U.S. patent application number 10/198250 was filed with the patent office on 2002-12-12 for compositions and methods for the treatment of anorectal disorders.
This patent application is currently assigned to Cellegy Pharmaceuticals, Inc.. Invention is credited to Lee, Charles, Lee, Jung-Chung, Mak, Vivien, Parks, Thomas P..
Application Number | 20020187990 10/198250 |
Document ID | / |
Family ID | 46277920 |
Filed Date | 2002-12-12 |
United States Patent
Application |
20020187990 |
Kind Code |
A1 |
Parks, Thomas P. ; et
al. |
December 12, 2002 |
Compositions and methods for the treatment of anorectal
disorders
Abstract
Compositions and methods for the treatment of anorectal
disorders are provided in which certain combinations of NO donors,
PDE inhibitors, superoxide (O.sub.2.sup.-) scavengers,
.beta.-adrenergic agonists, cAMP-dependent protein kinase
activators, .alpha..sub.1-adrenergic antagonists, L-type Ca.sup.2+
channel blockers, estrogens, ATP-sensitive K.sup.+ channel
activators and smooth muscle relaxants are used.
Inventors: |
Parks, Thomas P.; (San
Mateo, CA) ; Mak, Vivien; (Palo Alto, CA) ;
Lee, Jung-Chung; (Sunnyvale, CA) ; Lee, Charles;
(Union City, CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Cellegy Pharmaceuticals,
Inc.
South San Francisco
CA
|
Family ID: |
46277920 |
Appl. No.: |
10/198250 |
Filed: |
July 17, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10198250 |
Jul 17, 2002 |
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09919590 |
Jul 30, 2001 |
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10198250 |
Jul 17, 2002 |
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09460306 |
Dec 13, 1999 |
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6395736 |
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10198250 |
Jul 17, 2002 |
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09595390 |
Jun 14, 2000 |
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6391869 |
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10198250 |
Jul 17, 2002 |
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09769621 |
Jan 23, 2001 |
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60222267 |
Jul 31, 2000 |
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60112325 |
Dec 14, 1998 |
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60139916 |
Jun 17, 1999 |
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60155318 |
Sep 21, 1999 |
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Current U.S.
Class: |
514/269 ;
514/150; 514/509; 514/565; 514/652 |
Current CPC
Class: |
A61K 31/21 20130101;
A61K 9/0031 20130101; A61K 31/522 20130101; A61K 31/513 20130101;
A61K 31/52 20130101; A61K 31/519 20130101; A61K 31/198 20130101;
A61K 31/505 20130101 |
Class at
Publication: |
514/269 ;
514/150; 514/509; 514/565; 514/652 |
International
Class: |
A61K 031/655; A61K
031/513; A61K 031/137; A61K 031/198; A61K 031/21 |
Goverment Interests
[0002] This invention was made with government support under Grant
Number 1 R43 DK 56563-01 awarded by the National Institutes of
Health, National Institute of Diabetes and Digestive and Kidney
Diseases. The Government has rights in certain aspects of the
invention.
Claims
What is claimed is:
1. A composition for the treatment of an anorectal disorder, and
for controlling the pain associated therewith, said composition
comprising at least one internal anal sphincter relaxing agent
selected from the group consisting of NO donors, phosphodiesterase
type II inhibitors, phosphodiesterase type IV inhibitors,
phosphodiesterase type V inhibitors, nonspecific phosphodiesterase
inhibitors, superoxide scavengers, .beta.-adrenergic agonists,
cAMP-dependent protein kinase activators, .alpha..sub.1-cadrenergic
antagonists, estrogens, ATP-sensitive K.sup.+ channel activators,
adenosine receptor antagonists, and smooth muscle relaxants, with a
pharmaceutically acceptable carrier.
2. A composition in accordance with claim 1, wherein said
composition comprises a first agent which is a NO donor selected
from the group consisting of nitroglycerin, L-arginine, SNAP, GSNO
and SIN-1, and a second agent that is an adrenergic receptor
antagonist.
3. A composition in accordance with claim 1, wherein said carrier
is formulated for local application.
4. A composition according to claim 1, wherein said composition
comprises a first relaxing agent that is a NO donor selected from
the group consisting of nitroglycerin, L-arginine, SNAP, GSNO and
SIN-1 and a second agent that is a .beta..sub.2-adrenergic
agonist.
5. A composition according to claim 4, wherein said
.beta..sub.2-adrenergic agonist is salbutamol or terbutaline.
6. A composition in accordance with claim 1, wherein said
composition comprises a first relaxing agent which is a NO donor
selected from the group consisting of nitroglycerin, L-arginine,
SNAP, GSNO and SIN-1 and a second agent that is an ATP sensitive
K.sup.+ channel activator.
7. A composition in accordance with claim 6, wherein said second
agent is minoxidil or diazoxide.
8. A composition in accordance with claim 1, wherein said
composition comprises a first relaxing agent which is a NO donor
selected from the group consisting of nitroglycerin, L-arginine,
SNAP, GSNO and SIN-1 and a second agent that is an adenosine
receptor antagonist.
9. A composition in accordance with claim 8, wherein said second
agent is theophylline or dyphylline.
10. A composition according to claim 1, comprising an adenosine
receptor antagonist.
11. A composition according to claim 10, wherein said antagonist is
theophylline or dyphylline.
12. A composition according to claim 1, comprising a ATP sensitive
K.sup.+ channel opener.
13. A composition according to claim 12, wherein said opener is
minoxidil or diazoxide.
14. A composition according to claim 1, wherein said composition
comprises a .beta..sub.2-adrenergic agonist.
15. A composition according to claim 14, wherein said
.beta..sub.2-adrenergic agonist is salbutamol or terbutaline.
16. A method of treating an anorectal disorder, and for controlling
the pain associated therewith, the method comprising administering
to a subject in need of such treatment a therapeutically effective
amount of a composition that comprises at least one internal anal
sphincter relaxing agent selected from the group consisting of NO
donors, phosphodiesterase type II inhibitors, phosphodiesterase
type IV inhibitors, phosphodiesterase type V inhibitors,
nonspecific phosphodiesterase inhibitors, superoxide scavengers,
.beta.-adrenergic agonists, cAMP-dependent protein kinase
activators, .alpha..sub.1-adrenergic antagonists, estrogens, L-type
Ca.sup.2+ channel blockers, ATP-sensitive K.sup.+ channel
activators, adenosine receptor antagonists and smooth muscle
relaxants.
17. A method in accordance with claim 16, wherein said composition
comprises a first agent which is a NO donor selected from the group
consisting of nitroglycerin, L-arginine, SNAP, GSNO and SIN-1, and
a second agent that is an adrenergic receptor antagonist.
18. A method in accordance with claim 16, wherein said
administering is by local application.
19. A method according to claim 16, wherein said composition
comprises a first relaxing agent that is a NO donor selected from
the group consisting of nitroglycerin, L-arginine, SNAP, GSNO and
SIN-1 and a second agent that is a .beta..sub.2-adrenergic
agonist.
20. A method according to claim 19, wherein said
.beta..sub.2-adrenergic agonist is salbutamol or terbutaline.
21. A method in accordance with claim 16, wherein said composition
comprises a first relaxing agent which is a NO donor selected from
the group consisting of nitroglycerin, L-arginine, SNAP, GSNO and
SIN-1 and a second agent that is an ATP sensitive K.sup.+ channel
activator.
22. A method in accordance with claim 21, wherein said second agent
is minoxidil or diazoxide.
23. A method in accordance with claim 16, wherein said composition
comprises a first relaxing agent which is a NO donor selected from
the group consisting of nitroglycerin, L-arginine, SNAP, GSNO and
SIN-1 and a second agent that is an adenosine receptor
antagonist.
24. A method in accordance with claim 23, wherein said second agent
is theophylline or dyphylline.
25. A method according to claim 16, wherein said composition
comprises an adenosine receptor antagonist.
26. A method according to claim 25, wherein said antagonist is
theophylline or dyphylline.
27. A method according to claim 16, wherein said composition
comprises a ATP sensitive K.sup.+ channel opener.
28. A method according to claim 28, wherein said activator is
minoxidil or diazoxide.
29. A method according to claim 16, wherein said composition
comprises a .beta..sub.2-adrenergic agonist.
30. A method according to claim 29, wherein said
.beta..sub.2-adrenergic agonist is salbutamol or terbutaline.
31. A method in accordance with claim 16, wherein said anorectal
disorder is an anal fissure.
32. A method of claim 16, wherein said composition comprises a
terbutaline or salbutamol.
33. A method of claim 16, wherein said composition comprises
theophylline or diphylline.
34. A method of claim 16, wherein said composition comprises
minoxidil or diazoxide.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. 119(e) of
U.S. Patent Application No. 60/222,267, filed Jul. 31, 2000. This
application also is a Continuation-In-Part and claims priority to
U.S. patent application Ser. No. 09/460,306, filed Dec. 13, 1999;
U.S. patent application Ser. No. 09/595,390 filed on Jun. 14, 2000;
and U.S. patent application Ser. No. 09/769,621 filed Jan. 23, 2001
which each claim priority from U.S. Provisional Application No.
60/112,325, filed Dec. 14, 1998; U.S. Provisional Application No.
60/139,916, filed Jun. 17, 1999 and U.S. Provisional Application
No. 60/155,318, filed Sep. 21, 1999. The disclosure of each of the
above priority documents is incorporated herein by reference in its
entirety.
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK.
[0003] Not Applicable
BACKGROUND OF THE INVENTION
[0004] This invention is directed to compositions and methods for
treating anorectal disorders such as anal fissures, anal ulcer,
hemorrhoidal diseases and levator spasm by administering to an
appropriate anal area (for example, the internal anal canal) of a
subject in need of such treatment an agent or combination of agents
which relaxes the internal anal sphincter muscle. More
specifically, this invention describes compositions and methods for
treating anorectal disorders with agents which induce an increase
in cyclic nucleotides in the anal sphincter muscle or which mimic
the actions of cyclic nucleotides or reduce intracellular calcium
concentrations in the affected anal sphincter muscle tissue,
thereby reducing anal sphincter hypertonicity and/or spasm in
patients afflicted with such disorders.
[0005] In general, anal fissure (fissure-in-ano), anal ulcer,
hemorrhoidal diseases, and levator spasm (proctalgia fugax) are
relatively common benign conditions of the anorectal area which
affect subjects, including humans, of all ages, races, and sexes.
While hemorrhoids and anal fissures do not garner the attention
given to life threatening diseases, they are responsible for
considerable suffering and disability, affecting over 26 million
people in the U.S., Europe, and Japan.
[0006] An anal fissure or ulcer is a tear or ulcer of the mucosa or
lining tissue of the distal anal canal. An anal fissure or ulcer
can be associated with another systemic or local disease, but is
more frequently present as an isolated finding. The typical
idiopathic fissure or ulcer is confined to the anal mucosa and
usually lies in the posterior midline, distal to the dentate line.
An individual with an anal fissure or ulcer frequently experiences
anal pain and bleeding, the pain being more pronounced during and
after bowel movements.
[0007] Hemorrhoids are specialized vascular areas lying subjacent
to the anal mucosa. Symptomatic hemorrhoidal diseases are
manifested by bleeding, thrombosis and/or prolapse of the
hemorrhoidal tissues. Commonly, internal hemorrhoidal tissue bulges
into the anal canal during defecation and results in bleeding and
pain. As the tissue enlarges, further bleeding, pain, prolapse and
thrombosis can ensue. The thrombosis of hemorrhoids is yet another
cause of bleeding and pain.
[0008] Levator spasm is a condition affecting women more frequently
than men. This syndrome is characterized by spasm of the levator
ani muscle, a portion of the anal sphincter complex. The patient
suffering from levator spasm may experience severe, episodic rectal
pain. A physical exam may reveal spasm of the puborectalis muscle
and pain may be reproduced by direct pressure on this muscle.
Bleeding is normally not associated with this condition.
[0009] Hemorrhoids are the most prevalent anorectal disorder and
are the most common cause of hematochezia (i.e., passage of bloody
stools). Hemorrhoidal disease is the consequence of distal
displacement of the anal cushions, which normally play an important
role in continence. The causes of hemorrhoids are not known. The
most consistently demonstrated physiological abnormality is
increased resting anal pressure (Hancock B. D., Br J Surg
64(2):92-5 (1975); Loder, P. B., Br J Surg 81(7):946-54 (1994)).
Patients with non-prolapsing hemorrhoids appear to have higher anal
pressures than those with prolapsing hemorrhoids (Arabi, Y. et al.,
Am J Surg 134(5):608-10 (1977); Sun, W. M. et al., Br J Surg 77(4):
458-62, (1990)), although the therapeutic implications of this
observation remain unclear. Treatment is dependent on the degree of
hemorrhoid prolapse and symptoms. Most cases (first- and
second-degree hemorrhoids) generally respond to conservative
medical treatment (e.g., dietary changes, sitz baths) or
non-surgical procedures (e.g., rubber band ligation). Acutely
thrombosed external hemorrhoids are usually characterized by severe
anal pain, and internal anal sphincter hypertonia may play a role
in the etiology of this pain (Gorfine, S. R., Dis Colon Rectum
38(5): 453-7 (1995)). Surgical excision of symptomatic thrombosed
external hemorrhoids is indicated within 48 to 72 hours of the
onset of pain. Post-hemorrhoidectomy pain is severe,
disproportionate to the surgery itself, and requires the use of
narcotic analgesics, which unfortunately complicate recovery by
causing constipation. Anal dilatation and lateral internal
sphincterotomy as treatments to reduce anal sphincter pressure in
hemorrhoids have been used successfully, both as stand alone
procedures and in conjunction with hemorrhoidectomy (Keighley, M.
R. et al., Br Med J J2(6196):967-9 (1979); Schouten W. R. et al.,
Dis Colon Rectum 28(12), 869-72 (1986); Galizia et al., Eur J Surg
166(3):223-8 (2000)).
[0010] Others have reported that the addition of lateral internal
sphincterotomy to routine hemorrhoidectomy is unnecessary and
carries the added risk of incontinence (Mathai, V. et al., Br J
Surg. 83(3):380-2 (1996)).
[0011] Anal fissure is one of the most common causes of anorectal
pain. Anal fissures are tears in the mucosa of the distal anal
canal, usually along the posterior midline. The exact causes of
anal fissures remain unknown. They are often associated with
trauma, e.g., passage of a hard stool, but can also occur during
bouts of diarrhea, childbirth, or ulceration of a hemorrhoid (Lund,
J. N. et al., Br J Surg. 83(10): 1335-44 (1996)). The most common
symptom is pain at defecation, which can be quite severe and last
for a variable time afterwards. The pain is chiefly due to an
intense spasm of the internal anal sphincter muscle. Most anal
fissures are adequately treated with sitz baths, stool softeners,
and analgesics. Approximately 60% of acute anal fissures will heal
within three weeks using this treatment regimen. Acute anal
fissures, which do not heal, become chronic anal fissures or anal
ulcers. Hypertonicity of the internal anal sphincter muscle and
mucosal ischemia are thought to play an important role in the
pathogenesis of chronic anal fissures (Schouten W. R. et al., Dis
Colon Rectum 37(7):664-9 (1994); Lund, J. N. et al., Br J Surg
83(10): 1335-44 (1996)). Anodermal blood flow at the posterior
midline is less than other regions of the anal canal, and perfusion
of the posterior mucosa is inversely related to anal pressure.
Chronic anal fissures are typically not responsive to conservative
medical therapy. Current treatments are therefore directed at
relieving sphincter spasm, and include anal dilatation (under
anesthesia), or more commonly, lateral sphincterotomy of the
internal anal sphincter. Healing occurs following surgical
sphincterotomy in 95% of cases. Successful sphincterotomy (or anal
dilatation) is associated with a significant decrease in intra-anal
pressure and increase in anodermal blood flow (Lund, J. N. et al.,
Br J Surg 83(10): 1335-44, (1996); Schouten W. R. et al., Scan J
Gastroenterol. Suppl 218: 78-81 (1996)). However, up to 35% of
patients may experience some form of incontinence following the
surgical procedure (Sharp, F. R., Am J Surg 171(5):512-5 (1996)).
Incontinence of stool and flatulence is a humiliating disability
with numerous social, medical, and financial implications. There is
clearly a large unmet medical need to develop effective,
non-surgical treatments for anal fissure and other colorectal
conditions, including acute hemorrhoidal disease, hemorrhoidectomy
pain, proctalgia fugax, and severe constipation. Considerable
recent progress has been made in the understanding of anorectal
physiology and pharmacology. These new insights provide important
implications and opportunities for the pharmacological management
of colorectal disorders.
[0012] Sphincters are circular groups of smooth muscle that control
the orifices of hollow organs. They are present throughout the
gastrointestinal tract and control the passage of materials through
this system of the body. When constricted, sphincters close
orifices leading to or from the hollow organs, such as the stomach,
intestine, rectum, etc. In order for the orifice to open, the
sphincter must relax. The, sphincter that closes the anus
(sphincter ani) consists of two sphincter muscle groups. The
external anal sphincter is a thin flat plane of striated muscle
fibers adherent to the integument surrounding the margin of the
anus. It is innervated by motor neurons and is under voluntary
control. The internal anal sphincter (IAS) is a ring of smooth
muscle that surrounds the anal canal and is formed by a specialized
aggregation of involuntary circular smooth muscle fibers of the
intestine. The IAS is largely responsible for resting anal
sphincter pressure and continence which is maintained by intrinsic
myogenic tone and regulated by both intrinsic and extrinsic
innervation from the autonomic nervous system (Penninckx, F. et
al., Baillieres Clin Gastroenterol 6(1)193-214 (1992); Speakman, C.
