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(12) Patent Application Publication (10) Pub. No.: US 2004/0147509 A1 Landau (43) Pub US 2004O147509A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0147509 A1 Landau (43) Pub. Date: Jul. 29, 2004 (54) METHOD OF TREATING FUNCTIONAL (52) U.S. Cl. .................. 514/218; 514/252.16; 514/260.1 BOWEL DISORDERS (75) Inventor: Steven B. Landau, Wellesley, MA (US) Correspondence Address: (57)57 ABSTRACT HAMILTON, BROOK, SMITH & REYNOLDS, P.C. 530 VIRGINA ROAD The invention relates to a method of treating functional P.O. BOX 91.33 bowel disorders in a subject in need of treatment. The CONCORD, MA 01742-9133 (US) method comprises administering to a Subject in need of (73) Assignee: Dynogen Pharmaceuticals, Inc., Bos- treatment a therapeutically effective amount of a compound ton, MA that has 5-HT receptor antagonist activity and NorAdrena line Reuptake Inhibitor (NARI) activity. The invention fur (21) Appl. No.: 10/757,364 ther relates to a method of treating a functional bowel (22) Filed: Jan. 13, 2004 disorder in a subject in need thereof, comprising coadmin istering to Said Subject a first amount of a 5-HT antagonist Related U.S. Application Data and a second amount of a NARI, wherein the first and Second amounts together comprise a therapeutically effec (60) Provisional application No. 60/492,480, filed on Aug. tive amount or are each present in a therapeutically effective 4, 2003. Provisional application No. 60/440,077, filed amount. In addition, the method of the invention comprises on Jan. 13, 2003. administering a NARI alone. The functional bowel disorders Publication Classification which can be treated according to the method of the inven tion include IBS, functional abdominal bloating, functional (51) Int. Cl. ............................................. A61K 31/519 constipation and functional diarrhea. Patent Application Publication Jul. 29, 2004 Sheet 1 of 10 US 2004/0147509 A1 3O 25 20 15 10 - 2-le 5 -2. A. O O 15 30 60 Pressure (mmHg) -Er Responders -A-Non-Sensitized -e-Sensitized FIG. 1 O 15 30 60 Pressure (mmHg) -3-Vehicle mayo Non-Sensitized -O-Sensitized F.G. 2 Patent Application Publication Jul. 29, 2004 Sheet 2 of 10 US 2004/0147509 A1 O 15 30 60 Pressure (mm Hg) -A-Ondansetron 5mg/kg -X-Ondansetron 10mg/kg -O-Ondansetron 1 mg/kg. --Vehicle FIG. 3 Patent Application Publication Jul. 29, 2004 Sheet 3 of 10 US 2004/0147509 A1 25.0 es 200 5 is 15.0 E UO. 10.0 S 5 5.0 s: Pressure (mm Hg) -O-Nisoxetine 3mg/kg -X-Nisoxetine 30mg/kg -A-Nisoxetine 10mg/kg-HVehicle FIG. 4 Patent Application Publication Jul. 29, 2004 Sheet 4 of 10 US 2004/0147509 A1 25.0 200 15:0 10.0 5.0 0.0 Pressure (mm Hg) -O-MC-2253mg/kg -X-MC-225 30mg/kg -A-MC-225 10mg/kg. --Vehicle F.G. 5 Patent Application Publication Jul. 29, 2004 Sheet 5 of 10 US 2004/014.7509 A1 12.00 Home Cage 2 Sham Stress 2 WAS Basalt WAS Vehicle FIG. 6 ka C C) s O) Ol V) whatg s al s d s l s Vehicle Z MC 3mg/kg E MCI 10mg/kg EMC 30mg/kg FIG. 7 Patent Application Publication Jul. 29, 2004 Sheet 6 of 10 US 2004/0147509 A1 e O 1 2. O O ha OL w s d L s Vehicle 2 OND 1 mg/kg - OND 5mg/kg E. OND 10mg/kg FG. 9 Patent Application Publication Jul. 29, 2004 Sheet 7 of 10 US 2004/014.7509 A1 h O bn O. adg s al s U S Vehicle WAS 2 NS+OND FIG 10 Patent Application Publication Jul. 29, 2004 Sheet 8 of 10 US 2004/0147509 A1 100 i 80 C H 60 40 Gis 20 5 o SS Untreated Vehicle F.G. 11 100 N. 2 80 2 60 S 40 P NSN 20 SN NASA N SS Vehicle 3 10 30 MC-225 (mg/kg) F.G. 12 Patent Application Publication Jul. 29, 2004 Sheet 9 of 10 US 2004/0147509 A1 Nisoxetine (mg/kg) FIG. 13 Effect of Ondansetron on Small intestinal Transit 100 24 OO Vehicle 1 HH5 Ondansetron (mg/kg) - FIG. 14 Patent Application Publication Jul. 29, 2004 Sheet 10 of 10 US 2004/0147509 A1 Vehicle Nis 10 mg/kg+ Ond 5 mg/kg FG 15 US 2004/O147509 A1 Jul. 29, 2004 METHOD OF TREATING FUNCTIONAL BOWEL normal visceral Sensations are experienced at lower intralu DISORDERS minal volumes. While for a finding of allodynia, pain or discomfort is experienced at Volumes usually producing RELATED APPLICATIONS normal internal Sensations (see, for example, Mayer E. A. 0001) This application claims the benefit of U.S. Provi and Gebhart, G. F., Basic and Clinical Aspects of Chronic sional Application No. 60/492,480 filed on Aug. 4, 2003 and Abdominal Pain, Vol 9, 1 ed. Amsterdam: Elsevier, 1993:3- U.S. Provisional Application No. 60/440,077 filed on Jan. 28). 