Compositions and methods for prophylaxis and treatment of addictions

Abstract

The present invention relates to methods of treating or preventing addiction and relapse use of addictive agents, and treating or preventing addictive or compulsive behaviour and relapse practice of an addictive behaviour or compulsion, by administering a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, alone or in combination with another therapeutic agent, such as, for example, an opioid receptor antagonist or an antidepressant, or an addictive agent, such as, for example, an opioid agonist. The present invention also includes pharmaceutical compositions for treating or preventing addiction or relapse that include a PPARγ agonist and one or more other therapeutic or addictive agents, as well as unit dosage forms of such pharmaceutical compositions, which contain a dosage effective in treating or preventing addiction or relapse. The methods and compositions of the invention are useful in the treatment or prevention of addiction to any agent, including alcohol, nicotine, marijuana, cocaine, and amphetamines, as well as compulsive and addictive behaviours, including pathological gambling and pathological overeating.

Description

CROSS-REFERENCE(S) TO RELATED APPLICATION(S)[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 12 / 101,943, filed Apr. 11, 2008, now pending, and claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60 / 911,201 filed Apr. 11, 2007; U.S. Provisional Patent Application No. 61 / 159,377 filed Mar. 11, 2009; and U.S. Provisional Patent Application No. 61 / 167,824 filed Apr. 8, 2009, where these (three) provisional application are incorporated herein by reference in their entireties.BACKGROUND[0002]1. Technical Field[0003]The present invention is directed generally to the treatment or prevention of addictions using PPARγ agonists, alone or in combination with other therapeutic agents.[0004]2. Description of the Related Art[0005]The World Health Organization (WHO) defines substance addiction as using a substance repeatedly, despite knowing and experiencing harmful effects. Substance addiction is a chronic, relapsing disease cha...

AI Technical Summary

Benefits of technology

[0044]In another embodiment, the present invention provides a method of reducing one or more symptoms associated with physiological withdrawal from an addictive agent, comprising providing an effective amount of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist to a subject undergoing physiological withdrawal from an addictive agent.

[0045]In a related embodiment, the present invention provides a method of reducing one or more symptoms associated with physiological withdrawal from an addictive agent, comprising providing an effective amount of a peroxisome proliferator-activated receptor gamma (PPARγ) agonist and an additional therapeutic agent to a subject undergoing physiological withdrawal from an addictive agent, wherein each of the PPARγ agonist and the additional therapeutic agent contribute to reducing one or more symptoms associated with physical withdrawal from the addictive agent.

[0065]In additional embodiment, the present invention includes a method of preventing a subject from becoming addicted, or reducing the likelihood that a subject will become addicted, to an addictive therapeutic agent, comprising providing to a subject in need thereof an addictive therapeutic agent, and an effective amount of a peroxisome proliferator-activated receptor gamma (PPARγ agonist), wherein the effective amount of the PPARγ agonist is an amount effective in preventing the subject from becoming addicted, or reducing the likelihood that the subject will become addicted, to the addictive therapeutic agent. In particular embodiment, this method further comprises providing to the subject an additional therapeutic agent, wherein each of the PPARγ agonist and the additional therapeutic agent contribute to preventing the subject from becoming addicted, or reducing the likelihood that the subject will become addicted, to the addictive therapeutic agent. In one embodiment, the addictive therapeutic agent is an opioid agonist. In certain embodiments, the opioid agonist is codeine, morphine, noscapapine, hydrocodone, hydromorphone, oxycodone, tramadol, fentanyl, sufentanil, alfentanil, propoxyphene, methadone, butorphanol, destropropoxyphene, diamorphine, levorphanol, meptizinol, nalbuphine, pentazocine, dezocine, meperidine, or buprenorphine. In one embodiment, the PPARγ agonist is a TZD. In particular embodiments, the TZD is pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone or darglidazone. In one embodiment, the PPARγ agonist is pioglitazone, and the addictive therapeutic agent is oxycodone. In another embodiment, the PPARγ agonist is pioglitazone, and the addictive therapeutic agent is hydrocodone. In a further embodiment, the PPARγ agonist is rosiglitazone, and the addictive therapeutic agent is oxycodone. In a further embodiment, the PPARγ agonist is rosiglitazone, and the addictive therapeutic agent is hydrocodone. In another embodiment, the PPARγ agonist is pioglitazone, and the addictive therapeutic agent is fentanyl. In a further embodiment, the PPARγ agonist is rosiglitazone, and the addictive therapeutic agent is fentanyl.

