topiramate or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof, wherein the effective amount is sufficient to diminish, inhibit or eliminate said addiction-related behavior.

In another embodiment, the present invention provides a method for treating a mammal suffering from addiction to abused drugs which comprises administering to the mammal an effective amount of GVG or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

In another embodiment, the present invention provides a method for treating a mammal suffering from addiction to abused drugs which comprises administering to the mammal an effective amount of Topiramate or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

In yet another embodiment, the present invention provides a method for preventing addiction to abused drugs which comprises administering to the mammal an effective amount of GVG or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

In yet another embodiment, the present invention provides a method for preventing addiction to abused drugs which comprises administering to the mammal an effective amount of Topiramate or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

Other improvements which the present invention provides over the prior art will be identified as a result of the following description which sets forth the preferred embodiments of the present invention. The description is not in any way intended to limit the scope of the present invention, but rather only to provide a working example of the present preferred embodiments. The scope of the present invention will be pointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Substance Addiction

The present invention provides a highly efficient method for treating substance addiction and for changing addiction-related behavior of mammals, for example primates, suffering from substance addiction. In the present invention, substance addiction means dependency on drugs of abuse.

Drugs of Abuse

Drugs of abuse, for purposes of this invention, are defined as any substance that is consumed by a mammal and as result of said consumption, said mammal experiences addiction related behavior, cravings for the substance, rewarding/incentive effects, and dependency characteristics, or any combination thereof.

Drugs of abuse include, but are not limited, to psychostimulants, narcotic analgesics, alcohols and addictive alkaloids such as nicotine or combinations thereof.

Some examples of psychostimulants include but are not limited to amphetamine, dextroamphetamine, methamphetamine, phenmetrazine, diethylpropion, methylphenidate, cocaine, phencyclidine, methylenedioxymethamphetamine and pharmaceutically acceptable salts thereof.

Specific examples of narcotic analgesics include alfentanyl, alphaprodine, anileridine, bezitramide, codeine, dihydrocodeine, diphenoxylate, ethylmorphine, fentanyl, heroin, hydrocodone, hydromorphone, isomethadone, levomethorphan, levorphanol, metazocine, methadone, metopon, morphine, opium extracts, opium fluid extracts, powdered opium, granulated opium, raw opium, tincture of opium, oxycodone, oxymorphone, pethidine, phenazocine, piminodine, racemethorphan, racemorphan, thebaine and pharmaceutically acceptable salts thereof.

Drugs of abuse also include CNS depressants such as barbiturates, chlordiazepoxide, and alcohols such as ethanol, methanol and isopropyl alcohol.

Addiction-Related Behavior

As used herein, addiction-related behavior means behavior resulting from compulsive substance use and is characterized by apparent total dependency on the substance. Symptomatic of the behavior is (I) overwhelming involvement with the use of the drug, (ii) the securing of its supply, and (iii) a high probability of relapse after withdrawal.

For example, a cocaine user experiences three stages of effects when using the substance cocaine. The first stage, acute intoxication ("binge"), is euphoric, marked by decreased anxiety, enhanced self-confidence and sexual appetite, and may be marred by sexual indiscretions, irresponsible spending, and accidents attributable to reckless behavior. The second stage, the ("crash"), replaces euphoria by anxiety, fatigue, irritability and depression. Some users have committed suicide during this period. Finally, the third stage, "anhedonia," is a time of limited ability to derive pleasure from normal activities and of craving for the euphoric effects of cocaine which leads to use of this drug. See Gawin and Kleber, Medical Management of Cocaine Withdrawal, 6-8 (APT Foundation).

As related to cocaine users, addiction-related behavior includes behavior associated with all three stages of effects when using the substance cocaine.

Combinations of Drugs of Abuse

The method of the present invention can be used to treat mammals addicted to a combination of drugs of abuse. For example, the mammal may be addicted to ethanol and cocaine, in which case the present invention is particularly suited for diminishing, inhibiting or eliminating the addiction-related behavior of the mammal. This can be accomplished by administering an effective amount of GVG or Topiramate or a combination thereof.

Combinations of drugs of abuse, as defined herein, include any combination of two or more drugs of abuse. Combinations of abused drugs include combinations of psychostimulants, narcotic analgesics, alcohols and addictive alkaloids as discussed above. For example, combinations of abused drugs include cocaine, nicotine, methamphetamine, ethanol, morphine and heroin. A highly abused combination is cocaine and heroin.