13, 2003. The entire teachings of the above applications are 0009. As such, IBS is a functional bowel disorder in incorporated herein by reference. which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Therefore, IBS has BACKGROUND OF THE INVENTION elements of an intestinal motility disorder, a Visceral Sensa 0002 Functional Bowel Disorders (FBDs) are functional tion disorder, and a central nervous disorder. While the gastrointestinal disorders having Symptoms attributable to Symptoms of IBS have a physiological basis, no physiologi the mid or lower gastrointestinal tract. FBDS can include, cal mechanism unique to IBS has been identified. In Some Irritable Bowel Syndrome (IBS), functional abdominal cases, the same mechanisms that cause occasional abdomi bloating, functional constipation and functional diarrhea nal discomfort in healthy individuals operate to produce the (see, for example, Thompson et al., Gut, 45 (Suppl. II):II43 symptoms of IBS. The symptoms of IBS are therefore a II47 (1999)). Of these disorders, IBS alone accounts for up product of quantitative differences in the motor reactivity of to about 3.5 million physician Visits per year, and is the most the intestinal tract, and increased Sensitivity to Stimuli or common diagnosis made by gastroenterologists, accounting Spontaneous contractions. for about 25% of all patients (Camilleri and Choi, Aliment. 0010 Conventional treatments for IBS are based on the Pharm. Ther., 11:3-15 (1997)). Overall, it is estimated that Severity and the nature of the Symptoms being experienced IBS affects up to 20% of the adult population worldwide by the patient and whether any psychological factors are with only 10-50% of those afflicted with IBS actually involved. Treatment of IBS may include one or more of the Seeking medical attention. Women apparently are more often following: lifestyle changes, pharmacological treatment and affected than men. In addition, psychological factors, for example, emotional StreSS or overt psychological disease, psychological treatment. However, there is no general treat modulate and exacerbate the physiological mechanisms that ment which is applicable to all cases of IBS. operate in IBS. 0011. In certain cases, the exclusion of foods which 0003. Due to a lack of readily identifiable structural or aggravate IBS Symptoms is recommended. However, this biochemical abnormalities in IBS, the medical community type of treatment is only effective when the underlying or has developed a consensus definition and criteria, known as contributing cause of IBS is related to diet. Psychological the Rome II Criteria, to aid in diagnosis of IBS. Therefore, treatment can be used in the treatment of IBS. Again, diagnosis of IBS is one of exclusion and is based on the however, this treatment does not provide a universal cure for observed Symptoms in any given case. The Rome II criteria the symptoms of IBS since not all cases of IBS are due to for IBS, include at least 12 weeks in the preceding 12 psychological factors. months, which need not be consecutive, of abdominal pain 0012 Pharmacologically active agents are often used to or discomfort that has two of three features: treat IBS. Anti-diarrheals, Such as loperamide, diphenoxy late, and codeine phosphate, for diarrhea-predominant IBS; 0004) (1) Relieved with defecation; and/or and antispasmodic agents, Such as anticholinergicS and 0005 (2) Onset associated with a change in the Smooth muscle relaxants, Such as cimetropium bromide, frequency of Stools, and/or pinaverium bromide, octilium bromide, trimebutine, and mebeverine, for diarrhea-predominant IBS and abdominal 0006 (3) Onset associated with a change in form pain. Again, while the antichloinergics and Smooth muscle (appearance) of Stool. relaxants provide Some pain relief, their effects on other Symptoms associated with IBS is unclear. 0007. Other symptoms, such as abnormal stool fre quency, abnormal Stool form, abnormal Stool passage, pas 0013 Tricyclic antidepressants, such as amitriptyline, Sage of mucus, and/or bloating or feeling of abdominal imipramine, and doxepin, are frequently used to treat IBS. distension, cumulatively Support the diagnosis of IBS. The tricyclics have been selected for use in IBS based on the anticholinergic and analgesic properties which they possess, 0008 Further, subjects with IBS exhibit visceral hyper which are independent of their psychotropic effects. It has Sensitivity, the presence of which behavioral Studies have been reported that the anticholinergic and analgesic effects shown is the most consistent abnormality in IBS. For of the tricyclic antidepressants on the gastrointestinal tract example, patients and controls were evaluated for their pain occur within 24 to 48 hours and that the tricyclic antide thresholds in response to progressive distension of the preSSants can benefit patients with pain predominant IBS Sigmoid colon induced by a balloon. At the same Volume of distension, the patients reported higher pain Scores com and increased bowel frequency (See, Clouse, R.
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