T. Eur J Gastroenterol Hepatol 9(5):442-6 (1997)).
[0013] The IAS smooth muscle constantly generates rhythmic
electrical slow waves, but no action potentials. The slow waves are
linked to calcium fluxes via voltage-dependent, L-type calcium
channels that are responsible for mechanical force generation and
contraction of the sphincter. Accordingly, several calcium channel
antagonists, including diltiazem and nifedipine, have been
documented to reduce anal pressure in man (Jonard et al., Lancet
1(8535): 754 (1987); Chrysos, E. et al., Dis Colon Rectum 39(2):
212-6 (1996); Antropoli, C. et al., Dis Colon Rectum 42(8):1011-5
(1999); Carapeti, E. A. et al., Gut 45(5) 719-722 (1999); Carapeti,
E. A. et al., Br J Surg 86(2):267-70 (1999), and in several
reports, to heal chronic anal fissures (Cook, T. A. et al., Br J
Surg 86(10):1269-73 (1999); Brisinda, G. et al., Br J Surg 87(2):
251 (2000)).
[0014] Sympathetic innervation of the IAS, supplied by the
hypogastric nerves, is primarily excitatory and functions to
enhance myogenic tone through the action of norepinephrine on
smooth muscle a,-adrenergic receptors (Frenckner, B., et al., Gut
17(4):306-12 (1976); Speakman, C. T. et al., Dig Dis Sci
38(11)1961-9 (1993)). The .alpha..sub.1-adrenergic receptor
antagonists phentolamine and indoramin reduce anal canal pressure
when administered to healthy volunteers or patients with chronic
anal fissures (Speakman, C. T., Eur J. Gastroenterology 9(5):442-6
(1997); Pitt, J. et al., Dis Colon Rectum 43(6)800-803 (2000)).
Conversely, the .alpha.-receptor agonists methoxamine and
phenylephrine increase anal pressure (Speakman, C. T. 1997 supra;
Carapeti, E. A. et al., Br J Surg 86(2):267-70 (1999)). Low anal
pressure is associated with incontinence (Speakman, C. T.
Gastroenterology 9(5):442-6 (1997)). Speakman, C. T. et al.,
(Speakman, C. T. et al., Dig. Dis Sci. 38(11):1961-9 (1993))
reported that the IAS of incontinent patients exhibit reduced
sensitivity to norepinephrine. Although the a-adrenergic receptor
population is dominant, .beta.-adrenergic receptors are also
present on human IAS, and mediate relaxation (Parks, A. G., et al.,
Gut 10(8):674-7 (1969); Burleigh, D. E., et al., Gastroenterology
77(3): 484-90, (1979). The contractile response of the IAS to
norepinephrine can be converted to relaxation in the presence of
selective a-receptor blockade, both in vitro and in normal human
volunteers (Burleigh, D. E., et al., Gastroenterology 77(3):
484-90, (1979); Speakman, C. T., Eur J Gastroenterology 9(5):442-6
(1997)). Regadas and colleagues (Regadas, F. S. et al., Br J Surg
80(6):799-801 (1993)) demonstrated that isolated IAS strips from
chronic anal fissure patients were significantly more sensitive to
the relaxant effects of the .beta.-adrenergic agonist isoproterenol
than control tissues, whereas no differences were noted in the
contractile responses to phenylephrine and potassium chloride (a
membrane depolarizing agent). However, it remains to be determined
whether .beta.-adrenergic agonists offer disease-specific
advantages for the treatment of chronic anal fissure.
[0015] The IAS relaxes in response to rectal distention (the
rectoanal inhibitory reflex). The nerves mediating the rectoanal
inhibitory reflex lie entirely within the wall of the gut (enteric
inhibitory neurons), and descend from the rectum to the IAS.
Electrical field stimulation (EFS) mimics the effects of intrinsic
nerve stimulation on isolated smooth muscle strips. IAS strips are
relaxed by EFS, an effect that is abolished by the neurotoxin
tetrodotoxin, but is unaffected by antagonists of the classical
neurotransmitters, acetylcholine or norepinephrine. The inhibitory
nerves are thus classified as non-adrenergic, non-cholinergic
(NANC) nerves. Adenosine triphosphate (ATP) and vasoactive
intestinal peptide (VIP) were first suggested as NANC
neurotransmitter candidates since they mimicked the relaxation
elicited by electrical stimulation of motor nerve fibers
(Burnstock, G. et al., Br J Pharmacol. 46(2):234-42 (1972); Bitar,
K. N. et al., Science 216(4545): 531-3 (1982)). However, ATP and
VIP, either separately or together, could not account for all
inhibitory neurotransmission in gastrointestinal smooth muscle, and
their roles have not been established in man (Burleigh, D. E. et
al., Gastroenterology 77(3): 484-90 (1979); Burleigh, D. E., J
Pharm Pharmacol 35(4):258-60 (1983); Brookes, S. J., J
Gastroenterol Hepatol 8(6):590-603 (1993).
[0016] Recent studies indicate that NO plays an important role in
NANC nerve mediated relaxation of the IAS. In an animal model,
Rattan, S. et al., (Rattan, S. et al., Am J Physiol 262 (1 Pt
1):G107-12 (1992) demonstrated that IAS relaxation associated with
the rectoanal reflex (induced by rectal balloon distention), or
neural stimulation, was blocked by inhibition of NO synthase (NOS)
with L-NNA [N.sup.5-(nitroamidino)-L-2,5-diaminopentanoic acid],
but not with D-NNA. Block of the rectoanal reflex by L-NNR was
reversed by L-arginine in a stereospecific manner, implicating NO
or NO-like substances as mediators of NANC nerve mediated IAS
relaxation. NO was shown to directly relax the IAS in a
concentration-dependent manner in vitro, mimicking the effect of
NANC nerve stimulation by EFS. NANC nerve-mediated relaxation of
IAS strips in vitro was blocked by inhibition of NO synthase with
L-NNA, and the block was reversed by L-arginine, but not D-arginine
(Rattan, S. et al., Am J Physiol 262 (1 Pt 1):G107-12, (1992) and
Rattan, S. et al., Gastroenterology 103(1):43-50 (1992)). Similar
observations have been made using isolated muscle strips of human
IAS (Burleigh Gastroenterology 102(2): 679-83 (1992); O'Kelly, T.
J. et al., Br J Surg 80(10): 1337-41, (1993)). The direct release
of NO following NANC nerve stimulation of opossum IAS strips was
demonstrated using a specific chemiluminescence detection method
(Chakder, S. et al., Am J Physiol., 264 (4Pt 1)G702-7 (1993)).
O'Kelly (O'Kelly, T. J. et al., Dis Colon Rectum 37(4): 35-7
(1994)) recently demonstrated the presence of NOS in neurons of the
myenteric plexus that project throughout the IAS and lay in close
proximity to smooth muscle cells. In Hirschsprung's disease, a
condition in which the rectoanal reflex is absent, NOS containing
nerves were absent from the non-relaxing segment, but present in
the normal segment of the gut (O'Kelly, T. J. et al., J Pediatric
Surgery 29(2): 294-9 (1994)). These observations fulfill most of
the criteria for NO as an inhibitory mediator or
neurotransmitter.
[0017] A number of potent vasodilators and smooth muscle relaxants
are known to chemically release NO on or within target cells, and
thus are known as NO donors. Some NO donors, e.g., nitroglycerin,
are widely used therapeutically as coronary vasodilators to treat
heart disease. In keeping with the role of NO as an inhibitory
neurotransmitter mediating relaxation of the IAS, NO donors are
beginning to be explored clinically as drugs to treat anal
disorders associated with IAS hypertonicity. Significantly,
nitroglycerin (Gorfine, S. R., Dis Colon Rectum, 38(5):453-6
(1995); Watson, S. J. et al., Br J Surgery 83(6):771-5, 1996; Lund,
J. N. et al., Lancet 349: 9044 (1997)) and isosorbide dinitrate
have been used to effect a reversible chemical sphincterotomy in
patients with chronic anal fissure. These drugs reduce maximal
resting anal pressure and, improve anodermal blood flow, reduce
pain, and heal fissures in a majority of the patients.
Nitroglycerin has also been shown to reduce the throbbing pain of
acute hemorrhoidal thrombosis and proctalgia fugax (Gorfine, S. R.,
Dis Colon Rectum 38(5):453-6 (1995); Lowenstein, B. et al., Dis
Colon Rectum 41(5):667-8 (1998)).
[0018] U.S. Pat. Nos. 5,504,117 and 5,693,676 describe the use of
NO donors for the treatment of anorectal conditions. However, the
development of adverse side effects such as the development of
headaches has limited the use of NO donors in stand alone therapy,
especially at higher doses.
[0019] One problem associated with topical nitroglycerin therapy,
which may limit its effectiveness, is the incidence of headache,
particularly at higher doses (Palazzo, F. F. et al., J R Coll Surg
Edinb 45(3):168-70 (2000)). The headache is presumably due to
systemic effects of nitroglycerin and is generally transient, but
can affect patient compliance. There is a need for treatment
methods strategies which enhance the local effect of nitroglycerin
and minimize its systemic side effects. A second potential problem
of nitrates is the development of drug tolerance, a problem well
documented for nitrate therapy in cardiovascular disease (Fung, H.
L., et al., Cardiovasc Drugs Ther 8(3):489-99, (1994)). Tolerance,
if present, would limit the ability of nitroglycerin to produce a
sustained relaxation of the IAS, which may be necessary for healing
particularly refractant chronic anal fissures.
[0020] There is clearly a significant need for other non-surgical
treatments of anorectal disorders, including, for example, anal
fissures and other anorectal conditions caused by anal sphincter
spasm and or hypertonicity, including acute hemorrhoidal diseases
and proctalgia fugax.
[0021] There is thus a need for alternative methods and
compositions for reducing anal sphincter pressure that complement
or supplant nitroglycerin.
[0022] The use of a topical or intra-rectal pharmaceutical
preparation that complements or supplants nitroglycerin for the
treatment of chronic anal fissures and other anorectal disorders
can provide the first effective alternative to surgery for this
painful disorder.
BRIEF SUMMARY OF THE INVENTION
[0023] In one aspect, the present invention provides compositions
for the treatment of anorectal disorders comprising a nitric oxide
donor in combination with a second agent (typically one which
modulates levels of cAMP or cGMP). The second agent can be a
phosphodiesterase type V (PDE V) inhibitor, a phosphodiesterase
type II (PDE II) inhibitor, a phosphodiesterase type IV (PDE IV)
inhibitor, a nonspecific PDE inhibitor, a p-adrenergic agonist, a
cAMP-dependent protein kinase activator, an estrogen or
estrogen-like compound, or an .alpha..sub.1-adrenergic antagonist.
The agent can also be a superoxide anion (O.sub.2.sup.-) scavenger,
an ATP-sensitive K.sup.+ channel activator, a sympathetic nerve
terminal destroyer, or a smooth muscle relaxant, although these
agents do not directly modulate either cAMP or cGMP levels. The
present invention further provides methods of using these
compositions.
[0024] In another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising a
phosphodiesterase inhibitor, preferably a PDE II inhibitor, a PDE
IV inhibitor or a PDE V inhibitor, either alone or in combination
with another agent selected from .beta.-adrenergic receptor
agonists, .alpha..sub.1-adrenergic antagonists, estrogens, L-type
Ca.sup.2+ channel blockers, ATP-sensitive K.sup.+ channel
activators, or smooth muscle relaxants, in combination with a
pharmaceutically acceptable carrier. The present invention also
provides methods of using these compositions.
[0025] In another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising a
.beta.-adrenergic receptor agonist, preferably a .beta..sub.2- or
.beta..sub.3-adrenergic receptor agonist, either alone or in
combination with another agent selected from cAMP-hydrolyzing PDE
inhibitors (e.g., a PDE IV inhibitor), nonspecific PDE inhibitors,
.alpha..sub.1-adrenergic antagonists, estrogens or estrogen-like
compounds, L-type Ca.sup.2+ channel blockers, or ATP-sensitive
K.sup.+ channel activators, and methods of using those
compositions.
[0026] In yet another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising an
ATP-sensitive K.sup.+ channel activator, either alone or in
combination with another agent selected from cAMP-dependent protein
kinase activators, .alpha..sub.1-adrenergic antagonists, estrogens,
L-type Ca.sup.2+ channel blockers, or smooth muscle relaxants, and
methods of using those compositions.
[0027] In still another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising an
.alpha..sub.1-adrenergic antagonist, either alone or in combination
with another agent selected from cAMP-hydrolyzing PDE inhibitors
(preferably a PDE IV inhibitor) or smooth muscle relaxants, and
methods of using those compositions.
[0028] In another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising
.beta..sub.2-adrenergic agonists, either alone or in combination
with another agent. Methods for the use of these compositions are
also provided. In one group of embodiments, the
.beta..sub.2-adrenergic agonists are used alone. In a preferred
embodiment, the .beta..sub.2-adrenergic agonists is combined with a
phosphodiesterase inhibitor. In another embodiment, the
.beta..sub.2-adrenergic agonists are combined with one or more
other IAS relaxing agents.
[0029] In another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising
adenosine receptor antagonists, either alone or in combination with
another agent. Methods for the use of these compositions are also
provided. In one group of embodiments, adenosine receptor
antagonists are used alone. In another group of embodiments, the
adenosine receptor antagonists are combined with at least one other
IAS relaxing agent.
[0030] In another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising
cyclic nucleotide-dependent protein kinase activators, either alone
or in combination with another agent. Methods for the use of these
compositions are also provided. In one group of embodiments,
cGMP-dependent protein kinase activators are used alone. In another
group of embodiments, nonspecific cyclic nucleotide-dependent
protein kinase activators are used alone. In yet another group of
embodiments, nonspecific cyclic nucleotide-dependent protein kinase
activators are used in combination with smooth muscle relaxants. In
still another group of embodiments, cAMP-dependent protein kinase
activators are provided in combination with L-type Ca.sup.2+
channel blockers.
[0031] In yet another aspect, the present invention provides a
composition for the treatment of anorectal disorders comprising a
methylxanthine compound. In preferred embodiments, the compound is
theophylline or dyphylline. In still another embodiment, the
methylxanthine compound is used alone. In still another embodiment,
the methylxanthine compound is combined with another IAS relaxing
agent.
[0032] In yet another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising an
estrogen or other estrogenic compound, either alone or in
combination with another agent. Methods for the use of these
compositions are also provided. In one group of embodiments,
estrogenic compounds are used alone. In another group of
embodiments, the estrogenic compounds are used in combination with
a second agent selected from phosphodiesterase inhibitors,
.beta.-adrenergic receptor agonists, .alpha..sub.1-adrenergic
antagonists, L-type Ca.sup.2+ channel blockers, ATP-sensitive
K.sup.+ channel activators, or smooth muscle relaxants, in
combination with a pharmaceutically acceptable carrier. The present
invention further provides methods of using these compositions.
[0033] Where the compounds discussed above act through mechanisms
distinctly different from nitroglycerin, they can be used to
complement nitroglycerin therapy, or as stand alone products.
[0034] As noted above, methods of treating anorectal disorders are
also provided herein. The methods of the invention comprise
administering to a subject a suitable formulation of one or more of
the compositions above. In related methods, treatment is carried
out by administration of two or more agents in sequence, either by
the same route of administration or by different routes of
administration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 illustrates a typical waveform pattern for resting
IASP in a rat under conditions of a control experiment.
[0036] FIG. 2 illustrates the waveform pattern for IASP in a rat
following administration of 20 .mu.l of a 1% solution of
nitroglycerin in propylene glycol.
[0037] FIG. 3 illustrates the effect of a cGMP mimetic on internal
anal sphincter pressure in a rat. The figure shows a waveform
pattern for IASP for a rat following administration of 20 .mu.l of
a 10% solution of dibutyryl-cGMP in saline.
[0038] FIG. 4 illustrates the effect of a type V phosphodiesterase
inhibitor on internal anal sphincter pressure in a rat. The figure
shows a waveform pattern for IASP for a rat following
administration of 20 .mu.l of a 5% solution of zaprinast in
1-methyl-2-pyrrolidinone.
[0039] FIG. 5 illustrates the effect of a potassium channel opener
on internal anal sphincter pressure in a rat. The figure shows a
waveform pattern for IASP for a rat following administration of 20
.mu.l of a 4% solution of minoxidil in 62.5% propylene glycol.
[0040] FIG. 6 illustrates the effect of NTG administered to the IAS
as a bolus dose.
[0041] FIG. 7 illustrates the effect of NTG administered to the IAS
by continuous infusion over 4 hours.
[0042] FIG. 8 illustrates the effect of 8-bromo cAMP infused to the
IAS at 20 .mu.g/hour for three hours.
[0043] FIG. 9 illustrates the effect of dibutyryl cAMP infused to
the IAS at 20 .mu.g/hour for three hours.
[0044] FIG. 10 illustrates the effect of a bolus delivery of SOD
(200 .mu.g) to the IAS, followed by a bolus dose of NTG (200 .mu.g)
in the same vehicle.
[0045] FIG. 11 illustrates the effect of a bolus delivery of NTG
(200 .mu.g) to the IAS, followed by a bolus dose of SOD (200 .mu.g)
in the same vehicle.
[0046] FIG. 12 illustrates the effect on the IAS of a vehicle
injection followed after 30 minutes by bolus doses of NTG.
[0047] FIG. 13 illustrates the effect on the IASP of an i.p.
injection of zaprinast followed by bolus doses of NTG applied
topically to the IAS.
[0048] FIG. 14 illustrates the effect on the IASP of a bolus dose
of NTG applied topically to the IAS, wherein the first NTG dose is
provided at 2.75 hours after a vehicle injection.
[0049] FIG. 15 illustrates the effect on the IASP of an i.p.
injection of zaprinast followed by bolus doses of NTG, wherein the
first NTG dose is provided at 2.75 hours after zaprinast
injection.
[0050] FIG. 16 illustrates the effect on the IAS of a vehicle
injection followed after 50 minutes by bolus doses of NTG.
[0051] FIG. 17 illustrates the effect on the IAS of PDE V
inhibitor, dipyridarnole injected i.p. 50 minutes prior to bolus
doses of NTG.
[0052] FIG. 18 illustrates the effect on the IASP of PDE V
inhibitor MBCQ injected i.p. 30 minutes prior to bolus doses of
NTG.
[0053] FIG. 19 illustrates the effect on the IASP of .beta.-agonist
isoproterenol delivered to the IAS 30 minutes after saline
alone.
