Methods and compositions for stimulation of the intestinal enteroendocrine system for treating diseases or conditions related to the same

Abstract

This invention relates to methods of stimulating the activity of the human and animal enteric nervous system. The method comprises orally administering an aminoserol, such as squalamine, a naturally occurring aminosterol isolated from Squalus acanthias , or derivatives thereof, to a subject in need.

1 - 26 . (canceled) 
     
     
         27 . A method of treating or preventing Parkinson's disease comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         28 . The method of  claim 27 , wherein the method produces one or more of the following in the subject:
 (a) improved bowel function;   (b) improved fine motor skills;   (c) improved articulation;   (d) improved mood;   (e) improved speech;   (f) improved mood;   (g) improved tremors;   (h) improved coordination;   (i) improved stamina;   (j) improved balance;   (k) improved cognitive function;   (l) reduced dysphagia/improved swallowing;   (m) improved autonomic function;   (n) improved psychosis (hallucinations and delusions; and/or   (o) improved daytime wakefulness.   
     
     
         29 . The method of  claim 27 , wherein the aminosterol composition is co-administered or combined with one or more drugs commonly prescribed to treat Parkinson's disease or related symptoms. 
     
     
         30 . The method of  claim 29 , wherein the one or more drugs commonly prescribed to treat Parkinson's disease or related symptoms are selected from the group consisting of levodopa, a dopa decarboxylase inhibitor, a COMT inhibitor, dopamine agonists, MAO-B inhibitors, carbidopa, benserazide, tolcapone, entacapone, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride, rotigotine, selegiline, rasagiline, amantadine, anticholinergics, clozapine, cholinesterase inhibitors, and modafinil. 
     
     
         31 . The method of  claim 27 , wherein the method results in:
 (a) triggering the production of neuro-protective hormones or neuropeptides which function to prevent onset or development of Parkinson's Disease or related symptoms; and/or   (b) prevent the accumulation of alpha synuclein, thereby preventing onset or development of Parkinson's Disease or related symptoms.   
     
     
         32 . The method of  claim 27 , wherein:
 (a) the compound is an aminosterol that can inhibit the formation of actin stress fibers in endothelial cells stimulated by a ligand known to induce stress fiber formation, having the chemical structure of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 W is 24S —OSO 3  or 24R—OSO 3;    
 X is 3β—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH— or 3α—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—; 
 Y is 20R—CH 3 ; and 
 Z is 7α or 7β—OH; or
 (b) the aminosterol is represented by the family of related compounds (compounds 1-8) isolated from  Squalus acanthias : 
 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 27 , wherein the aminosterol:
 (a) is Aminosterol 1436;   (b) is squalamine;   (c) comprises a sterol nucleus and a polyamine, attached at any position on the sterol, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (d) comprises a bile acid nucleus and a polyamine, attached at any position on the bile acid, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (e) is modified to include one or more of the following: (1) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; (2) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and (3) substitution of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system; and/or   (f) is a derivative of squalamine or natural aminosterol modified through medical chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof.   
     
     
         34 . A method of treating or preventing Alzheimer's disease comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         35 . The method of  claim 34 , wherein administration of the aminosterol:
 (a) triggers the production of neuro-protective hormones or neuropeptides in the brain, which function to prevent onset or development of Alzheimer's Disease or related symptoms; and/or   (b) physically reduces the concentration of membrane bound beta-amyloid from its target membranes, which functions to prevent onset or development of Alzheimer's Disease or related symptoms.   
     
     
         36 . The method of  claim 34 , wherein the aminosterol composition is co-administered or combined with one or more drugs commonly prescribed to treat Alzheimer's disease or related symptoms. 
     
     
         37 . The method of  claim 36 , wherein the one or more drugs commonly prescribed to treat Alzheimer's disease or related symptoms are selected from the group consisting of Glutamate, Antipsychotic drugs, Huperzine A, acetylcholinesterase inhibitors, NMDA receptor antagonists, memantine, donepezil, galantamine, and rivastigmine. 
     
