Compositions and methods for treating digestive disorders

Abstract

Provided are electrokinetically-altered fluids (e.g., gas-enriched (e.g., oxygen-enriched) electrokinetic fluids) comprising an ionic aqueous solution of charge-stabilized oxygen-containing nanostructures in an amount sufficient to provide, upon contact with a cell, modulation of at least one of cellular membrane potential and cellular membrane conductivity, and therapeutic compositions and methods for using same in treating digestive disorders or at least one symptom thereof. The electrokinetically altered fluid compositions and methods include electrokinetically-altered ionic aqueous fluids optionally in combination with other therapeutic agents. Particular aspects provide for regulating or modulating intracellular signal transduction associated with said digestive disorders by modulation of at least one of cellular membranes, membrane potential, membrane proteins such as membrane receptors, including but not limited to G-Protein Coupled Receptors (GPCR), and intercellular junctions (e.g., tight junctions, gap junctions, zona adherins and desmasomes). Other embodiments include particular routes of administration or formulations for the electrokinetically-altered fluids and therapeutic compositions.

1 . A method for treating a digestive disorder or digestive disease, or at least one symptom thereof, comprising administering to a subject in need thereof a therapeutically effective amount of an oxygenated ionic aqueous solution of charge-stabilized oxygen-containing nanobubbles having an average diameter of less than 100 nanometers sufficient for treating a digestive disorder or at least one symptom thereof. 
     
     
         2 . The method of  claim 1 , wherein the charge-stabilized oxygen-containing nanobubbles are the major charge-stabilized gas-containing nanostructure species in the ionic aqueous solution. 
     
     
         3 . The method of  claim 1 , wherein the percentage of dissolved oxygen molecules present in the ionic aqueous solution as the charge-stabilized oxygen-containing nanobubbles is a percentage greater than 0.01%. 
     
     
         4 . The method of  claim 1 , wherein the total dissolved oxygen is substantially present in the ionic aqueous solution as the charge-stabilized oxygen-containing nanobubbles. 
     
     
         5 . The method of  claim 1 , wherein the charge-stabilized oxygen-containing nanobubbles have an average diameter of less than 90 nm. 
     
     
         6 . The method of  claim 1 , wherein the ionic aqueous solution comprises a saline solution. 
     
     
         7 . The method of  claim 1 , wherein the ionic aqueous solution is superoxygenated. 
     
     
         8 . The method of  claim 1 , wherein the ionic aqueous solution comprises a form of solvated electrons. 
     
     
         9 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the digestive disorder or disease, or the at least one symptom thereof is related to at least one condition selected from the group consisting of gastritis, peptic ulcer, duodenal ulcer, gastroesophageal reflux disease (GERD), acid reflux, eosinophilic esophagitis, inflammatory bowel disease including Crohn's disease, irritable bowel syndrome, infection or trauma to the gastrointestinal tract including infection by  H. pylori, Salmonella, Shigella, Staphylococcus, Campylobacter, Clostridium, Escherichia coli, Yersinia, Vibrio, Candida, Giardia, Entamoeba histolytica , rotavirus, norovirus, adenovirus and astrovirus, inflammation in the gastrointestinal tract, mixed connective tissue disease (MCTD), and ulcerative colitis. 
     
     
         13 . The method of  claim 1 , wherein the digestive disorder or disease, or the at least one symptom thereof comprises at least one selected from the group consisting of acid reflux including gastroesophageal reflux disease (GERD), eosinophilic esophagitis, and inflammation in the gastrointestinal tract. 
     
     
         14 . The method of  claim 1 , wherein the digestive disorder or disease, or the at least one symptom thereof comprises at least one of acid reflux including gastroesophageal reflux disease (GERD), eosinophilic esophagitis. 
     
     
         15 . The method of  claim 1 , further comprising combination therapy, wherein at least one additional therapeutic agent is administered to the patient. 
     