[0054] FIG. 20 illustrates the effect on the IASP of
.beta..sub.2-agonist terbutaline in saline infused continuously at
20 .mu.g/hour.
[0055] FIG. 21 illustrates the effect on the IASP of
.beta..sub.2-agonist salbutamol in saline infused continuously at
20 .mu.g/hour.
[0056] FIG. 22 illustrates the effect on the IASP of PDE IV
inhibitor rolipram in DMSO/acetone/olive oil infused continuously
at 20 .mu.g/hour.
[0057] FIG. 23 illustrates a bolus dose of salbutamol followed by a
single bolus dose of salbutamol and PDE IV inhibitor etazolate.
[0058] FIG. 24 illustrates a bolus dose of etazolate followed by a
single bolus dose of salbutamol and etazolate.
[0059] FIG. 25 illustrates the effect on the IASP of PDE IV
inhibitor Ro 20-1724 in DMSO/acetone/olive oil infused continuously
at 20 .mu.g/hour.
[0060] FIG. 26 illustrates a vehicle control for the treatments
provided in FIG. 27.
[0061] FIG. 27 illustrates the effect on the IASP of the specific
adenyl cyclase activator forskolin, in DMSO/acetone/olive oil
infused continuously at 20 .mu.g/hour.
[0062] FIG. 28 illustrates the effect on the IASP of the
.alpha..sub.1-blocker, prazosin, in DMSO/acetone/olive oil infused
continuously at 20 .mu.g/hour.
[0063] FIG. 29 illustrates the effect on the IASP of the
nonspecific PDE inhibitor IBMX, in DMSO/acetone/olive oil infused
continuously at 200 .mu.g/hour.
[0064] FIG. 30 illustrates the effect on the IASP of the
nonspecific PDE inhibitor IBMX, in DMSO/acetone/olive oil infused
continuously at 20 .mu.g/hour.
[0065] FIG. 31 illustrates the effect on the IASP of a single bolus
dose of the K.sup.+-ATP channel opener minoxidil in propylene
glycol/water.
[0066] FIG. 32 illustrates the effect on the IASP of the
K.sup.+-ATP channel opener diazoxide, in DMSO/acetone/olive oil
infused continuously at 20 .mu.g/hour.
[0067] FIG. 33 illustrates the effect on the IASP of the
Ca.sup.+2-channel blocker diltiazem in saline infused continuously
at 20 .mu.g/hour.
[0068] FIG. 34 illustrates the effect on the IASP of the
Ca.sup.+2-channel blocker verapamil in saline infused continuously
at 20 .mu.g/hour.
[0069] FIG. 35 illustrates the effect on the IASP of the
sympathetic nerve terminal destroyer 6-hydroxydopamine when
administered to the IAS in bolus doses of 200 .mu.g per day for 5
days.
[0070] FIG. 36 illustrates the effect on the IASP of a control
vehicle i.p injection of 1-methyl-2-pyrollidinone followed after 30
minutes by continuous infusion of a sub-threshold dose of
isoproterenol in saline (0.2 .mu.g/hour).
[0071] FIG. 37 illustrates the effect on the IASP of the PDE III/IV
inhibitor zardaverine when injected i.p. (10 mg in vehicle)
followed after 30 minutes by a continuous infusion of
isoproterenol.
[0072] FIG. 38 illustrates the effect on the IASP of the PDE III/IV
inhibitor zardaverine when injected i.p. (7.5 mg in vehicle)
followed after 30 minutes by a continuous infusion of 5%
dextrose.
[0073] FIG. 39 illustrates the effect on the IASP of the PDE III/IV
inhibitor zardaverine when injected i.p. (7.5 mg in vehicle)
followed after 30 minutes by a continuous infusion of a
sub-threshold dose of isoproterenol.
[0074] FIG. 40 illustrates the effect on the IASP of the adenosine
antagonist and non-specific PDE inhibitor, theophylline when
continuously infused at 200 .mu.g/hour in 5% dextrose.
[0075] FIG. 41 illustrates the effect on the IASP of theophylline
when continuously infused at 20 .mu.g/hour in 5% dextrose.
[0076] FIG. 42 illustrates the effect on the IASP of theophylline
when continuously infused at 2 .mu.g/hour in 5% dextrose.
[0077] FIG. 43 illustrates the effect on the IASP of dyphylline
when continuously infused at 20 .mu.g/hour in 5% dextrose.
DETAILED DESCRIPTION OF THE INVENTION
[0078] Abbreviations and Definitions
[0079] cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine
monophosphate; NO, nitric oxide; NTG, nitroglycerin; SOD,
superoxide dismutase; PDE, phosphodiesterase; IASP, internal anal
sphincter pressure; Rp-cAMPS, Rp-Adenosine-3',5'-cyclic
monophosphorothioate; Sp-cAMPS, Sp-Adenosine-3',5'-cyclic
monophosphorothioate; 8-CPT cAMP,
8-(4-Chlorophenylthio)-adenosine-3',5'-cyclic monophosphate, sodium
salt; Sp-5,6-DCI-cBiMPS,
Sp-5,6-dichloro-1-b-D-ribofuranosylbenzimidazole-3',5'-
-monophosphorothioate; Dibutyryl-cAMP,
N6,2'-O-Dibutyryladenosine-3',5'-cy- clic monophosphate, sodium
salt monohydrate; Sp-8-pCPT-cGMPS,
Sp-8-(4-Chlorophenylthio)-quanosine-3',5'-cyclic monophosphate,
sodium salt; 8-Bromo-cGMP, 8-Bromoguanosine-3',5'-cyclic
monophosphate, sodium salt; Rp-8-Br-cGMPS,
Rp-8-Bromoguanosine-3',5'-cyclic monophosphorothioate, sodium salt;
Dibutyryl-cGMP, N2,2'-O-Dibutyrylguanosine-3',5'-cyclic
monophosphate, sodium salt; EHNA,
erythro-9-(2-Hydroxy-3-nonyl)adenine HCI; IBMX,
3-Isobutyl-1-methylxanthi- ne; MY-5445,
1-(3-Chlorophenylamino)-4-phenylphthalazine; Ro 20-1724,
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; MBCQ,
4-((3,4-(Methylenedioxy) benzyl)amino)-6-chloroquinazoline.
[0080] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by those
of ordinary skill in the art to which this invention belongs. The
following references provide one of skill with a general definition
of many of the terms used in this invention: Singleton et al.,
DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2d ed. 1994); THE
CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker ed., 1988);
and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY
(1991). As used herein, the following terms have the meanings
ascribed to them unless specified otherwise. Although any methods
and materials similar or equivalent to those described herein may
be used in the practice or testing of the present invention, the
preferred methods and materials are described. For purposes of the
present invention, the following terms are defined below.
[0081] The terms "treatment", "therapy" and the like include, but
are not limited to, changes in the recipient's status. The changes
can be either subjective or objective and can relate to features
such as symptoms or signs of the disease or condition being
treated. For example, if the patient notes decreased itching,
reduced bleeding, reduced discomfort or decreased pain, then
successful treatment has occurred. Similarly, if the clinician
notes objective changes, such as by histological analysis of a
biopsy sample, then treatment has also been successful.
Alternatively, the clinician may note a decrease in the size of
lesions or other abnormalities upon examination of the patient.
This would also represent an improvement or a successful treatment.
Preventing the deterioration of a recipient's status is also
included by the term. Therapeutic benefit includes any of a number
of subjective or objective factors indicating a response of the
condition being treated as discussed herein.
[0082] "Drug", "pharmacological agent", "pharmaceutical agent",
"active agent", and "agent" are used interchangeably and are
intended to have their broadest interpretation as to any
therapeutically active substance which is delivered to a living
organism to produce a desired, usually beneficial effect.
[0083] "Pharmaceutically-acceptable" or
"therapeutically-acceptable" refers to a substance which does not
interfere with the effectiveness or the biological activity of the
active ingredients and which is not toxic to the hosts, which may
be either humans or animals, to which it is administered.
"Therapeutically-effective amount" refers to the amount of an
active agent sufficient to induce a desired biological result. That
result may be alleviation of the signs, symptoms, or causes of a
disease, or any other desired alteration of a biological system.
The term "therapeutically effective amount" is used herein to
denote any amount of the formulation which causes a substantial
improvement in a disease condition when applied to the affected
areas repeatedly over a period of time. The amount will vary with
the condition being treated, the stage of advancement of the
condition, and the type and concentration of formulation applied.
Appropriate amounts in any given instance will be readily apparent
to those skilled in the art or capable of determination by routine
experimentation.
[0084] The term "anorectal area" is defined herein to include both
the anus and the rectum region of a mammal. More particularly, the
term includes the internal anal canal, the external anus and the
lower rectum.
[0085] "Hypertonicity" refers to being in state of greater than
normal muscular tension or of incomplete relaxation.
[0086] The term "cyclic nucleotide" refers to cyclic adenosine
monophosphate and cyclic guanosine monophosphate.
[0087] The term "modulation" refers to any systematic variation or
graded change in a characteristic (e.g. frequency, concentration,
amplitude, effectiveness, etc.) of a sustained oscillation
sufficient to affect a biological function. The term "change"
includes an increase or decrease in the characteristic.
[0088] The term "subject" as used herein includes any animal, such
as a mammal, including a human.
[0089] The term "anorectal disorder" includes any disorder
associated with an anal rectal disease, including an acute or
chronic anal fissure, an internally or externally thrombosed
hemorrhoid, a hemorrhoidal disease, a disorder associated with
endoscopic hemorrhoidal ligation or pain caused by such ligation,
levator spasm, constipation, and other anorectal disorder caused by
hypertonicity or spasm of the anal sphincter muscle. The term also
refers to post-surgical pain associated with hemorrhoidectomy or
other anorectal surgery that leads to intense anal spasms. The term
"anal fissure" is also referred to as "anal rhagades" and spasms of
the anal sphincter are also referred to as "rectal tenesmus."
Additionally, the term is meant to include pain which can be
associated with any of the above disorders or conditions.
[0090] The terms "signs, symptoms and causes of anorectal disease"
and "signs and symptoms of anorectal disease" include, but are not
limited to, anal sphincter hypertonicity; anal and rectal ischemia,
itching, inflammation, pain or bleeding; thrombosed or prolapsed
hemorrhoidal tissue; spasticity of the levator ani muscle, spasm of
the puboretalis muscle or anal sphincter muscles, and linear or
ischemic ulcers or crack-like sores in the anal canal or on the
margin of the anus.
[0091] The term "desirable therapeutic effects" in the treatment of
anorectal diseases and conditions includes, but is not limited to,
anal sphincter relaxation; reduction of anal sphincter pressure;
maintenance of reduced anal sphincter pressure; reduction or
elimination of ischemia, itching, inflammation, pain, bleeding, or
muscle spasm; restoration or improvement of anoderm blood flow;
dilation of blood vessels in the anus and rectum; and partial or
complete healing of linear or ischemic ulcers or crack-like sores
in the anal canal or on the margin of the anus.
[0092] The terms "potassium channel opener" and "potassium channel
activator" refer generally to a class of drugs that cause an
increased flow of potassium ions from inside an electrically
excitable cell to outside the cell via a membrane of the cell which
has at least one potassium channel. Potassium channel opener
activity may be observed by measuring a hyperpolarization of the
cell membrane potential (i.e. a more negative membrane potential)
caused by an increase in the flow of potassium ions from inside a
cell to outside the cell via a potassium channel in the cell
membrane.
[0093] The term "pharmaceutical composition" means a composition
suitable for pharmaceutical use in a subject, including an animal
or human. A pharmaceutical composition generally comprises an
effective amount of an active agent and a pharmaceutically
acceptable carrier.
[0094] The term "pharmaceutically acceptable carrier" encompasses
any of the standard pharmaceutical carriers, buffers and
excipients, including phosphate-buffered saline solution, water,
and emulsions (such as an oil/water or water/oil emulsion), and
various types of wetting agents and/or adjuvants. Suitable
pharmaceutical carriers and their formulations are described in
REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton,
19th ed. 1995). Preferred pharmaceutical carriers depend upon the
intended mode of administration of the active agent. Typical modes
of administration are described below.
[0095] The term "effective amount" means a dosage sufficient to
produce a desired result. The desired result may comprise a
subjective or objective improvement in the recipient of the
dosage.
[0096] A "prophylactic treatment" is a treatment administered to a
subject who does not exhibit signs of a disease or exhibits only
early signs of a disease, wherein treatment is administered for the
purpose of decreasing the risk of developing pathology.
[0097] A "therapeutic treatment" is a treatment administered to a
subject who exhibits signs of pathology, wherein treatment is
administered for the purpose of diminishing or eliminating those
pathological signs.
[0098] The term "appropriate anal area" means any area or tissue of
the anus or sphincter that is affected by or subject to anal
disorder or disease, including, for example, the external or
internal anus, the external or internal anal sphincter, anal
sphincter muscle, or external or internal anal canal.
[0099] As used herein, the term "NO donor" refers to any organic or
inorganic compound that can deliver nitric oxide in a physiologic
setting. Also included are those compounds that can be metabolized
in vivo into a compound which delivers nitric oxide (e.g., a
prodrug form of a NO donor, or a binary NO generating system).
[0100] General
[0101] A promising new approach for treating anal disorders is the
topical application of a nitric oxide (NO) donor to an appropriate
anal area. Nitric oxide has been shown to bring about a
concentration-dependent reduction in the resting tension of
internal sphincter smooth muscle strips in vitro (Rattan, S. et
al., Am J Physiol 262:G107-112 (1992)), and NO donors (e.g.,
nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and
L-arginine) have been shown to reduce anal pressure in humans.
Schouten, W. R. et al., "Pathophysiological aspects and clinical
outcome of intra-anal application of isosorbide dinitrate in
patients with chronic anal fissure," Gut 39:465-9 (1996); Farid,
M., Br J Surg 84:1 (1997); and Hechtman, H. B. et al., Arch. Surg
131:775-778 (1996). NO has also been shown to mediate adaptive
relaxation of other sphincters in the gastrointestinal tract
including the lower esophageal sphincter (Conklin et al.,
Gastroenterology 104:1439-1444 (1993); Tottrup et al., Br J
Pharmacol 104:113-116 (1991)), pyloric sphincter (Bayguinov et al.,
Am J Physiol 264:G975-983 (1993), sphincter of Oddi (Mourelle et
al., Gastroenterology 105:1299-1305 (1993)), and the ileocolic
sphincter (Ward et al., Br J Pharmacol 105:776-782 (1992)). It is
thought that NO or NO-like substances serve as important control
mechanisms for the general phenomenon of gastrointestinal adaptive
relaxation.
[0102] Despite the initial promise of NO donors, tachyphylaxis has
been observed for members of this class of agents. Surprisingly,
the present invention provides compositions which are useful to
overcome side effects and problems associated with the current
therapies.
[0103] Description of the Embodiments
[0104] NO Donors in Combination with a Second Agent
[0105] In one aspect, the present invention provides compositions
for the treatment of anal disorders comprising a nitric oxide donor
in combination with a second agent which modulates levels of cAMP
or cGMP. In one group of embodiments the second agent is a
phosphodiesterase type V (PDE V) inhibitor. In another group of
embodiments the second agent is a phosphodiesterase type IV (PDE
IV) inhibitor. In another group of embodiments the second agent is
a phosphodiesterase type II (PDE II) inhibitor. In another group of
embodiments the second agent is a nonspecific PDE inhibitor. In
still another group of embodiments the second agent is a superoxide
anion (O.sub.2.sup.-) scavenger. In yet another group of
embodiments the second agent is a .beta.-adrenergic agonist. In
another group of embodiments, the second agent is a cAMP-dependent
protein kinase activator. In another group of embodiments the
second agent is an .alpha..sub.1-adrenergic antagonist. In another
group of embodiments the second agent is an estrogen, estrogen
analog, or estrogenic compound. In another group of embodiments the
second agent is an L-type Ca.sup.2+ channel blocker. In still
another group of embodiments the second agent is an ATP-sensitive
K.sup.+ channel activator. The present invention further provides
methods of using the compositions provided above. In a related
aspect, the present invention provides compositions comprising a NO
donor and a smooth muscle relaxant.
[0106] In each of the above embodiments, the nitric oxide donor can
be any of a variety of NO donors including, for example, organic NO
donors, inorganic NO donors and prodrug forms of NO donors.
Preferably, the NO donor includes at least one organic nitrate
(including esters of nitric acid) and can be either a cyclic or
acyclic compound. For example, suitable NO donors include
nitroglycerin (NTG), L-arginine, isosorbide dinitrate (ISDN),
isosorbide mononitrate (ISMN) which may include
isosorbide-2-mononitrate (IS2MN) and/or isosorbide-5-mononitrate
(IS5MN), erythrityl tetranitrate (ETN), pentaerythrityl
tetranitrate (PETN), ethylene glycol dinitrate, isopropyl nitrate,
glyceryl-1-mononitrate, glyceryl-1,2-dinitrate,
glyceryl-1,3-dinitrate, butane-1,2,4-triol trinitrate, and the
like. More preferably, the NO donor is NTG. Nitroglycerin and other
organic nitrates including ISDN, ETN, and PETN, have been given
regulatory approval for use in treatments in other fields of
medicine on human subjects. Additional NO donors include sodium
nitroprusside, N,O-diacetyl-N-hydroxy-4-chlorobenzenesulfonamide,
N.sup.G-hydroxy-L-arginine (NOHA), hydroxyguanidine sulfate,
molsidomine, 3-morpholinosydnonimine (SIN-1),
(.+-.)-S-nitroso-N-acetylpenicillamine (SNAP), S-nitrosoglutathione
(GSNO), (.+-.)-(E)-ethyl-2-[(E)hydroxyimino]-
-5-nitro-3-hexeneamide (FK409),
(.+-.)-N-[(E)-4-ethyl-3-[(Z)-hydroxyimino]-
-5-nitro-3-hexen-1-yl]-3-pyridinecarboxamide (FRI44420), and
4-hydroxymethyl-3-furoxancarboxamide.