[0071]In a further related embodiment, the present invention includes a method of preventing a subject from becoming addicted, or reducing the likelihood that a subject will become addicted, to an addictive therapeutic agent, comprising providing to a subject in need thereof an addictive therapeutic agent and an effective amount of a thiazolidinedione (TZD), wherein the effective amount of the TZD is an amount effective in preventing the subject from becoming addicted, or reducing the likelihood that the subject will become addicted, to the addictive therapeutic agent.

Problems solved by technology

Additionally, alcoholism leads to serious liver and cardiovascular disease and generates dependence resulting in severe mental disorders, social problems and adverse consequences including the division of families, tragic accidents and the reduction of work performance.

Globally, alcohol abuse leads to about 1.8 million deaths per year.

Compulsive behaviour towards the consumption of alcohol is a core symptom of the disorder.

However, despite some promising results none of these medications, including naltrexone, is of sufficient efficacy in alcoholism and prognosis remains poor.

Cigarette smoking is associated with 430,000 deaths a year in the US alone and is estimated to cost the nation 80 billion dollars yearly in health care costs.

Smoking also causes lung diseases such as chronic bronchitis and emphysema; exacerbates asthma symptoms; and increases the risk of heart disease, including stroke, heart attack, vascular disease, and aneurysm.

Most therapies developed for nicotine addiction have shown only moderate success in preventing relapse, leading to a high failure rate in attempts to quit smoking.

Acute effects of marijuana use include memory and learning problems, distorted perception, difficulty problem solving, loss of coordination, and increased heart rate.

Long term abuse can cause the same respiratory problems observed in tobacco smokers, such as daily cough, phlegm production, increased risk of lung infections, and an increased chance of developing cancer of the head, neck and lungs.

Long term marijuana use can result in addiction with compulsive use that interferes with daily activities.

Cravings and withdrawal symptoms, such as irritability, increased aggression, sleeplessness, and anxiety make it difficult for addicts to stop using marijuana.

There are no pharmaceutical treatments available for treating marijuana addiction and relapse.

Furthermore, the past few years have seen a marked increase in the use of opioid medications in the United States and an even greater increase in problems associated with such use.

Conversely, protracted treatments with these agents have been associated with development of addiction in up to 18% of patients.

Antagonists provide no relief from pain or other withdrawal symptoms; rather, they can precipitate withdrawal, and their therapeutic use was associated with increased accidental opioid agonists overdosing and increased lethality.

Use of agonists with a lower affinity for the receptors results in the least severe withdrawal symptoms, but it can lead to a dependence on the substitute opiate.

These substances first increase dopamine transmission, but long term drug usage results in a reduction of dopamine activity, leading to dysregulation of the brain reward system and dysporia.

Chronic cocaine abuse can result in hyperstimulation, tachycardia, hypertension, mydriasis, muscle twitching, sleeplessness, extreme nervousness, hallucinations, paranoia, aggressive behaviour, and depression.

Cocaine overdose may lead to tremors, convulsions, delirium, and death resulting from heart arrhythmias and cardiovascular failure.

Current treatments for amphetamine addiction include phenothiazines, haloperidol, and chlorpromazine for hallucinations, but potential side effects of these drugs include postural hypotension and severe extrapyramidal motor disorders.

In the past, treatment for substance addictions focused on behavioural therapy, but dependence on many of these highly addictive substances is hard to break.

The long-lasting, chronic nature of many addictions and high rates of recidivism present a considerable challenge for the treatment of drug and alcohol addiction, such that understanding of the neurobiological basis of relapse has emerged as a central issue in addiction research.

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