U.S. patent application number 13/413480 was filed with the patent office on 2012-06-28 for dopamine 3 receptor agonist and antagonist treatment of gastrointestinal motility disorders.
This patent application is currently assigned to The Board of Regents of the University of Texas System. Invention is credited to Maria-Adelaide Micci, Pankaj Jay Pasricha.
Application Number | 20120164139 13/413480 |
Document ID | / |
Family ID | 36336993 |
Filed Date | 2012-06-28 |
United States Patent
Application |
20120164139 |
Kind Code |
A1 |
Pasricha; Pankaj Jay ; et
al. |
June 28, 2012 |
Dopamine 3 receptor agonist and antagonist treatment of
gastrointestinal motility disorders
Abstract
Provided herein are methods of treating gastrointestinal
motility disorders by targeting the dopamine 3 receptor (D3R). A
D3R agonist is administered to a subject to decrease
gastrointestinal motility to treat the disorder. A D3R antagonist
is administered to a subject to decrease gastrointestinal motility
to treat the disorder.
Inventors: |
Pasricha; Pankaj Jay;
(Cupertino, CA) ; Micci; Maria-Adelaide; (League
City, TX) |
Assignee: |
The Board of Regents of the
University of Texas System
Austin
TX
|
Family ID: |
36336993 |
Appl. No.: |
13/413480 |
Filed: |
March 6, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12653936 |
Dec 21, 2009 |
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13413480 |
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11266686 |
Nov 3, 2005 |
7659306 |
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12653936 |
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60624603 |
Nov 3, 2004 |
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Current U.S.
Class: |
424/133.1 ;
424/523; 424/653; 424/682; 514/161; 514/171; 514/20.5; 514/217.02;
514/229.8; 514/29; 514/338; 514/365; 514/370; 514/400; 514/428;
514/56 |
Current CPC
Class: |
A61K 31/727 20130101;
A61P 1/08 20180101; A61P 7/10 20180101; A61K 31/485 20130101; A61P
25/00 20180101; A61P 3/04 20180101; A61K 31/56 20130101; A61P 31/00
20180101; A61P 1/00 20180101; A61P 37/02 20180101; A61P 29/00
20180101; A61K 31/445 20130101; A61P 1/06 20180101; A61K 31/135
20130101; A61K 31/4745 20130101; A61P 1/04 20180101; A61K 31/525
20130101 |
Class at
Publication: |
424/133.1 ;
514/428; 514/229.8; 514/171; 514/161; 514/20.5; 424/523; 424/653;
514/56; 514/338; 514/365; 514/370; 514/400; 424/682; 514/29;
514/217.02 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 31/5383 20060101 A61K031/5383; A61K 31/565
20060101 A61K031/565; A61K 31/57 20060101 A61K031/57; A61K 31/573
20060101 A61K031/573; A61K 31/606 20060101 A61K031/606; A61K 38/13
20060101 A61K038/13; A61K 35/60 20060101 A61K035/60; A61K 33/24
20060101 A61K033/24; A61K 31/727 20060101 A61K031/727; A61K 31/4439
20060101 A61K031/4439; A61K 31/426 20060101 A61K031/426; A61K
31/4164 20060101 A61K031/4164; A61K 33/06 20060101 A61K033/06; A61K
31/7048 20060101 A61K031/7048; A61K 31/55 20060101 A61K031/55; A61P
1/00 20060101 A61P001/00; A61P 29/00 20060101 A61P029/00; A61P
31/00 20060101 A61P031/00; A61P 25/00 20060101 A61P025/00; A61P
1/06 20060101 A61P001/06; A61P 1/04 20060101 A61P001/04; A61P 7/10
20060101 A61P007/10; A61P 37/02 20060101 A61P037/02; A61P 3/04
20060101 A61P003/04; A61P 1/08 20060101 A61P001/08; A61K 31/40
20060101 A61K031/40 |
Claims
1. A method of treating a gastrointestinal motility disorder
associated with an increase in gastrointestinal motility in a
subject, comprising the step of: administering a therapeutically
effective amount of a dopamine 3 receptor agonist or a
pharmaceutically acceptable salt thereof to the subject.
2. The method of claim 1, wherein the subject is an animal or a
human.
3. The method of claim 1, wherein the gastrointestinal motility
disorder is at least one of inflammatory bowel disease, ulcerative
colitis, granulomatous enteritis, an infectious disease of the
small or large intestine, pyloric spasm, abdominal cramps, a
functional bowel disorder, mild dysenteries, diverticulitis, acute
enterocolitis, neurogenic bowel disorders, splenic flexure
syndrome, neurogenic colon, or spastic colitis.
4. The method of claim 1, wherein the increase in gastrointestinal
motility is caused by one or more medications.
