Methods for treating gi tract disorders

Abstract

Provided herein are methods, compositions, and kits for the treatment of an enteric nervous system disorder. Such methods may comprise administering to a subject an effective amount of a phenothiazine compound, a peripherally restricted dopamine decarboxylase inhibitor, and/or a peripherally restricted dopamine D2 receptor antagonist that does not substantially inhibit hERG channels.

1 . A method of treating an enteric nervous system disorder in a human subject in need thereof, comprising administering to the subject an effective dose of a compound of formula III 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, solvate, or metabolite thereof, wherein the administering occurs for over 5 days. 
     
     
         2 . The method of  claim 1 , wherein the administering occurs for over 7 days. 
     
     
         3 . The method of  claim 1 , wherein the administering occurs for over 12 weeks. 
     
     
         4 . The method of  claim 1 , wherein the administering occurs four times per day. 
     
     
         5 . The method of  claim 1 , wherein the effective dose is more than 30 mg of the compound a day. 
     
     
         6 . The method of  claim 1 , further comprising co-administering to the human subject an additional therapeutic agent. 
     
     
         7 . The method of  claim 6 , wherein the additional therapeutic agent is selected from the group consisting of serotonin agonists, serotonin antagonists, selective serotonin reuptake inhibitors, anticonvulsants, opioid receptor agonists, bradykinin receptor antagonists, NK receptor antagonists, adrenergic receptor agonists, benzodiazepines, gonadotropin-releasing hormone analogues, calcium channel blockers, and somatostatin analogs. 
     
     
         8 . The method of  claim 6 , wherein the co-administering comprises administering the additional therapeutic agent sequentially with the compound. 
     
     
         9 . The method of  claim 6 , wherein the co-administering comprises administering the additional therapeutic agent simultaneously with the compound. 
     
     
         10 . The method of  claim 1 , further comprising co-administering to the human subject an effective dose of a dopamine decarboxylase inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the dopamine decarboxylase inhibitor does not cross a blood-brain barrier of the human subject. 
     
     
         12 . The method of  claim 11 , wherein the dopamine decarboxylase inhibitor is carbidopa. 
     
     
         13 . The method of  claim 1 , wherein the enteric nervous system disorder is a chronic disorder. 
     
     
         14 . The method of  claim 1 , wherein the enteric nervous system disorder is selected from the group consisting of irritable bowel syndrome, lysosomal storage disorders, intestinal dysmotility, ganglioneuroma, multiple endocrine neoplasia type 2B (MEN2B), gastrointestinal neuropathy, and intestinal neuronal dysplasia. 
     
     
         15 . The method of  claim 1 , wherein the enteric nervous system disorder is gastroparesis. 
     
     
         16 . The method of  claim 1 , wherein the enteric nervous system disorder causes a symptom which is selected from the group consisting of nausea, vomiting, delayed gastric emptying, diarrhea, abdominal pain, gas, bloating, gastroesophageal reflux, reduced appetite, and constipation. 
     
     
         17 . The method of  claim 1 , wherein the enteric nervous system disorder causes a symptom, wherein the symptom is associated with Scleroderma, Parkinson's Disease, gastroesophageal reflux disease, Menetrier's Disease, a vestibular disorder, chemotherapy, cancer, drug use, or functional dyspepsia. 
     
     
         18 . The method of  claim 1 , wherein the administering is oral, parenteral, enteral, intraperitoneal, topical, transdermal, ophthalmical, intranasal, local, via spray, subcutaneous, intravenous, intratonsillal, intramuscular, buccal, sublingual, rectal, intra-arterial, by infusion, or intrathecal. 
     
     
         19 . The method of  claim 1 , wherein the compound is in a pharmaceutical composition comprising a physiologically acceptable vehicle. 
     
     
         20 . The method of  claim 19 , wherein the pharmaceutical composition is formulated as a tablet, a capsule, a cream, a lotion, an oil, an ointment, a gel, a paste, a powder, a suspension, a syrup, an enema, an emulsion, a solution, or a controlled-release formulation. 
     
     
         21 - 30 . (canceled)