[0107] In general, the organic nitric oxide donor (e.g., the
organic nitrate) is present in any amount less than that which is
effective in the practice of the treatment of anal disease when
used alone. In typical practice of the invention the organic nitric
oxide donor can be present in a concentration from about 0.01 to
about 10 percent by weight. All weight percentages herein are based
on the total weight of the composition. For NTG, preferred
concentrations are in the range of from about 0.01 to about 5
percent by weight.
[0108] In one group of embodiments, the composition contains an
agent which is a phosphodiesterase (PDE) inhibitor. Inhibitors of
phosphodiesterases (PDE), are agents which can block the breakdown
of cAMP and cGMP in the tissue. PDE inhibitors include both
non-specific PDE inhibitors and specific PDE inhibitors (those
which inhibit a single type of phosphodiesterase with little, if
any, effect on any other type of phosphodiesterase). Still other
useful PDE inhibitors are the dual selective PDE inhibitors (e.g.,
PDE III/IV inhibitors).
[0109] In one group of embodiments, the PDE inhibitor is a PDE V
inhibitor. Useful phosphodiesterase type V inhibitors include
zaprinast, MBCQ, MY-5445, dipyridamole and sildenifil.
[0110] In another group of embodiments, the composition contains an
agent which is a phosphodiesterase type II (PDE II) inhibitor.
Suitable phosphodiesterase type II inhibitors include EHNA.
[0111] In yet another group of embodiments, the composition
contains an agent which is a phosphodiesterase type IV (PDE IV)
inhibitor. Suitable phosphodiesterase type IV inhibitors include
ariflo (SB207499), RP73401, Ro-201724, CDP840, rolipram and
LAS31025.
[0112] In still another group of embodiments, the composition
contains an agent which is a dual selective phosphodiesterase
inhibitor, preferably a PDE III/IV inhibitor such as, for example,
zardaverine.
[0113] In yet another group of embodiments, the composition
contains an agent which is a nonspecific phosphodiesterase
(nonspecific PDE) inhibitor. Suitable nonspecific phosphodiesterase
inhibitors include IBMx, theophylline, dyphylline theobromine,
aminophylline, pentoxifylline, papaverine, caffeine and other
methyl xanthine and non-xanthine derivatives (Goodman &
Gilman's "The Pharmacological Basis of Therapeutics" The
McGraw-Hill Companies, 1996).
[0114] In still another group of embodiments, the composition
contains an agent which is a superoxide anion (O.sub.2.sup.-)
scavenger. Superoxide can react with NO and dramatically reduce its
biological effects. Accordingly, agents that scavenge superoxide
anion (e.g., exogenous Mn- or Cu/Zn superoxide dismutase (SOD) or
small molecule SOD mimetics, e.g. Mn(III) tetra(4-benzoic acid)
porphyrin chloride (MnTBAP) and M40403, see Salvemini, et al.,
Science 286(5438):304-306 (1999)) can enhance the effects of NO.
SODs are relatively stable enzymes and can be used in topical
formulations with NO donors such as, for example, NTG, to boost the
local potency of NO generated from NTG. The nitric oxide formed
from NTG acts only locally due to its short half-life. However, NTG
itself is stable enough to exert systemic effects following mucosal
absorption. By enhancing the local efficacy of NTG with SOD or a
SOD mimetic, less NTG is required to produce the same degree of
internal anal sphincter relaxation, and less NTG is absorbed,
leading to a reduction in systemic side effects.
[0115] In yet another group of embodiments, the composition
contains an agent which is a .beta.-adrenergic agonist, preferably
a .beta..sub.2- or .beta..sub.3-adrenergic receptor agonist. A
variety of .beta.-adrenergic agonists have been described in the
literature and are useful in the present invention. Suitable
.beta..sub.3-adrenergic agonists are described in, for example,
Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 33,
Chap. 19, pp 193-202, Academic Press (1998). Preferred
.beta.-adrenergic agonists include salbutamol, terbutaline,
procaterol, clenbuterol, isoproterenol, zinterol, BRL 37344,
CL316243, CGP-12177A, GS 332, L-757793, L-760087, L-764646, and
L-766892.
[0116] In another group of embodiments, the agent is a
cAMP-dependent protein kinase activator. A variety of cyclic
nucleotide-dependent protein kinase activators are useful in the
present invention including, for example, cAMP mimetics and dual
cGMP/cAMP-dependent protein kinase activators. cAMP mimetics are
well known to those of skill in the art and include 8-bromo-cAMP,
dibutyryl-cAMP, Rp-cAMPS, and Sp-cAMPS. Dual activators include
Sp-8-pCPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT-cAMP.
[0117] In yet another group of embodiments, the composition
contains an agent which is an estrogen or estrogen analog or
mimetic. As used herein, the term "estrogens" is meant to include
all forms of estrogen and estrogen-like compounds such as those
compounds having estrogen like activity (e.g., those which bind to
the estrogen receptor in a competitive binding assay). The
estrogens can be either steroidal or nonsteroidal (see, for
example, Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY,
VOL. 31, Chap. 19, pp 181-190, Academic Press (1996), and
references cited therein). Estrogen-like compounds include but are
not limited to 17-beta-estrodiol, estrone, mestranol, estradiol
valerate, estrodiol dypionate, ethinyl estrodiol, quinestrol,
estrone sulfate, phytoestrogens such as flavones, isoflavones (e.g.
genistein), resveratrol, coumestan derivatives, other synthetic
estrogenic compounds including pesticides (e.g. p,p'-DDT),
plasticizers (e.g. bisphenol A), and a variety of other industrial
chemicals (e.g. polychlorinated biphenyls).
[0118] In yet another group of embodiments, the composition
contains an agent which is an .alpha..sub.1-adrenergic antagonist.
The sympathetic neurotransmitter norepinephrine contracts sphincter
smooth muscle via .alpha..sub.1-adrenergic receptors.
Pharmacological interference with norepinephrine release or binding
to .alpha..sub.1-adrenergic receptors by administering
sympatholytic agents to the appropriate anal area of a subject can
also lead to anal sphincter relaxation, reduction of anal sphincter
pressure, maintenance of reduced anal sphincter pressure, and
improvement of the signs and symptoms of anorectal disorders. Such
sympatholytic agents include .alpha..sub.1-adrenergic receptor
antagonists (e.g. prazosin, doxazosin, phentolamine, tolazoline,
and the like as described in Goodman & Gilman's THE
PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G
Hardman, et al., McGrawHill 1996), .alpha..sub.2-adrenergic
agonists which block norepinephrine release (e.g. clonidine), nerve
terminal norepinephrine depleting agents (e.g. guanethidine,
bretylium, reserpine), norepinephrine synthesis inhibitors (e.g.
.alpha.-methyl tyrosine), and agents which destroy sympathetic
nerve terminals (e.g. 6-hydroxy dopamine). Accordingly, in a
related embodiment, the composition contains an alternative
sympatholytic agent, such as an .alpha..sub.2-adrenergic receptor
agonist, a nerve terminal norepinephrine depleting agent, a
norepinephrine synthesis inhibitor or another agent which destroys
sympathetic nerve terminals.
[0119] In still another group of embodiments the agent is an
ATP-sensitive K.sup.+ channel activator. ATP, along with NO, is
thought to serve as an inhibitory neurotransmitter released from
the enteric non-adrenergic, non-cholinergic nerves that mediate
adaptive relaxation of gastrointestinal smooth muscle (Burnstock,
Pharmacol Rev. 24:509-81 (1972)). ATP appears to act primarily by
opening ATP-sensitive potassium (K.sub.ATP) channels which
hyperpolarize the cell membrane, reducing intracellular calcium
concentrations, leading to smooth muscle relaxation. Synthetic
compounds that activate ATP-sensitive K+ channels are smooth muscle
relaxants, e.g. minoxidil, minoxidil sulfate, pinocidil, diazoxide,
levcromokalim, cromakalim, etc. (see White, et al., Eur J
Pharmacol. 357(1):41-51 (1998)). ATP-sensitive potassium channels
are expressed in GI smooth muscle (Koh, et al., Biophys. J.
75:1793-80 (1998)). Accordingly, specific potassium channel openers
will be useful for relaxing internal anal sphincter smooth muscle,
reducing anal sphincter pressure, maintaining reduced anal
sphincter pressure, and improving the signs and symptoms of
anorectal disorders. It should be noted that other K.sup.+ channels
can also influence smooth muscle tone, including apamin-sensitive
low conductance calcium-activated K.sup.+ channels and
charybdotoxin-sensitive high conductance calcium-activated K.sup.+
channels.
[0120] In still other embodiments, the compositions will comprise
NO donors and smooth muscle relaxants. Preferred smooth muscle
relaxants include, for example, hydralazine, papaverine,
tiropramide, cyclandelate, isoxsuprine or nylidrin.
[0121] In yet other embodiments, the compositions will comprise NO
donors and a second agent which is a methyl xanthine or adenosine
receptor antagonist. Preferred second agents include theophylline,
dyphylline, aminophylline, caffeine, and theobromine.
[0122] In a preferred embodiment, a second agent is a K.sup.+ATP
channel opener, an adenosine receptor antagonist, or a
.beta.2-adrenergic receptor agonist. In yet further embodiments, a
second agent is preferably selected from the group consisting of
theophylline, dyphylline, minoxidil, diazoxide, terbutaline, and
salbutamol.
[0123] Phosphodiesterase Inhibitor Compositions
[0124] In another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising a
phosphodiesterase inhibitor, preferably a PDE II inhibitor, a PDE
IV inhibitor or a PDE V inhibitor, either alone or in combination
with another agent selected from .beta.-adrenergic receptor
agonists, .alpha..sub.1-adrenergic antagonists, estrogens, L-type
Ca.sup.2+ channel blockers, ATP-sensitive K.sup.+ channel
activators, or smooth muscle relaxants, in combination with a
pharmaceutically acceptable carrier. In other embodiments, the
compositions will comprise a dual-selective PDE inhibitor (e.g., a
PDE III/IV inhibitor such as zardaverine). The present invention
also provides methods of using these compositions.
[0125] Phosphodiesterase inhibitors (PDE inhibitors) are agents
which can block the breakdown of cAMP and cGMP in the tissue. PDE
inhibitors include non-specific PDE inhibitors and specific PDE
inhibitors. A non-specific PDE inhibitor inhibits more than one
type of phosphodiesterase, while a specific PDE inhibitor inhibits
only one type of phosphodiesterase with little, if any, effect on
any other type of phosphodiesterase. Specific inhibitors of five
cyclic nucleotide PDE isozyme families have been characterized:
8-methoxymethyl-IBMX (isobutyl methylxanthine) or vinpocetine
(Ca.sup.2+, calmodulindependent PDE type I);
EHNA(erythro-9-(2-hydroxy-3-nonyl)adenine HCI) (cGMPstimulated PDE
type II); milrinone (cGMP-inhibited PDE type III); rolipram
(cAMP-specific PDE type IV); and zaprinast and DMPPO (1,3
dimethyl-6-(2-propoxy-5-methane
sulphonylamidophenyl)-pyrazolo[3,4-d]pyri- midin-4-(5H)-one)
(cGMP-specific PDE type V). Current knowledge suggests that there
are at least nine classes of PDE isozymes with type 9A having been
recently discovered (see, Fisher, et al., J Biol. Chem.
273(25):15559-15564 (1998)). Agents which are non-specific
inhibitors of PDEs include, for example, IBMX, theophylline,
aminophylline, theobromine, dyphylline caffeine, etc. (see,
Vemulapalli, et al., J Cardiovasc. Pharmacol 28(6):862-9
(1996)).
[0126] Preferably, the compositions for treating anorectal
disorders contain one or more compounds selected from the classes
of PDE II, PDE IV and PDE V inhibitors, or a dual PDE III/W
inhibitor in a formulation suitable for local treatment. Members of
each of these classes can be advantageously combined with a second
agent selected from the group of .beta.-adrenergic receptor
agonists, preferably .beta..sub.2- or .beta..sub.3-adrenergic
receptor agonists, .alpha..sub.1-adrenergic antagonists, L-type
Ca.sup.2+ channel blockers, estrogens, ATP-sensitive K.sup.+
channel activators, sympathetic nerve terminal destroyers,
adenosine receptor antagonists, methylxanthines, or smooth muscle
relaxants. Preferred members from each class of additional agent
are those which have been described above for use with NO
donors.
[0127] In embodiments comprising a second active agent with a PDE,
a second agent is preferably a K.sup.+ATP channel opener, an
adenosine receptor antagonist, or a .beta.2-adrenergic receptor
agonist. In yet further embodiments, a preferred second agent is a
compound selected from the group consisting of theophylline,
dyphylline, minoxidil, diazoxide, terbutaline, and salbutamol.
[0128] .beta.-adrenergic Receptor Agonist Compositions
[0129] In another aspect, the present invention provides
pharmaceutical compositions for the treatment of anorectal
disorders comprising a .beta.-adrenergic receptor agonist,
preferably a .beta..sub.2- or .beta..sub.3-adrenergic receptor
agonist, either alone or in combination with another agent selected
from cAMP-hydrolyzing PDE inhibitors (e.g., a PDE IV inhibitor),
nonspecific PDE inhibitors, al-adrenergic antagonists, estrogens,
L-type Ca.sup.2+ channel blockers, ATP-sensitive K.sup.+ channel
activators, or smooth muscle relaxants, and a pharmaceutically
acceptable carrier. The present invention further provides methods
of using those compositions.
[0130] In this aspect of the invention, the .beta.-adrenergic
receptor agonist can be essentially any of the .beta.-adrenergic
receptor agonists provided above for use in combination with NO
donors. Preferably, the .beta.-adrenergic agonist, is a
.beta..sub.2- or .beta..sub.3-adrenergic receptor agonist.
Particularly preferred .beta.-adrenergic agonists are those
described in Bristol, et al., ANNUAL REPORTS IN MEDICINAL
CHEMISTRY, VOL. 33, Chap. 19, pp 193-202, Academic Press (1998) or
are selected from salbutamol, terbutaline, procaterol, clenbuterol,
isoproterenol, zinterol, BRL 37344, CL316243, CGP-12177A, GS 332,
L-757793, L-760087, L-764646, and L-766892.
[0131] Terbutaline and salbutamol (albuterol) are
.beta.2-adrenergic agonists commonly used for the long-term
treatment of obstructive airway diseases and acute bronchospasm in
asthma. Beta-adrenergic agents, like VIP, potently relax smooth
muscle, including IAS smooth muscle by raising intracellular cyclic
AMP levels (Parks et al., Gut 10(8): 674-7 (1969); Chakder, S. et
al., Amer J Physiol. 264 (1 pt 1):G7-12, (1993); Chakder, S. et
al., Amer J Physiol. 264 (4 pt 1): G702-7, (1993); O'Kelly, T. J.
et al., Gut 34(5): 689-93, (1993)); O'Kelly, T. J. et al., Br J
Surg 80(10): 1337-41, (1993)). Cyclic AMP induces smooth muscle
relaxation through phosphorylation of smooth muscle regulatory
proteins (e.g., myosin light chain kinase) and by decreasing
intracellular calcium concentrations (e.g., via K.sup.+-ATP channel
activation). Terbutaline and salbutamol have weaker cardiovascular
effects than non-specific .beta.-receptor agonists, e.g.,
isoproterenol, because they do not stimulate cardiac
.beta..sub.1-adrenergic receptors at therapeutic doses. They are
commonly administered by inhalation (i.e., topically). Tolerance is
a potential downside effect of .beta..sub.2-adrenergic agonists.
Long-term systemic administration of .beta.-adrenergic agonists
leads to down-regulation of .beta. receptors in some tissues and
decreased pharmacological responses, and has been demonstrated in
patients with asthma.sup.1. .sup.1Goodman & Gilman's "The
Pharmacological Basis of Therapeutics" 9th edition. Chapter 10,
Catecholamines, Sympathornimetic Drugs and Adrenergic Receptor
Antagonists. Brian B. Hoffman and Robert J. Lefkowitz, 1996.
[0132] In one group of embodiments, the compositions comprise
forskolin. Forskoline directly activates adenyl cyclase avoiding
tolerance.
[0133] In one group of embodiments, the composition contains a
suitable .beta.-adrenergic receptor agonist and a pharmaceutically
acceptable carrier, preferably one formulated for local delivery to
the site of the anorectal disease or disorder.
[0134] In another group of embodiments, the composition contains
another agent selected from cAMP-hydrolyzing PDE inhibitors (e.g.,
a PDE IV inhibitor), nonspecific PDE inhibitors,
.alpha..sub.1-adrenergic antagonists, adenosine receptor
antagonists including methyl xanthines, estrogens, L-type Ca.sup.2+
channel blockers, ATP-sensitive K.sup.+ channel activators or
smooth muscle relaxants.
[0135] In one preferred group of embodiments, the agent is a
cAMP-hydrolyzing PDE inhibitor, more preferably a phosphodiesterase
type IV inhibitor. Preferred phosphodiesterase type IV (also
referred to as PDE IV and PDE4) inhibitors are described in, for
example, Bristol, et al., Annual Reports in Medicinal Chemistry,
Vol. 33, Chap. 10, pp 91-109, Academic Press (1998). Most
preferably, the PDE IV inhibitor is rolipram, Ro 20-1724 or
Etazolate.
[0136] In another group of preferred embodiments, the agent is a
nonspecific PDE inhibitor such as, for example, IBMX,
aminophylline, theophylline, pentoxifylline, theobromine,
dyphylline, lisophylline and papaverine.
[0137] In yet another group of preferred embodiments, the agent is
an aladrenergic antagonist. Suitable .alpha..sub.1-adrenergic
receptor antagonists (e.g. prazosin, doxazosin, phentolamine,
tolazoline, and the like) are described in Goodman & Gilman's
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G
Hardman, et al., McGrawHill (1996). Preferred agents for use in
these compositions are selected from prazosin, doxazosin,
phentolamine, tolazoline and their derivatives.