5. The method of claim 1, wherein the dopamine 3 receptor agonist
is PD 128907 hydrochloride or
7-hydroxy-2-dipropylaminotetralin.
6. The method of claim 1, wherein the agonist of dopamine 3
receptor is present in a pharmaceutically acceptable sustained
release formulation.
7. The method of claim 1, further comprising: administerting the
dopamine 3 receptor agonist in combination with at least one other
pharmaceutically active compound.
8. The method of claim 7, wherein the at least one other
pharmaceutically active compound is a ganglionic blocker, a
nicotinic-receptor antagonist, a gastrointestinal motility altering
agent, antispasmodic, an antimuscarinic agent, an opiate, a 5-HT
receptor agonist, a 5-HT receptor antagonist, a calcium channel
blocker, a beta adrenergic receptor blocker, an agent that alters
fluid transport across the gut, an agent that alters fluid
transport into or out of gastrointestinal cells, a diuretic, an
anti-diarrheal, an H.sub.2-antihistamine, a proton pump inhibitor,
an antacid, an anti-inflammatory agent, a steroid, a
mineralocorticoid, a corticosteroid, an anti-infective agent, an
immunomodulator, or fish oil.
9. The method of claim 8, wherein the at least one other
pharmaceutically active compound is hexamethonium, trimethaphan,
chloroisondamine, erysodine, beta.-dihydroerythrodine, amantidine,
perpidine, succinylcholine, decamethonium, tubocurarine,
atracurium, doxacurium, mivicurium, pancuronium, rocuronium,
vencuronium, glycopyrrolate, atropine, hyscomine, scopolamine,
loperamide, difenoxine, codeine, morphine, oxymorphone, oxycontin,
dihydrocodeine, fentanyl, alosetron hydrochloride, verapamil,
amiloride, furosemide, bismuth, sandostatin, sulfasalazine,
estrogens, prednisone, prednisolone, cortisol, cortisone,
fluticasone, dexamethasone, betamethasone, 5-aminosalicylic acid,
metronidazole, ciprofloxacin, azathioprine, 6-mercaptopurine,
cyclosporine, methotrexate, fish oil, remicade, heparin, or
nicotine.
10. The method of claim 1, wherein the agonist of dopamine 3
receptor is administered via oral, nasal, intradermal, parenteral,
mucosal, buccal, rectal or topical route.
11. A method of treating a gastrointestinal motility disorder
associated with a decrease in gastrointestinal motility in a
subject, comprising the step of: administering a therapeutically
effective amount of a dopamine 3 receptor antagonist or a
pharmaceutically acceptable salt thereof to the subject.
12. The method of claim 11, wherein the subject is an animal or a
human.
13. The method of claim 11, wherein the gastrointestinal motility
disorder is or caused by at least one of gastroparesis,
gastroesophageal reflux disease, diabetes, infections, endocrine
disorders, scleroderma, neuromuscular diseases, cancer, radiation
treatment, surgery of the upper intestinal tract, surgery of the
stomach, surgery of the esophagus, surgery of the duodenum,
anorexia nervosa, or bulimia.
14. The method of claim 11, wherein the decrease in
gastrointestinal motility is caused by a narcotic pain medication,
a calcium channel blocker or an antidepressant.
15. The method of claim 11, wherein the antagonist of dopamine 3
receptor is UH232, GR 103691, U-99194A or nafadotride.
16. The method of claim 11, wherein the antagonist of dopamine 3
receptor comprises a pharmaceutically acceptable sustained release
formulation.
17. The method of claim 11, further comprising: administerting the
dopamine 3 receptor antagonist in combination with at least one
other pharmaceutically active compound.
18. The method of claim 17, wherein the at least one other
pharmaceutically active compound is a proton pump inhibitor, a
histamine H2 receptor blocker, an anti acid agent, a
gastrointestinal stimulant, a dopamine receptor 2 blocker, a 5-HT4
agonist, a 5-Ht3 antagonist, an agent for treating anorexia, an
agent for treating gall bladder stasis, an agent for treating
postoperative paralytic ileus, an agent for treating scleroderma,
an agent for treating intestinal pseudo-obstruction, an
anti-gastritis agent, an anti-emesis agent, an anti-constipation
agent, an agent for treating irritable bowel syndrome, an agent for
treating functional dyspepsia, and an agent for treating colonic
hypomotility.
19. The method of claim 18, wherein the at least one other
pharmaceutically active compound is esomeprazole, lansoprazole or
omeprazole, nizatidine, famotidine, cimetidine, ranitidine,
aluminum antacids, calcium antacids, magnesium antacids,
metoclopramide, domperidone, fenoldapam mesylate, cabergoline,
pramipexole, pergolide mesylate, ropinirole, amanitidine HCL,
tegaserod, alosetron, pilocarpine, fluoxetine, paroxetine,
erythromycin, and dexloxiglumide.
