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United States Patent 19 11 Patent Number: 5,648,355 Theoharides 45 Date of Patent: *Jul

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United States Patent 19 11 Patent Number: 5,648,355 Theoharides 45 Date of Patent: *Jul US005648355A United States Patent 19 11 Patent Number: 5,648,355 Theoharides 45 Date of Patent: *Jul. 15, 1997 54 METHOD OF TREATMENT OF Weston, et al. "Terminal Ileal Mucosal Mast Cells in Irri ENDOGENOUS, PAINFUL table Bowel Syndrome", Digestive Diseases and Sciences, GASTRONTESTNAL CONDITIONS OF 38(9): 1590–1595, 1993. NON-INFLAMMATORY, NON-ULCERATIVE Read, “Irritable Bowel Syndrome (IBS)-Definition and ORIGN Pathophysiology”, Scand. Jrn. Gastroenterol, 130:7-13, 1987. 75 Inventor: Theoharis C. Theoharides, Brookline, Stefanini, et al. “Oral Disodium Cromoglycate Treatment on Mass. Irritable Bowel Syndrome: An Open Study on 101 Subjects with Diarrheic Type", Am. Jrml. of Gastroenterology, 73 Assignee: KOS Pharmaceutical, Inc., Miami, 87(1):55-57, 1992. Fla. Martin, et al. "Comparison of the Inhibitory Effects of * Notice: The term of this patent shall not extend Spermine, Papaverine and Adrenaline Upon Isolated Seg beyond the expiration date of Pat. No. ments . ', Clin. & Exper: Pharma. & Physiology, 5,250,529. 13:87–90, 1986. Cartagena, et al. “Inhibition of Mast Cell Degranulation by Natural Polyamines", Federation Proceedings, 45:1648, 21 Appl. No.: 193597 1986. 22 Filed: Feb. 9, 1994 Page, et al. “Treatment of the Irritable Syndrome with (51 Int. Cl. ................ A61K 31/495; A61K 31/42; Bentyle) (Dicyclomine Hydrochloride)". Clin. Gastroen A61K31/35; A61K 3/21 terol, 3:153-156, 1981. 52 U.S. Cl. ......................... 514/255; 514/381: 514/457: Aihara, et ai. "Polyamine Inhibition of Gastric Ulceration 514/510; 514/579; 514/650; 514/673 and Secretion in Rats'. Biochemical Pharmacology, 58. Field of Search .................................... 514/255,381, 32(11):1733-1736, 1983. 514/457, 510,579, 650, 673 McCormack, et al. "Polyamines are necessary for cell migration by a small intestinal crypt cell line”, Am. Jnl. of 56) References Cited Physiology, 264(2):G367-G374, 1993. Auricchio, et al. “Amines Protect in Vitro the Celiac Small U.S. PATENT DOCUMENTS Intestine From the Damaging Activity of Gliadin Peptides”, 4,507,321 3/1985 Raisfeld .................................. 514f673 Gastroenterology, 99:1668–1674, 1990. 4,843,074 6/1989 Rzeszotarski et al. 54/228.2 Stern, et al. "Contribution to pharmacology of spermidine”, 5,057,322 10/1991 Frost ....................................... 424/474 Glas Srpske Akademije Nauka, 24:43-50, 1971 (See 5,250,529 10/1993 Theoharides ............................ 514/255 abstract). FOREIGN PATENT DOCUMENTS Chemical Abstracts; Ferzoco et al., "Counterregulation of a Prokinetic Calcium-Dependent Mechanism by CAMP-De WO93/2773 8/1993 WIPO pendent Agents in Isolated Segments of Terminal Ileum”; OTHER PUBLICATIONS Abstract No. 119: 41390 (See Abstract). Pothoulakis et al., “CP-96.345, a substance Pantagonist, inhibits rat intestinal responses to Clostridium difficile toxin Primary Examiner-Kevin E. Weddington A but no cholera toxin'". Proc. Natl. Acad. Sci., vol. 91, pp. 57 ABSTRACT 947-951, Feb. 1994. Pothoulakis et al., "Ketotifen Inhibits Clostridium difficile A method for treating endogenous, painful gastrointestinal Toxin A-Induced Enteritis in Rat Ileum”, Gastroenterology conditions of non-inflammatory, non-ulcerative origin, such 1993, vol. 105, pp. 701-707. as abdominal migraine and irritable bowel syndrome, entails Castagliuolo et al., “Neuronal Involvement In The Intestinal administering a pharmacologically effective amount of a Effects Of Clostridium difficile Toxin AAnd Vibrio Cholera mast cell degranulation-blocking agent. Enterotoxin. In Rat Ileum”, Gastroenterology, 104:A677, 104:A679, 1993. 21 Claims, No Drawings 5,648,355 1. 2 METHOD OF TREATMENT OF absence of a headache and still be considered a "migraine ENEDOGENOUS, PAINFUL equivalent,” especially in children. Lundbert, Headache 15: GASTRONTESTINAL CONDITIONS OF 122-25 (1975). NON-INFLAMMATORY, NON-ULCERATIVE It is appropriate, therefore, to consider the pathophysiol ORIGIN ogy and therapy of the category of endogenous, painful gastrointestinal conditions of non-inflammatory, non BACKGROUND OF THE INVENTION ulcerative origin, including but not limited to abdominal The present invention relates to treating endogenous, migraine and IBS. painful gastrointestinal conditions, such as abdominal There is no effective therapy for IBS or related, endog migraine and irritable bowel syndrome, which involve nei 10 enous gastrointestinal conditions. Thus, while various con ther inflammation nor ulcers. "Endogenous” in this context pounds have been described as useful in treating IBS, denotes a condition that is not attributed to an exogenous including 9H-fluorenyl-substituted amino acid derivatives casual factor such as a food allergy, a bacterial or viral (U.S. Pat. No. 5,079.260), benzodiazepine derivatives (U.S. infection, a parasitic infestation, a drug reaction or trauma. Pat. No. 4970,207), certain substituted sulfonamides More specifically, the present invention relates to treating a 15 (European application No. 0404 440), and mu opiate patient suffering from such a condition with a pharmaceu receptor antagonists or “blockers" (U.S. Pat. No. 4,684,620), tically effective amount of a mast cell degranulation none of the disclosed treatment approaches in fact have blocking agent. proven successful. See, for example, J. Gastroenterol. 