     
         16 . The method of  claim 15 , wherein the at least one additional therapeutic agent is selected from the group consisting proton pump inhibitors, including omeprazole, pantoprazole, lansoprazole, esomeprazole, tenatoprazole, and rabeprazole; histamine H2 receptor blockers, including ranitidine, famotidine, cimetidine, and nizatidine; antacids, including aluminum hydroxide, magnesium hydroxide, aluminum carbonate, magnesium carbonate, calcium carbonate, sodium bicarbonate, hydrotalcite, and magaldrate-simethicone; prokinetics, including itopride, domperidone, metoclopramide, erythromycin, prucalopride, and cisapride; antidiarrheal agents, including bismuth subsalicyte, loperamide, and diphenocylate; corticosteroids, including hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methyprednisolone, and prednisone; antispasmodics including dicyclomine, atropine, atropine methonitrate, mebeverine, scopolamine, and pirenzepine; immunomodulators including azathioprine, mercaptopurine, and methotrexate; antibiotics, including amoxicillin (penicillins), clarithromycin, levofloxacin, metronidazole; biologics including infliximab, etanercept, adalimumab, certolizumab, and natalizumab; anti-inflammatory agents, including 4-Aminosalicylic acid and 5 Aminosalicylic acid; laxatives including lubiprostone and tegaserod; alginic acid; sucralfate; misoprostol; and mosapride and combinations thereof. 
     
     
         17 . The method of  claim 15 , wherein the at least one additional therapeutic agent is selected from the group consisting of proton pump inhibitors, histamine H2 receptor blockers, antacids, prokinetics, antidiarrheals, anticholinergics, corticosteroids (inhaled or otherwise), systemic corticosteroids, glucocorticoids, antispasmodics, immunomodulators, antibiotics, biologics, anti-inflammatory agents, laxatives, and combinations thereof. 
     
     
         18 . The method of  claim 15 , wherein the at least one additional therapeutic agent is selected from the group consisting of albuterol, budesonide, esomeprazole (Nexium) and omeprazole (Prilosec), and active derivatives thereof. 
     
     
         19 . The method of  claim 15 , wherein the at least one additional therapeutic agent is selected from the group consisting of TSLP antagonists, TSLPR antagonists and combinations thereof. 
     
     
         20 . The method of  claim 19 , wherein the antagonist is selected from the group consisting of neutralizing antibodies specific for TSLP or the TSLP receptor, soluble TSLP receptor molecules, TSLP receptor fusion proteins, TSLPR-immunoglobulin Fc molecules and combinations thereof. 
     
     
         21 . The method of  claim 1 , wherein the ionic aqueous solution modulates localized or cellular levels of nitric oxide. 
     
     
         22 . The method of  claim 1 , wherein the ionic aqueous solution promotes a localized decrease at the site of administration of at least one cytokine selected from the group consisting of: IL-1beta, IL-8, TNF-alpha, and TNF-beta. 
     
     
         23 . The method of  claim 1 , further comprising a synergistic or non-synergistic inhibition or reduction in inflammation by simultaneously or adjunctively treating the subject with another anti-inflammatory agent. 
     
     
         24 - 33 . (canceled) 
     
     
         34 . The method of  claim 1 , comprising administration to a cell network or layer, and further comprising modulation of an intercellular junction therein. 
     
     
         35 . The method of  claim 34 , wherein the intracellular junction comprises at least one selected from the group consisting of tight junctions, gap junctions, zona adherins and desmasomes. 
     
     
         36 . The method of  claim 34 , wherein the cell network or layers comprises at least one selected from the group consisting of esophageal epithelium, gastric epithelium, large intestinal epithelium including epithelium of the cecum and colon regions thereof, small intestinal epithelium, including the epithelium or the duodenum, jejunum, and ileum regions thereof. 
     
     
         37 . The method of  claim 1 , wherein the oxygen in the ionic aqueous solution is present in an amount of at least 15 ppm at atmospheric pressure. 
     
     
         38 . The method of any one of  claim 1 , wherein the ionic aqueous solution comprises at least one of a form of solvated electrons, and electrokinetically modified or charged oxygen species. 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 38 , wherein the ionic aqueous solution comprises solvated electrons stabilized by molecular oxygen. 
     
     
         41 . The method of  claim 1 , wherein administration is by oral, sublingual, buccal, parenteral, rectal, topical, or injection route. 
     
     
         42 . The method of  claim 41 , wherein the administration route is by transdermal, intravaginal, intraoccular, intraotical, intranasal, inhalation, injection or insertion of implantable devices or materials. 
     
     
         43 . The method of  claim 41 , wherein the injection route is subcutaneous, intramuscular, intra-arterial, intraperitoneally, intracisternally, intravesically, intrathecally, or intravenous. 
     
     
         44 . The method of  claim 1 , wherein the ionic aqueous solution comprises oxygen-enriched water. 
     
     
         45 - 47 . (canceled)