Therapeutic Treatment For Metabolic Syndrome, Type 2 Diabetes, Obesity, Or Prediabetes

Abstract

The present invention is directed to a method for treating a patient suffering from the metabolic syndrome, Type 2 diabetes, obesity, or prediabetes, comprising the step of increasing the ratio of dopaminergic neuronal to noradrenergic neuronal activity within the central nervous system and particularly the hypothalamus of the central nervous system of the patient. In another aspect, the present invention is directed to a method for treating a patient suffering from a metabolic disorder such as the metabolic syndrome, Type 2 diabetes, obesity, or prediabetes, and the metabolic sequale of these diseases including cardiovascular, cerebrovascular, renal and hepatic diseases, comprising the step of: administering to a patient suffering from the metabolic syndrome, Type 2 diabetes, obesity, or prediabetes a pharmaceutical composition comprising (1) at least one compound that stimulates an increase in central dopaminergic neuronal activity level in the subject, and (2) at least one compound that stimulates a decrease in central noradrenergic neuronal activity level in the subject. The present invention is also directed to pharmaceutical compositions that include the above compounds and a pharmaceutically acceptable carrier.

What is claimed is: 
     
         1 . A method for treating a patient suffering from a metabolic disorder, comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of a dopamine/norepinephrine neuronal activity ratio-increasing therapeutic. 
     
     
         2 . A method for treating a patient suffering from a metabolic disorder, comprising the step of administering to a patient in need of such treatment a dopamine/norepinephrine, neuronal activity ratio-increasing therapeutic that increases the ratio of dopaminergic neuronal to noradrenergic neuronal activity within the central nervous system or within the hypothalamus of the central nervous system of said patient. 
     
     
         3 . A method for treating a patient suffering from a metabolic disorder, comprising the step of:
 administering to a patient suffering from the metabolic syndrome, Type 2 diabetes, obesity, or prediabetes a pharmaceutical composition comprising (1) at least one compound that stimulates an increase in central dopaminergic neuronal activity level in said subject, and (2) at least one compound that stimulates a decrease in central noradrenergic neuronal activity level in said subject,   
     
     
         4 . The method of  claim 1 ,  2 , or  3 , wherein the metabolic disorder is selected from the group consisting of the metabolic syndrome, Type 2 diabetes, obesity, prediabetes, key elements of any metabolic disorder, insulin resistance, hyperinsulinemia, cardiovascular disease, elevated plasma norepinephrine, elevated cardiovascular-related inflammatory factors or potentiators of vascular endothelial dysfunction, hyperlipoproteinemia, atherosclerosis, hyperphagia, hyperglycemia, hyperlipidemia, hypertension, and high blood pressure. 
     
     
         5 . The method of  claim 4 , wherein said key elements of a metabolic disorder is selected from the group consisting of impaired fasting glucose, impaired glucose tolerance, increased waist circumference, increased visceral fat content, increased fasting plasma glucose, increased fasting plasma triglycerides, increased fasting plasma free fatty acids, decreased fasting plasma high density lipoprotein level, increased systolic or diastolic blood pressure, increased plasma postprandial triglyceride or free fatty acid levels, increased cellular oxidative stress or plasma indicators thereof, increased circulating hypercoagulative state, arteriosclerosis, coronary artery disease, peripheral vascular disease, congestive heart failure, hepatic steatosis, renal disease including renal insufficiency, and cerebrovascular disease. 
     
     
         6 . The method of  claims 1 ,  2 , or  3 , wherein said treatment comprises:
 a. Treatment of endothelial dysfunction or pro-oxidant state associated with cardiovascular disease; or   b. Treatment of hypertension, vascular pro-inflammatory state, pro-coagulative state and pro-oxidant state simultaneously; or   c. Treatment of at least two of hypertension, vascular pro-inflammatory state, pro-coagulative state, or pro-oxidant state simultaneously; or   d. Treatment of at least one of hypertension, vascular pro-inflammatory state, pro-coagulative state, or a pro-oxidant state.   
     
     
         7 . A method of treating at least one non-metabolic derangement in a patient, comprising the step of administering to a patient suffering from said non-metabolic derangement a therapeutically effective amount of a dopamine/norepinephrine neuronal activity ratio-increasing therapeutic, said dopamine/norepinephrine neuronal activity ratio-increasing therapeutic effective to treat said at least one non-metabolic derangement in said patient. 
     
     
         8 . The method of  claim 7 , wherein said non-metabolic derangement is selected from the group consisting of a vascular pro-inflammatory state, pro-coagulative state, pro-oxidant state, or endothelial dysfunction. 
     
     
         9 . A method of treating at least one metabolic derangement and at least one non-metabolic derangement in a patient, comprising the step of administering to a patient suffering from said metabolic derangement and said non-metabolic derangement a therapeutically effective amount of a dopamine/norepinephrine neuronal activity ratio-increasing therapeutic, said a dopamine/norepinephrine neuronal activity ratio-increasing therapeutic effective to treat said at least one metabolic derangement and said at least one non-metabolic derangement in said patient. 
     
