Methods for treating irritable bowel syndrome

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

2001-04-13

2002-08-06

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

06429209

ABSTRACT:

The invention relates to a new medical use for compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5HT
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-imidazoie4-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-1 H-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.
According to one aspect the invention therefore provides a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof for use in the treatment of nonconstipated female IBS.
In one preferred aspect the invention provides a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof for use in the treatment of diarrhoea predominant female IBS.
In another preferred aspect the invention provides a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof for use in the treatment of alternating constipation/diarrhoea IBS.
By pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt or solvate of a 5-HT
3
receptor antagonist or any other compound, which upon administration to the recipient is capable of providing (directly or indirectly) a 5-HT
3
receptor antagonist or an active metabolite or residue thereof.
In one preferred aspect the invention provides a compound of Group A or a pharmaceutically acceptable derivative thereof for use in the treatment of nonconstipated female IBS.
In a further preferred aspect the invention therefore provides alosetron or a pharmaceutically acceptable derivative thereof for use in the treatment of nonconstipated female IBS.
Suitable pharmaceutically acceptable salts of alosetron include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarballylates, citrates, fumarates and maleates), and solvates (for example hydrates) thereof.
In a preferred embodiment of the present invention alosetron is employed in the form of its hydrochloride.
In another aspect, the invention provides the use of a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of nonconstipated female IBS.
In another aspect, the invention provides a method of treatment of nonconstipated female IBS which comprises administering an effective amount of a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof.
Within the above aspects and preferred aspects of the invention, the use of a 5-HT
3
receptor antagonist of Group A, more preferably alosetron, is especially preferred.
It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
Conveniently, a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients. Thus a 5-HT
3
receptor antagonist or a pharmaceutically acceptable derivative thereof may, for example, be formulated for oral, sub-lingual, buccal, parenteral, rectal or intranasal administration, or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose), or in a form suitable for topical administration.
For oral administration the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrates (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle

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