Compositions and methods for minimizing or reversing agonist-induced desensitization

Abstract

Methods and compositions are provided for preventing or reversing loss of the therapeutic effect of a drug, where the loss is associated with the repeated administration of the drug to a patient. The method includes administering to the patient a dopamine receptor agonist or partial agonist or a drug that increases the extracellular level of dopamine by enhancing release of dopamine, decreasing the removal of dopamine from the extracellular space, enhancing the synthesis of dopamine within the brain, or decreasing metabolic degradation of dopamine; and also administering to the patient an opioid receptor antagonist in an ultra-low dose amount, wherein the ultra-low dose amount is effective to prevent or reverse loss of therapeutic effects associated with the repeated administration of the drug to the patient. The methods are useful for various treatments, including treating Parkinson's Disease, Restless Leg Syndrome, depression, schizophrenia, psychostimulant drug abuse, or attention deficit disorder.

1 - 23 . (canceled) 
     
     
         24 . A method for treating Parkinson's Disease, comprising administering to a patient in need thereof:
 a dopamine receptor agonist or partial agonist; and   an opioid receptor antagonist in an ultra-low dose amount,   wherein the dopamine receptor agonist or partial agonist is administered in an amount that is therapeutically effective when co-administered with the opioid receptor antagonist in an ultra-low dose amount.   
     
     
         25 . The method of  claim 24 , wherein the opioid receptor antagonist is selected from naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
     
     
         26 . The method of  claim 24 , wherein the dopamine receptor agonist or partial agonist is selected from pramipexole, ropinirole, bromocriptine, pergolide, preclamol, talipexole, roxindole, rotigotine, SDZ 208-911, SDZ 208-912, bifeprunox, aripiprazole, PD 158771, PD128483, N-propylnorapomorphine, apomorphine, sumanirole, aplindore, BP897, CJB090, RGH237, and combinations thereof. 
     
     
         27 . The method of  claim 24 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
     
     
         28 . The method of  claim 24 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
     
     
         29 - 32 . (canceled) 
     
     
         33 . The method of  claim 24 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.1 ng/kg and about 100 μg/kg. 
     
     
         34 . (canceled) 
     
     
         35 . A method for treating Parkinson's Disease comprising administering to a patient in need thereof:
 a dopamine receptor agonist or partial agonist, levodopa, a monoamine oxidase inhibitor, a catechol-O-methyl transferase inhibitor, or a combination thereof; and   an opioid receptor antagonist in a ultra-low dose amount.   
     
     
         36 . The method of  claim 35 , wherein the opioid receptor antagonist is selected from naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
     
     
         37 . The method of  claim 35 , wherein the dopamine agonist or partial agonist is selected from pramipexole, ropinirole, bromocriptine, pergolide, preclamol, talipexole, roxindole, rotigotine, SDZ 208-911, SDZ 208-912, bifeprunox, aripiprazole, PD 158771, PD128483, N-propylnorapomorphine, apomorphine, sumanirole, aplindore, BP897, CJB090, RGH237, and combinations thereof. 
     
     
         38 . The method of  claim 35 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
     
     
         39 . The method of  claim 35 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
     
     
         40 . A method for treating depression comprising administering to a patient in need thereof:
 a therapeutically effective amount of a dopamine agonist, a dopamine partial agonist, a dopamine reuptake inhibitor, a monoamine oxidase inhibitor, a dopamine releasing drug, a selective serotonin dopamine reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, or a serotonin-norepinephrine-dopamine reuptake inhibitor;   an opioid receptor antagonist in a ultra-low dose amount effective to prevent or reduce receptor desensitization in dopamine augmentation.   
     
     
         41 . The method of  claim 40 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
     
     
         42 . The method of  claim 40 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 40 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.1 ng/kg and about 100 μg/kg. 
     
     
         45 - 49 . (canceled) 
     
     
         50 . The method of  claim 40 , wherein the opioid receptor antagonist is selected from naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
     
     
         51 - 60 . (canceled) 
     
     
         61 . The method of  claim 40 , wherein the opioid receptor antagonist in an ultra-low dose amount comprises naltrexone orally administered. 
     
     
         62 . The method of  claim 40 , wherein the opioid receptor antagonist in an ultra-low dose amount comprises naltrexone administered by depot injection. 
     
     
         63 . (canceled)