     
         10 . The method of  claim 9 , wherein said non-metabolic derangement is selected from the group consisting of a vascular pro-inflammatory state, pro-coagulative state, pro-oxidant state, or endothelial dysfunction. 
     
     
         11 . The method of  claim 9 , wherein said metabolic derangement is selected from the group consisting of insulin resistance, hypertriglyceridemia, and hypertension. 
     
     
         12 . The method of  claim 9 , wherein said patient also suffers from Metabolic Syndrome or Type 2 diabetes, and said method also treats Metabolic Sydrome and Type 2 diabetes. 
     
     
         13 . A method of treating at least one vascular disease in a patient, comprising the step of administering to a patient suffering from said at least one vascular disease a therapeutically effective amount of a dopamine/norepinephrine neuronal activity ratio-increasing therapeutic, said dopamine/norepinephrine neuronal activity ratio-increasing therapeutic effective to treat said at least one vascular disease in said patient. 
     
     
         14 . The method of  claim 13 , wherein said vascular disease is selected from the group consisting of cardiovascular disease, microvascular disease, macrovascular disease, peripheral vascular disease, cerebrovascular disease, arteriosclerosis, myocardial infarction, stroke, angina, and congestive heart failure. 
     
     
         15 . The method of  claim 13 , wherein said patient also suffers from one or more of Metabolic Syndrome, endothelial dysfunction, or Type 2 diabetes, and said method also treats Metabolic Sydrome and Type 2 diabetes. 
     
     
         16 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein said increase in central dopaminergic neuronal activity level occurs within neurons innervating the hypothalamus and the hypothalamus itself. 
     
     
         17 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein said at least one compound that stimulates an increase in central dopaminergic neuronal activity level is selected from the group consisting of dopamine reuptake inhibitor compounds, dopamine presynaptic transporter inhibitor compounds, dopamine presynaptic autoreceptor antagonists; presynaptic dopamine release enhancer compounds, post synaptic dopamine receptor agonist compounds, dopamine synthesis stimulator compounds, dopamine catabolism is inhibitor compounds, and combinations thereof. 
     
     
         18 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein said at least one compound that stimulates an increase in central dopaminergic neuronal activity level is selected from the group consisting of GBR-12935, BDNF, quinpirole, SKF38393, deprenyl, apomorphine, pramipexole, GBR-12909, methylphenidate, phenylaminotetralins, quinelorane, talexipole, and combinations thereof. 
     
     
         19 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein said decrease in central noradrenergic neuronal activity level occurs within the brain stem region that innervates the hypothalamus and the hypothalamus itself. 
     
     
         20 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein said at least one compound that stimulates a decrease in central noradrenergic neuronal activity level is selected from the group consisting of postsynaptic noradrenergic receptor blockade compounds (antagonists), inhibitors of noradrenalin release, inhibitors of noradrenalin synthesis, activators of noradrenalin presynaptic reuptake, and activators of noradrenalin catabolism presynaptically and in the synapse, and combinations thereof. 
     
     
         21 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein said at least one compound that stimulates a decrease in central noradrenergic neuronal activity level is selected from the group consisting of prazosin, propranolol, clonidine, fusaric acid, dopamine, phenoxybenzarnine, phentolamine, guanfacine, pantethine, and combinations thereof. 
     
     
         22 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein the ratio of said at least one compound that stimulates an increase in central dopaminergic neuronal activity level to said at least one compound that stimulates a decrease in central noradrenergic neuronal activity level in said pharmaceutical composition ranges from about 500:1 to 1:500 on a weight-to-weight (w:w) basis. 
     
     
         23 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein the ratio of said at least one compound that stimulates an increase in central dopaminergic neuronal activity level to said at least one compound that stimulates a decrease in central noradrenergic activity level in said pharmaceutical composition ranges from about 100:1 to 1:100 on a weight-to-weight (w:w) basis. 
     
     
         24 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , further comprising the step of:
 administering to a patient suffering from the metabolic syndrome, Type 2 diabetes, obesity, or prediabetes a pharmaceutical composition comprising at least one compound that simultaneously stimulates (1) an increase in central (central nervous system) dopaminergic neuronal activity level, and (2) a decrease in central noradrenergic neuronal activity level.   
     
     
         25 . The method of  claim 24 , wherein said pharmaceutical composition treats:
 a. endothelial dysfunction or pro-oxidant state associated with cardiovascular disease; or   b. hypertension, vascular pro-inflammatory state, pro-coagulative state, and pro-oxidant state simultaneously; or   c. at least two of hypertension, vascular pro-inflammatory state, pro-coagulative state, or pro-oxidant state simultaneously; or   d. at least one of hypertension, vascular pro-inflammatory state, pro-coagulative state, or pro-oxidant state.   
     
