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.

1 . 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. 
     
     
         2 . The method of  claim 1 , further comprising 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. 
     
     
         3 . The method of  claim 1 , wherein the addictive therapeutic agent is an opioid agonist. 
     
     
         4 . The method of  claim 3 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, beta-hydroxy 3-methylfentanyl, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, destropropoxyphene, dextromoramide, dezocine, diacetylmorphine (heroin), diamorphine, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, LMM, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptizinol, metapon, metazocine, methadone, methadyl acetate, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, noscapine, opium, oxycodone, oxymorphone, papaverine, pentazocine, phenadoxone, phenomorphan, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, remifentanil, sufentanil, thebaine, tildine, or tramadol, or any combination thereof. 
     
     
         5 . The method of  claim 3 , wherein the PPARγ agonist is a thiazolidinedione (TZD). 
     
     
         6 . The method of  claim 5 , wherein the TZD is selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglidazone. 
     
     
         7 . The method of  claim 6 , wherein the TZD is pioglitazone. 
     
     
         8 . The method of  claim 7 , wherein the addictive therapeutic agent is oxycodone or hydrocodone. 
     
     
         9 . A pharmaceutical compositions comprising an effective amount of 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. 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the addictive therapeutic agent is an opioid agonist. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, beta-hydroxy 3-methylfentanyl, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, destropropoxyphene, dextromoramide, dezocine, diacetylmorphine (heroin), diamorphine, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, LMM, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptizinol, metapon, metazocine, methadone, methadyl acetate, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, noscapine, opium, oxycodone, oxymorphone, papaverine, pentazocine, phenadoxone, phenomorphan, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, remifentanil, sufentanil, thebaine, tildine, or tramadol, or any combination thereof. 
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the PPARγ agonist is a thiazolidinedione (TZD). 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein the TZD is selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglidazone. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the TZD is pioglitazone. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the addictive therapeutic agent is oxycodone or hydrocodone. 
     
     
         16 . A unit dosage form of a pharmaceutical composition, wherein said unit dosage form comprises an effective amount of 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. 
     
     
         17 . The unit dosage form of  claim 16 , wherein the addictive therapeutic agent is an opioid agonist. 
     
     
         18 . The unit dosage form of  claim 17 , wherein the opioid agonist is selected from the group consisting of alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, benzylmorphine, beta-hydroxy 3-methylfentanyl, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, destropropoxyphene, dextromoramide, dezocine, diacetylmorphine (heroin), diamorphine, diampromide, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, fentanyl, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, LMM, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptizinol, metapon, metazocine, methadone, methadyl acetate, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, noscapine, opium, oxycodone, oxymorphone, papaverine, pentazocine, phenadoxone, phenomorphan, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, remifentanil, sufentanil, thebaine, tildine, or tramadol, or any combination thereof. 
     
     
         19 . The unit dosage form of  claim 17 , wherein the PPARγ agonist is a thiazolidinedione (TZD). 
     
     
         20 . The unit dosage form of  claim 19 , wherein the TZD is selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglidazone. 
     
     
         21 . The unit dosage form of  claim 20 , wherein the TZD is pioglitazone. 
     
     
         22 . The unit dosage form of  claim 21 , wherein the addictive therapeutic agent is oxycodone or hydrocodone. 
     
     
         23 . A method of reducing nicotine use or preventing relapse nicotine use, comprising:
 determining that a subject has or is at risk of developing a nicotine addiction; and   providing to the subject an amount of an agonist of a peroxisome proliferator-activated receptor gamma (PPARγ agonist) effective for reducing nicotine use or preventing relapse nicotine use.   
     
     
         24 . The method of  claim 23 , wherein the PPARγ agonist is a thiazolidinedione (TZD). 
     
     
         25 . The method of  claim 24 , wherein the TZD is selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglidazone. 
     
     
         26 . The method of  claim 25 , wherein the TZD is pioglitazone. 
     
     
         27 . A kit comprising one or more unit dosage forms of a peroxisome proliferator-activated receptor gamma (PPARγ agonist) and one or more unit dosage forms of nicotine. 
     
     
         28 . The kit of  claim 27 , wherein the PPARγ agonist is a thiazolidinedione (TZD). 
     
     
         29 . The kit of  claim 28 , wherein the TZD is selected from the group consisting of pioglitazone, rosiglitazone, ciglitazone, troglitazone, englitazone, rivoglitazone and darglidazone. 
     
     
         30 . The kit of  claim 29 , wherein the TZD is pioglitazone. 
     
     
         31 . A delivery system comprising an amount of nicotine and an amount of a peroxisome proliferator-activated receptor gamma (PPARγ agonist) effective for the treatment of nicotine addition. 
     
     
         32 . The delivery system of  claim 31 , wherein the amount of nicotine and the amount of the PPARγ agonist are present in a transdermal patch, an oral lozenge, or a chewing gum. 
     
     
         33 . 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. 
     
     
         34 . A unit dosage form of a pharmaceutical composition, wherein said unit dosage form comprises an effective amount of 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. 
     
     
         35 . The unit dosage form of  claim 34 , wherein the addictive therapeutic agent is an opioid agonist. 
     
     
         36 . A delivery system comprising an amount of nicotine and an amount of a thiazolidinedione (TZD) effective for the treatment of nicotine addition.