     
         38 . The method of  claim 35 , wherein:
 (a) the compound is an aminosterol that can inhibit the formation of actin stress fibers in endothelial cells stimulated by a ligand known to induce stress fiber formation, having the chemical structure of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 W is 24S —OSO 3  or 24R—OSO 3;    
 X is 3β—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH— or 3α—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—; 
 Y is 20R—CH 3 ; and 
 Z is 7α or 7β—OH; or
 (b) the aminosterol is represented by the family of related compounds (compounds 1-8) isolated from  Squalus acanthias : 
 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         39 . The method of  claim 34 , wherein the aminosterol:
 (a) is Aminosterol 1436;   (b) is squalamine;   (c) comprises a sterol nucleus and a polyamine, attached at any position on the sterol, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (d) comprises a bile acid nucleus and a polyamine, attached at any position on the bile acid, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (e) is modified to include one or more of the following: ( 1 ) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; (2) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and (3) substitution of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system; and/or   (f) is a derivative of squalamine or natural aminosterol modified through medical chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof.   
     
     
         40 . The method of  claim 34 , wherein:
 (a) the effective daily dosing amount is about 0.1 to about 20 mg/kg body weight; and/or   (b) the effective dose is established by defining the initial dose required to induce the Aminosterol-Induced GI Response, which is the initial dose required to stimulate a change in bowel activity, nausea, secretory diarrhea, or any combination thereof.   
     
     
         41 . The method of  claim 34 , comprising administering to the subject in need a combination of:
 (a) a pharmaceutically acceptable grade of squalamine; and   (b) a pharmaceutically acceptable grade of Aminosterol 1436,   wherein the squalamine and Aminosterol 1436 are present in the same or separate compositions.   
     
     
         42 . A method of treating or preventing Huntington's Disease and/or Huntington's chorea comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         43 . The method of  claim 44 , wherein administration of the aminosterol triggers the production of neuro-protective hormones or neuropeptides in the brain, which function to prevent onset or development of Huntington's Disease or related symptoms. 
     
     
         44 . The method of  claim 42 , wherein the aminosterol composition is co-administered or combined with one or more drugs commonly prescribed to treat Huntington's disease or related symptoms. 
     
     
         45 . The method of  claim 44 , wherein the one or more drugs commonly prescribed to treat Huntington's disease or related symptoms are selected from the group consisting of antipsychotic drugs, drugs used to treat dystonia, GABA-regulating drugs, dopamine-regulators, anticonvulsants, drugs used to treat depression, and other drugs commonly used to treat Huntington's disease such as amantadine, tetrabenazine, Dopamine blockers, and co-enzyme Q10. 
     
     
         46 . The method of  claim 42 , wherein:
 (a) the compound is an aminosterol that can inhibit the formation of actin stress fibers in endothelial cells stimulated by a ligand known to induce stress fiber formation, having the chemical structure of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 W is 24S —OSO 3  or 24R—OSO 3;    
 W is 24S —OSO 3  or 24R—OSO 3;    
 X is 3β—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH— or 3α—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—; 
 Y is 20R—CH 3 ; and 
 Z is 7α or 7β—OH; or
 (b) the aminosterol is represented by the family of related compounds (compounds 1-8) isolated from  Squalus acanthias : 
 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         47 . The method of  claim 42 , wherein the aminosterol:
 (a) is Aminosterol 1436;   (b) is squalamine;   (c) comprises a sterol nucleus and a polyamine, attached at any position on the sterol, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (d) comprises a bile acid nucleus and a polyamine, attached at any position on the bile acid, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (e) is modified to include one or more of the following: (1) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; (2) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and (3) substitution of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system; and/or   (f) is a derivative of squalamine or natural aminosterol modified through medical chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof.   
     
     
         48 . The method of  claim 42 , wherein:
 (a) the effective daily dosing amount is about 0.1 to about 20 mg/kg body weight; and/or   (b) the effective dose is established by defining the initial dose required to induce the Aminosterol-Induced GI Response, which is the initial dose required to stimulate a change in bowel activity, nausea, secretory diarrhea, or any combination thereof.   
     
     
         49 . The method of  claim 42 , comprising administering to the subject in need a combination of:
 (a) a pharmaceutically acceptable grade of squalamine; and   (b) a pharmaceutically acceptable grade of Aminosterol 1436,   wherein the squalamine and Aminosterol 1436 are present in the same or separate compositions.   
     
