U.S. patent application number 11/415428 was filed with the patent office on 2006-11-16 for treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5ht1a receptors.
This patent application is currently assigned to AGI Therapeutics Ltd., AGI Therapeutics. Invention is credited to T. G. Dinan, P. W.N. Keeling.
Application Number | 20060258732 11/415428 |
Document ID | / |
Family ID | 36915522 |
Filed Date | 2006-11-16 |
United States Patent
Application |
20060258732 |
Kind Code |
A1 |
Dinan; T. G. ; et
al. |
November 16, 2006 |
Treatment and prevention of gastrointestinal disease using
antagonists or partial agonists of 5HT1a receptors
Abstract
The present invention provides a method for preventing and
treating gastrointestinal diseases such as dyspepsia, irritable
bowel disease and chemotherapy associated nausea by administering
an antagonist or partial agonist of 5HT1A receptors.
Inventors: |
Dinan; T. G.; (Cobh, IE)
; Keeling; P. W.N.; (Dublin, IE) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
AGI Therapeutics Ltd., AGI
Therapeutics
|
Family ID: |
36915522 |
Appl. No.: |
11/415428 |
Filed: |
May 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09687384 |
Oct 13, 2000 |
7098232 |
|
|
11415428 |
May 2, 2006 |
|
|
|
60161117 |
Oct 22, 1999 |
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Current U.S.
Class: |
514/419 |
Current CPC
Class: |
A61K 31/405
20130101 |
Class at
Publication: |
514/419 |
International
Class: |
A61K 31/404 20060101
A61K031/404 |
Claims
1. A method for preventing and treating gastrointestinal disease by
means of administration of an effective amount of an antagonist or
partial agonist of 5HT1a receptors.
2. A method according to claim 1 employing an effective amount of
the racemic substance RS pindolol or a salt thereof.
3. A method according to claim 1 employing an effective amount of
one of the enantiomers, S (-) pindolol of claim 2 or a salt
thereof.
4. A method according to claim 1 in which effective amounts of
RS-pindolol or S(-) pindolol or their salts are administered in a
pharmaceutical dosage form that permits rapid release of the active
substances.
5. A method according to claim 1 in which effective amounts of RS
pindolol or S(-) pindolol or their salts are administered in a
pharmaceutical dosage form that releases the active substances in a
slow or controlled fashion that in turn permits administration of
the active substances at lesser frequency than in claim 4.
6. A method according to claim 1 in which the gastrointestinal
diseases are characterised as non-ulcerative dyspepsia or irritable
bowel syndrome or chemotherapy-associated disorders of motility,
including nausea.
Description
[0001] This application claims the priority of Provisional
Application 60/161,117 filed Oct. 22, 1999.
FIELD OF THE INVENTION
[0002] The present invention provides a method for preventing and
treating gastrointestinal diseases such as dyspepsia, irritable
bowel disease and chemotherapy-associated nausea by administering
an antagonist or partial agonist of 5HT1a receptors.
BACKGROUND OF THE INVENTION
[0003] Dyspepsia is a common symptom ranging in prevalence from 26%
in the United States to 41% in England (1). Whilst only 1 in 4
patients seek medical help (2) the condition results in significant
health care costs (3) and an organic cause is found in only 40% of
patients. The Rome criteria for diagnosing idiopathic or nonulcer
dyspepsia (NUD) were put forward in 1991 and consist of chronic or
recurrent upper abdominal pain or discomfort in the absence of
obvious pathology (4). The Rome group suggested subcategorising NUD
into ulcer-like, reflux-like, dysmotility-like and non-specific
dyspepsia. This classification has been questioned on the grounds
that there is a marked overlap of symptoms and an overlap between
the symptoms and those of the irritable bowel syndrome (5).
[0004] Conventional diagnostic evaluation (endoscopy,
ultrasonography, 24 h ambulatory pH monitoring) does not reveal a
structural or biochemical abnormality to explain NUD Attempts at
elucidating the pathophysiology of the condition have produced
inconsistent findings (6) and a wide array of theories are
currently put forward (7).
[0005] Serotonin (5HT) is a neurotransmitter both in the enteric
nervous system (8) and in the brain (9). It plays a key role in
regulating gut physiology, including peristalsis and intestinal
tone (10). Animal studies have shown that intracerebroventricular
injection of fenfluramine (a serotonin releasing agent) inhibits
gastric emptying (11). Selective serotonin reuptake inhibitors,
such as fluoxetine and sertraline, are widely used in the treatment
of depression and produce a transient syndrome similar to NUD in up
to 30% of patients treated (12).
[0006] Studies indicate that a central 5HT1a receptor
hypersensitivity may be involved in the pathophysiology of NUD
(13,14). The release of prolactin from the anterior pituitary is
under dopamine inhibition and under 5HT stimulation, probably at
the level of the hypothalamus (15). Buspirone is an
azaspirodecanedione, which acts as a partial agonist at the 5HT1a
receptor (16) and stimulates prolactin release. We have established
that prolactin release following buspirone challenge is enhanced in
NUD indicating 5HT1a receptor supersensitivity in this
condition.
