Method for treatment of diarrhea-predominant irritable bowel syndrome

Abstract

The present invention provides methods for treating diarrhea-predominant irritable bowel syndrome comprising administering to a patient in need thereof, an inhibitor of chloride-ion transport in an amount sufficient to treat diarrhea-predominant irritable bowel syndrome (d-IBS). Treatment of d-IBS includes the treatment of the diarrhea component of d-IBS as well as the pain, abdominal discomfort and other symptoms associated with d-IBS. In one embodiment, the inhibitor of chloride-ion transport is crofelemer.

1 . A method of treating pain and diarrhea associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a molecule that inhibits secretion of chloride ions from a cell (inhibitor molecule) effective to treat pain and diarrhea associated with d-IBS. 
   
   
       2 . A method of treating abdominal discomfort and diarrhea associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a molecule that inhibits secretion of chloride ions from a cell (inhibitor molecule) effective to treat abdominal discomfort and diarrhea associated with d-IBS. 
   
   
       3 . A method of treating pain associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a molecule that inhibits secretion of chloride ions from a cell (inhibitor molecule) effective to treat pain associated with d-IBS. 
   
   
       4 . A method of treating abdominal discomfort associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a molecule that inhibits secretion of chloride ions from a cell (inhibitor molecule) effective to treat abdominal discomfort associated with d-IBS. 
   
   
       5 . The method of any one of  claims 1  to  4 , in which the inhibitor is an extract from  Croton  spp. or  Calophyllum  spp. 
   
   
       6 . The method of any one of  claims 1  to  4 , in which the inhibitor is latex from  Croton  spp. or  Calophyllum  spp. 
   
   
       7 . The method of any one of  claims 1  to  4 , in which the inhibitor is an inhibitor of CFTR function. 
   
   
       8 . The method of  claim 7 , in which the inhibitor of CFTR function is selected from the group consisting of 2-thioxo-4-thiazolidinone compounds and 3-[(3-trifluoromethy)phenyl]-5-[(3-carboxyphenyl) methylene]-2-thioxo-4-thiazolidinone, tolbutamide, glibenclamide and fluorescein or a derivative thereof, diazoxide, lemakalim, minoxidil sulfate and analogs thereof; 8-bromo-cAMP, 8-(4-chlorophenylthio) (CPT)-cAMP and 8-bromo-cGMP, CPT-cGMP; verapamil, nifedipine, diltiazem, disulfonic stilbene compounds, diphenylamine-2-carboxylate (DPC) or 5-nitro-2(3-phenylpropylamino)benzoate (NPPB); anthracene-9-carboxylic acid (9-AC); 3-[(3-trifluoromethy)phenyl]-5-[(3-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone; N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycinehydrazide (GlyH-101) or derivatives thereof; malonic acid dihydrazides or derivatives thereof; loperamide; racecadotril; lidamidine hydrochloride; lonidamine; vanadate; bumetanide; pp2a; PP1; PP2B; bismuth subsalicylate; diphenoxylate hydrochloride; and sparteine. 
   
   
       9 . The method of any one of  claims 1  to  4 , in which the inhibitor is a synthetic or naturally-occurring polymer composition. 
   
   
       10 . The method of  claim 9 , in which the polymer composition comprises at least one monomer selected from the group consisting of catechin, epicatechin, gallocatechin and epigallocatechin. 
   
   
       11 . The method of any one of  claims 1  to  4 , in which the inhibitor is a proanthocyanidin polymer composition. 
   
   
       12 . The method of  claim 11 , in which the polymer composition is isolated from a Croton species or a Calophyllum species. 
   
   
       13 . The method of any one of  claims 1  to  4 , in which the inhibitor is crofelemer. 
   
   
       14 . The method of  claim 13 , in which crofelemer enteric coated and is orally administered in an amount of between about 50 mg per day and about 750 mg per day. 
   
   
       15 . The method of  claim 14 , in which crofelemer is administered in an amount of about 250 mg per day. 
   
   
       16 . The method of any one of  claims 1  to  4 , in which pain- or discomfort-free days increased by at least 10%. 
   
   
       17 . The method of any one of  claims 1  to  4 , in which the inhibitor is not systemically absorbed. 
   
   
       18 . A method of treating diarrhea associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a molecule that inhibits secretion of chloride ions from a cell (inhibitor molecule) effective to treat the diarrhea associated with d-IBS, with the proviso that the inhibitor molecule is not a polymeric proanthocyanidin composition isolated from  Croton  spp. or  Calophyllum  spp. or that the inhibitor molecule is not crofelemer. 
   
   
       19 . A method of treating abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a molecule that inhibits secretion of chloride ions from a cell (inhibitor molecule) effective to treat the abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS, with the proviso that the inhibitor molecule is not a polymeric proanthocyanidin composition isolated from  Croton  spp. or  Calophyllum  spp. or that the inhibitor molecule is not crofelemer. 
   
