Chemistry: analytical and immunological testing – Biospecific ligand binding assay – Utilizing isolate of tissue or organ as binding agent
Reexamination Certificate
2000-11-28
2002-09-03
Kemmerer, Elizabeth (Department: 1647)
Chemistry: analytical and immunological testing
Biospecific ligand binding assay
Utilizing isolate of tissue or organ as binding agent
C530S350000, C435S007100
Reexamination Certificate
active
06444477
ABSTRACT:
IBS (irritable bowel syndrome) is a gastrointestinal disorder which is amongst the most commonly encountered in primary care. It is approximately twice as prevalent in women as it is in men and presents as a collection of symptoms which vary between patients and, within a single patient, over time. Symptoms always include lower abdominal pain which may be associated with constipation and/or diarrhoea.
Diagnosis of IBS is performed by excluding other diseases, followed by positive symptomatic diagnosis which is carried out according to the Manning or Rome criteria. A recent review by experts in the field has led to publication of revised diagnostic criteria (Rome 2), and updated diagnosis and treatment recommendations, based on research results. Recent approaches to the treatment of IBS have been based around the finding that levels of the neurotranmitter 5-hydroxytrptamine (5-HT) and it's metabolites are raised in the plasma of patients with IBS. 5-HT has a number of different receptor subtypes found in the human body.
Observations in animal studies have shown that both 5-HT
3
and 5-HT
4
receptors are present on myenteric neurones and mediate the release of excitatory neurotransmitters which cause contraction of gastrointestinal smooth muscle. This has led to the development of both 5-HT
4
agonists and antagonists, and 5-HT
3
antagonists. However, studies in man have not revealed the presence of either 5-HT
4
or 5-HT
3
receptors on myenteric neurones, so the specific receptors exerting neuronal control of gastrointestinal function are unknown.
The prior art has also speculated that a 5 -HT
2B
antagonist may have use in the treatment of irritable bowel disorders these speculations are in the public domain. However, the basis for credible development of such an approach has not previously been determined. The supposition is based on observations in rat, where the receptor is present in the stomach fundus, and mediates contraction. Similarly, the authors of U.S. Pat. No. 5,457,101 (and later WO 96/24351 and WO 97/35578) base their proposal for the use of 5-HT
2B
antagonists on the observation of 5-HT
2B
mediated contraction of rat colon smooth muscle.
U.S. Pat. No. 5,952,331 also proposes a role for 5-HT in the pathology of IBS. However, the claim that 5-HT
2B
receptors might be beneficial in the treatment of IBS is based on three indirect observations:
5-HT
2B
receptors are present in human intestine. However, the two references cited in U.S. Pat. No. 5,952,331 report the presence of 5-HT
2B
receptors which contract small intestinal smooth muscle. There is no evidence, either experimental or clinical, that this mechanism of action has any relevance to IBS. In addition, there is no evidence that these actions in human intestinal tissue are accompanied by production of nitric oxide, leading to the sensitization of sensory nerve fibres.
Non-selective 5-HT
2B
receptor antagonists are clinically effective in reducing the pain associated with IBS. The first of these studies investigated the use of mianserin in the treatment of lBS and non-ulcer dyspepsia, and showed the treatment to offer alleviation of symptoms. Mianserin is a non-selective alpha-2 adrenoceptor, 5-HT1, 2 and 3, and histamine H1 and H2 receptor antagonist, and it's beneficial effects can not therefore be attributed solely to 5-HT
2B
receptor stimulation. In the second reference, the disease under investigation was “abdominal migraine” which shares little similarity to IBS. Entry criteria for the trial included at least bimonthly attacks, abdominal pain with facial pallor, and at least one first-degree (or two second degree) relatives with a history of migraine or recurrent headaches. These authors themselves stated that there is no reason to believe that the treatment [pizotifen] would be effective in patients with abdominal pain who did not meet these criteria, and it is therefore difficult to find evidence from this trial to support the use of pizotifen in IBS. In addition, pizotifen is a non-selective 5-HT
2
receptor, which is non-surmountable at 5-HT
2A
receptors (Prins et al., 1997), and additionally shows significant affinity for 5-HT
3
receptors (Schmidt & Peroutka, 1989). The evidence (from these clinical studies) to support the use of 5-HT
2B
receptor antagonists in IBS is therefore not credible.