[0007] We have demonstrated this in a clinical study that extends
our previous findings reported in U.S. Pat. No. 5,403,848.
[0008] A total of 109 subjects, 50 NUD patients (39 female/11 male)
and 59 healthy comparison subjects (32 female/28 male) gave fully
informed consent to take part in the study, which had Ethics
Committee approval. The mean.+-.SD age of the patients was
35.6.+-.12.2 years (Range 20-62) and of the comparison group
27.2.+-.7.6 years (Range 20-52). At 0830 h subjects had a cannula
inserted in a forearm vein. Buspirone (30 mg) or matching placebo
was administered orally at 0900 h (Time 0). Blood was taken at 0,
30, 60. 90, 120 and 180 min. Prolactin levels rose in all subjects
challenged with buspirone. The mean.+-.SD AUC in patients was
46.+-.35 and in healthy subjects 24.+-.35. A 2-way repeated
measures ANOVA yields a significant group X time interaction, with
differences significant at 60 min (p<0.05), 90 min (p<0.01)
and 120 min (p<0.05). Prolactin concentration at 90 min provided
the best discrimination between the two groups.
[0009] According to the present invention, what is required to
treat non-ulcerative dyspepsia is the administration of effective
amounts of a substance that reduces the sensitivity of 5HT1a
receptors and we have discovered that pindolol, which has affinity
for 5HT1a receptors has beneficial effects in subjects suffering
from non-ulcerative dyspepsia.
SUMMARY OF THE INVENTION
[0010] The present invention provides a means for prevention and
treatment of gastrointestinal disease by administration of a
substance that reduces the sensitivity of 5HT1a receptors. A
preferred means is the administration of RS pindolol or a salt
thereof. An especially preferred means is the administration of S
(-) pindolol or a salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0011] As noted earlier, this invention can use any substance that
is an antagonist or a partial agonist of 5HT1a receptors such that
the sensitivity of 5HT1a receptors described above is reduced.
[0012] Pindolol is a beta adrenergic antagonist, used in the
treatment of hypertension and angina. It also has affinity for
5HT1a receptors of a similar magnitude as its affinity for beta
adrenergic receptors. Until now, no therapeutic applications of
this phenomenon have been discovered. Pindolol is used
therapeutically in hypertension and angina as the racemic
substance, RS pindolol. Most or all of the pharmacological effects
of pindolol are possessed by the isomer S (-) pindolol. The present
invention utilizes pindolol to reduce the sensitivity of 5HT1a
receptors and as a result to provide the means for prevention and
treatment certain gastrointestinal diseases, including
non-ulcerative dyspepsia. A preferred embodiment of the invention
is the isomer S (-) pindolol or salts thereof. Another method
utilizes the administration of cyproheptadine, described in U.S.
Pat. Nos. 5,324,738 and 5,403,848. The latter also describes a
method for diagnosis of non-ulcerative dyspepsia by measuring the
responsiveness of 5HT1a receptors. RS pindolol has an advantage
over cyproheptadine of greater selectivity for the 5HT1a receptor
and S (-) pindolol has further advantages of greater potency and
specificity.
[0013] The invention is likely to be effective in various
presentations of gastrointestinal disease in which there is altered
sensitivity of 5HT1a receptors. We have specific demonstration of
the role of 5HT1a receptors in non-ulcerative dyspepsia, but there
is likely to be also benefit in certain cases of irritable bowel
syndrome, especially that occurring in the upper intestinal region
and in certain cases of motility disorders (including nausea)
caused by cancer chemotherapy.
[0014] Various pharmaceutical presentations are possible, including
(but not limited to) tablets, capsules, oral solutions and
suspensions and parenteral solutions. Included are also
pharmaceutical formulations for oral use in which the active
substance is released in a controlled and slower fashion such that
the treatment may be administered less frequently.
[0015] The usual doses of RS pindolol and S (-) pindolol will be in
the range of 2.5 mg to 50 mg daily in single or divided doses,
depending upon the therapeutic response and the pharmaceutical
form. The usual doses of S (-) pindolol will be lesser than those
of RS pindolol since the former will be more potent because it is
responsible for most or all of the pharmacological effects.
[0016] The invention is intended for the treatment of mammals,
including humans.
[0017] The ability of the invention to treat gastrointestinal
disease has been demonstrated in a clinical study.
EXAMPLE
[0018] Eleven patients suffering from non-ulcerative dyspepsia were
recruited to a clinical study and gave informed consent. All were
treated with pindolol 2.5 mg three times daily. Seven of the 11
patients showed a significant improvement in symptoms within 1 week
of commencing treatment. A further patient improved in the second
week. Their responses were quantified using a standard rating scale
(GSRS scores). The results demonstrated a substantial improvement
with a reduction in average symptom severity of approximately 68%
in three weeks, with the greatest improvement observed within one
week. TABLE-US-00001 TABLE 1 Mean symptom score (average of 11
patients) Week Mean GSRS Score 0 9 1 4.2 2 3.5 3 2.9
REFERENCES TO PREVIOUS PATENTS
[0019] T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,324,783
[0020] T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,403,848
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