[0138] In still other preferred embodiments, the .beta.-adrenergic
receptor agonist is combined with an L-type Ca.sup.2+ channel
blocker, such as, for example, nifedipine, nimodipine, felopidine,
nicardipine, isradipine, amlodipine, diltiazem, mentol, pinavarium
bromide (a gastrointestinal tract selective calcium channel
blocker; Awad R A et al., Acta Gastroent. Latinoamer. 27:247-251,
1997) and verapamil.
[0139] In yet other preferred embodiments, the .beta.-adrenergic
receptor agonist is combined with an ATP-sensitive K.sup.+ channel
activator. Preferred agents within this group are the same as those
that have been provided above for use with NO donors.
[0140] Additional compositions are those in which a
.beta.-adrenergic receptor agonist is combined with an estrogen or
estrogen like compound, or with a smooth muscle relaxant. Suitable
compounds within each of these classes have been described above
for use with NO donors.
[0141] In embodiments comprising a second active agent with a
.beta..sub.2-adrenergic receptor agonist, a second agent is
preferably a K.sup.+ATP channel opener or an adenosine receptor
antagonist. In yet further embodiments, a preferred second agent is
a compound selected from the group consisting of theophylline,
dyphylline, minoxidil, and diazoxide.
[0142] Potassium Channel Activator Compositions
[0143] In yet another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising an
ATP-sensitive K.sup.+ channel activator, either alone or in
combination with another agent selected from cAMP-dependent protein
kinase activators, estrogens, .alpha..sub.1-adrenergic antagonists,
L-type Ca.sup.2+ channel blockers, sympathetic nerve terminal
destroyers, or smooth muscle relaxants, and a pharmaceutically
acceptable carrier. The present invention further provides methods
of using those compositions.
[0144] In this aspect of the invention, the selected combinations
are made from the components described in detail above for the NO
donor compositions. Additional description of ATP-sensitive
potassium ion channel activators can be found in, for example,
Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 29,
Chap. 8, pp 73-82, Academic Press (1991). In preferred embodiments
the potassium ion channel activator is diazoxide, minoxidil, PCO
400, pinocidil, levcromokalin, or cromokalim.
[0145] In some embodiments, the composition comprises an additional
agent which is a cAMP-dependent protein kinase activator, an
estrogen or estrogen like compound, an .alpha..sub.1-adrenergic
antagonist, an L-type Ca.sup.2+ channel blocker, a sympathetic
nerve terminal destroyer, or a smooth muscle relaxant. Preferably,
the cAMP-dependent protein kinase activator is a cAMP mimetic or a
dual cGMP/cAMP-dependent protein kinase activator. More preferably,
the cAMP mimetic is 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS, or
Sp-cAMPS, and the dual activator is selected from Sp-8-pCPT-cGMPS,
Sp-8-bromo-cGMPS and 8-CPT-cAMP.
[0146] In one group of embodiments, an al-adrenergic antagonist is
combined with an ATP-sensitive potassium ion channel activator.
Preferably, the .alpha..sub.1-adrenergic antagonist is prazosin,
phentolamine or tolazoline.
[0147] In another group of embodiments, an L-type Ca.sup.2+ channel
blocker is combined with an ATP-sensitive potassium ion channel
activator. Preferably, the L-type Ca.sup.2+ channel blocker is
nifedipine, nimodipine, felopidine, nicardipine, isradipine,
amlodipine, diltiazem, menthol, pinavarium bromide (a
gastrointestinal tract selective calcium channel blocker; Awad R A
et al., Acta Gastroent. Latinoamer. 27:247-251, 1997) or
verapamil.
[0148] Diazoxide and minoxidil have been used for the treatment of
hypertension. These drugs are vasodilators that hyperpolarize
arterial smooth muscle cells by activating ATP-sensitive K.sup.+
channels (Meisheri et al., J Pharmacol Exp Ther 245(3): 751-60
(1988); Standen et al., Science 245: 177-80 (1989)). Membrane
hyperpolarization inactivates voltage-gated calcium channels,
reduces intracellular calcium concentrations, and causes muscle
relaxation. ATP released by NANC nerve stimulation probably relaxes
the IAS through this mechanism (Brookes J Gastroenterol Heaptol
8(6): 590-603 (1993); Rae et al., J Physiol (London) 493 (Pt 2):
517-27 (1996)). Baird and Muir (Baird et al., Br J Pharmacol
100(2)329-35 (1990)) demonstrated that cromakalim, a K.sup.+-ATP
channel opener, inhibited spike discharge, hyperpolarized the
membrane and relaxed the guinea pig IAS. In our studies, diazoxide
and minoxidil relaxed the rat IAS in vivo. The adverse effects of
these drugs are predictable and can be divided into three major
categories: 1) fluid and salt retention, 2) cardiovascular effects,
and 3) hypertrichosis. Topical minoxidil, inspired by the
hypertrichosis side effect, is marketed for stimulating hair
growth. This product has an excellent safety record and is now sold
over the counter.
[0149] In still another group of embodiments, a smooth muscle
relaxant is combined with an ATP-sensitive potassium ion channel
activator. Preferably, the smooth muscle relaxant is hydralazine,
papaverine, tiropramide, cyclandelate, isoxsuprine or nylidrin.
[0150] In embodiments comprising a second active agent with a
K.sup.+ATP channel opener, a second agent is preferably a
K.sup.+ATP channel opener, a .beta..sub.2-adrenergic receptor
agonist, or an adenosine receptor antagonist. In yet further
embodiments, a preferred second agent is a compound selected from
the group consisting of theophylline, dyphylline, terbutaline, and
salbutamol.
[0151] .alpha..sub.1-Adrenergic Antagonist Compositions
[0152] In still another aspect, the present invention provides
compositions for the treatment of anorectal disorders comprising an
.alpha..sub.1-adrenergic antagonist, either alone or in combination
with another agent selected from cAMP-hydrolyzing PDE inhibitors
(preferably a PDE IV inhibitor), estrogens, sympathetic nerve
terminal destroyers, or smooth muscle relaxants, and a
pharmaceutically acceptable carrier. The present invention further
provides methods of using those compositions.
[0153] .alpha..sub.1-Adrenergic antagonists which are useful in
this aspect of the invention have been described above and can be
found in, for example, Goodman & Gilman's THE PHARMACOLOGICAL
BASIS OF THERAPEUTICS, ninth edition, ed. J G Hardman, et al.,
McGraw-Hill (1996). Preferred .alpha..sub.1-adrenergic antagonists
are prazosin, phentolamine and tolazoline.
[0154] For those embodiments in which an .alpha..sub.1-adrenergic
antagonist is combined with a cAMP-hydrolyzing PDE inhibitor
(preferably a PDE IV inhibitor), an estrogen or estrogen like
compound, a sympathetic nerve terminal destroyer, or a smooth
muscle relaxant, the preferred members of each class are those
which have been described above for use with NO donors.
[0155] In embodiments comprising a second active agent with a
.alpha..sub.1-adrenergic antagonist, a second agent is preferably a
K.sup.+ATP channel opener, a .beta..sub.2-adrenergic receptor
agonist or an adenosine receptor antagonist. In yet further
embodiments, a preferred second agent is a compound selected from
the group consisting of theophylline, dyphylline, minoxidil,
diazoxide, terbutaline, and salbutamol.
[0156] Cyclic Nucleotide-Dependent Protein Kinase Activator
Compositions
[0157] In another aspect, the present invention provides
pharmaceutical compositions for the treatment of anorectal
disorders comprising cyclic nucleotide-dependent protein kinase
activators, either alone or in combination with another agent.
Methods for the use of these compositions are also provided. In one
group of embodiments, cGMP-dependent protein kinase activators are
used alone. In another group of embodiments, nonspecific cyclic
nucleotide-dependent protein kinase activators are used alone. In
yet another group of embodiments, nonspecific cyclic
nucleotide-dependent protein kinase activators are used in
combination with smooth muscle relaxants. In still another group of
embodiments, cAMP-dependent protein kinase activators are provided
in combination with L-type Ca.sup.2+ channel blockers.
[0158] In embodiments comprising a second active agent with the
protein kinase activator, a second agent is preferably a K.sup.+ATP
channel opener, a .beta..sub.2-adrenergic receptor agonist or an
adenosine receptor antagonist. In yet further embodiments, a
preferred second agent is a compound selected from the group
consisting of theophylline, dyphylline, terbutaline, minoxidil,
diazoxide and salbutamol.
[0159] In each instance, preferred members of the recited classes
of compounds are those that have been described above for use alone
or in other combinations.
[0160] Estrogen and Estrogen Mimetic Compositions
[0161] In another aspect, the present invention provides
pharmaceutical compositions for the treatment of anorectal
disorders comprising estrogen or an estrogen mimetic, either alone
or in combination with another agent from any of the classes of
agents described above. Estrogen-like compounds include but are not
limited to 17-beta-estrodiol, estrone, mestranol, estradiol
valerate, estrodiol dypionate, ethinyl estrodil, quinestrol,
estrone sulfate, phytoestrogens such as flavones, isoflavones (e.g.
genistein), resveratrol, coumestan derivatives, other synthetic
estrogenic compounds including pesticides (e.g. p,p'-DDT),
plasticizers (e.g. bisphenol A), and a variety of other industrial
chemicals (e.g. polychlorinated biphenyls) (Goodman & Gilman's
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G
Hardman, et al., McGraw-Hill (1996). Preferred agents are selected
from those described with reference to the compositions of single
agents or combinations above. Methods for the use of these
compositions are also provided.
[0162] In embodiments comprising a second active agent with the
estrogenic agent, a second agent is preferably a K.sup.+ATP channel
opener, a .beta..sub.2-adrenergic receptor agonist or an adenosine
receptor antagonist. In yet further embodiments, a preferred second
agent is a compound selected from the group consisting of
theophylline, dyphylline, terbutaline, minoxidil, diazoxide and
salbutamol.
[0163] Sympathetic Nerve Terminal Destroyer Compositions
[0164] In another aspect, the present invention provides
pharmaceutical compositions for the treatment of anorectal
disorders comprising a sympathetic nerve terminal destroyer, either
alone or in combination with another agent from any of the classes
of agents described above. The sympathetic nerve terminal destroyer
compounds include but are not limited to 6-hydroxydopamine and its
analogs See, Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF
THERAPEUTICS, ninth edition, ed. J G Hardman, et al., McGraw-Hill
(1996). Preferred agents are selected from those described with
reference to the compositions of single agents or combinations
above. Methods for the use of these compositions are also
provided.
[0165] Adenosine Receptor Antagonists/Methylxanthines
[0166] In another aspect, the present invention provides
pharmaceutical compositions for the treatment of anorectal
disorders comprising a adenosine receptor antagonist, either alone
or in combination with another agent from any of the classes of
agents described above. Examples of adenosine receptor antagonists
include theophylline and dyphylline. See, Goodman & Gilman's
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. J G
Hardman, et al., McGraw-Hill (1996). Preferred agents are selected
from those described with reference to the compositions of single
agents or combinations above. Methods for the use of these
compositions are also provided.
[0167] Theophylline, a plant-derived methylxanthine, has been used
for the treatment of bronchial asthma for decades. Theophylline
relaxes smooth muscle, notably bronchial muscle, that has been
contracted experimentally with a spasmogen, or clinically in
asthma. We found that theophylline relaxed the rat IAS when
instilled into the distal anal canal. Proposed mechanisms of
methylxanthine-induced physiologic and pharmacological effects
include: 1) inhibition of phosphodiesterases, thereby increasing
intracellular cyclic AMP, 2) direct effects on intracellular
calcium concentration, 3) indirect effects on intracellular calcium
concentrations via cell membrane hyperpolarization, 4) uncoupling
of intracellular calcium increases with muscle contractile
elements, and 5) antagonism of adenosine receptors. Adenosine
receptor antagonism is thought to be the most important factor
responsible for most of the pharmacological effects of
methylxanthines in therapeutically administered doses.sup.2.
.sup.2Goodman & Gilman's "The Pharmacological Basis of
Therapeutics" 9th edition. Chapter 28, Drugs Used in the Treatment
of Asthma. William E. Serafin, 1996.
[0168] We have found the related compound, dyphylline, to also
reduce IASP in tests. Dyphylline is not metabolized by the liver
and is excreted unchanged by the kidneys, therefore its
pharmacokinetics and plasma levels are independent of factors that
effect liver enzymes such as smoking, age, congestive heart
failure, or the use of other drugs that affect liver function.
[0169] In embodiments comprising a second active agent with the
adenosine receptor antagonist, a second agent is preferably a
K.sup.+ATP channel opener or a .beta..sub.2-adrenergic receptor
agonist. In yet further embodiments, a preferred second agent is a
compound selected from the group consisting of terbutaline,
minoxidil, diazoxide and salbutamol.
[0170] Formulations for the Treatment of Anorectal Disorders
[0171] Many of the individual components of the compositions above
have been described for use in a variety of disease states.
However, certain classes and combinations of classes have now been
found to be useful for the treatment of anorectal diseases and can
be provided in formulations best suited for delivery to an
appropriate anal area. Preferred formulations are those in which
the components are combined in a topical formulation for local
application to the external or internal anus, the external or
internal anal sphincter, anal sphincter muscle, the external or
internal anal canal and the lower rectum above the anal canal.
[0172] Accordingly, each of the compositions provided above will
typically be presented in an appropriate pharmaceutical formulation
comprising an effective amount of the noted agents (e.g., NO
donors, .beta..sub.2- or .beta..sub.3-adrenergic receptor agonists,
cAMP-hydrolyzing PDE inhibitors, nonspecific PDE inhibitors,
.alpha..sub.1-adrenergic antagonists, L-type Ca.sup.2+ channel
blockers, ATP-sensitive K.sup.+ channel activators, adenosine
receptor antagonists, and the like).
[0173] One of skill in the art will appreciate that suitable
formulations are dependent on the form of delivery to be employed;
and all such forms are contemplated by the present invention.
Additionally, in some embodiments, combinations of agents are
employed in a single formulation, while in other embodiments,
agents are formulated separately, but administered in combination,
or sequentially. In the discussion below, compositions of single
agents will be understood to also include compositions of two or
more agents. Still further, different formulations can be used for
those embodiments in which agents are administered separately or
sequentially, by different routes of administration.
[0174] Topical Compositions
[0175] In view of the above, the present invention provides topical
compositions useful for treating anorectal disorders (including
those related to hypertonicity and/or spasm of the internal anal
sphincter muscle, e.g. hemorrhoidal pain) and for treating spasms
of the mammal, including humans, which comprise an effective amount
of an agent that reduces the contraction of anal sphincter muscle
or maintains a reduced contraction of the anal sphincter muscle,
and a pharmaceutically acceptable carrier. In one embodiment, the
agent is an ATP-sensitive potassium channel opener. In another
embodiment, the agent is a phosphodiesterase inhibitor, a cyclic
nucleotide mimic, .beta.-adrenergic agonist, an estrogen or
estrogen like compound, an .alpha..sub.1-adrenergic antagonist or a
potassium channel opener.
[0176] In related embodiments, the present invention provides
topical pharmaceutical compositions in unit dosage form comprising
per unit dosage an amount of the agent or combination provided
above, which is effective for treating an anal disorder in a
subject in need of such treatment. Typically the agents are in
combination with a pharmaceutically acceptable carrier. Such
compositions are useful in treating or reducing pain associated
with anal disorders, such as hemorrhoidal pain, and for treating
spasms and/or hypertonicity of the sphincters, including the
internal anal sphincter, lower esophageal sphincter, pyloric
sphincter, sphincter of Oddi, and the ileocolic sphincter. The
topical composition is also useful in treating conditions resulting
from spasms and/or hypertonicity of sphincters of the anorectal
region including anal fissure, post-operative rectal pain,
hypertrophic pyloric stenosis, and pancreatitis, as well as
conditions resulting from general spasm of the muscles of the GI
tract including Zenkers diverticulum, achalasia, esophageal spasm
(nutcracker esophagus), irritable bowel disease, and Hirshprungs
disease (bowel obstruction). In addition, the topical compositions
are useful for relaxing the anal sphincter, reducing anal sphincter
pressure or maintaining reduced anal sphincter pressure and
reducing pain and discomfort before, during and after examinations
of the anus, rectum and lower gastrointestinal system, insertion of
instruments, and procedures such as colonoscopy, cystoscopy and
surgery.
[0177] Dosage Forms
[0178] Topical Administration
[0179] Dosage forms for the topical administration of the anal
sphincter relaxing agents of this invention include powders,
sprays, ointments, pastes, creams, lotions, gels, solutions,
patches, suppositories and liposomal preparations. The dosage forms
may be formulated with mucoadhesive polymers for sustained release
of the active compound(s) at the anal mucosa. The active compound
may be mixed under sterile conditions with a pharmaceutically
acceptable carrier, and with any preservatives, buffers, or
propellants, which may be required. Topical preparations can be
prepared by combining the anal sphincter relaxing agent with
conventional pharmaceutical diluents and carriers commonly used in
topical dry, liquid, cream and aerosol formulations. Ointment and
creams may, for example, be formulated with an aqueous or oily base
with the addition of suitable thickening and/or gelling agents.
Such bases may include water and/or an oil such as liquid paraffin
or a vegetable oil such as peanut oil or castor oil. Thickening
agents which may be used according to the nature of the base
include soft paraffin, aluminum stearate, cetostearyl alcohol,
propylene glycol, polyethylene glycols, woolfat, hydrogenated
lanolin, beeswax, and the like. Lotions may be formulated with an
aqueous or oily base and, in general, also include one or more of
the following: stabilizing agents, emulsifying agents, dispersing
agents, suspending agents, thickening agents, coloring agents,
perfumes, and the like. Powders may be formed with the aid of any
suitable powder base, e.g., talc, lactose, starch, and the like.
Drops may be formulated with an aqueous base or non-aqueous base
also comprising one or more dispersing agents, suspending agents,
solubilizing agents, and the like.
[0180] The ointments, pastes, creams and gels also may contain
excipients, such as animal and vegetable fats, oils, waxes,
paraffins, starch, tragacanth, cellulose derivatives, polyethylene
glycols, silicones, bentonites, silicic acid, talc and zinc oxide,
or mixtures thereof. Powders and sprays also can contain excipients
such as lactose, talc, silicic acid, aluminum hydroxide, calcium
silicates and polyamide powder, or mixtures of these substances.