20. The method of claim 12, wherein the antagonist of dopamine 3
receptor is administered via oral, nasal, intradermal, parenteral,
mucosal, buccal, rectal or topical route.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This divisional application claims benefit of priority under
35 U.S.C. .sctn.120 of pending non-provisional application U.S.
Ser. No. 11/266,686, filed Nov. 3, 2005, which claims benefit of
priority under 35 U.S.C. .sctn.119(e) of provisional application
U.S. Ser. No. 60/624,603, filed Nov. 3, 2004, now abandoned, the
entirety of both of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to the fields of
gastric functions and dopamine receptor research. More
specifically, the present invention relates to uses of dopamine 3
receptor agonists and antagonists in the treatment of
gastrointestinal disorders.
[0004] 2. Description of the Related Art
[0005] Gastrointestinal (GI) motility regulates the orderly
movement of ingested material through the gut to ensure adequate
absorption of nutrients, electrolytes and fluids. Appropriate
transit through the esophagus, stomach, small intestine and colon
depends on regional control of intraluminal pressure and several
sphincters that regulate forward movement and prevent back-flow of
gastrointestinal contents. The normal gastrointestinal motility
pattern can be impaired by a variety of circumstances including
disease and surgery.
[0006] Disorders of gastrointestinal motility can include, for
example, gastroparesis and gastroesophageal reflux disease (GERD).
Gastroparesis is characterized by delayed emptying of stomach
contents. Symptoms of gastroparesis include stomach upset,
heartburn, nausea and vomiting. Acute gastroparesis can be caused
by drugs, viral enteritis and hyperglycemia. The most common
underlying disease resulting in gastroparesis is diabetes.
[0007] Gastroesophageal reflux is a physical condition in which
stomach contents, e.g., stomach acid, reflux or flow back from the
stomach into the esophagus. Frequent reflux episodes, e.g., two or
more times per week, can result in a more severe problem known as
gastroesophageal reflux disease (GERD). The most common symptom of
gastroesophageal reflux disease is a burning sensation or
discomfort behind the breastbone or sternum and is referred to as
dyspepsia or heartburn. Dyspepsia can also mimic the symptoms of
myocardial infarction or severe angina pectoris. Other symptoms of
gastroesophageal reflux disease disease include dysphagia,
odynophagia, hemorrhage, water brash and respiratory manifestations
such as asthma, recurrent pneumonia, chronic coughing, intermittent
wheezing due to acid aspiration and/or stimulation of the vagus
nerve, earache, hoarseness, laryngitis and pharyngitis.
[0008] Reflux episodes which result in gastroesophageal reflux
disease, can occur both during the daytime, when the subject is in
a waking state, and at nighttime, when the subject is in a
non-waking state. Gastroesophageal reflux disease occurring at
nighttime is commonly referred to as nocturnal gastroesophageal
reflux disease. Nocturnal gastroesophageal reflux disease is
distinct from daytime or diurnal gastroesophageal reflux disease
not only in the timing of the reflux episode, but in the severity
of the damage which occurs as a result of the reflux. More
specifically, nocturnal gastroesophageal reflux disease can be
particularly damaging to the pharynx and larynx and a strong
association between nocturnal gastroesophageal reflux disease and
asthma exists. The increased damage associated with nocturnal
gastroesophageal reflux disease is due to a decrease in natural
mechanisms that normally help protect against reflux, e.g., saliva
production and swallowing, which occur when the patient is
sleeping. This decrease leaves the esophagus more vulnerable to
damage and can increase microaspiration. In addition, while asleep
the body is in the recumbent position, eliminating the effect of
gravity, which can clear gastric content from the esophagus. Sleep
disorders are also associated with nocturnal gastroesophageal
reflux disease resulting in daytime sleepiness and a significant
decrease in the overall quality of life.
[0009] On a chronic basis, gastroesophageal reflux disease subjects
the esophagus to ulcer formation or esophagitis and can result in
more severe complications such as, esophageal erosion, esophageal
obstruction, significant blood loss and perforation of the
esophagus. Severe esophageal ulcerations occur in 20-30% of
patients over age 65. In addition to esophageal erosion and
ulceration, prolonged exposure of the esophageal mucosa to stomach
acid can lead to a condition known as Barrett's Esophagus.
Barrett's Esophagus is an esophageal disorder that is characterized
by replacement of normal squamous epithelium with abnormal columnar
epithelium. This change in tissue structure is clinically important
not only as an indication of severe reflux, but as an indication of
cancer.