95: The phrase "abdominal pain” indicates pain associated 232-41 (1988). with the gastrointestinal tract. Functional abdominal pain 20 Similarly, no effective remedy exists for abdominal usually is classified either as dyspepsia not associated with migraine. Development of a treatment has been hindered in ulcers or as irritable bowel syndrome. part by the fact that the condition often presents without Irritable bowel syndrome (IBS), also known as "spastic headache and any of the prodromal symptoms (nausea, colon' and “mucous colitis,” is an intestinal motility disor vomiting, photophobia, sonophobia) typically associated der and ranks among the most common pathological con 25 with ordinary migraine. ditions of the intestine. IBS is characterized by periodic or For example, agents that prevent vasodilation, such as the chronic bowel symptoms which include abdominal pain, B-blocker propranolol, seem not to work, since the abdomi diarrhea, constipation, a sense of incomplete evacuation, nal pain appears not to be associated with the vasculature, in bloating, and excess gas sensation. This disorder seems to contrast to the migraine headache. By the same token, none afflict type A (highly driven, perfectionist) personalities 30 of the drugs used prophylactically or acutely predominantly, and is two to five times more prevalent in (symptomatically) for the treatment of migraine headaches women (20 times higher in Jewish women) than in men. It would be expected to work, since the prophylactic agents affects about 3 percent of the population. Drossman, Hos prevent vasodilation while the acute agents constrict dilated pital Practice 93:95-108 (1988). vessels. Moreover, drugs effective against migraine head Pain and flatulence are the most prominent symptoms in 35 aches must cross the blood-brain barrier, while a drug patients suffering from IBS. The pain is usually situated in effective against abdominal migraine would be concentrated the left lower quadrant or suprapubically. It may be worse preferentially in the intestine. Also, intracranial mast cells just before defecation and may lessen slowly afterward. which have been associated with migraine headaches, see Certain foods may precipitate the symptoms. When diarrhea Theoharides, Life Sciences 46:607-17 (1980), and U.S. Pat. is the main complaint, the stool often is watery but not No. 5.250,529, differ from gastrointestinal mast cells. For bloody. The diarrhea frequently is worst in the morning and instance, the former but not the latter are inhibited by improves during the day. Some patients complain of pain in disodium cromoglycate. Pierce et al., J. Immunol. 128: the left upper quadrant that is often brought on by meals and 2481-86 (1982); Labracht-Hall et al., Neuroscience is very consistent in nature. In these patients, plain abdomi 39:199-207 (1990). nal X-rays demonstrate air in the splenic flexure. Although 45 this variant of IBS has been called "splenic flexure SUMMARY OF THE INVENTION syndrome,” there is no evidence that its pathogenesis differs It is an object of the present invention, therefore, to from that of other manifestations of the disorder. provide an effective treatment for the above-described cat Many patients relate an exacerbation of symptoms to 50 egory of endogenous gastrointestinal conditions which episodes of emotional stress. Fear of underlying cancer is avoids the lack of success and other problems associated common. In children of school age, IBS presents primarily with past efforts to this end. with pain. Pain is usually periumbilical or in the left lower In accomplishing this objective and others, there has been quadrant and is cramping in nature. provided, in accordance with one aspect of the present Many patients also experience abdominal pain that is 55 invention, a method for treating endogenous, painful gas endogenous but that is associated with nausea, bowel peri trointestinal conditions of non-inflammatory, non-ulcerative stalsis and flatulence without diarrhea or constipation, the origin, which method comprises administering to a patient a symptoms commonly seen with IBS. Such abdominal pain pharmacologically effective amount of a mast cell also can be associated with classic symptoms of migraine,
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