Compositions and methods for minimizing or reducing 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 . A method for preventing or reversing loss of the therapeutic effect of a dopamine receptor agonist or partial agonist associated with the repeated administration of the dopamine receptor agonist or partial agonist to a patient comprising:
 administering to the patient a dopamine receptor agonist or partial agonist; and   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 a therapeutic effect, the loss being associated with the repeated administration of the dopamine receptor agonist or partial agonist to the patient.   
   
   
       2 . The method of  claim 1 , 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. 
   
   
       3 . The method of  claim 1 , wherein the opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof 
   
   
       4 . The method of  claim 1 , wherein the dopamine receptor agonist or partial agonist is selected from the group consisting of 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. 
   
   
       5 . The method of  claim 1 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
   
   
       6 . The method of  claim 1 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
   
   
       7 . The method of  claim 1 , wherein the ultra-low dose opioid receptor antagonist is administered from a device, a composition, or a combination device/composition, which is separate from a device, a composition, or a combination device/composition for administering the full or partial opioid dopamine agonist. 
   
   
       8 . The method of  claim 1 , wherein the ultra-low dose opioid receptor antagonist is administered by depot injection at a dose from about 0.01 ng/kg to about 100 μg/kg. 
   
   
       9 . A method for preventing or reversing loss of the therapeutic effect of a drug associated with the repeated administration of the drug to a patient comprising:
 administering to the patient a drug that increases the extracellular level of dopamine by enhancing release of dopamine, decreasing the removal of dopamine from the extracellular space, decreasing metabolic degradation of dopamine, or enhancing the synthesis of dopamine within the brain; and   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 a therapeutic effect, the loss being associated with the repeated administration of the drug to the patient.   
   
   
       10 . The method of  claim 9 , wherein the drug releases dopamine from the dopamine neuron, blocks the reuptake of dopamine into the dopamine neuron by blocking the dopamine transporter, decreases the metabolic degradation of dopamine in the brain, or increases the synthesis of dopamine, and wherein the drug is administered in a therapeutically effective amount when co-administered with the opioid receptor antagonist in an ultra-low dose amount. 
   
   
       11 . A pharmaceutical formulation comprising:
 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, decreasing metabolic degradation of dopamine, or enhancing the synthesis of dopamine within the brain; and   an opioid receptor antagonist in an ultra-low dose amount.   
   
   
       12 . The pharmaceutical formulation of  claim 11 , wherein the pharmaceutical formulation comprises at least one unit dosage form. 
   
   
       13 . The pharmaceutical formulation of  claim 11 , which comprises a dopamine receptor agonist or partial agonist, and the dopamine receptor agonist or partial agonist is present in an amount that is therapeutically effective when co-administered with the opioid receptor antagonist in an ultra-low dose amount. 
   
   
       14 . The pharmaceutical formulation of  claim 13 , wherein the dopamine receptor agonist or partial agonist is selected from the group consisting of 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. 
   
   
       15 . The pharmaceutical formulation of  claim 11 , which comprises a drug which increases extracellular dopamine levels and the drug is present in an amount that is therapeutically effective when co-administered with the opioid receptor antagonist in an ultra-low dose amount. 
   
   
       16 . The pharmaceutical formulation of  claim 15 , wherein the drug comprises L-DOPA, amphetamine, methylphenidate, a monoamine oxidase inhibitor, a catechol-O-methyl transferase inhibitor, buproprion, a serotonin dopamine reuptake inhibitor, a serotonin norepinephrine reuptake inhibitor, a triple uptake inhibitor, a triple reuptake inhibitor, a dopamine reuptake inhibitor, or a combination thereof. 
   
   
       17 . The pharmaceutical formulation of  claim 15 , wherein the drug comprises sertraline, duloxetine, venlaxafin, desvenlafaxin, JNJ 7925476, tesofensine, DOV216303, atomoxetine, clozapine, ziprasidone, olanzapine, risperidone, quetiapine, phenelzine, tranylcypromine, selegiline, rasagiline, tolcapone, or a combination thereof. 
   
   
       18 . The pharmaceutical formulation of  claim 11 , wherein the opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
   
   
       19 . The pharmaceutical formulation of  claim 11 , wherein the dopamine receptor agonist or partial agonist, the opioid receptor antagonist, or both, are in an oral dosage form. 
   
   
       20 . The pharmaceutical formulation of  claim 11 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
   
   
       21 . The pharmaceutical formulation of  claim 11 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
   
   
       22 . The pharmaceutical formulation of  claim 11 , wherein the opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof, and wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
   
   
       23 . The pharmaceutical formulation of  claim 22 , which comprises a dopamine receptor agonist or partial agonist, and the dopamine receptor agonist or partial agonist is selected from the group consisting of 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. 
   
   
       24 . A method for treating Restless Leg Syndrome, Parkinson's Disease, or another dopamine-related movement disorder in a patient comprising:
 administering to the patient a dopamine receptor agonist or partial agonist; and   administering to the patient 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 the group consisting of 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 the group consisting of 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 . A method for treating Restless Leg Syndrome (RLS) in a patient comprising:
 administering to the patient a dopamine receptor agonist or partial agonist; and   administering to the patient an opioid receptor antagonist in an ultra-low dose amount.   
   