[0010] Many factors are believed to contribute to the onset of
GERD. A number of factors involve failure of the lower esophageal
sphincter mechanism to work properly. The lower esophageal
sphincter is tonically contracted to prevent reflux of gastric
contents. In a healthy person the muscle relaxes only during
swallowing to allow food to pass and also on average three to four
times an hour in a phenomenon known as transient lower esophageal
sphincter relaxations. In gastroesophageal reflux disease
sufferers, the frequency of transient lower esophageal sphincter
relaxations can be much higher, for example, as high as eight or
more times an hour and weakness of the lower esophageal sphincter
allows reflux to occur. Other factors that can contribute to
gastroesophageal reflux disease include delayed stomach emptying
and ineffective esophageal clearance. Delayed stomach emptying
leads to reflux of the gastric contents into the esophagus.
[0011] Current methods to treat gastroesophageal reflux disease
include lifestyle changes such as weight loss, avoidance of certain
foods that exacerbate the symptoms of gastroesophageal reflux
disease and avoidance of excessive bending. Elevation of the head
of the bed helps reduce nocturnal reflux. While these avoidance
strategies can be useful, the efficacy of lifestyle modification
alone for the treatment of gastroesophageal reflux disease is not
supported.
[0012] Medications for the treatment of gastroesophageal reflux
disease include conventional antacids, for example, TUMS.RTM. and
ROLAIDS.RTM. which provide only short term relief. H.sub.2 receptor
antagonists, for example, nizatidine (AXID.RTM.), ranitidine
(ZANTAC), famotidine (PEPCID and PEPCID COMPLETE), roxatidine
(ROTANE or ZORPEX) and cimetidine (TAGAMET), are more effective in
controlling gastroesophageal reflux disease, but do not treat the
underlying disease. However, patients receiving H.sub.2 receptor
antagonists develop tolerance to the drugs rendering the drugs
ineffective in their ability to inhibit acid secretion.
[0013] More powerful secretory inhibitors, such as the proton pump
inhibitors, for example, esomeprazole (NEXIUM), omeprazole
(PRILOSEC and RAPINEX.), lansoprazole (PREVACID), rabeprazole
(PARIET, ACIPHEX) and pantoprazole (PROTONIX) are more effective
than the H.sub.2receptor antagonists but are very expensive and
their efficacy relies on inhibition of active proton pumps as
stimulated by meals, thereby having little or no effect on the
occurrence of nocturnal gastroesophageal reflux disease.
[0014] Prokinetic drugs are another type of drug used in the
treatment of gastrointestional motility disorders. Prokinetic drugs
act to stimulate gastrointestinal motility. Stimulation can occur
by direct action on smooth muscle or by an action on the myenteric
plexus. The motor functions of the gastrointestinal tract are
expressions of a balance at the level of smooth muscle cells
between inhibitory mechanisms mainly regulated by dopamine and
stimulatory events mainly regulated through the release of
acetylcholine. Therefore gastrointestinal motility can be
stimulated by dopamine receptor 2 antagonists such as
metoclopramide and domperidone, or by substances which release
acetylcholine, such as metoclopramide or the 5-HT.sub.4 receptor
agonist, cisapride (PROPULSID), or directly by cholinergic drugs
which bind on muscarinic receptors of the smooth muscle cell such
as bethanechol. Prokinetic drugs can both stimulate motility and
coordinate the activity between different segments of the
gastrointestinal tract. However, there are currently no prokinetic
drugs available that are both effective and safe. For example,
serious cardiac arrhythmias including ventricular tachycardia,
ventricular fibrillation, torsades de pointes, and QT prolongation
have been reported in patients taking the prokinetic of choice,
cisapride. As a result, strict limitations have been imposed on the
prescribing of this drug. Further, the use of the dopamine
antagonists, metoclopramide and domperidone, is associated with
lack of patient tolerability, undesirable CNS effects, such as
diskinesia and undesirable cardiovascular effects, such as QT
prolongation.
[0015] Dopamine (DA) is present in large amounts in the gut and it
regulates gastrointestinal (GI) function via inhibition of
gastrointestinal motility. This is believed to be due to
dopamine-induced suppression of acetylcholine release, which is a
principal excitatory neurotransmitter in the gut, from enteric
cholinergic neurons. Although dopamine is an important modulator of
enteric function, much remains to be understood about its exact
role in the gastrointestinal tract. Traditionally, dopamine has
been thought to exert its effects via the D2 receptor (D2R) and
hence antagonists of this receptor (metoclopramide and domperidone)
are administered to alleviate symptoms associated with various
gastrointestinal motility disorders.
[0016] The role of newly discovered dopamine receptors such as D3
and D4 in the regulation of gastrointestinal motility is not well
known. Due to the side effects associated with current prokinetic
drugs in the treatment of disorders related to gastrointestinal
motility, it is important to develop newer drugs to manage such
disorders. The presence of D3 and D4 dopamine receptors in the GI
tract opens up new avenues for treating GI motility disorders that
target these receptors.
