WO2002009714A1 - Compositions and methods for the treatment of anorectal disorders - Google Patents

Compositions and methods for the treatment of anorectal disorders Download PDF

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Publication number
WO2002009714A1
WO2002009714A1 PCT/US2001/023971 US0123971W WO0209714A1 WO 2002009714 A1 WO2002009714 A1 WO 2002009714A1 US 0123971 W US0123971 W US 0123971W WO 0209714 A1 WO0209714 A1 WO 0209714A1
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agent
composition
anal
adrenergic
accordance
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PCT/US2001/023971
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English (en)
French (fr)
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WO2002009714A9 (en
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Thomas P. Parks
Vivien Mak
Jung-Chung Lee
Charles Lee
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Cellegy Pharmaceuticals, Inc.
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Priority to MXPA03000931A priority Critical patent/MXPA03000931A/es
Priority to AU2001279104A priority patent/AU2001279104A1/en
Priority to KR1020037001579A priority patent/KR100863758B1/ko
Priority to EP01957348A priority patent/EP1315499A4/en
Priority to CA002417848A priority patent/CA2417848A1/en
Priority to IL15420201A priority patent/IL154202A0/xx
Priority to JP2002515267A priority patent/JP2004516244A/ja
Publication of WO2002009714A1 publication Critical patent/WO2002009714A1/en
Publication of WO2002009714A9 publication Critical patent/WO2002009714A9/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • 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.
  • anorectal disorders such as anal fissures, anal ulcer, hemorrhoidal diseases and levator spasm
  • 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.
  • anal fissure fissure-in-ano
  • anal ulcer a fissure-in-ano
  • hemorrhoidal diseases a malignant neoplasm originating from a central nervous system
  • levator spasm levator spasm
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • conservative medical treatment e.g., dietary changes, sitz baths
  • 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.
  • 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. ⁇ . et al., Br JSurg. 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.
  • 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 JSurg 83(10): 1335-44, (1996); Schouten W.R. et al., Scan J Gastroenterol. Suppl 218: 78-81 (1996)).
  • 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 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 LAS 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)).
  • 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.
  • 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.
  • 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
  • the ⁇ 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)).
  • the ⁇ -receptor agonists methoxamine and phenylephrine increase anal pressure (Speakman, C.T. 1997 supra; Carapeti, E.A.
  • ⁇ -adrenergic receptor population is dominant, ⁇ - 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 ⁇ -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.
  • 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 mimics the effects of intrinsic nerve stimulation on isolated smooth muscle strips. LAS 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.
  • ATP ATP
  • VLP vasoactive intestinal peptide
  • ATP and VLP 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)).
  • ATP and VLP 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.
  • 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.
  • NO donors 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.
  • NO donors e.g., nitroglycerin
  • nitroglycerin are widely used therapeutically as coronary vasodilators to treat heart disease.
  • NO donors are beginning to be explored clinically as drugs to treat anal disorders associated with IAS hypertonicity.
  • nitroglycerin Gorfine, S.R., Dis Colon Rectum, 38(5):453-6 (1995); Watson, S.J. et al, BrJ Surgery 83(6):771-5, 1996; Lund, J.N.
  • 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 LAS, which may be necessary for healing particularly refractant chronic anal fissures.
  • 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 IN (PDE IV) inhibitor, a nonspecific PDE inhibitor, a ⁇ -adrenergic agonist, a cAMP-dependent protein kinase activator, an estrogen or estrogen-like compound, or an ⁇ t-adrenergic antagonist.
  • the agent can also be a superoxide anion (O " ) scavenger, an ATP-sensitive K channel activator, a sympathetic nerve terminal destroyer, or a smooth muscle relaxant, although these agents do not directly modulate either cAMP or cGMP levels.
  • O " superoxide anion
  • the present invention further provides methods of using these compositions.
  • the present invention provides compositions for the treatment of anorectal disorders comprising a phosphodiesterase inhibitor, preferably a PDE II inhibitor, a PDE IN inhibitor or a PDE N inhibitor, either alone or in combination with another agent selected from ⁇ -adrenergic receptor agonists, o ⁇ -adrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier.