There is synergy observed with use of a combination of abused drugs. For example, when heroin, an indirect dopamine releaser and cocaine, a dopamine reuptake inhibitor, are administered to rodents, a synergistic increase is observed in cerebral NAc dopamine levels. Synergy may be shown, for example, by greater increases in cerebral dopamine levels than would be expected with either drug alone. Preferably, synergy is demonstrated by from about 500% to about 1000% increase in cerebral NAc dopamine levels with the combination of cocaine and heroin as compared to administering either drug alone.

Compulsive Drug Use

Compulsive drug use includes three independent components: tolerance, psychological dependence and physical dependence. Tolerance produces a need to increase the dose of the drug after several administrations in order to achieve the same magnitude of effect.

Physical dependence is an adaptive state produced by repeated drug administration and which manifests itself by intense physical disturbance when drug administration is halted.

Psychological dependence is a condition characterized by an intense drive, craving or use for a drug whose effects the user feels are necessary for a sense of well being. See Feldman, R. S. and Quenzer, L. F. "Fundamentals of Neuropsychopharmocology" 418-422 (Sinaur Associates, Inc. 1984) incorporated herein by reference as if set forth in full.

Dependency Characteristics

Based on the foregoing definitions, as used herein "dependency characteristics" include all characteristics associated with compulsive drug use, characteristics that can be affected by biochemical composition of the host, physical and psychological properties of the host.

Rewarding/Incentive Effects

As explained above, the compulsive use of drugs of abuse or to the combination of abused drugs gives rise to a euphoric stage followed by a stage of craving for the euphoric effects of that drug which leads to use of the drug or combinations of drugs.

As used herein the rewarding/incentive effects of drugs of abuse refers to any stimulus (in this case, a drug) that produces anhedonia or increases the probability of a learned response. This is synonymous with reinforcement. With respect to experimental animals, a stimulus is deemed to be rewarding by using paradigms that are believed to measure reward.

Aversive/Appetitive Response in Measuring Reward

Measurement of reward can be accomplished by measuring whether stimuli produce an approach response, also known as an appetitive response or a withdrawal response, as when the animal avoids the stimuli, also known as an aversive response.

Conditioned Place Preference

Conditioned place preference (CPP) is a paradigm that measures approach (appetitive) or withdrawal (aversive) responses. One can infer that rewarding stimuli produce approach behavior. In fact, one definition of reward is any stimulus that elicits approach behavior. Furthermore, the consequences of reward would be to enhance the incentive properties of stimuli associated with the reward.

Reward can also be measured by determining whether the delivery of a reward is contingent upon a particular response, thereby increasing the probability that the response will reappear in a similar situation, i.e. reinforcement paradigm. For example, a rat pressing a bar a certain number of times for an injection of cocaine is an example of reinforcement.

Yet another way to measure reward is by determining if a stimulus (e.g. a drug), through multiple pairings with neutral environmental stimuli, can cause the previously neutral environmental stimuli to elicit behavioral effects initially only associated with the drug—this conditioned reinforcement. CPP is considered to be a form of conditioned reinforcement.

The incentive motivational value of a drug (or other stimuli) can be assessed using conditioned place preference (CPP). With respect to cocaine, nicotine, heroin, morphine, methamphetamine, ethanol or other drugs of abuse or combinations thereof, animals are tested in a drug-free state, to determine whether they prefer an environment in which they previously received the abused drug as compared to an environment in which they previously received saline. In the CPP paradigm, animals are given a drug in one distinct environment and are given the appropriate vehicle in an alternative environment.

The CPP paradigm is widely used to evaluate the incentive motivational effects of drugs in laboratory animals (Van Der Kooy, 1995). Following conditioning or pairing with the drug, if the animal, in a drug-free state, consistently chooses the environment previously associated with the drug of abuse, the inference is drawn that the appetitive value of the drug of abuse was encoded in the brain and is accessible in the drug-free state.

CPP is reflected in an increased duration spent in the presence of the drug-associated stimuli relative to vehicle-injected control animals. It can also be used to assess addiction to a combination of abused drugs.

Alteration of Locomotor Function

Locomotor function in a mammal, as defined herein, means the ability of a mammal to move around in a coordinated or "normal" fashion. An alteration in the locomotor function of a mammal would result in an inability or impairment of the mammal's ability to move around in a coordinated or "normal" fashion.

Craving

It has been postulated that since craving at the human level is often elicited by sensory stimuli previously associated with drug-taking, conditioning paradigms like CPP may be used to model craving in laboratory animals.

As used herein, craving an abused drug or a combination of abused drugs is an intense desire to self-administer the drug(s) previously used by the mammal. The mammal does not need the abused drug to prevent withdrawal symptoms.