[0017] The instant invention is directed to novel methods of
treating GI motility disorders by targeting the dopamine 3
receptors in the GI tract. Prior art is deficient in the lack of
useful agents to regulate gastrointestinal motility especially
agents that target the dopamine 3 receptor. The present invention
fulfills this long-standing need in the art.
SUMMARY OF THE INVENTION
[0018] The present invention discloses the role of dopamine D3
receptors (D3R) in the regulation of gastrointestinal motility. In
one embodiment, there is provided a method of using an agonist of
dopamine 3 receptor or a pharmaceutically acceptable salt thereof
to decrease gastrointestinal tract motility or gastric emptying in
an animal or human.
[0019] In one embodiment the present invention discloses a method
for treating gastrointestinal motility disorder caused by at least
one condition chosen from inflammatory bowel disease, ulcerative
colitis, granulomatous enteritis, infectious diseases of the small
or large intestine, pyloric spasm, abdominal cramps, a functional
bowel disorder, mild dysenteries, diverticulitis, acute
enterocolitis, neurogenic bowel disorders, splenic flexure
syndrome, neurogenic colon or spastic colitis by administering an
effective dose of a dopamine 3 receptor agonist.
[0020] In another embodiment of the present invention, there is
provided a method of decreasing gastrointestinal tract motility or
gastric emptying in a subject, comprising the step of administering
a therapeutically effective amount of PD 128907 hydrochloride or
7-hydroxy-2-dipropylaminotetralin to the subject.
[0021] In another embodiment of the present invention, there is
provided a method of treating increased gastrointestinal motility
in a subject by administering at least one other pharmaceutically
active compound besides a dopamine 3 receptor agonist. Some
examples of such pharmaceutically active compounds are
hexamethonium, trimethaphan, chloroisondamine, erysodine,
beta-dihydroerythrodine, amantidine, perpidine, succinylcholine,
decamethonium, tubocurarine, atracurium, doxacurium, mivicurium,
pancuronium, rocuronium, vencuronium, glycopyrrolate, atropine,
hyscomine, scopolamine, loperamide, difenoxine, codeine, morphine,
oxymorphone, oxycontin, dihydrocodeine, fentanyl, alosetron
hydrochloride, verapamil, amiloride, furosemide, bismuth,
sandostatin, sulfasalazine, estrogens, prednisone, prednisolone,
cortisol, cortisone, fluticasone, dexamethasone, betamethasone,
5-aminosalicylic acid, metronidazole, ciprofloxacin, azathioprine,
6-mercaptopurine, cyclosporine, methotrexate, fish oil, remicade,
heparin, and nicotine.
[0022] In another embodiment of the present invention, there is
provided a method of using an antagonist of dopamine 3 receptor or
a pharmaceutically acceptable salt thereof to increase
gastrointestinal tract motility or gastric emptying in an animal or
human.
[0023] In one embodiment the present invention discloses a method
for treating gastrointestinal motility disorder caused by at least
one condition chosen from diabetes, infections, endocrine
disorders, scleroderma, neuromuscular diseases, cancer, radiation
treatment, surgery of the upper intestinal tract, surgery of the
stomach, surgery of the esophagus, surgery of the duodenum,
anorexia nervosa and bulimia by administering an effective dose of
a dopamine 3 receptor antagonist.
[0024] In another embodiment of the present invention, there is
provided a method of increasing gastrointestinal tract motility or
gastric emptying in a subject, comprising the step of administering
a therapeutically effective amount of UH232, GR 103691, U-99194A or
nafadotride to the subject.
[0025] In another embodiment of the present invention, there is
provided a method of treating increased gastrointestinal motility
in a subject by administering at least one other pharmaceutically
active compound besides a dopamine 3 receptor antagonist. Some
examples of such pharmaceutically active compounds are
esomeprazole, lansoprazole or omeprazole, nizatidine, famotidine,
cimetidine, ranitidine, aluminum antacids, calcium antacids,
magnesium antacids, metoclopramide, domperidone, fenoldapam
mesylate, cabergoline, pramipexole, pergolide mesylate, ropinirole,
amanitidine HCL, tegaserod, alosetron, pilocarpine, fluoxetine,
paroxetine, erythromycin, and dexloxiglumide.
[0026] Other and further aspects, features, and advantages of the
present invention will be apparent from the following description
of the presently preferred embodiments of the invention. These
embodiments are given for the purpose of disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 shows that intraperitoneal injections of dopamine 3
receptor (D3R) agonist significantly delayed gastric emptying in
rats (44.+-.8.26% gastric emptying in D3R agonist-treated group
versus 78.+-.4.86% in vehicle-treated group, **p<0.01 by
Student's t-test).