  • a phosphodiesterase inhibitor preferably a PDE II inhibitor, a PDE IN inhibitor or a PDE N inhibitor
  • another agent selected from ⁇ -adrenergic receptor agonists, o ⁇ -adrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, or smooth muscle relaxants in combination with a pharmaceutically acceptable carrier.
  • the present invention also provides methods of using these compositions.
  • compositions for the treatment of anorectal disorders comprising a ⁇ -adrenergic receptor agonist, preferably a ⁇ 2 - or ⁇ 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, cci-adrenergic antagonists, estrogens or estrogen-like compounds, L-type Ca 2+ channel blockers, or ATP-sensitive K + channel activators, and methods of using those compositions.
  • PDE inhibitors e.g., a PDE IV inhibitor
  • nonspecific PDE inhibitors e.g., a PDE IV inhibitor
  • nonspecific PDE inhibitors e.g., cci-adrenergic antagonists
  • estrogens or estrogen-like compounds e.g., estrogens or estrogen-like compounds
  • L-type Ca 2+ channel blockers e.g., ATP-sensitive K + channel activators
  • the present invention provides compositions for the treatment of anorectal disorders comprising an ATP-sensitive K + channel activator, either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, ⁇ radrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, or smooth muscle relaxants, and methods of using those compositions.
  • an ATP-sensitive K + channel activator either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, ⁇ radrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, or smooth muscle relaxants, and methods of using those compositions.
  • the present invention provides compositions for the treatment of anorectal disorders comprising ⁇ 2 -adrenergic agonists, either alone or in combination with another agent. Methods for the use of these compositions are also provided.
  • the ⁇ 2 -adrenergic agonists are used alone.
  • the ⁇ -adrenergic agonists is combined with a phosphodiesterase inhibitor.
  • the ⁇ 2 -adrenergic agonists are combined with one or more other IAS relaxing agents.
  • 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.
  • adenosine receptor antagonists are used alone.
  • the adenosine receptor antagonists are combined with at least one other LAS relaxing agent.
  • 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.
  • cGMP-dependent protein kinase activators are used alone.
  • nonspecific cyclic nucleotide-dependent protein kinase activators are used alone.
  • nonspecific cyclic nucleotide-dependent protein kinase activators are used in combination with smooth muscle relaxants.
  • cAMP- dependent protein kinase activators are provided in combination with L-type Ca 2+ channel blockers.
  • the present invention provides a composition for the treatment of anorectal disorders comprising a methylxanthine compound.
  • the compound is theophylline or dyphylline.
  • the methylxanthine compound is used alone.
  • the methylxanthine compound is combined with another IAS relaxing agent.
  • 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.
  • estrogenic compounds are used alone.
  • the estrogenic compounds are used in combination with a second agent selected from phosphodiesterase inhibitors, ⁇ -adrenergic receptor agonists, ⁇ i- adrenergic antagonists, L-type Ca 2+ channel blockers, ATP-sensitive K+ channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier.
  • the present invention further provides methods of using these compositions.
  • methods of treating anorectal disorders comprise administering to a subject a suitable formulation of one or more of the compositions above.
  • 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.
  • Figure 1 illustrates a typical waveform pattern for resting LASP in a rat under conditions of a control experiment.
  • Figure 2 illustrates the waveform pattern for LASP in a rat following administration of 20 ⁇ l of a 1% solution of nitroglycerin in propylene glycol.
  • Figure 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 ⁇ l of a 10% solution of dibutyryl-cGMP in saline.
  • Figure 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 ⁇ l of a 5% solution of zaprinast in l-methyl-2- pyrrolidinone.
  • 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 ⁇ l of a 4% solution of minoxidil in 62.5% propylene glycol.
  • Figure 6 illustrates the effect of NTG administered to the IAS as a bolus dose.
  • Figure 7 illustrates the effect of NTG administered to the IAS by continuous infusion over 4 hours.