   
       20 . The method of  claim 18  or  19 , in which the method further comprises administering an analgesic agent or an anti-inflammatory agent. 
   
   
       21 . The method of any one of  claims 18  to  20 , in which the inhibitor is a small molecule inhibitor of CFTR. 
   
   
       22 . The method of any one of  claims 18  to  20 , in which the inhibitor is an isolated naturally occurring inhibitor of CFTR, or a synthetic or semisynthetic form of a naturally occurring inhibitor of CFTR. 
   
   
       23 . The method of  claim 21 , in which the small molecule inhibitor of CFTR is selected from the group consisting of: 2-thioxo-4-thiazolidinone compounds and 3-[(3-trifluoromethy)phenyl]-5-[(3-carboxyphenyl) methylene]-2-thioxo-4-thiazolidinone, tolbutamide, glibenclamide and fluorescein or a derivative thereof, diazoxide, lemakalim, minoxidil sulfate and analogs thereof; 8-bromo-cAMP, 8-(4-chlorophenylthio) (CPT)-cAMP and 8-bromo-cGMP, CPT-cGMP; verapamil, nifedipine, diltiazem, disulfonic stilbene compounds, diphenylamine-2-carboxylate (DPC) or 5-nitro-2(3-phenylpropylamino)benzoate (NPPB); anthracene-9-carboxylic acid (9-AC); 3-[(3-trifluoromethy)phenyl]-5-[(3-carboxyphenyl)methylene]-2-thioxo-4-thiazolidinone; N-(2-naphthalenyl)-[(3,5-dibromo-2,4-dihydroxyphenyl)methylene]glycine hydrazide (GlyH-101) or derivatives thereof; malonic acid dihydrazides or derivatives thereof; loperamide; racecadotril; lidamidine hydrochloride; lonidamine; vanadate; bumetanide; pp2a; PP1; PP2B; bismuth subsalicylate; diphenoxylate hydrochloride; and sparteine. 
   
   
       24 . The method of  claim 22 , in which the inhibitor is selected from arachidonic acid; linoleic acid;oleic acid, elaidic acid, palmitic acid, myristic acid, lysophosphatidic acid, and niflumic acid; flavonoids, flavonols, polyphenols, proanthocyanidins, oligomeric proanthocyanidins, (OPCs), procyanidolic oligomers(PCOs), condensed tannins, leukocynanidins, anthocyanidins, procyanidins, cyanidins, prodelphinidins, delphinidin, catechins, epicatechins, gallocatechins, epigallocatechins, epigallocatechin gallate, epicatechin gallate, catechin gallate, gallocatechin gallate, quercetin, sesquiterpenes, diterpenes, terpenes, and terpenoid derivatives, tannins, alkaloids, saponins, morin, and luteolin. 
   
   
       25 . A method of treating diarrhea associated with d-IBS comprising orally administering to a patient in need of such treatment, an amount of enterically-protected crofelemer (CAS 148465-45-6) effective to treat the diarrhea associated with d-IBS, in which said amount is between about 50 mg per day and about 750 mg per day. 
   
   
       26 . A method of treating abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS comprising orally administering to a patient in need of such treatment, an amount of enterically-protected crofelemer effective to treat the abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS, in which said amount is between about 50 mg per day and about 750 mg per day. 
   
   
       27 . A method of treating diarrhea associated with d-IBS comprising orally administering to a patient in need of such treatment, an amount of crofelemer (CAS 148465-45-6) effective to treat the diarrhea associated with d-IBS, in which the crofelemer is formulated to be protected from the stomach in a formulation other than enteric coated, said amount bioequivalent to enteric-coated crofelemer at a dosage of about 50 mg per day to about 750 mg per day. 
   
   
       28 . A method of treating abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS comprising orally administering to a patient in need of such treatment, an amount of crofelemer effective to treat the abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS, in which the crofelemer is formulated to be protected from the stomach in a formulation other than enteric-coated, said amount bioequivalent to enteric-coated crofelemer at a dosage of about 50 mg per day to about 750 mg per day. 
   
   
       29 . A method of treating diarrhea associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a polymeric proanthocyanidin composition isolated from  Croton  spp. or  Calophyllum  spp. effective to treat the diarrhea associated with d-IBS, in which said amount is bioequivalent to an orally administered dose of about 50 mg per day to about 750 mg per day of crofelemer. 
   
   
       30 . A method of treating abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS comprising administering to a patient in need of such treatment, an amount of a polymeric proanthocyanidin composition isolated from  Croton  spp. or  Calophyllum  spp. effective to treat the abnormal stool frequency, abnormal stool consistency or presence of urgency associated with d-IBS, in which said amount is bioequivalent to an orally administered dose of about 50 mg per day to about 750 mg per day of crofelemer. 
   
   
       31 . The method of any one of  claims 1 - 4 ,  18 ,  19  or  25 - 30 , in which the patient is a human female.