[0028] FIG. 2 shows the reduced electric field stimulation induced
relaxation of pyloric strips derived from adult male Sprague-Dawley
rats in an organ bath in the presence of the D3R agonist, PD 128907
hydrochloride (D3RA, P=0.011 by two-way ANOVA). The pyloric
function was assessed by measuring the relaxation of pyloric strips
in an organ bath in response to electric field stimulation in the
presence of D3R agonist ranging from 0.1-10 mM (1 mM vs control,
P<0.05; 10 mM vs control, P=0.001).
[0029] FIG. 3 shows the partial reversal of the effect of dopamine
on gastric emptying by the dopamine 3 receptor (D3R) antagonist,
nafadotride. Gastric emptying was assessed in adult male
Sprague-Dawley rats by the phenol red method. Twenty minutes after
feeding a non-nutrient methylcellulose meal to rats treated with
dopamine (DA, 1 mg/kg i.p.) or with dopamine plus varying doses of
nafadotride (D3R Antag, 0.1 or 1 mg/kg i.p.). Control rats received
vehicle (PBS).
DETAILED DESCRIPTION OF THE INVENTION
[0030] Results presented herein indicate that the dopamine 3
receptor may play an important role in the regulation of gastric
motility and contribute to the overall negative effect of dopamine
on gastric emptying. An understanding of the role of dopamine and
its receptors in the modulation of enteric function will help
improve therapeutic strategies for the treatment of several
gastrointestinal motility disorders.
[0031] Intraperitoneal injections of a dopamine 3 receptor (D3R)
agonist, PD 128907, significantly delayed gastric emptying in rats
(44% gastric emptying in the dopamine 3 receptor agonist-treated
group versus 78% in the vehicle-treated group, P<0.01, FIG. 1).
This agonist was also shown to reduce the electric field
stimulation induced relaxation of pyloric strips of adult male
Sprague-Dawley rats when tested in an organ bath. Thus, endogenous
dopamine may be acting via the dopamine 3 receptor and antagonism
of dopamine 3 receptor may represent an important and novel
mechanism to accelerate gastric emptying. Conversely, dopamine 3
receptor agonists may be useful to delay gastric emptying and cause
satiety. Hence, modulating dopamine activity through dopamine 3
receptor may be useful in treating patients with gastroparesis,
obesity, and gastrointestinal dysmotility.
[0032] In one embodiment, there is provided a method of using a
therapeutically effective amount of a dopamine 3 receptor agonist
or a pharmaceutically acceptable salt thereof to decrease
gastrointestinal tract motility or gastric emptying in an animal or
human. Preferably, the method is useful for treating a human
suffering from nausea, vomiting and obesity.
[0033] In one embodiment, a dopamine 3 receptor agonist may be used
to treat increased gastrointestinal motility caused by at least one
condition selected from the group comprising of inflammatory bowel
disease, ulcerative colitis, granulomatous enteritis, infectious
diseases of the small or large intestine, pyloric spasm, abdominal
cramps, a functional bowel disorder, mild dysenteries,
diverticulitis, acute enterocolitis, neurogenic bowel disorders,
splenic flexure syndrome, neurogenic colon and spastic colitis.
[0034] The invention also discloses the use of dopamine 3 receptor
agonists to treat an increase in gastrointestinal motility caused
by medications. Representative examples of useful dopamine 3
receptor agonists include PD 128907 hydrochloride or
7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT).
[0035] The present invention further discloses that a dopamine 3
receptor agonist may be administered in combination with at least
one other pharmaceutically active compound to treat a
gastrointestinal motility disorder. Examples of such
pharmaceutically active compounds include hexamethonium,
trimethaphan, chloroisondamine, erysodine, beta-dihydroerythrodine,
amantidine, perpidine, succinylcholine, decamethonium,
tubocurarine, atracurium, doxacurium, mivicurium, pancuronium,
rocuronium, vencuronium, glycopyrrolate, atropine, hyscomine,
scopolamine, loperamide, difenoxine, codeine, morphine,
oxymorphone, oxycontin, dihydrocodeine, fentanyl, alosetron
hydrochloride, verapamil, amiloride, furosemide, bismuth,
sandostatin, sulfasalazine, estrogens, prednisone, prednisolone,
cortisol, cortisone, fluticasone, dexamethasone, betamethasone,
5-aminosalicylic acid, metronidazole, ciprofloxacin, azathioprine,
6-mercaptopurine, cyclosporine, methotrexate, fish oil, remicade,
heparin, and nicotine.
[0036] In another embodiment, there is provided a method of using a
therapeutically effective amount of a dopamine 3 receptor
antagonist or a pharmaceutically acceptable salt thereof to
increase gastrointestinal tract motility or gastric emptying in an
animal or human. Preferably, the method is useful for treating
gastroparesis from any cause including but not limited to diabetic
gastroparesis, gastroesophageal reflux disease, anorexia, bulimia,
scleroderma, neuromuscular diseases and endocrine disorders. FIG. 3
illustrates the partial reversal of the effect of dopamine on
gastric emptying by the dopamine 3 receptor antagonist,
nafadotride. This demonstrates that dopamine 3 receptor antagonists
can effectively increase gastrointestinal tract motility or gastric
emptying in an animal or human.