  • Figure 8 illustrates the effect of 8-bromo cAMP infused to the IAS at 20 ⁇ g/hour for three hours.
  • Figure 9 illustrates the effect of dibutyryl cAMP infused to the IAS at 20 ⁇ g/hour for three hours.
  • Figure 10 illustrates the effect of a bolus delivery of SOD (200 ⁇ g) to the LAS, followed by a bolus dose of NTG (200 ⁇ g) in the same vehicle.
  • Figure 11 illustrates the effect of a bolus delivery of NTG (200 ⁇ g) to the IAS, followed by a bolus dose of SOD (200 ⁇ g) in the same vehicle.
  • Figure 12 illustrates the effect on the LAS of a vehicle injection followed after 30 minutes by bolus doses of NTG.
  • Figure 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.
  • Figure 14 illustrates the effect on the IASP of a bolus dose of NTG applied topically to the LAS, wherein the first NTG dose is provided at 2.75 hours after a vehicle injection.
  • Figure 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.
  • Figure 16 illustrates the effect on the IAS of a vehicle injection followed after 50 minutes by bolus doses of NTG.
  • Figure 17 illustrates the effect on the IAS of PDE V inhibitor, dipyridamole injected i.p. 50 minutes prior to bolus doses of NTG.
  • Figure 18 illustrates the effect on the IASP of PDE V inhibitor MBCQ injected i.p. 30 minutes prior to bolus doses of NTG.
  • Figure 19 illustrates the effect on the IASP of ⁇ -agonist isoproterenol delivered to the IAS 30 minutes after saline alone.
  • Figure 20 illustrates the effect on the IASP of ⁇ -agonist terbutaline in saline infused continuously at 20 ⁇ g/hour.
  • Figure 21 illustrates the effect on the IASP of ⁇ 2 -agonist salbutamol in saline infused continuously at 20 ⁇ g/hour.
  • Figure 22 illustrates the effect on the IASP of PDE IV inhibitor rolipram in DMSO/acetone/olive oil infused continuously at 20 ⁇ g/hour.
  • Figure 23 illustrates a bolus dose of salbutamol followed by a single bolus dose of salbutamol and PDE IV inhibitor etazolate.
  • Figure 24 illustrates a bolus dose of etazolate followed by a single bolus dose of salbutamol and etazolate.
  • Figure 25 illustrates the effect on the IASP of PDE IN inhibitor Ro 20-
  • Figure 26 illustrates a vehicle control for the treatments provided in Figure 27.
  • Figure 27 illustrates the effect on the IASP of the specific adenyl cyclase activator forskolin, in DMSO/acetone/olive oil infused continuously at 20 ⁇ g/hour.
  • Figure 28 illustrates the effect on the IASP of the ⁇ t -blocker, prazosin, in DMSO/acetone/olive oil infused continuously at 20 ⁇ g/hour.
  • Figure 29 illustrates the effect on the IASP of the nonspecific PDE inhibitor LBMX, in DMSO/acetone/olive oil infused continuously at 200 ⁇ g/hour.
  • Figure 30 illustrates the effect on the IASP of the nonspecific PDE inhibitor LBMX, in DMSO/acetone/olive oil infused continuously at 20 ⁇ g/hour.
  • Figure 31 illustrates the effect on the IASP of a single bolus dose of the
  • K + -ATP channel opener minoxidil in propylene glycol/water.
  • Figure 32 illustrates the effect on the IASP of the K + -ATP channel opener diazoxide, in DMSO/acetone/olive oil infused continuously at 20 ⁇ g/hour.
  • Figure 33 illustrates the effect on the IASP of the Ca +2 -channel blocker diltiazem in saline infused continuously at 20 ⁇ g/hour.
  • Figure 34 illustrates the effect on the IASP of the Ca +2 -channel blocker verapamil in saline infused continuously at 20 ⁇ g/hour.
  • Figure 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 ⁇ g per day for 5 days.