These separate and independent pieces of evidence are claimed as support for the use of 5-HT
2B
receptor antagonists in the treatment of IBS. However, U.S. Pat. No. 5,952,331 provides no experimental evidence to support this claim.
DISCLOSURE OF THE INVENTION
The present inventors have investigated the location and action of 5-HT
2B
receptors in human colon tissue. The inventors have demonstrated, however, that 5-HT
2B
receptors in human colon have no significant effect on basal tone in human colon (i.e. no effect on resting colon), but that their activation potentiates contractile responses to neuronal stimulation. In other words, it is believed that in the human colon, 5-HT acts on 5-HT
2B
receptors to make the colon hypersenstive to neuronally-mediated stimulation. It is this mechanism which it is believed to be the key to the involvement of 5-HT
2B
receptors in the pathogenesis of IBS, rather than merely by causing direct smooth muscle contraction.
Thus for the first time, it is shown herein that 5-HT
2B
receptors are present on both nerves and smooth muscle of human colon, and that their activation potentiates neuronally-mediated responses, and are thus causative in the abnormal motility and pain associated with IBS. For this reason, there is provided direct experimental evidence that 5-HT
2B
receptors will be useful in the treatment of IBS.
The demonstration of 5-HT
2B
receptors localised on neuronal elements within the human GI tract is not in the public domain, nor is the potentiation of neuronally-induced contractions induced by activation of 5-HT
2B
receptors. Thus the present findings allow the development of a rational approach to the development of an IBS treatment.
The present invention thus provides, for the first time, a rational approach to the treatment of IBS via 5HT2B antagonists, as well as a novel means for the development of novel compounds useful in the treatment of IBS.
In a first aspect, the invention provides for a method of treatment of IBS which comprises providing to a patient in need of treatment an effective amount of a 5HT2B receptor antagonist which acts on 5HT2B receptors located in the colon of said patient.
Alternatively, the invention provides the use of a 5HT2B receptor antagonist for the manufacture of a medicament which acts upon 5HT2B receptors of the colon for the treatment of ISS.
In a further aspect, the invention provides a composition comprising a 5HT2B receptor antagonist adapted for administration to a human subject such that the antagonist is released in the colon. Such compositions included delayed release formulations, taken orally, as well as compositions adapted to be delivered to the colon, such as depot formulations and suppositories.
In another embodiment, the present findings provide a novel means in the development of compounds for use in the treatment of GI disorders, the means being the use of human colon smooth muscle preparation as an assay for the detection of compounds which may be beneficial in the treatment of GI disorder, and particularly IBS. The colon smooth muscle preparation may be used in an assay in which it is electrically-stimulated, so as to contract in the presence of such stimulation, and compounds assayed for the ability to inhibit 5-HT-induced potentiation of such contraction. Such an assay provides a means of detecting compounds with 5-HT2B activity.
REFERENCES:
patent: 5863924 (1999-01-01), Berger et al.
patent: 5952331 (1999-09-01), Berger et al.
patent: 5958934 (1999-09-01), Berger et al.
patent: WO 97/44326 (1997-11-01), None
patent: WO 01/08668 (2001-02-01), None
De Ponti, et al, 1998, Pharmacol. Ther., 80(1):49-88, esp. pp 53-60.*
Briejer, et al, 1995, Arch int. Pharmacodyn. 329: 1
Baxter Gordon S.
Borman Richard A.
Tilford Nicholas S.
Kemmerer Elizabeth
Pharmagene Laboratories Limited
Wegert Sandra
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