Methods for treating irritable bowel syndrome

Details Methods for treating irritable bowel syndrome Methods for treating irritable bowel syndrome

2002-06-10

2003-07-15

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S183000, C514S230500, C514S254060, C514S284000, C514S304000, C514S305000, C514S306000, C514S394000, C514S397000

Reexamination Certificate

active

06593336

ABSTRACT:

The invention relates to a new medical use for compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT
3
receptors.
5-HT
3
receptor antagonists may be identified by methods well known in the art, for example by their ability to inhibit 3-(5-methyl-1H-imidazole-4-yl)-1-[1-[
3
H]-methyl-1H-indol-3-yl]-1-propanone binding in rat entorhinal cortex homogenates (following the general procedure described by G Kilpatrick et al, Nature, 1987, 330, 746-748), and/or by their effect on the 5-HT-induced Bezold-Jarisch (B-J) reflex in the cat (following the general method described by A Butler et al, Br. J. Pharmacol., 94, 397-412 (1988)).
A number of different 5-HT
3
receptor antagonists have been disclosed, for example those of group A: indisetron, Ro-93777, YM-114, granisetron, talipexole, azasetron, tropisetron, mirtazapine, ramosetron, ondansetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620, lintopride, KAE-393, itasetron, mosapride and dolasetron.
In UK Patent No. 2209335, incorporated herein by reference, there is disclosed, inter alia, the compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, now known as alosetron, which may be represented by the formula (I):
and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular its hydrochloride salt.
5-HT
3
receptor antagonists are known to be useful in the treatment of a variety of conditions involving 5-HT
3
receptor-mediated mechanisms, including in particular emesis.
Irritable bowel syndrome (IBS) is the most common diagnosis made by gastroenterologists (1) and is characterised by abdominal pain and discomfort and altered bowel functions (2-4). To date, no laboratory or structural defects have been identified in IBS and the formal diagnosis is based upon a constellation of symptoms defined by either the Manning (5) or Rome Criteria (6).
The current understanding of the pathophysiology or aetiology of IBS is limited, and no proven effective therapy is available (3,7). Moreover, many patients gain slight or even no relief from such therapies. Thus, there is a real need to develop new medicines for the treatment of IBS.
Over the last two decades compelling evidence has accumulated that a state of enhanced perception of visceral stimuli develops in patients with IBS (2,3,8-10). In balloon distension studies of the colon or rectum the threshold for sensation of pain is lower in IBS patients compared to controls, and this has been proposed as a biological marker for IBS (11). In view of the evidence for enhanced visceral perception in IBS and the frequent occurrence of pain, any agent considered to be of utility in the treatment of IBS should demonstrate effectiveness in the relief of pain.
Of the classes of therapeutic agents which have been proposed for the treatment of abdominal pain in IBS, 5-HT
3
receptor antagonists are among the most promising. In animal models, these agents have been shown to decrease visceral pain responses (12,13). Furthermore, the 5-HT
3
receptor antagonist, ondansetron, has been shown to slow colonic transit in normal volunteers (14-15). In patients with IBS ondansetron increases rectal compliance (16) and in diarrhoea-predominant IBS patients ondansetron improves stool consistency (17-19). Ondansetron also inhibits the contractile response of the colon in healthy volunteers in the early postprandial period (20), the time when many IBS patients experience symptoms. A second 5-HT
3
receptor antagonist, granisetron, has also been shown to produce a decrease in rectal sensitivity, and reduce post-prandial motor activity in IBS patients (21).
Alosetron is a potent and selective 5-HT
3
receptor antagonist, and in preliminary reports, alosetron has been shown to improve abdominal pain (22), and to slow colonic transit in IBS patients (23).
Surprisingly, it has now been found that 5-HT
3
receptor antagonists represent a particularly effective and well tolerated therapy in nonconstipated female IBS patients.


REFERENCES:
patent: 5017573 (1991-05-01), Kon et al.
patent: 6284770 (2001-09-01), Mangel et al.
patent: 0254584 (1988-01-01), None
patent: 0279512 (1988-08-01), None
patent: 0306323 (1989-03-01), None
patent: 0315390 (1989-05-01), None
patent: 0336759 (1989-10-01), None
patent: 0347229 (1989-12-01), None
patent: 0357416 (1990-03-01), None
patent: 0364274 (1990-04-01), None
patent: 0377967 (1990-07-01), None
patent: 0385722 (1990-09-01), None
patent: 0387431 (1990-09-01), None
patent: WO89 09217 (1989-10-01), None
patent: WO92 05174 (1992-04-01), None
patent: WO92 10494 (1992-06-01), None
patent: WO92 11259 (1992-07-01), None
patent: WO92 12149 (1992-07-01), None
patent: WO94 01095 (1994-01-01), None
K. Bardhan et al., “A Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Aolsetron in the Treatment of Irritable Bowel Syndrome (IBS),” Gastroenterology, vol. 110, No. 4, Apr. 1996, p. A630.
J.M. Foster et al., “Alosetron Slows Colonic Transit in Patients with Irritable Bowel Syndrome (IBS),” Gastroenterologgy, vol. 112, May 11-14, 1997, p. A732.
D.G. Maxton et al., “Selective 5-hydroxytryptamine antagonism: a role in irritalble bowel syndrome and functional dyspepsia?”, Aliment. Pharmacol. Ther. vol. 10, No. 4, Aug. 1996, pp. 595-599.
J. Zighelboim et al., “Visceral Perception in Irritable Bowel Syndrome,” Dig. Sis, Sci., vol. 40, No. 4, Apr. 1995, pp 819-827.
C.J. Steadman et al., “Selective 5-Hydroxytryptamine Type 3 Receptor Antagonism with Ondansetron Treatment for Diarrhea-Predominant Irritable Bowel Syndrome: A Pilot Study,” May Clinic Proc., vol. 67, No. 8, Aug. 1992, pp 732-738.
P.H. Hsyu et al., “Safety and Age, Gender, and Time Dependent Pharmacokinetics of Alosetron,” Pharmaceutical Research, vol. 12, No. 9 Suppl., Sep. 1995, p S387.
M. Delvaux et al., “Effect of alosetron on responses to colonic distension in patients with irritable bowel syndrome,” Aliment. Pharmacol. Ther., vol. 12, No. 9, Sep. 1998, pp 849-855.
R. Berkow et al., “The Merck Manual of Diagnosis and Therapy, 16thEdition,” 1992, Merck Research Laboratories, Rahway, N.J., pp 841-845.
A.R. Northcutt et al., “Alosetron, A5HT3-Receptor Antagonist, Is Effective in the Treatment of Female Irritable Bowel Syndrome patients,” Gastroenterology, vol. 114, No. 4 Part 2, Apr., 1998, p. A812.

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