The addictive liability of drugs of abuse, such as for example, cocaine, nicotine, methamphetamine, morphine, heroin, ethanol, phencyclidine, methylenedioxmethamphetamine or other drugs of abuse has been linked to their pharmacological actions on mesotelencephalic dopamine (DA) reinforcement/reward pathways in the central nervous system (CNS). Dopaminergic transmission within these pathways is modulated by gamma-amino butyric acid (GABA).

Virtually all drugs of abuse, including nicotine, have been shown to acutely increase extracellular dopamine concentrations in the nucleus accumbens of mammals. This increase is clearly associated with the addictive liability of these compounds. Based on this unique biochemical fingerprint, drugs that attenuate or abolish this response may be quite effective for the treatment of substance abuse.

For example cocaine, nicotine, methamphetamine, morphine, heroin and ethanol inhibit the presynaptic reuptake of monoamines. Dopaminergic neurons of the mesocorticolimbic DA system, whose cell bodies lie within the ventral tegmental area (VTA) and project primarily to the nucleus accumbens (NACC), appear to be involved in cocaine, nicotine, methamphetamine, morphine, heroin or ethanol reinforcement. Electrical stimulation of reward centers within the VTA increases extracellular DA levels in the NACC, while 6-hydroxy dopamine lesions of the NACC abolish cocaine, nicotine, methamphetamine, morphine, heroin or ethanol self-administration. In vivo microdialysis studies confirm cocaine, nicotine, methamphetamine, morphine, heroin and ethanol's ability to increase extracellular DA in the NACC.

γ-Amino butyric acid (GABA)ergic neurons in the NACC and ventral pallidum project onto DA neurons in the VTA. Pharmacologic and electrophysiologic studies indicate these projections are inhibitory. Inhibition of VTA-DA neurons is likely the result of GABA_B receptor stimulation. In addition, microinjection of baclofen into the VTA, acting via these receptor subtypes, can decrease DA concentrations in the NACC. Taken together, it is evident that pharmacologic manipulation of GABA may effect DA levels in the NACC through modulation of VTA-DA neurons.

Gamma Vinyl GABA

Gamma vinyl GABA (GVG) is a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition. It is also known that GVG alters cocaine's biochemical effects by causing a dose-dependent and prolonged elevation of extracellular endogenous brain GABA levels.

GVG is C₆H₁₁NO₂ or 4-amino-5-hexanoic acid available as Vigabatrin® from Hoechst Marion Roussel and can be obtained from Marion Merell Dow of Cincinnati, Ohio. GVG does not bind to any receptor or reuptake complex, but increases endogenous intracellular GABA levels by selectively and irreversibly inhibiting GABA-transaminase (GABA-T), the enzyme that normally catabolizes GABA.

As used herein GVG includes the racemic compound or mixture which contains equal amounts of S(+)-gamma-vinyl GABA, and R(-)-gamma vinyl GABA. This racemic compound of GVG is available as Vigabatrin® from Hoechst Marion Roussel and can be obtained from Marion Merell Dow of Cincinnati, Ohio.

GVG contains asymmetric carbon atoms and thus is capable of existing as enantiomers. The present invention embraces any enantiomeric form of GVG including the racemates or racemic mixture of GVG. In some cases there may be advantages, i.e. greater efficacy, to using a particular enantiomer when compared to the other enantiomer or the racemate or racemic mixture in the methods of the instant invention and such advantages can be readily determined by those skilled in the art.

For example, the enantiomer S(+)-gamma-vinyl GABA is more effective at increasing endogenous intracellular GABA levels than the enantiomer R(-)-gamma-vinyl GABA.

Different enantiomers may be synthesized from chiral starting materials, or the racemates may be resolved by conventional procedures which are well known in the art of chemistry such as chiral chromatography, fractional crystallization of diastereomeric salts, and the like.

Administration of Gamma Vinyl GABA

In living mammals (in vivo), GVG or pharmaceutically acceptable salts thereof, can be administered systemically by the parenteral and enteral routes which also includes controlled release delivery systems. For example, GVG can easily be administered intravenously, or intraperitoneal (i.p.) which is a preferred route of delivery. Intravenous or intraperitoneal administration can be accomplished by mixing GVG in a suitable pharmaceutical carrier (vehicle) or excipient as understood by practitioners in the art.

Oral or enteral use is also contemplated, and formulations such as tablets, capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like can be employed to provide GVG or pharmaceutically acceptable salts thereof

As used herein, pharmaceutically acceptable salts include those salt-forming acids and bases which do not substantially increase the toxicity of the compound. Some examples of suitable salts include salts of mineral acids such as hydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, as well as salts of organic acids such as tartaric, acetic, citric, malic, benzoic, glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g. p-toluenesulfonic acids, and the like.