Sprays can additionally contain customary propellants, such as
chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,
such as butane and propane.
[0181] Representative compositions include topical compositions
comprising one or more of the following first pharmacologic agents:
an NO donor, phosphodiesterase inhibitor, cyclic nucleotide
mimetic, .beta.-adrenergic agonist, L-type calcium channel blocker,
.alpha.-adrenergic antagonist, ATP-sensitive potassium channel
activator, sympathetic nerve terminal destroyer, estrogen or
estrogen-like compound or botulinum toxin in combination with a
pharmaceutically acceptable carrier and at least one of the
following second pharmacologic agents: a local anesthetic (e.g.,
lidocaine, prilocaine, etc.), local antiinflammatory agent (e.g.,
naproxen, pramoxicam, etc.), corticosteroid (e.g., cortisone,
hydrocortisone, etc.), anti-itch agent (e.g., loperamide
diphylenoxalate, etc.), an agent that interferes with the
activation of peripheral sensory neurons, including divalent and
trivalent metal ions (e.g., manganese, calcium, strontium, nickel,
lanthanum, cerium, zinc, etc.), analgesic agents, yeast-based
product (e.g., lyophilized yeast, yeast extract, etc.),
growth-promoting and/or wound healing-promoting agent known to
promote re-epithelialization (e.g., platelet-derived growth factor
PDGF, interleukin-11 (IL-11) etc.), anti-microbial agent (e.g.,
neosporin, polymyxin B sulfate, bacitracin zinc, etc.),
mucoadhesive agent (e.g., cellulose derivatives, etc.),
cytoprotectant agent (e.g., colloidal bismuth, misoprostol, etc.,
with the exception of sucralfate) as defined in GOODMAN &
GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, supra, an agent
that promotes local tissue sclerosis (e.g., alum, etc.), or
menthol. The first pharmacologic agent is typically present in the
composition in unit dosage form effective for treatment of a first
medical condition(s), such as an anal disease or pain associated
with an anal disease. The second pharmacologic agent is typically
present in the composition in unit dosage form effective for
treatment of a second medical condition(s), or a condition(s),
symptom(s) or effect(s) associated with or resulting from the first
medical condition(s).
[0182] In one aspect, the invention provides compositions for
treating anorectal disorders which comprise an active agent and a
pharmaceutically acceptable carrier. The active agent comprises an
agent that stimulates or causes an increase of either CGMP or cAMP
through activation of guanylyl or adenylyl cyclase, respectively, a
cyclic nucleotide mimetic, PDE inhibitor, .alpha.-adrenergic
receptor antagonist, or .beta.-adrenergic receptor agonist, or
potassium channel opener. In one aspect, the active agent is
present in compositions of the invention in an amount of from about
0.001% to about 15% by weight of the composition. In another
aspect, the active agent is present in an amount of from about
0.01% to about 7.5% by weight, more preferably from about 0.05% to
about 2% by weight of the composition.
[0183] For example, in one group of embodiments, the invention
provides compositions for treating anorectal disorders comprising a
pharmaceutically acceptable carrier and an amount of from about
0.001% to about 15% sildenafil by weight. In another aspect,
compositions comprising a pharmaceutically acceptable carrier and
an amount of from about 0.01% to about 7.5% or from about 0.05% to
about 2% sildenafil by weight are provided.
[0184] The topical pharmaceutical compositions can also include one
or more preservatives or bacteriostatic agents, e.g., methyl
hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium
chlorides, and the like. The topical pharmaceutical compositions
also can contain other active ingredients such as antimicrobial
agents, particularly antibiotics, anesthetics, analgesics, and
antipruritic agents.
[0185] One example of a topical formulation includes 75% (w/w)
white petrolatum USP, 4% (w/w) paraffin wax USP/NF, lanolin 14%
(w/w), 2% sorbitan sesquioleate NF, 4% propylene glycol USP, and 1%
anal sphincter relaxing agent.
[0186] The dosage of a specific anal sphincter relaxing agent
depends upon many factors that are well known to those skilled in
the art, for example, the particular agent; the condition being
treated; the age, weight, and clinical condition of the recipient
patient; and the experience and judgment of the clinician or
practitioner administering the therapy. An effective amount of the
compound is that which provides either subjective relief of
symptoms or an objectively identifiable improvement as noted by the
clinician or other qualified observer. The dosing range varies with
the compound used, the route of administration and the potency of
the particular compound.
[0187] Transmucosal (i.e., sublingual, rectal, colonic, pulmonary,
buccal and vaginal) drug delivery provides for an efficient entry
of active substances to systemic circulation and reduces immediate
metabolism by the liver and intestinal wall flora (See Chien Y. W.,
NOVEL DRUG DELIVERY SYSTEMS, Chapter 4 "Mucosal Drug Delivery,"
Marcel Dekker, Inc. (1992). Transmucosal drug dosage forms (e.g.,
tablet, suppository, ointment, gel, pessary, membrane, and powder)
are typically held in contact with the mucosal membrane and
disintegrate and/or dissolve rapidly to allow immediate local and
systemic absorption. These formulations are used along with the
anti-inflammatory agents of the present invention for reducing or
eliminating inflammation of transmucosal membranes.
[0188] In order to enhance transmucosal absorption efficiency and
bioavailability of the active agents, selected mucosal adhesive
polymers or dosages can be employed. For example, a selected
potassium channel opener, e.g. minoxidil can be formulated in a
liquid suppository in which mucoadhesive polymers such as
polyvinylpyrrolidone (PVP, BASF, Germany), polycarbophil (Goodrich,
USA), or sodium alginate (Hayashi Pure Chemicals, Tokyo, Japan),
etc. are incorporated. This type of liquid suppository has a
gelation temperature between 30 to 36.degree. C. and has a
mucoadhesive force of 430 to 5800 dyne/cm. As a result, the
suppository remains as an easy to apply liquid at room temperature,
gels at physiological temperature and remain adhered to the anal
mucosal membrane for a sustained period of time (Rye J M et al.,
Journal of Controlled Release, 59:163-172. 1999; Chem Pharm Bull,
46 (2):309-313, 1998; J Pharm Sci, 81(11):1119-1125, 1992; Chem
Pharm Bull, 37(3):766-770, 1989; J Pharmacobiodyn,
9(6):526-531,1986; J Pharm Sci. 84(1):15-20, 1995).
[0189] Preferred formulations are either as solutions or semi-solid
preparations (gel, ointment, suspension, lotion, cream, etc.).
Suitable excipients, depending on the agent, include petrolatum,
lanolin, methylcellulose, sodium carboxymethylcellulose,
hydroxpropylcellulose, sodium alginate, carbomers, glycerin,
glycols, oils, glycerol, benzoates, parabens and surfactants. It
will be apparent to those of skill in the art that the solubility
of a particular compound will, in part, determine how the compound
is formulated. An aqueous gel formulation will is suitable for
soluble compounds. Where a compound is insoluble at the
concentrations required for activity, a cream or ointment
preparation will typically be preferable. In this case, oil phase,
aqueous/organic phase and surfactant may be required to prepare the
formulations. Thus, based on the solubility and excipient-active
interaction information, the dosage forms can be designed and
excipients can be chosen to formulate the prototype preparations.
Particularly preferred preparations include those in a suppository
or sustained release format.
[0190] Sustained or Controlled Delivery Formulations
[0191] In yet other embodiments, the invention provides topical
sustained and prolonged release pharmaceutical compositions
comprising one or more anal sphincter relaxant, including nitric
oxide donors (such as nitroglycerin, isosorbide dinitrate, and
L-arginine) or the pharmacological agents described above and a
pharmaceutically acceptable carrier, to treat anorectal disorders.
The compositions are useful in the treatment of such disorders as
reducing anal sphincter pressure, maintaining reduced anal
sphincter pressure, and in controlling and reducing pain associated
with such disorders. Such compositions may comprise a unit dosage
of one or more active agents (e.g., nitric oxide donor) which is
effective in treating anal disorders and in controlling and
alleviating pain associated therewith. Preferably, the compositions
are administered in unit dosage form to a subject in need of such
treatment. In other embodiments, the compositions contain an NO
donor in an amount which is less than an effective amount when used
alone, but which is effective when used in combination with a
second agent which modulates levels of cAMP or cGMP in a subject.
Topical sustained and prolonged release compositions are typically
variants which include 1) an absorbent in a hydrophilic base; 2) an
absorbent in a hydrophobic base; and 3) coated beads containing an
absorbent matrix dispersed in a suitable vehicle. Also provided are
methods of treating anal or GI tract disorders comprising topically
administering an effective amount of such compositions (e.g., in
unit dosage form) to the appropriate anal area of the subject in
need of such treatment.
[0192] Such hydrophilic compositions and preparations of the
invention comprise a nitric oxide donor (or other suitable agent or
combination of agents) and a polymer, such as cellulose (methyl
cellulose, ethyl cellulose, hydroxy propyl cellulose, etc.), higher
molecular weight polyethylene glycol, methacrylic-acrylic acid
emulsion, hydrogel, carbopol, ethyl vinyl acetate copolymer, or
polyester, etc., to bind the nitric oxide donor to the polymer. The
nitric oxide donor-polymer matrix or agent-polymer matrix is then
dispersed in a hydrophilic vehicle to form a semi-solid. After
administration of such hydrophilic composition into the appropriate
anal area, such as the anal canal or anal sphincter, the water in
the semi-solid preparation is adsorbed and the polymer matrix with
the active ingredient--the nitric oxide donor or other
agent--remains as a coating in the anal region or area to which it
has been applied. The nitric oxide donor is then slowly released
from this coating.
[0193] Hydrophobic compositions and preparations of the inventions
employ similar polymers as used in the hydrophilic preparations,
but the polymer/nitric oxide donor matrix is dispersed into a
vehicle, such a plastibase, in the hydrophobic compositions and
preparations. Plastibase is a mineral oil base that only partially
dissolves the nitric oxide donor. The semi-solid composition forms
a thin coating on the anal region to which the composition has been
applied (such as the anal canal or anal sphincter area) and slowly
releases the active. The prolonged action is controlled principally
by the solubility of the active ingredient (nitric oxide donor) in
the vehicle.
[0194] The present invention also provides coated beads which are
produced by first absorbing the nitric oxide donor or other agent
or combination of agents on a cellulosic material blended with
polyethylene glycol, filler, binder and other excipients. The
resulting matrix is then extruded and spheronized (e.g., the
process of making into spheres) to create small beads. The beads
are then coated to an appropriate thickness with one or more of a
suitable material, such as a methacrylic-acrylic polymer,
polyurethane, ethyl vinyl acetate copolymer, polyester, silastic,
etc. The coating on the beads acts as a rate controlling membrane
which regulates the release of the agent from the core beads.
[0195] Oral Formulations
[0196] In still another embodiment, the invention provides
pharmaceutical compositions suitable for oral administration which
are provided in unit dosage form comprising per unit dosage a
phosphodiesterase inhibitor, cyclic nucleotide mimetic, or
.beta.-adrenergic agonist, and a pharmaceutically acceptable
carrier. Such compositions are useful for treating anorectal
disorders, including those disorders and conditions provided
above.
[0197] For delivery to the buccal membranes, typically an oral
formulation, such as a lozenge, tablet, or capsule is used. The
method of manufacture of these formulations are known in the art,
including but not limited to, the addition of a pharmacological
agent to a pre-manufactured tablet; cold compression of an inert
filler, a binder, and either a pharmacological agent or a substance
containing the agent (as described in U.S. Pat. No. 4,806,356); and
encapsulation. Another oral formulation is one that can be applied
with an adhesive, such as the cellulose derivative, hydroxypropyl
cellulose, to the oral mucosa, for example as described in U.S.
Pat. No. 4,940,587. This buccal adhesive formulation, when applied
to the buccal mucosa, allows for controlled release of the
pharmacological agent into the mouth and through the buccal mucosa.
The anti-inflammatory agents of the present invention can be
incorporated into these formulations as well.
[0198] Aerosol Formulations
[0199] For delivery to the nasal or bronchial membranes, typically
an aerosol formulation is employed. The term "aerosol" includes any
gas-borne suspended phase of the pharmacological agent which is
capable of being inhaled into the bronchioles or nasal passages.
Specifically, aerosol includes a gas-borne suspension of droplets
of the compounds of the instant invention, as may be produced in a
metered dose inhaler or nebulizer, or in a mist sprayer. Aerosol
also includes a dry powder composition of a compound of the
pharmacological agent suspended in air or other carrier gas, which
may be delivered by insufflation from an inhaler device, for
example. For solutions used in making aerosols, the preferred range
of concentration of the pharmacological agent is 0.1-100 milligrams
(mg)/milliliter (mL), more preferably 0.1-30 mg/mL, and most
preferably, 1-10 mg/mL. Usually the solutions are buffered with a
physiologically compatible buffer such as phosphate or bicarbonate.
The usual pH range is 5 to 9, preferably 6.5 to 7.8, and more
preferably 7.0 to 7.6. Typically, sodium chloride is added to
adjust the osmolarity to the physiological range, preferably within
10% of isotonic. Formulation of such solutions for creating aerosol
inhalants is discussed in Remington's Pharmaceutical Sciences, see
also, Ganderton and Jones, DRUG DELIVERY TO THE RESPIRATORY TRACT,
Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic
Drug Carrier Systems 6:273-313; and Raeburn et al., (1992) J
Pharmacol Toxicol Methods 27:143-159.
[0200] Solutions of the pharmacological agent may be converted into
aerosols by any of the known means routinely used for making
aerosol inhalant pharmaceuticals. In general, such methods comprise
pressurizing or providing a means of pressurizing a container of
the solution, usually with an inert carrier gas, and passing the
pressurized gas through a small orifice, thereby pulling droplets
of the solution into the mouth and trachea of the animal to which
the drug is to be administered. Typically, a mouthpiece is fitted
to the outlet of the orifice to facilitate delivery into the mouth
and trachea.
[0201] Parenteral Formulations
[0202] In yet another embodiment, the invention provides
pharmaceutical compositions suitable for parental administration
which are provided in unit dosage form comprising per unit dosage a
phosphodiesterase inhibitor, cyclic nucleotide mimetic, or
.beta.-adrenergic agonist, and a pharmaceutically acceptable
carrier. Such compositions are useful for treating anorectal
disorders and conditions as described above.
Methods of Treating Anorectal Disorders
[0203] In another aspect, the present invention provides methods
for treating anorectal disorders which comprise administering to an
appropriate anal area or affected anal tissue (e.g., external or
internal anal tissue or anal canal) of a subject in need of such
treatment an effective amount of any of the compositions provided
above. By use of such methods of the invention, anorectal
hypertonicity and/or spasms are relieved, anal sphincter pressure
is reduced, reduced anal sphincter pressure is maintained, and
signs and symptoms associated with anorectal disorders, e.g. anal
fissures, anal ulcers and hemorrhoids, and pain are improved. The
methods described herein are also applicable to the treatment of
recurrent anal diseases, and are also useful for relaxing the anal
sphincter and reducing pain during anorectal exams (in patients
with and without disorders), particularly during procedures when
instruments are inserted into the anus.
[0204] The present invention further provides methods of using the
compositions above in combination with local anesthetic agents, for
example lidocaine, prilocaine, etc. Each of the compositions will
typically be in a pharmaceutically acceptable dosage form as an
effective treatment for a medical condition such as hemorrhoidal
pain and for treating spasms and/or hypertonicity of the sphincters
including the internal anal sphincter, lower esophageal sphincter,
pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter.
These pharmaceutical preparations are also useful in treating
conditions resulting from spasms and/or hypertonicity of sphincters
of the anorectal region including anal fissure, post-operative
rectal pain, hypertrophic pyloric stenosis, and pancreatitis, as
well as conditions resulting from general spasm of the muscles of
the GI tract including Zenkers diverticulum, achalasia, esophageal
spasm (nutcracker esophagus), irritable bowel disease, and
Hirschsprung's disease (bowel obstruction). In another aspect, the
present invention provides methods for treating anal disorders
which comprise administering an effective amount of such
composition along with a local anesthetic agent to a subject in
need of such treatment. Such compositions can be administered
orally, topically, or parenterally.
[0205] Similarly, the invention provides methods of using the
compositions above in combinations with local anti-inflammatory
agents, for example, naproxen, piroxicam, etc. in a
pharmaceutically acceptable dosage form as an effective treatment
for a medical condition such as hemorrhoidal pain and for treating
hypertonicity and/or spasms of the sphincters including the
internal anal sphincter, lower esophageal sphincter, pyloric
sphincter, sphincter of Oddi, and the ileocolic sphincter. These
pharmaceutical preparations are also useful in treating conditions
resulting from spasms and/or hypertonicity of sphincters of the
anorectal region including anal fissure, post-operative rectal
pain, hypertrophic pyloric stenosis, and pancreatitis, as well as
conditions resulting from general spasm of the muscles of the GI
tract including Zenkers diverticulum, achalasia, esophageal spasm
(nutcracker esophagus), irritable bowel disease, and Hirschsprung's
disease (bowel obstruction). In another aspect, the present
invention provides methods for treating anal disorders which
comprise administering an effective amount of such composition
along with a local anesthetic agent to a subject in need of such
treatment. Such compositions can be administered orally, topically,
or parenterally.
[0206] Additional methods provided by the present invention are
those in which two or more agents selected from NO donors,
phosphodiesterase type V (PDE V) inhibitor, a phosphodiesterase
type II (PDE II) inhibitor, a nonspecific PDE inhibitor, a
dual-selective PDE inhibitor, a .beta.-adrenergic agonist, a
cAMP-dependent protein kinase activator, an
.alpha..sub.1-adrenergic antagonist, a superoxide anion
(O.sub.2.sup.-) scavenger, an ATP-sensitive K.sup.+ channel
activator, an estrogen or estrogen mimetic, a sympathetic nerve
terminal destroyer, an adenosine receptor antagonist, or a smooth
muscle relaxant, are administered either in combination or
sequentially to provide an enhanced therapeutic benefit. In
particular, the use of an NO donor and a second agent from those
provided above can provide fewer and less severe side effects than
equally effective doses of NO donors, if used alone. More
particularly, the use of an NO donor in combination with a second
agent allows for decreased amounts of the NO donor to be used to
achieve the same benefit relative to use alone, while extending the
period of reduction of anal sphincter pressure, and provides
significantly reduced occurrence and duration of headaches.