[0037] In one embodiment, the invention discloses the use of
dopamine 3 receptor antagonist to treat a decrease in
gastrointestinal motility caused by medications such as narcotic
pain medications, calcium channel blockers and antidepressants.
[0038] In one embodiment, a dopamine 3 receptor antagonist may be
used to treat a decrease in gastrointestinal motility caused by at
least one condition selected from the group comprising of diabetes,
infections, endocrine disorders, scleroderma, neuromuscular
diseases, cancer, radiation treatment, surgery of the upper
intestinal tract, surgery of the stomach, surgery of the esophagus,
surgery of the duodenum, anorexia nervosa and bulimia.
[0039] Representative examples of useful dopamine 3 receptor
antagonists include GR 103691, UH232, U-99194A and nafadotride.
[0040] The present invention further discloses that a dopamine 3
receptor antagonist may be administered in combination with at
least one other pharmaceutically active compound to treat a
gastrointestinal motility disorder. Examples of such
pharmaceutically active compounds include esomeprazole,
lansoprazole or omeprazole, nizatidine, famotidine, cimetidine,
ranitidine, aluminum antacids, calcium antacids, magnesium
antacids, metoclopramide, domperidone, fenoldapam mesylate,
cabergoline, pramipexole, pergolide mesylate, ropinirole,
amanitidine HCL, tegaserod, alosetron, pilocarpine, fluoxetine,
paroxetine, erythromycin, and dexloxiglumide.
[0041] A "therapeutically effective amount" as used in the instant
invention refers to an amount effective, at dosages and for periods
of time necessary, to achieve the desired therapeutic result, such
as decreasing or increasing gastrointestinal tract motility or
gastric emptying. A therapeutically effective amount of dopamine 3
receptor agonist or antagonist may vary according to factors such
as the disease state, age, sex, and weight of the individual. A
therapeutically effective amount is also one in which any toxic or
detrimental effects are outweighed by the therapeutically
beneficial effects. One of ordinary skill in the art would readily
adjust dosage regimens to provide optimum therapeutic response
without undue experimentation.
[0042] When the dopamine 3 receptor agonist or antagonist is
administered in combination with at least one other
pharmaceutically active compound, the other active pharmaceutical
compound may be used, for example, in those amounts indicated in
the PDR or as otherwise determined by one of ordinary skill in the
art.
[0043] The dopamine receptor 3 antagonist or agonist can be
administered for any of the uses described herein by any suitable
means, for example, orally, such as in the form of tablets,
capsules, granules or powders; sublingually; bucally; parenterally,
such as by subcutaneous, intravenous, intramuscular, or
intrasternal injection or infusion techniques, e.g., as sterile
injectable aqueous or non-aqueous solutions or suspensions;
nasally, including administration to the nasal membranes, such as
by inhalation spray; topically, such as in the form of a cream or
ointment; or rectally such as in the form of suppositories; in
dosage unit formulations containing non-toxic, pharmaceutically
acceptable vehicles or diluents. The present compounds can, for
example, be administered in a form suitable for immediate release
or extended release. Immediate release or extended release can be
achieved by the use of suitable pharmaceutical compositions
comprising the present compounds, or, particularly in the case of
extended release, by the use of devices such as subcutaneous
implants or osmotic pumps. The present compounds can also be
administered liposomally.
[0044] Representative examples of oral administration include
suspensions which can contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which can contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The dopamine 3 receptor agonist or antagonist can
also be delivered through the oral cavity by sublingual and/or
buccal administration. Molded tablets, compressed tablets or
freeze-dried tablets are exemplary forms which may be used.
Exemplary compositions include formulations with fast dissolving
diluents such as mannitol, lactose, sucrose and/or cyclodextrins.
Also included in such formulations may be high molecular weight
excipients such as celluloses (avicel) or polyethylene glycols
(PEG). Such formulations can also include an excipient to aid
mucosal adhesion such as hydroxypropyl cellulose (HPC),
hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl
cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and
agents to control release such as polyacrylic copolymer (e.g.
Carbopol 934). Lubricants, glidants, flavors, coloring agents and
stabilizers may also be added for ease of fabrication and use.
[0045] Exemplary compositions for nasal, aerosol, or inhalation
administration include solutions in saline which can contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0046] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which can contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid, or
Cremaphor.
[0047] Exemplary compositions for rectal administration include
suppositories which can contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquefy and/or dissolve in the rectal cavity to
release the drug.