An effective amount as used herein is that amount effective to achieve the specified result of diminishing, inhibiting or eliminating addiction-related behavior, dependency characteristics, rewarding/incentive effects and cravings associated with drugs of abuse or combinations of drugs of abuse, of a mammal.

An effective amount as used herein is that amount effective to prevent addiction to drugs of abuse. It is an amount that will diminish or relieve one or more symptoms or conditions resulting from cessation or withdrawal of the psychostimulant, narcotic analgesic, alcohol, nicotine or combinations thereof. It should be emphasized, however, that the invention is not limited to any particular dose.

Preferably, GVG is administered in an amount which has little or no adverse effects. For example, the amount administered can be from about 15 mg/kg to about 2 g/kg or from about 15 mg/kg to about 600 mg/kg.

For example, to treat cocaine addiction, GVG is administered in an amount of from about 15 mg/kg to about 2 g/kg, preferably from about 100 mg/kg to about 200 mg/kg or from about 15 mg/kg to about 600 mg/kg and most preferably from about 150 mg/kg to about 300 mg/kg or from about 75 mg/kg to about 150 mg/kg.

To treat nicotine addiction, for example, GVG is administered in an amount of from about 15 mg/kg to about 2 g/kg or from about 15 mg/kg to about 600 mg/kg, preferably from about 100 mg/kg to about 300 mg/kg or from about 150 mg/kg to about 300 mg/kg and most preferably from about 18 mg/kg to about 20 mg/kg or from about 75 mg/kg to about 150 mg/kg.

To treat methamphetamine addiction, for example, GVG is administered in an amount of from about 15 mg/kg to about 2 g/kg, preferably from about 100 mg/kg to about 300 mg/kg or from about 15 mg/kg to about 600 mg/kg and most preferably from about 150 mg/kg to about 300 mg/kg or from about 75 mg/kg to about 150 mg/kg to a mammal.

When the mammal is addicted to a combination of abused drugs, such as for example, cocaine and heroin, GVG is administered in an amount of from about 15 mg/kg to about 2 g/kg, preferably from about 100 mg/kg to about 300 mg/kg or from about 15 mg/kg to about 600 mg/kg and most preferably from about 150 mg/kg to about 300 mg/kg or from about 75 mg/kg to about 150 mg/kg to a mammal.

Mammals include, for example, humans, baboons and other primates, as well as pet animals such as dogs and cats, laboratory animals such as rats and mice, and farm animals such as horses, sheep, and cows.

Gamma vinyl GABA (GVG) is a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition. It is also known that GVG alters cocaine's biochemical effects by causing a dose-dependent and prolonged elevation of extracellular endogenous brain GABA levels.

Based on the knowledge that cocaine, as well as other drugs of abuse, increases extracellular NACC DA and the fact that GABA inhibits DA in the same nuclei, we have shown that GVG can attenuate cocaine, nicotine, methamphetamine, and ethanol-induced changes in extracellular DA. In one example, in vivo microdialysis techniques were used in freely moving animals to show, the effects of acute (single injection) and chronic (11 days) GVG administration on cocaine-induced increases in extracellular DA concentration in the NACC. See specifically Morgan, A. E., et al. "Effects of Pharmacologic Increases in Brain ABA Levels on Cocaine-Induced Changes in Extracellular Dopamine," Synapse 28:60-65 (1998) the contents of which are incorporated herein as if set forth in full.

It has unexpectedly been found that intake of GVG alters behavior, and especially addiction-related behavior associated with the biochemical changes resulting from intake of drugs of abuse. For example, GVG significantly attenuated cocaine-induced increases in neostriatal synaptic DA in the primate (baboon) brain as assessed by positron emission tomography (PET) and abolished both the expression and acquisition of cocaine-induced conditioned place preference or CPP. It had no effect, however, on CPP for a food reward or on the delivery of cocaine to the brain locomotor activity. Locomotor activity involves the use of the organs which control locomotion or movement.

These findings suggest the possible therapeutic utility in cocaine addiction of a pharmacologic strategy targeted at the GABAergic neurotransmitter system, a system distinct from but functionally linked to the DA mesotelencephalic reward/reinforcement system. However, rather than targeting the GABA receptor complex with a direct GABA agonist, this novel approach with GVG takes advantage of the prolonged effects of an irreversible enzyme inhibitor that raises endogenous GABA levels without the addictive liability associated with GABA agonists acting directly at the receptor itself.

The present invention embraces any enantiomeric form of gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fengabine, cetylGABA, Topiramate, tiagabine, or acamprosate, including the racemates or racemic mixtures thereof.