EXAMPLES
Example 1
[0207] This example illustrates the effect of cGMP mimetics, alone
and in combination with a NO donor in a rat internal anal sphincter
(IAS) relaxation model.
[0208] Male Sprague-Dawley rats (300-400 gm) were anesthetized with
ketamine (90 mg/kg), xylazine (9 mg/kg) given intramuscularly and
supplemented as needed with 1/3.sup.rd dose. Rats were gently
restrained on their backs on a heated surgical table (Harvard
Apparatus) for the duration of the experiments. The diuretic
effects of anesthesia was offset by rehydration with saline through
an intraperitoneal implanted 24 gauge angiocatheter (VWR, San
Francisco, Calif.). The constriction/relaxation measurement
assembly included a Millar catheter/transducer (1.67 mm diameter.)
connected to a Digi-Med Low Pressure Analyzer (Micro-Med) accurate
for pressure measurements between -50 and 150 mmHg. The data were
integrated and converted to waveforms with the Digi-Med System
Integrator software. Blood pressure changes were monitored using an
arterial catheter/transducer and a Digi-Med Blood Pressure Analyzer
with the DMSI software. Respiratory changes were monitored using a
mercury strain gauge/transducer, wrapped around the rib-cage of the
rat, hooked up to a Digi-Med Analog Signal Analyzer along with the
DMSI software. Drug delivery was accomplished through two Hamilton
syringes with no dead space using PE 10 tubing adjacent to the
catheter sensor. Drugs, typically were applied soon after stable
baseline readings are recorded. Although unanesthetized restrained
rats had been used in other studies, no differences have been
observed in resting anal pressures after anesthesia; therefore,
these studies were carried out with anesthetized rats to avoid
undue distress to the animals.
[0209] Typical resting mean internal anal sphincter pressures
(IASP) varied between 30 and 60 mmHg in this model. The Millar
catheter sensor allowed for accurate, isolated recordings of the
IAS. FIG. 1 represents a typical waveform pattern for resting IASP
in a rat under conditions of a control experiment. The first 10
minutes after treatment with nitroglycerin is shown in FIG. 2.
[0210] Using the same experimental protocol, the effect of a cGMP
mimetic, dibutyryl-cGMP was studied. FIG. 3 shows that 20 .mu.l of
a 10% solution of dibutyrylcGMP in saline applied to the anal canal
reduced the mean IASP by 45% over 2.5 hours following treatment.
The average IASP over the last hour prior to terminating the
experiment had dropped 60%.
[0211] The IASP was still reduced 34% by the following morning
indicating a potential long-term effect of the drug. A subsequent
dose of 1% nitroglycerin dropped the IASP by 24% for 30 minutes and
71% for the first 10 minutes following treatment. After IASP
returned to pre-treatment levels, a further dose of dibutyryl-cGMP
was administered and found to lower IASP 15% over the ensuing 3
hours and 10 minutes.
[0212] These results support the effect of cGMP mimetics in
relaxing anal sphincter muscle tone, and more importantly, suggest
a potential benefit of using a combination of NO donor and cGMP
mimetic due the quick onset of action of the NO donor and the more
prolonged duration of relaxation produced by the cGMP mimetics.
Example 2
[0213] This example illustrates the effect of phosphodiesterase
inhibitors in a rat internal anal sphincter relaxation model.
[0214] Using the same experimental protocol described above, an
application of 20 .mu.L of a 5% zaprinast solution in
1-methyl-2-pyrrolidinone reduced mean IASP by 21% over 32 minutes
compared with vehicle treatment alone. The effect of
phosphodiesterase inhibitors could be further enhanced by minimal
concentrations of NO donors, such as nitroglycerin that produced a
quicker onset and sustained sphincter relaxation without headache
and other adverse reactions observed with high dose of NO donors
alone (see FIG. 4).
Example 3
[0215] This example illustrates the effect of a potassium channel
opener (minoxidil) in a rat internal anal sphincter
constriction/relaxation model.
[0216] Following the same experimental protocol as described above,
a single 20 .mu.L dose of a 4% solution of minoxidil in 62.5%
propylene glycol resulted in a 64% reduction of the IASP over 2.5
hours following treatment. The vehicle alone had little effect on
IASP (see FIG. 5).
Example 4
[0217] This example illustrates the use of a variety of
compositions of the invention for the relaxation of the IAS.
[0218] In this example, male Sprague-Dawley rats (250-300 g each)
from Charles River were used. The rats were anesthetized
intramuscularly with ketamine (90 mg/kg) and xylazine (9 mg/kg) and
kept warm on a heated surgical table. All internal anal sphincter
pressures (IASP) were measured with Millar catheter/transducers
(MPC-500 mikrotip; Millar Instruments, Houston) on low pressure
analyzers and blood pressure analyzers and recorded by DMSI
software provided by Micro-Med (Louisville). Rats were provided
with saline i.p. for rehydration due to the diuretic effects of the
anesthesia and re-anesthetized as needed with approximately 1/3 the
original dosage. In most experiments, the IASP was allowed to reach
a stable baseline level prior to drug delivery. Drugs were
delivered to the anal sphincter mainly via PE 20 tubing attached to
the catheter(s) near the sensor(s) from 100 .mu.l or 250 .mu.l
Hamilton syringes either manually or by infusion with a
programmable Harvard automatic infusion pump.
Example 5
[0219] This example illustrates the effect of repeated or prolonged
dosing of a nitric oxide donor (NTG) on the responsiveness of the
rat IAS.
[0220] One issue with chronic or subchronic therapy with nitric
oxide or nitric oxide donors such as NTG is the extent of any
tachyphylaxis or tolerance to the relaxant effect of nitric oxide.
Clinical studies have shown that the human cardiovascular system
develops tolerance to nitric oxide donors. We have found that in
the rat model, cardiovascular tolerance, as measured in vivo by the
mean arterial blood pressure, also develops with repeated dosing of
NTG. At the biochemical level, using in vitro assays, we have shown
that NTG-induced increases in cGMP levels were attenuated
dramatically in vascular smooth muscle. Thus, it seemed likely that
the IAS would also develop tolerance to the effects of nitric oxide
upon repeated or prolonged dosing.
[0221] In FIG. 6, 0.1% NTG in 5% dextrose/water with 1% propylene
glycol was administered in bolus doses directly to the IAS via a
Hamilton syringe attached to a Harvard automatic infusion pump at
20 .mu.g/min every 30 minutes. Each successive dose represented by
asterisks produced a dramatic drop in resting IASP followed by a
complete recovery to resting levels; a slight decline in resting
pressures is observed over time, for most experiments, possibly due
to the effects of anesthesia. Since each NTG administration was
able to provide similar level and duration of pressure reduction,
no nitrate related pressure tolerance was noted with repeated NTG
administration.
[0222] FIG. 7 demonstrates that a continuous infusion of NTG at 20
.mu.g/hour produced a steady and sustained decline in resting LASP
with no evidence of recovery in IASP during the entire treatment
period, ruling out the incidence of tolerance, even after 4 hours
of perfusion; asterisks indicate hours following initiation of NTG
infusion. Similar results were obtained using a ten-fold higher
dose of NTG. Since there was no rebound of pressure reduction with
continuous NTG administration, no nitrate related pressure
tolerance was noted with continuous NTG administration.
[0223] Surprisingly, we have found that tachyphylaxis to the
relaxant effect of NTG on the IAS does not develop with repeated or
prolonged dosing in vivo. Our in vitro studies have also found that
NTG-induced increases in cGMP levels in the muscle of the IAS which
were not as attenuated as those in vascular smooth muscle.
Example 6
[0224] This example illustrates the use of cyclic nucleotide
analogs to affect IASP in the rat model.
[0225] 8-bromo cAMP (0.1% in saline) was infused to the IAS at 20
.mu.g/hour for 3 hours. Minimal pressure reduction was noted; this
could due to the poor absorption of the 8-bromon cAMP from saline
to the sphincter tissue during the study duration (see FIG. 8).
[0226] Dibutyryl cAMP (0.1% in saline) was infused to the IAS at 20
.mu.g/hour for 3 hours. A minor depression in IASP was noted (see
FIG. 9). cGMP analogs also elicited very little depression of IASP,
possibly due to the poor bioavailability through the in vivo
topical dosage form.
[0227] Since increasing levels of cGMP and cAMP in the IAS with NTG
or ISO resulted in an expected decrease in IASP; introduction of
the aqueous-soluble 8-bromo and dibutyryl analogues of cGMP and
cAMP were fully expected to also lower resting IASP in the rat
model. Surprisingly, the cGMP analogs provided almost no effect on
IASP (data not shown), whereas dibutyryl cAMP proved to be more
efficacious in the rat model than the 8-bromo derivative as
demonstrated in the following figures. These results may reflect
differences in bioavailability of the analogs and/or direct effects
of the butyrate moiety on smooth muscle relaxation.
Example 7
[0228] This example illustrates the varying ability of superoxide
scavengers to potentiate the effect of nitric oxide/nitric oxide
donors in vivo.
[0229] The ability of superoxide scavenger superoxide dismutase
(SOD) to potentiate the relaxing effects of NTG by prolonging the
half-life of nitric oxide (NO) was examined using the rat model.
NO, produced from the enzymatic degradation of NTG within cells,
has a half-life of only a few seconds before it is acted upon by
oxygen radicals such as the superoxide anion to form peroxynitrite
(Weller, 1997). Perfusion of the anal sphincter with SOD prior to
NTG treatment, theoretically should remove superoxide from the
equation, providing a longer half-life for NO in the tissue and
resulting in more sustained cGMP levels, potentiating the
NTG-induced relaxation of the IAS.
[0230] Vehicle (20 .mu.l of 5% dextrose/water with 10% propylene
glycol) was delivered to the IAS followed in 30 minutes by a 200
.mu.g bolus delivery of superoxide dismutase (SOD) in vehicle,
followed 15 minutes later with a bolus dose of 200 .mu.g NTG in the
same vehicle. A significant potentiation of NTG effect, e.g.
increasing the duration of action on reducing anal sphincter was
observed (see FIG. 10). This result indicates that the activity of
the NO donor in the presence of a superoxide anion scavenger is
enhanced.
[0231] Vehicle (20 .mu.l of 5% dextrose/water with 10% propylene
glycol) was delivered to the IAS followed in 30 minutes by a 200
.mu.g bolus delivery of NTG in vehicle, followed 15 minutes later
with a bolus dose of 20 .mu.g SOD. No significant potentiation of
NTG was observed suggesting that the potentiation effect of SOD is
most pronounced when administered prior to NTG (see FIG. 11). This
result suggests that the NTG-derived NO has already dissipated from
the tissue.
[0232] Surprisingly, the synthetic superoxide scavenger Mn (III)
tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), did not
demonstrate significant NO enhancing activity in this model.
[0233] Further, as FIGS. 10 and 11 demonstrate, SOD alone has
little effect on IASP since the resting IAS has low endogenous
levels of NO to act upon by superoxide anion.
Example 8
[0234] This example illustrates the potentiation of NTG in the rat
model by PDE V inhibitor blockage of the cGMP-specific PDE
activity.
[0235] Zaprinast:
[0236] The vehicle, 1-methyl 2-pyrollidinone (1M2P) was injected
intraperitoneal (i.p.). (100 .mu.l), 30 minutes prior to bolus
doses of NTG (20 .mu.g/min every 30 minutes). The duration of
depression of IASP due to NTG was constant with each dose (see FIG.
12).
[0237] Zaprinast (10 mg in 100 .mu.l M2P) was injected i.p. 30
minutes prior to bolus doses of NTG (20 .mu.g/min every 30
minutes). There was an increasing duration of IASP depression with
consecutive doses of NTG demonstrating potentiation of NTG by a
selective PDE V inhibitor (see FIG. 13).
[0238] The vehicle, 1-methyl 2-pyrollidinone (IM2P) was injected
intraperitoneal (i.p.). (100 .mu.l), followed after 2.75 hours by
the first dose of NTG (20 .mu.g/min every 30 minutes). The duration
of depression of IASP was consistent with each NTG dose (see FIG.
14).
[0239] Zaprinast (10 mg in 100 .mu.l M2P) was injected i.p. 2.75
hours prior to bolus doses of NTG (20 .mu.g/min every 30 minutes).
The duration of depression of IASP continued to increase with each
NTG dose and peaked at around 3.5-4 hours and decreased with
additional doses of NTG. This study suggests that an i.p. dose of
zaprinast reaches maximal levels in the IAS between 3.5-4 hours and
causes potentiation with NTG (see FIG. 15).
[0240] These results show that potentiation of NTG activity can be
achieved by agents protecting from PDE degradation the cGMP formed
through NO activation of guanylyl cyclase.
[0241] Dipyridamole:
[0242] The vehicle, 1-methyl 2-pyrollidinone (1M2P) was injected
i.p. (100 .mu.l), 50 minutes prior to bolus doses of NTG (20
.mu.g/min every 30 minutes). The duration of depression of IASP due
to NTG was constant with each dose (see FIG. 16).
[0243] Dipyridamole (10 mg in 100 .mu.l 1M2P) was injected i.p. 50
minutes prior to bolus doses of NTG (20 .mu.g/min every 30
minutes). The duration of depression of IASP due to NTG was
constant with each dose and approximately twice that for the
vehicle-treated rat (see FIG. 17).
[0244] MBCQ:
[0245] MBCQ (10 mg in 100 .mu.l 1M2P) was injected i.p. 30 minutes
prior to bolus doses of NTG (20 .mu.g/min every 30 minutes). No
noticeable potentiation of NTG was observed with this PDE V
inhibitor in this experiment (see FIG. 18). Bioavailability of MBCQ
could be the cause of the minimal effect seen with this
compound.
[0246] Whereas dipyridamole demonstrated less striking potentiation
with NTG, the most potent of the PDE V inhibitors under in vitro
conditions, MBCQ, did not demonstrate significant activity,
potentially due to diminished bioavailability of this drug in the
in vivo model (data not shown).
Example 9
[0247] This example illustrates the effect of non-selective
.beta.-adrenergic agonists using isoproterenol. These agonists
activate adenyl cyclase, thereby increasing cAMP levels, and act on
the IASP through the direct smooth muscle relaxing activity of
cAMP.
[0248] A bolus dose of 200 .mu.g isoproterenol produced a dramatic
drop in IASP eliminating significant pressure readings by the
catheter/transducer in fact, isoproterenol proved to be a very
potent IAS relaxant and had to be titred down, in another study, to
a continuous dose of 0.2 .mu.g/hour in order to avoid significant
drops in IASP (see FIG. 19).
Example 10
[0249] This example illustrates the effect of .beta..sub.2-agonists
on the IASP.
[0250] The .beta..sub.2-agonist, terbutaline (in saline) was
infused continuously at 20 .mu.g/hour. A steady and sustained
decline in IASP over the 3 plus hours of infusion (FIG. 4n, 20)
resulted. The significant drop in IASP throughout the experiment
reached a plateau between 1.5 and 2 hours post initiation of
treatment.
[0251] This sustained, however moderate, drop in IASP is considered
desirable for prolonging the increased blood flow to the anoderm
necessary for healing anal fissures, without inducing a complete
relaxation of the IAS which might result in temporary
incontinence.
[0252] The .beta..sub.2-agonist, salbutamol (in saline) was infused
continuously at 20 .mu.g/hour and demonstrated a significant drop
in IASP throughout the experiment similar to terbutaline (see FIG.
21).
Example 11
[0253] This example illustrates the effects of cAMP levels on the
IASP and the effects of PDE IV inhibitor blockage of the
cAMP-specific PDE activity in the rat model.
[0254] Effects of Rolipram:
[0255] The PDE IV inhibitor rolipram, in 5% DMSO/Acetone:Olive oil
1:1 was continuously infused at 20 .mu.g/hour rate. A pattern
including significant drops in IASP followed by shorter recovery
phases occurred prior to 1 hour after initiating the drug infusion
(see FIG. 22).
[0256] Etazolate Potentiation of Salbutamol:
[0257] Delivery of 200 .mu.g of salbutamol in saline to the IAS
produced no short-term effects on the IASP; however a subsequent
treatment with salbutamol plus the PDE IV inhibitor etazolate, also
at 200 .mu.g in saline, produced a dramatic and sustained drop in
IASP, suggesting a potentiation effect of a .beta..sub.2-agonist
with a PDE IV inhibitor on anal sphincter pressure reduction (see
FIG. 23).
[0258] This experiment is similar to that described above for FIG.
23, however the order of the delivery of the drugs was reversed.
The results were similar (see FIG. 24).
[0259] Smooth muscle relaxation is caused by agents that elevate
cAMP levels via phosphorylation of myosin light chain kinase by
cAMP-dependent protein kinase (PKA). PDE type IV inhibitors prevent
degradation of cAMP by cAMP-specific PDE. As seen with the above
PDE IV inhibitor etazolate potentiation of the effects of the
.beta..sub.2-adrenergic agonist, salbutamol, potentiation of agents
which activate adenylyl cyclase, can be achieved with PDE type IV
inhibitors.
[0260] Effects of RO-20-1724:
[0261] The PDE IV inhibitor RO-20-1724 was infused at 20 .mu.g/hour
in the vehicle 5% DMSO/Acetone:Olive oil 1:1. The drop in IASP was
minimal suggesting either lack of bioavailability of the drug from
the current route of administration (see FIG. 25).
[0262] Effects of Forskolin
[0263] The specific adenyl cyclase activator forskolin, was infused
at 20 .mu.g/hour in the vehicle 5% DMSO/Acetone:Olive oil 1:1. A
significant and sustained drop in IASP was observed (see FIGS. 26
(control) and 27). This experiment clearly demonstrates the
contribution of cAMP in inducing relaxation of the internal anal
sphincter.