[0048] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0049] The effective amount of a dopamine 3 receptor agonist or
antagonist to treat a gastrointestinal motility disorder can be
determined by one of ordinary skill in the art, and includes
exemplary dosage amounts for a adult human of from about 0.001 to
100 mg/kg of body weight of active compound per day, preferably
0.01 to 1 mg/kg of body weight of active compound per day, that can
be administered in a single dose or in the form of individual
divided doses, such as from 1 to 4 times per day. It is well
understood that the specific dose level and frequency of dosage for
any particular subject can be varied and will depend upon a variety
of factors including the activity of the specific compound
employed, the metabolic stability and length of action of that
compound, the species, age, body weight, general health, sex and
diet of the subject, the mode and time of administration, rate of
excretion, drug combination, and severity of the particular
condition. Preferred subjects for treatment include animals, most
preferably mammalian species such as humans, and domestic animals
such as dogs, cats and the like, subject to motility-associated
conditions.
[0050] The following examples are given for the purpose of
illustrating various embodiments of the invention and are not meant
to limit the present invention in any fashion. The present
examples, along with the methods, procedures, treatments,
molecules, and specific compounds described herein are presently
representative of preferred embodiments. One skilled in the art
will appreciate readily that the present invention is well adapted
to carry out the objects and obtain the ends and advantages
mentioned, as well as those objects, ends and advantages inherent
herein. Changes therein and other uses which are encompassed within
the spirit of the invention as defined by the scope of the claims
will occur to those skilled in the art.
EXAMPLE 1
Gastric Emptying Test
[0051] A solution of 50 mg phenol red in 100 ml aqueous
methylcellulose (1.5%) was used as a test meal. Methylcellulose
(1.5 g, 400 centipoises) was dispersed in 100 ml of hot water
(80.degree. C.) under continuous shaking. The solution was allowed
to cool to 35.degree. C., and then phenol red was added. Intensity
and duration (5 hr) of agitation were kept constant to obtain
solutions of reproducible viscosity.
[0052] Conscious rats were fed the 0.05% phenol red methylcellulose
solution and euthanized after 20 minutes. The stomach was clamped
at the pylorus and cardiac ends before removal. The stomach and its
contents were homogenized with 100 ml of 0.1N NaOH. A baseline
control for each phenol red solution preparation was used by mixing
1.5 ml with 100 ml of 0.1N NaOH. The mixture was then kept for 1 hr
at room temperature: 5 ml of the supernatant was added to 0.5 ml of
trichloroacetic acid solution (20% w/v) to precipitate the
proteins. After centrifugation (2500.times.g for 20 min) the
supernatant was added to 4 ml of NaOH (0.5 N) to develop maximum
intensity of the color. The solutions were then read with a
spectrophotometer at a wavelength of 560 nm.
[0053] Gastric emptying (G.E.) for each rat was calculated
according to the following formula: (1-Absorbance of test
sample)/(Absorbance of baseline control).times.100%. Values were
expressed as mean.+-.SEM. Two-tailed Student's t-test was used for
comparison between groups.
EXAMPLE 2
Effect of Dopamine 3 Receptor Agonist on Gastric Emptying
[0054] Adult male Sprague-Dawley rats (weighing 200-250 g) were
deprived of food 18 hr prior to experiments but allowed free access
to water. The animals were intraperitoneally injected with a
dopamine 3 receptor agonist, PD 128907 hydrochloride, at 1 mg/kg or
with physiological saline (control) before administration by oral
tube of 1.5 ml of pre-warmed (35.degree. C.) 0.05% phenol red
solution. As shown in FIG. 1, systemic activation of dopamine 3
receptor (D3R) significantly delays gastric emptying in the rat,
suggesting D3R plays an important role in the regulation of gastric
motility.
EXAMPLE 3
Effect of Dopamine 3 Receptor Agonist on Pyloric Function
[0055] Pyloric function was assessed in an organ bath by measuring
the relaxation of pyloric strips of adult male Sprague-Dawley rats
in the presence of the dopamine 3 receptor agonist, PD 128907
hydrochloride. FIG. 2 illustrates the significant reduction in
electric field stimulation induced relaxation of pyloric strips in
the presence of the agonist. The figure clearly shows that this
effect was dose dependent, showing a greater decrease in relaxation
with increasing doses of the D3R agonist.
EXAMPLE 4
Effect of Dopamine 3 Receptor Antagonist on Gastric Emptying
[0056] Adult male Sprague-Dawley rats were used in the study.
Gastric emptying was assessed by the phenol red method 20 minutes
after feeding a non-nutrient methylcellulose meal to rats treated
intraperitoneally with dopamine or dopamine plus varying doses of a
selective dopamine 3 receptor antagonist, nafadotride (0.1 or 1
mg/kg body weight). Control rats were given an intraperitoneal
injection of the vehicle, phosphate buffered saline. Nafadotride
was able to partially reverse the effect of dopamine on the gastric
emptying time as illustrated in FIG. 3.
* * * * *