  • Figure 36 illustrates the effect on the IASP of a control vehicle i.p injection of l-methyl-2-pyrollidinone followed after 30 minutes by continuous infusion of a sub-threshold dose of isoproterenol in saline (0.2 ⁇ g/hour).
  • Figure 37 illustrates the effect on the IASP of the PDE III/IN inhibitor zardaverine when injected i.p. (10 mg in vehicle) followed after 30 minutes by a continuous infusion of isoproterenol.
  • Figure 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.
  • Figure 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.
  • Figure 40 illustrates the effect on the IASP of the adenosine antagonist and non-specific PDE inhibitor, theophylline when continuously infused at 200 ⁇ g/hour in 5% dextrose.
  • Figure 41 illustrates the effect on the IASP of theophylline when continuously infused at 20 ⁇ g/hour in 5% dextrose.
  • Figure 42 illustrates the effect on the IASP of theophylline when continuously infused at 2 ⁇ g/hour in 5% dextrose.
  • Figure 43 illustrates the effect on the IASP of dyphylline when continuously infused at 20 ⁇ g/hour in 5% dextrose.
  • 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-l-b-D- ribofuranosylbenzimidazole-3 ',5 '-monophosphorothioate
  • treatment 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.
  • Therapeutic benefit includes any of a number of subjective or objective factors indicating a response of the condition being treated as discussed herein.
  • 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.
  • “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.
  • 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.
  • cyclic nucleotide refers to cyclic adenosine monophosphate and cyclic guanosine monophosphate.
  • 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.
  • change includes an increase or decrease in the characteristic.
  • subject as used herein includes any animal, such as a mammal, including a human.
  • 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.
  • 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.
  • signals, 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.
  • 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.
  • 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 hyperpolarizationOf 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.
  • a hyperpolarizationOf the cell membrane potential i.e. a more negative membrane potential
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • the second agent is a phosphodiesterase type V (PDE V) inhibitor.
  • the second agent is a phosphodiesterase type JV (PDE IV) inhibitor.
  • the second agent is a phosphodiesterase type II (PDE II) inhibitor.
  • the second agent is a nonspecific PDE inhibitor.
  • the second agent is a superoxide anion (O 2 " ) scavenger.
  • the second agent is a ⁇ -adrenergic agonist.
  • the second agent is a cAMP-dependent protein kinase activator.
  • the second agent is an a t -adrenergic antagonist.
  • the second agent is an estrogen, estrogen analog, or estrogenic compound.
  • the second agent is an L-type Ca 2+ channel blocker.
  • the second agent is an ATP-sensitive K + channel activator.
  • 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.
  • the NO donor includes at least one organic nitrate (including esters of nitric acid) and can be either a cyclic or acyclic compound.
  • 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-l,3-dinitrate, butane-l,2,4-triol trinitrate, and the like. More preferably, the NO donor is NTG. Nitroglycerin and other organic nitrates including ISDN, ETN, and
  • NO donors include sodium nitroprusside, N,O-diacetyl-N- hydroxy-4-chlorobenzenesulfonamide, N°-hyc oxy-L-argmme (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-l-yl]-3-pyridinecarboxamide (FR144420), and 4-hydroxymethyl-3- furoxan
  • the organic nitric oxide donor e.g., the organic nitrate
  • the organic nitric oxide donor is present in any amount less than that which is effective in the practice of the treatment of anal disease when used alone.
  • 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.
  • the composition contains an agent which is a phosphodiesterase (PDE) inhibitor.
  • PDE phosphodiesterase
  • 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
  • the PDE inhibitor is a PDE V inhibitor.
  • Useful phosphodiesterase type V inhibitors include zaprinast, MBCQ, MY-5445, dipyridamole and sildenifil.
  • the composition contains an agent which is a phosphodiesterase type II (PDE II) inhibitor.
  • PDE II phosphodiesterase type II
  • Suitable phosphodiesterase type II inhibitors include EHNA.
  • the composition contains an agent which is a phosphodiesterase type IV (PDE IV) inhibitor.