     
         50 . A method of treating or preventing multiple sclerosis comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         51 . The method of  claim 50 , wherein the method results in triggering the production of neuro-protective hormones or neuropeptides which function to prevent onset or development of Parkinson's Disease or Parkinson's Disease symptoms. 
     
     
         52 . The method of  claim 50 , wherein the aminosterol composition is co-administered or combined with one or more drugs commonly prescribed to treat multiple sclerosis or related symptoms. 
     
     
         53 . The method of  claim 52 , wherein the one or more drugs commonly prescribed to treat multiple sclerosis or related symptoms are selected from the group consisting of corticosteroids, methylprednisolone, plasmapheresis, fingolimod, interferon beta-la, interferon beta-1b, glatiramer acetate, mitoxantrone, natalizumab, alemtuzumab, daclizumab, rituximab, dirucotide, BHT-3009, cladribine, dimethyl fumarate, estriol, fingolimod, laquinimod, minocycline, statins, temsirolimus teriflunomide, naltrexone, and vitamin D analogs. 
     
     
         54 . The method of  claim 50 , wherein:
 (a) the compound is an aminosterol that can inhibit the formation of actin stress fibers in endothelial cells stimulated by a ligand known to induce stress fiber formation, having the chemical structure of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein:
 W is 24S —OSO 3  or 24R—OSO 3;    
 X is 3β—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH— or 3α—H 2 N—(CH 2 ) 4 —NH—(CH 2 ) 3 —NH—; 
 Y is 20R—CH 3 ; and 
 Z is 7α or 7β—OH; or
 (b) the aminosterol is represented by the family of related compounds (compounds 1-8) isolated from  Squalus acanthias : 
 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         55 . The method of  claim 50 , wherein the aminosterol:
 (a) is Aminosterol 1436;   (b) is squalamine;   (c) comprises a sterol nucleus and a polyamine, attached at any position on the sterol, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (d) comprises a bile acid nucleus and a polyamine, attached at any position on the bile acid, such that the molecule exhibits a net charge of at least +1, the charge being contributed by the polyamine;   (e) is modified to include one or more of the following: (1) substitutions of the sulfate by a sulfonate, phosphate, carboxylate, or other anionic moiety chosen to circumvent metabolic removal of the sulfate moiety and oxidation of the cholesterol side chain; (2) replacement of a hydroxyl group by a non-metabolizable polar substituent, such as a fluorine atom, to prevent its metabolic oxidation or conjugation; and (3) substitution of various ring hydrogen atoms to prevent oxidative or reductive metabolism of the steroid ring system; and/or   (f) is a derivative of squalamine or natural aminosterol modified through medical chemistry to improve bio-distribution, ease of administration, metabolic stability, or any combination thereof.   
     
     
         56 . The method of  claim 50 , wherein:
 (a) the effective daily dosing amount is about 0.1 to about 20 mg/kg body weight; and/or   (b) the effective dose is established by defining the initial dose required to induce the Aminosterol-Induced GI Response, which is the initial dose required to stimulate a change in bowel activity, nausea, secretory diarrhea, or any combination thereof.   
     
     
         57 . The method of  claim 50 , comprising administering to the subject in need a combination of:
 (a) a pharmaceutically acceptable grade of squalamine; and   (b) a pharmaceutically acceptable grade of Aminosterol 1436,   wherein the squalamine and Aminosterol 1436 are present in the same or separate compositions.   
     
     
         58 . A method of treating acute traumatic injury to the central nervous system comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         59 . A method of treating stroke comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         60 . A method of treating acute head injury comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         61 . A method of treating a spine injury comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         62 . A method of treating cerebral palsy comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         63 . A method of treating or preventing epilepsy comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         64 . A method of treating or preventing peripheral sensory neuropathy comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject. 
     
     
         65 . A method of treating or preventing diabetes mellitus or diabetic neuropathy comprising orally administering a composition comprising a pharmaceutically acceptable grade of at least one aminosterol, or a pharmaceutically acceptable salt or derivative thereof, in an amount sufficient to produce a beneficial neuro-protective effect in the subject.