As previously stated, in some cases there may be advantages, i.e. greater efficacy, to using a particular enantiomer when compared to the other enantiomer or the racemate or racemic mixture in the methods of the instant invention and such advantages can be readily determined by those skilled in the art.

The present invention embraces compositions or medicaments which include prodrugs of GABA or drugs which contain GABA as a moiety in its chemical structure. These prodrugs become pharmacologically active when metabolically, enzymatically or non-enzymatically biotransformed or cleaved into GABA in the CNS. An example of a prodrug of GABA is progabide which, upon crossing the blood brain barrier, increases endogenous CNS GABA levels.

As previously stated, Gamma vinyl GABA (GVG) is a selective and irreversible inhibitor of GABA-transaminase (GABA-T) known to potentiate GABAergic inhibition. Other compositions or medicaments which inhibit GABA re-uptake in the CNS are also encompassed by the present invention.

Other Drugs that Enhance the Production or Release of GABA in the CNS

It will be understood by those skilled in the arts that other compositions or medicaments can be used which are known to potentiate the GABAergic system or increase extracellular endogenous GABA levels in the CNS.

Such compositions or medicaments include drugs which enhance the production or release of GABA in the CNS. These drugs include, but are not limited to, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fengabine, cetylGABA, Topiramate, tiagabine, acamprosate (homo-calcium-acetyltaurine) or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

The following drugs enhance the production or release of GABA in the CNS, these drugs include, but are not limited to, gabapentin, valproic acid, progabide, gamma-hydroxybutyric acid, fengabine, cetylGABA, Topiramate, tiagabine, acamprosate (homo-calcium-acetyltaurine) or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof.

For example, an effective amount of gabapentin administered to the mammal is an amount from about 500 mg to about 2 g/day. Gabapentin is available as Neurontin® from Parke-Davis in the United States.

An effective amount of valproic acid administered to the mammal, for example, is preferably, an amount from about 5 mg/kg to about 100 mg/kg/day. Valproic acid is available as Depakene® from Abbott in the United States.

An effective amount of progabide administered to the mammal is, preferably, an amount from about 250 mg to about 2 g/day. Progabide is available as Gabrene® from Synthelabo, France. The chemical formula of progabide is C₁₇H₁₆N₂O₂.

An effective amount of fengabine administered to the mammal is, preferably, an amount from about 250 mg to about 4 g/day. Fengabine is available as SL 79229 from Synthelabo, France. The chemical formula of fengabine is C₁₇H₁₇C₁₂NO.

Preferably, an effective amount of gamma-hydroxybutyric acid administered to the mammal is an amount from about 5 mg/kg to about 100 mg/kg/day. Gamma-hydroxybutyric acid is available from Sigma Chemical. The chemical formula of gamma-hydroxybutyric acid is C₄H₇O₃Na.

Topiramate

Topiramate is a sulfamate-substituted monosaccharide of the formula C₁₂H₂₁NO₈S and is available commercially as Topomax®. Topiramate increases the amount of GABA in the central nervous system.

An effective amount of Topiramate as used herein is that amount effective to achieve the specified result of changing addiction-related behavior of the mammal. It is an amount which will diminish, inhibit or eliminate one or more symptoms or conditions resulting from cessation or withdrawal of the psychostimulant, narcotic analgesic, alcohol, nicotine or combinations thereof. It should be emphasized, however, that the invention is not limited to any particular dose.

Accordingly, Topiramate administration in the methods of the present invention is useful in potentiating the GABAergic system or increasing extracellular endogenous GABA levels in the CNS. As used herein, enhancing or increasing endogenous CNS GABA levels is defined as increasing or up-regulating GABA levels substantially over normal levels in vivo, within a mammal. Preferably, endogenous CNS GABA levels are enhanced at least by from about 10% to about 600% over normal levels.

Preferably, an effective amount of Topiramate administered to the mammal is, for example, an amount from about 25 mg to about 1 g/day. Topiramate is available as Topamax® from McNeil in the United States.

Effective Amount

An effective amount as used herein is that amount effective to achieve the specified result of changing addiction-related behavior of the mammal. It is an amount which will diminish or relieve one or more symptoms or conditions resulting from cessation or withdrawal of the psychostimulant, narcotic analgesic, alcohol, nicotine or combinations thereof. It should be emphasized, however, that the invention is not limited to any particular dose.

Claim 1 of 20 Claims

1. A method for treating addiction to cocaine in a mammal, wherein said method comprises administering an effective amount of a composition consisting essentially of topiramate or a pharmaceutically acceptable salt thereof, or an enantiomer or a racemic mixture thereof, to said mammal.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]