Example 12
[0264] This example illustrates the use of .alpha.-adrenergic
antagonists to reduce IASP in the rat model.
[0265] The .alpha..sub.1-blocker, prazosin in 5% DMSO/Acetone:Olive
oil 1:1 was infused at 20 .mu.g/hour. A significant and sustained
drop in IASP that plateaued after 1 hour was observed suggesting
that the increase of cAMP level leads to relaxation of internal
anal sphincter pressure (see FIG. 28).
Example 13
[0266] This example illustrates the effect of non-selective PDE
Inhibitors on IASP in the rat model.
[0267] Isobutyl methylxanthine (IBMX) in 5% DMSO/Acetone:Olive oil
1:1 was infused at 200 .mu.g/hour. A significant and sustained drop
in IASP that leveled off at 1 hour after initiation of the infusion
was observed (see FIG. 29).
[0268] Isobutyl methylxanthine (IBMX) in 5% DMSO/Acetone:Olive oil
1:1 was infused at a lower dose, i.e. 20 .mu.g/hour. The results
were similar as for the experiment described in FIG. 29 (see FIG.
30).
[0269] The non-selective PDE inhibitor, IBMX is thought to act on
smooth muscle by a number of potential mechanisms including: 1) PDE
inhibition and increasing cAMP levels; 2) effects on intracellular
calcium concentration; 3) effects on membrane hyperpolarization; 4)
uncoupling of increased calcium levels with muscle contractility;
and 5) adenosine receptor antagonism (Goodman & Gilman's "The
Pharmacological Basis of Therapeutics" 9.sup.th edition. Section
IV-Autocoids; Drug Therapy of Inflammation).
Example 14
[0270] This example illustrates the use of K.sup.+-ATP Channel
Openers to relax the IAS.
[0271] The K.sup.+-ATP channel openers, minoxidil and diazoxide,
induce hyperpolarization of the cell membranes of smooth muscle,
and thereby inactivate voltage-gated Ca.sup.2+ channels.
[0272] Minoxidil (830 .mu.g in 20 .mu.l 62.5% propylene
glycol/water) was delivered to the IAS. A significant and sustained
drop in IASP was observed shortly after delivery of the drug (see
FIG. 31).
[0273] Diazoxide in 5% DMSO/Acetone:Olive oil 1:1 was infused at 20
.mu.g/hour. A dramatic drop in IASP was observed for the duration
of the experiment (see FIG. 32).
Example 15
[0274] This example illustrates the use of Ca.sup.2+-channel
blockers
[0275] Diltiazem in saline was infused at 20 .mu.g/hour. The drug
produced a dramatic and sustained drop in IASP for the duration of
the experiment (see FIG. 33).
[0276] Verapamil in saline was infused at 20 .mu.g/hour. The drug
produced a dramatic and sustained drop in IASP for the duration of
the experiment (see FIG. 34).
Example 16
[0277] This example illustrates the use of sympathetic nerve
terminal destroyers to achieve a long term reduction in IASP in the
rat model following a short term administration of the active
agent.
[0278] Neurogenic tone of the IAS is largely due to sympathetic
adrenergic innervation; norepinephrine released by the nerves acts
on .alpha..sub.1-adrenergic receptors to contract smooth muscle.
Earlier reports suggested that .alpha.-blockers reduced anal
pressure in man (Speakman, C. T., Dig Dis Sci 38(11):1961-9 (1993);
Parks, A. G., Gut 10(8): 674-7 (1969)). Recent clinical trials
using one of the most potent toxins known, botulinus toxin,
produced by Clostridium botulinum, have demonstrated success in
healing anal fissures after multiple injections of the toxin
directly into the IAS. Botulinus toxin presumably relaxes the IAS
through its action of blocking acetylcholine (ACH) release from
cholinergic pre-synaptic fibers (Kao, I., et al., Science 193,
1256-8 (1976)). However, cholinergic innervation of the IAS is not
thought to contribute significantly to IAS tone. We decided to use
a drug that can be applied topically to the IAS, and that destroys
adrenergic nerve terminals, thereby blocking the actions of
norepinephrine in maintaining sphincter tone.
[0279] 6-hydroxydopamine in saline was delivered to the IAS in
bolus doses of 200 .mu.g to a rat each day for 5 days. The IASP was
measured over three weeks. A continuous drop in IASP was noted
through day 16, 11 days after termination of the treatment. By day
19 a partial recovery in IASP was observed, and by day 22 the
average IASP was 36% below the original baseline pressure (see FIG.
35).
[0280] Thus, treatment with 6-hydroxydopamine (6-OHDA), resulted in
a prolonged reduction in IASP over at least a 3 week period
following 5 daily topical doses of 200 .mu.g in saline to the rat
IAS.
Example 17
[0281] This example illustrates the effects of a PDE III/IV
inhibitor on IASP under a variety of experimental conditions.
[0282] This experiment serves as a control for the experiment
described in FIG. 37. An i.p. injection of 100 .mu.l 1M2P was
followed in 30 minutes by a continuous infusion of isoproterenol in
saline at 0.2 .mu.g/hour. This sub-threshold dose of isoproterenol
had no significant effect on lowering IASP (see FIG. 36).
[0283] The PDE III/IV inhibitor, zardaverine (10 mg in 100 .mu.l
1M2P) was injected i.p. followed in 30 minutes by a continuous
infusion of isoproterenol in saline at 0.2 .mu.g/hour. A rapid drop
in IASP was noted immediately after the i.p. injection of
zardaverine, and a sustained decrease in average IASP followed
isoproterenol infusion. A continuous slow wave pattern of
decreasing and increasing IASP was observed after isoproterenol
infusion (see FIG. 37).
[0284] The PDE III/IV inhibitor, zardaverine (7.5 mg in 100 .mu.l
1M2P) was injected i.p. followed in 30 minutes by a continuous
infusion of 5% dextrose at 20 .mu.l/hour. The zardaverine injection
produced a rapid but transient drop in IASP that soon returned to
normal baseline levels. The subsequent infusion of 5% dextrose had
no effect on lowering the IASP (see FIG. 38).
[0285] The PDE III/IV inhibitor, zardaverine (7.5 mg in 100 .mu.l
1M2P) was injected i.p. followed in 30 minutes by a continuous
infusion of isoproterenol in saline at 0.2 .mu.g/hour. Zardaverine,
again induced a rapid and transient decrease in IASP. The
isoproterenol infusion further reduced the IASP to almost zero mmHg
(see FIG. 39). These experiments (FIGS. 36-39) suggest a
potentiation of subthreshold levels of isoproterenol by
zardaverine.
Example 18
[0286] This example illustrates the use of adenosine antagonists to
relax the IAS in the rat model.
[0287] Theophylline:
[0288] Theophylline, an adenosine antagonist, was continuously
infused at 200 .mu.g/hour in 5% dextrose. A dramatic and sustained
drop in IASP was observed throughout the 4 hour duration of the
experiment (see FIG. 40).
[0289] Theophylline was continuously infused at 20 .mu.g/hour in 5%
dextrose. A moderate drop in average IASP was observed throughout
the 3 hour duration of the experiment (see FIG. 41).
[0290] Theophylline was continuously infused at a lower dose, i.e.
2 .mu.g/hour in 5% dextrose. A minimal drop in average IASP was
observed throughout the 3 hour duration of the experiment (see FIG.
42).
[0291] Dyphylline:
[0292] FIG. 43 shows the IAS relaxing effects of a 20 .mu.g/hr
continuous dose of dyphylline [7-(2,3-dihydroxypropyl)
theophylline], a theophylline derivative that is not metabolized by
the liver and is excreted unchanged by the kidneys, providing this
drug with a low toxicity potential.
Example 19
[0293] This example illustrates a method for treating anal
disorders in an individual using phosphodiesterase inhibitors and
other agents to reduce pain associated with the disorders,
including acute and chronic anal fissures.
[0294] Patients with severe anal pain and especially during and
after bowel movement can be treated with the following therapies:
zaprinast, zaprinast and nitroglycerin, minoxidil, nitroglycerin
and cGMP mimetics, isoproterenol, or sildenafil, either one to
three times daily or as required to effectively reduce anal rectal
pain. Pain reduction (indicated by a reduction in the average pain
and/or the defecation pain) will be evaluated and the time to pain
reduction will also be evaluated. Therapy that is effective in
relieving anal pain will eventually leads to effective resolution
of these anal rectal disorders. Additionally, drugs that can
effectively reduce anal sphincter pressure, maintain reduced anal
sphincter pressure, or prevent recurrence of the diseases and yet
cause minimal or no adverse reactions such as headache, dizziness,
and hypotension will be of great therapeutic benefit.
Example 20
[0295] This example illustrates a method for treating anal
disorders in an individual using phosphodiesterase inhibitors and
other agents to promote healing in acute and chronic anal
fissures.
[0296] Patients with anal fissures can be treated with the
following therapies: zaprinast, zaprinast and nitroglycerin,
minoxidil, nitroglycerin and cGMP mimetics, isoproterenol, or
sildenafil, either one to three times daily or as required to
effectively promote healing. Healing is indicated by improving
re-epithelization of the observed fissure and can be evaluated
along with the time needed to complete healing. Therapy that is
effective in healing anal fissures eventually leads to complete
resolution of these anal rectal disorders. Furthermore, drugs that
can effectively reduce anal sphincter pressure, maintain reduced
anal sphincter pressure, or prevent recurrence of the diseases and
yet cause minimal or no adverse reactions such as headache will
provide significant medical benefit.
Example 21
[0297] This example illustrates a method to reduce bleeding in
patients with hemorrhoidal symptoms or diseases.
[0298] Patients with hemorrhoidal symptoms or diseases can be
treated with the following therapies: zaprinast, zaprinast and
nitroglycerin, minoxidil, nitroglycerin and cGMP mimetics,
isoproterenol, or sildenafil, either one to three times daily or as
required to effectively reduce bleeding and promote healing.
Disease resolution indicated by reduction in bleeding and or pain
can be evaluated along with the time to healing. Therapy that is
effective in improving hemorrhoidal symptoms will eventually lead
to complete resolution of these anal rectal disorders. Furthermore,
drugs that can effectively reduce anal sphincter pressure, maintain
reduced anal sphincter pressure, or prevent recurrence of the
diseases while causing minimal or no adverse reactions such as
headache are of significant medical benefit.
Example 22
[0299] A composition of a base gel comprising 1.0 gm of salbutamol,
0.6 gm of carbopol 1342 USP, 35.44 gm of propylene glycol, 15.16 gm
of dehydrated ethanol USP, 15.16 gm of isopropyl alcohol USP, 2.5%
oleic acid, triethanolamine HCl 1N to adjust the pH from 6.0 to
7.0, 0.05 gm of butylated hydroxytoluene NF, and 29.72 gm of
purified water USP. Other concentrations of salbutamol can be added
in the same gel base to achieve the therapeutically effective dose;
this can also be achieved by adjusting the concentration of other
.beta.-agonists with gel base excipients such as oleic acid.
Example 23
[0300] One example of a topical composition comprises 0.05 to 1%
sildenafil, 75% (w/w) white petrolatum USP, 4% (w/w) paraffin wax
USP/NF, lanolin 14% (w/w), 2% sorbitan sesquioleate NF, and 4%
propylene glycol USP at the therapeutic effective dose to the
anorectal area. Typically, the 50 mg to 600 mg of sildenafil
ointment can be applied to the anorectal area in order to reduce
the signs and/or symptoms associated with anorectal disorders, for
example, anal fissure, anal ulcers, and hemorrhoidal diseases. The
concentration of sildenafil, or other phosphodiesterase inhibitors
can be varied by adjusting the ratio between the sildenafil with
excipients facilitate either the attachment of sildenafil to the
local tissue, or agents enhance absorption to the afflicted
tissue.
[0301] Yet another example of a topical composition comprises
nitroglycerin at 0.1% concentration and sildenafil at 0.1%
concentration can be incorporated in the same ointment base as
mentioned above. This composition can be applied topically from a
metered dosing device where a 50 mg to 1.5 gm dose of the
composition is administered to the afflicted anorectal tissue to
achieve the desired therapeutic effects.
[0302] Another therapeutic regimen is to provide patients afflicted
with the anorectal disorders with both oral sildenafil tablets and
topical nitroglycerin ointment. These two dosage forms can be used
in combinations which provide the best efficacy and compliance
among these patients.
Example 24
[0303] A composition of aminothylline topical spray composition
comprises 0.1 to 5.0% (w/w) of aminothylline, acetylated lanolin
alcohol, aloe vera, butane, cetyl acetate, hydrofluorocarbon,
methyl paraben, PEG-8 laurate and polysorbate 80 in a 2 oz. pump
spray bottle. The concentration of aminophylline or other
non-specific phosphodiesterase inhibitor can vary between 0.5% to
5%. Other non-hydrofluorocarbon propellant can also be used instead
of hydrofluorocarbon in the current composition. This composition
can be sprayed directly onto the afflicted tissue once to four
times daily to achieve the desired relief of signs and/or symptoms
associated with anorectal disorders. This composition can also
include menthol and benzocaine to provide the immediate local pain
relief and soothing sensation whereas aminophylline provides the
longer lasting relaxation of anal sphincter pressure.
Example 25
[0304] A base cream composition comprises 2 gm prazosin
hydrochloride (2.0% w/w), 54.3 gm of purified water USP, 2 gm of
Sepigel 305, 4.5 gm of Crodamol, 5.0 gm of glycerin, 6.0 gm sesame
oil, 15.0 gm of white petrolatum USP, 2.0 gm of lanolin USP, 7.0 gm
of 1,3-butylene glycol, 0.2 gm of methylparaben and 2.0 gm of
silicon HL88.
[0305] A base cream can be prepared by first separate mixings of
aqueous versus non-aqueous, i.e. oil phase, components of the
cream. Once the aqueous phase containing the prazosin hydrochloride
is well mixed, the melted oil phase is gently stirred into the
aqueous phase to form a uniform cream base.
Example 26
[0306] Sildenafil, a specific inhibitor of type V
phosphodiesterase, can be given orally via a tablet, parenterally
or can be applied topically to patients diagnosed with anal
fissures, either acute or chronic anal fissures, or other anorectal
disorders. Sildenafil can be given one to three times daily for 8
weeks, especially in the case of patients afflicted with chronic
anal fissure to cause the reduction of signs and symptoms
associated with anorectal disorders.
[0307] For topical application, an approximate 50 mg to 900 mg dose
of the cream measured by a metered dosing device, containing
sildenafil, at the concentration from 0.02% to 5%, can be applied
to the afflicted anorectal region using an applicator or by finger,
one to four times daily to achieve the desirable therapeutic
effects. Alternatively, the oral and topical treatment can be used
in a defined regimen to achieve the best therapeutic effects.
Example 27
[0308] A phosphodiesterase inhibitor, for example aminophylline,
can be given either orally via a tablet, parenterally or can be
applied to patients diagnosed with anal fissures or other anorectal
disorders, either acute or chronic anal fissures from a topical
dosage form, e.g. a cream. For topical application, an approximate
50 mg to 900 mg of the cream measured by a metered dose device, can
be applied to the afflicted anorectal region using an applicator or
by finger, one to four times daily to achieve the desirable
therapeutic effects.
Example 28
[0309] A .beta.-adrenergic agonist, for example salbutamol, can be
given from a suppository dosage form to patients diagnosed with
anal fissures or other anorectal disorders, either acute or chronic
anal fissures from a topical dosage form, e.g. a cream. For
suppository application, an approximate 300 mg to 3 gm of the
suppository unit can be applied to the afflicted anorectal region
using an applicator or by finger, one to four times daily. Once the
suppository melts in the anal cavity, the salbutamol released from
the dosage form is available to achieve the desirable therapeutic
effects.
Example 29
[0310] An .alpha.-adrenergic antagonist, i.e. prazosin can be
applied from a topical spray to patients diagnosed with
hemorrhoidal disorders, alone or in combination with a local
anesthetic, for example, lidocaine, or in combination with a mixed
.beta..sub.2- and .beta..sub.3-adrenergic agonist, for example
salbutamol, or in combination with a PDE IV inhibitor, for example,
ariflo (SB207499), RP73401, CDP840, rolipram and LAS31025. Prazosin
can be applied directly to the afflicted area with the propellant
from the spray and can be used as needed to relieve the local pain
and anal sphincter hypertonicity. Eventually, the application of
prazosin leads to healing of the hemorrhoidal disorders.
Example 30
[0311] This example illustrates the preparation of a theophylline
topical formulation from theophylline oral tablets.
[0312] Five Theo-24 tablets (400 mg of theophylline per tablet; UCB
Pharmaceuticals, Inc.) were combined and ground into a fine powder.
To this powder, 50 ml of ethanol was added and the solution was
stirred at room temperature for 15 minutes. Next, 48 ml of
propylene glycol and 100 ml of distilled water were added to the
ethanol mixture while stirring. This mixture was stirred for 15
minutes, at which time the powder was completely dissolved. A
solution of carbopol in distilled water was then added to the
mixture while stirring, forming a 1% topical theophylline gel. The
resulting gel was then stirred for another 15 minutes.
Example 31
[0313] A methylxanthine derivative, for example diphylline or
theophyllline, can be given either orally via a tablet,
parenterally or can be applied to patients diagnosed with anal
fissures or other anorectal disorders, either acute or chronic anal
fissures from a topical dosage form, e.g. a cream or a rectal
suppository.
[0314] For topical application, an approximate 50 mg to 900 mg of
the cream measured by a metered dose device, can be applied to the
afflicted anorectal region using an applicator or by finger, one to
four times daily to achieve the desirable therapeutic effects.
[0315] It is understood that the examples and embodiments described
herein are for illustrative purposes only and that various
modifications or changes in light thereof will be suggested to
persons skilled in the art and are to be included within the spirit
and purview of this application and scope of the appended claims.
All publications, patents, and patent applications cited herein are
hereby incorporated by reference in their entirety for all
purposes.
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