     
         26 . The method of  claim 24 , wherein said increase in central dopaminergic neuronal activity level occurs within neurons innervating the hypothalamus and the hypothalamus itself. 
     
     
         27 . The method of  claim 24 , wherein said decrease in central noradrenergic neuronal activity level occurs within the brain stem region that innervates the hypothalamus and the hypothalamus itself. 
     
     
         28 . The method of  claim 24 , wherein said compound is selected from the group consisting of catecholamine modifiers, histamine receptor  1  agonists, and combinations thereof. 
     
     
         29 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13  wherein the therapeutically effective amount of a dopamine/norepinephrine neuronal activity ratio-increasing therapeutic is administered to a human subject between the time interval of 0400 and 1200 hours of the day. 
     
     
         30 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13  wherein the therapeutically effective amount of a dopamine/norepinephrine neuronal activity ratio-increasing therapeutic is administered to a human subject to effectuate a peak in central dopaminergic neuronal activity between the time interval of 0400 and 1200 hours of the day. 
     
     
         31 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein said at least one compound that stimulates an increase in central dopaminergic neuronal activity is a mixed dopamine/noradrenaline neuronal reuptake inhibitor or mixed dopamine/noradrenaline release enhancer utilized in conjunction with one or more compounds that reduces noradrenergic neuronal activity. 
     
     
         32 . The method of  claim 31 , wherein said mixed dopamine/noradrenaline neuronal reuptake inhibitor or mixed dopamine/noradrenaline release enhancer compounds are from the list of bupropion, mazindol, amphetamine, methylphenidate, nomifensine, and tesofensine. 
     
     
         33 . The method of  claim 31 , wherein said one or more compounds that reduce noradrenergic neuronal activity is a dopamine D2 receptor agonist. 
     
     
         34 . The method of  claim 33 , wherein said dopamine receptor agonist is an ergot-related compound. 
     
     
         35 . The method of  claim 34 , wherein said ergot-related compound is bromocriptine, lisuride, or terguride. 
     
     
         36 . The method of  claim 31 , wherein said one or more compounds that reduce noradrenergic neuronal activity is selected from the group consisting of postsynaptic noradrenergic receptor blockade compounds (antagonists), inhibitors of noradrenalin release, inhibitors of noradrenalin synthesis, activators of noradrenaline presynaptic reuptake, and activators of noradrenalin catabolism presynaptically and in the synapse, and combinations thereof 
     
     
         37 . The method of  claims 1 ,  2 ,  3 ,  7 ,  9 , or  13 , wherein an ergot-related dopamine receptor agonist compound is combined with either one or more compounds that increase dopaminergic neuronal activity and/or one or more compounds that decrease noradrenergic neuronal activity. 
     
     
         38 . The method of  claim 17 , wherein said dopamine catabolism inhibitor compound is an inhibitor of dopamine monooxygenase. 
     
     
         39 . A pharmaceutical composition effective for treating the metabolic syndrome, Type 2 diabetes, obesity, or prediabetes, said composition comprising:
 (1) at least one central dopaminergic neuronal activity activator;   (2) at least one central noradrenergic neuronal activity inhibitor; and   (3) a pharmaceutically acceptable carrier.   
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein said at least one central dopaminergic neuronal activity activator is selected from the group consisting of GBR-12935, BDNF, quinpirole, SKF38393, deprenyl, apomorphine, pramipexole, GBR-12909, methylphenidate, phenylaminotetralins and combinations thereof. 
     
     
         41 . The pharmaceutical composition of  claim 39 , wherein said at least one central noradrenergic neuronal activity inhibitor is selected from the group consisting of prazosin, propranolol, clonidine, fusaric acid, dopamine, phenoxybenzamine, phentolamine, guanfacine, and combinations thereof. 
     
     
         42 . The pharmaceutical composition of  claim 39 , wherein the ratio of said at least one central dopaminergic neuronal activity activator to said at least one central noradrenergic neuronal activity inhibitor ranges from about 500:1 to 1:500 on a weight-to-weight (w:w) basis. 
     
     
         43 . The pharmaceutical composition of  claim 39 , wherein the ratio of said at least one central dopaminergic neuronal activity activator to said at least one central noradrenergic neuronal activity inhibitor ranges from about 100:1 to 1:100 on a weight-to-weight (w:w) basis. 
     
     
         44 . A pharmaceutical composition effective for treating the metabolic syndrome, Type 2 diabetes, obesity, or prediabetes, said composition comprising
 at least one compound that simultaneously stimulates (1) an increase in central dopaminergic neuronal activity level, and (2) a decrease in central noradrenergic neuronal activity level, said compound selected from the group consisting of catecholamine modifiers and   a pharmaceutically acceptable carrier.