   
       30 . The method of  claim 29 , wherein the opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
   
   
       31 . The method of  claim 29 , wherein the dopamine receptor agonist or partial agonist is selected from the group consisting of 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. 
   
   
       32 . The method of  claim 29 , wherein the dopamine receptor agonist or partial agonist comprises pramiprexole or ropinirole. 
   
   
       33 . The method of  claim 29 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
   
   
       34 . The method of  claim 29 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
   
   
       35 . A method for treating Parkinson's Disease in a patient comprising:
 administering to the patient a dopamine receptor agonist or partial agonist, levodopa, a monoamine oxidase inhibitor, a catechol-O-methyl transferase inhibitor, or a combination thereof; and   administering to the patient an opioid receptor antagonist in a ultra-low dose amount.   
   
   
       36 . The method of  claim 35 , wherein the opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
   
   
       37 . The method of  claim 35 , wherein the dopamine agonist or partial agonist is selected from the group consisting of 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 in a patient comprising:
 administering to the patient 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;   administering to the patient 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 . A method for treating schizophrenia in a patient comprising:
 administering to the patient a therapeutically effective amount of a partial dopamine agonist or of a drug increasing extracellular dopamine levels; and   administering to the patient an opioid receptor antagonist in a ultra-low dose amount effective to prevent or reduce receptor desensitization in dopamine augmentation.   
   
   
       44 . The method of  claim 43 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
   
   
       45 . The method of  claim 43 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
   
   
       46 . A method for treating psychostimulant abuse in a patient comprising:
 administering to the patient a therapeutically effective amount of a dopamine D2 and/or D3 agonist or partial agonist, a dopamine reuptake inhibitor, or a dopamine releasing drug; and   administering to the patient an opioid receptor antagonist in an ultra-low dose amount effective to prevent or reduce receptor desensitization in dopamine augmentation.   
   
   
       47 . The method of  claim 46 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
   
   
       48 . The method of  claim 46 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
   
   
       49 . A method for treating attention deficit hyperactivity disorder (ADHD) in a patient comprising:
 administering to the patient a therapeutically effective amount of a drug that increases extracellular dopamine levels; and   administering to the patient an opioid receptor antagonist in an ultra-low dose amount effective for receptor stabilization.   
   
   
       50 . The method of  claim 49 , wherein the opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
   
   
       51 . The method of  claim 49 , wherein the drug that increases extracellular dopamine levels is selected from methylphenidate formulations, amphetamine formulations, or norepinephrine transporter inhibitors. 
   
   
       52 . The method of  claim 49 , wherein the norepinephrine dopamine transporter inhibitor comprises atomoxetine. 
   
   
       53 . The method of  claim 49 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 1.5 μg/kg. 
   
   
       54 . The method of  claim 49 , wherein the ultra-low dose amount of the opioid receptor antagonist is between about 0.01 ng/kg and about 150 ng/kg. 
   
   
       55 . A method for treating a dopamine deficiency disease or condition in a patient comprising:
 administering to the patient a therapeutically effective amount of a dopamine D2 and/or D3 receptor agonist or partial agonist; and   administering to the patient an opioid receptor antagonist in an ultra-low dose amount effective to prevent or reverse loss of therapeutic effects after repeated administration of the dopamine D2 and/or D3 receptor agonist or partial agonist.   
   
   
       56 . The method of  claim 55 , wherein the dopamine deficiency disease or condition is selected from the group consisting of Parkinson's Disease, Restless Leg Syndrome, depression, schizophrenia, attention deficit disorder, and psychostimulant abuse. 
   
   
       57 . The method of  claim 55 , wherein the opioid receptor antagonist is selected from the group consisting of naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine, and combinations thereof. 
   
   
       58 . The method of  claim 55 , wherein the dopamine D2 and/or D3 receptor agonist or partial agonist and/or the opioid receptor antagonist is/are administered via a depot injection, a topical cream or gel, a transdermal device, or a pump. 
   
   
       59 . A method for the treatment of pituitary adenomas in a patient, comprising:
 administering to the patient a therapeutically effective amount of a dopamine D2 agonist; and   administering to the patient an opioid receptor antagonist in an ultra-low dose amount effective to reduce or prevent desensitization of dopamine D2 receptors.   
   
   
       60 . The method of  claim 59 , wherein the dopamine D2 agonist comprises bromocriptine. 
   
   
       61 . The method of  claim 59 , wherein the opioid receptor antagonist in an ultra-low dose amount comprises naltrexone orally administered in a daily dose of 0.01 ng/kg to 1.5 μg/kg. 
   
   
       62 . The method of  claim 54 , wherein the opioid receptor antagonist in an ultra-low dose amount comprises naltrexone administered by depot njection of between about 0.01 ng/kg and about 100 μg/kg. 
   
   
       63 . A method of treatment comprising:
 identifying a patient having a condition selected from the group consisting of Parkinson's Disease, Restless Leg Syndrome, depression, schizophrenia, psychostimulant drug abuse, and attention deficit disorder; and   administering to the patient an opioid receptor antagonist in an ultra-low dose amount in combination with a non-opioid therapeutic agent for the condition.