  • PDE IV phosphodiesterase type IV
  • Suitable phosphodiesterase type LV inhibitors include ariflo (SB207499), RP73401, Ro-201724, CDP840, rolipram and
  • the composition contains an agent which is a dual selective phosphodiesterase inhibitor, preferably a PDE III/TV inhibitor such as, for example, zardaverine.
  • the composition contains an agent which is a nonspecific phosphodiesterase (nonspecific PDE) inhibitor.
  • Suitable nonspecific phosphodiesterase inhibitors include LBMX, theophylline, dyphylline theobromine, aminophylline, pentoxifylline, papaverine, caffeine and other methyl xanthine and non-xanthine derivatives (Goodman & Gilman's "The Pharmacological Basis of
  • the composition contains an agent which is a superoxide anion (O 2 " ) scavenger.
  • superoxide can react with NO and dramatically reduce its biological effects.
  • 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)
  • SOD exogenous Mn- or Cu/Zn superoxide dismutase
  • MnTBAP small molecule SOD mimetics
  • 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.
  • NO donors such as, for example, NTG
  • the nitric oxide formed from NTG acts only locally due to its short half-life.
  • NTG itself is stable enough to exert systemic effects following mucosal absorption.
  • the composition contains an agent which is a ⁇ -adrenergic agonist, preferably a ⁇ - or ⁇ -adrenergic receptor agonist.
  • a ⁇ -adrenergic agonist preferably a ⁇ - or ⁇ -adrenergic receptor agonist.
  • Suitable ⁇ 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 ⁇ -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.
  • the agent is a cAMP-de endent protein kinase activator.
  • 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 S ⁇ -8-pCPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT-cAMP.
  • the composition contains an agent which is an estrogen or estrogen analog or mimetic.
  • 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).
  • pesticides e.g. p,p'-DDT
  • plasticizers e.g. bisphenol A
  • industrial chemicals e.g. polychlorinated biphenyls
  • the composition contains an agent which is an ⁇ radrenergic antagonist.
  • the sympathetic neurotransmitter norepinephrine contracts sphincter smooth muscle via o ⁇ -adrenergic receptors.
  • Pharmacological interference with norepinephrine release or binding to ⁇ t -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 ⁇ radrenergic receptor antagonists (e.g.
  • the composition contains an alternative sympatholytic agent, such as an ⁇ - adrenergic receptor agonist, a nerve terminal norepinephrine depleting agent, a norepinephrine synthesis inhibitor or another agent which destroys sympathetic nerve terminals.
  • an alternative sympatholytic agent such as an ⁇ - adrenergic receptor agonist, a nerve terminal norepinephrine depleting agent, a norepinephrine synthesis inhibitor or another agent which destroys sympathetic nerve terminals.
  • the agent is an ATP-sensitive K + 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, P z ⁇ rm ⁇ co/ Rev. 24:509-81 (1972)).
  • ATP appears to act primarily by opening ATP-sensitive potassium (K AT P) channels which hyperpolarize the cell membrane, reducing intracellular calcium concentrations, leading to smooth muscle relaxation.
  • K AT P ATP-sensitive potassium
  • Synthetic compounds that activate ATP-sensitive K+ channels are smooth muscle relaxants, e.g.
  • 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 + channels can also influence smooth muscle tone, including apamin-sensitive low conductance calcium-activated K channels and charybdotoxin-sensitive high conductance calcium-activated K + channels.
  • compositions will comprise NO donors and smooth muscle relaxants.
  • smooth muscle relaxants include, for example, hydralazine, papaverine, tiropramide, cyclandelate, isoxsuprine or nylidrin.
  • compositions will comprise NO donors and a second agent which is a methyl xanthine or adenosine receptor antagonist.
  • second agents include theophylline, dyphylline, aminophylline, caffeine, and theobromine.
  • a second agent is a K + ATP channel opener, an adenosine receptor antagonist, or a ⁇ 2-adrenergic receptor agonist.
  • a second agent is preferably selected from the group consisting of theophylline, dyphylline, minoxidil, diazoxide, terbutaline, and salbutamol.
  • 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 ⁇ -adrenergic receptor agonists, on -adrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier.
  • 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.
  • Phosphodiesterase 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.
  • PDE isozymes with type 9 A having been recently discovered (see, Fisher, et al., JBiol. Chem. 273(25):15559-15564 (1998)).
  • Agents which are non-specific inhibitors of PDEs include, for example, LBMX, theophylline, aminophylline, theobromine, dyphylline caffeine, etc. (see, Vemulapalli, et al., JCardiovasc. Pharmacol 28(6):862-9 (1996)).
  • 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/IN 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 ⁇ -adrenergic receptor agonists, preferably a ⁇ 2 - or ⁇ 3 -adrenergic receptor agonists, ⁇ i- adrenergic antagonists, L-type Ca 2+ channel blockers, estrogens, ATP-sensitive K + 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.
  • a second agent is preferably a K + ATP channel opener, an adenosine receptor antagonist, or a ⁇ 2-adrenergic receptor agonist.
  • a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, minoxidil, diazoxide, terbutaline, and salbutamol.
  • the present invention provides pharmaceutical compositions for the treatment of anorectal disorders comprising a ⁇ -adrenergic receptor agonist, preferably a ⁇ 2 - or ⁇ 3 -adrenergic receptor agonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (e.g., a PDE JV inhibitor), nonspecific PDE inhibitors, ⁇ radrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, or smooth muscle relaxants, and a pharmaceutically acceptable carrier.
  • PDE inhibitors e.g., a PDE JV inhibitor
  • nonspecific PDE inhibitors e.g., ⁇ radrenergic antagonists
  • ⁇ radrenergic antagonists e.g., estrogens, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, or smooth muscle relaxants
  • the present invention further provides methods of using those compositions.
  • the ⁇ -adrenergic receptor agonist can be essentially any of the ⁇ -adrenergic receptor agonists provided above for use in combination with NO donors.
  • the ⁇ -adrenergic agonist is a ⁇ 2 - or ⁇ 3 -adrenergic receptor agonist.
  • Particularly preferred ⁇ -adrenergic agonists are those described in Bristol, et al., ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL. 33, Chap.
  • Terbutaline and salbutamol are ⁇ 2-adrenergic agonists commonly used for the long-term treatment of obstructive airway diseases and acute bronchospasm in asthma.
  • Beta-adrenergic agents like VLP, potently relax smooth muscle, including IAS smooth muscle by raising infracellular cyclic AMP levels (Parks et al., Gut 10(8): 674-7 (1969); Chakder, S. et al., AmerJ Physiol. 264 (1 pt 1):G7-12, (1993); Chakder, S. et al., AmerJ Physiol.
  • Cyclic AMP induces smooth muscle relaxation through phosphorylation of smooth muscle regulatory proteins (e.g., myosin light chain kinase) and by decreasing infracellular calcium concentrations (e.g., via K + -ATP channel activation).
  • smooth muscle regulatory proteins e.g., myosin light chain kinase
  • infracellular calcium concentrations e.g., via K + -ATP channel activation
  • Terbutaline and salbutamol have weaker cardiovascular effects than non-specific ⁇ -receptor agonists, e.g., isoproterenol, because they do not stimulate cardiac ⁇ i-adrenergic receptors at therapeutic doses. They are commonly administered by inhalation (i.e., topically). Tolerance is a potential downside effect of ⁇ 2 - adrenergic agonists. Long-term systemic administration of ⁇ -adrenergic agonists leads to down-regulation of ⁇ receptors in some tissues and decreased pharmacological responses, and has been demonstrated in patients with asthma 1 .
  • the compositions comprise forskolin. Forskoline directly activates adenyl cyclase avoiding tolerance .
  • the composition contains a suitable ⁇ - adrenergic receptor agonist and a pharmaceutically acceptable carrier, preferably one formulated for local delivery to the site of the anorectal disease or disorder.
  • the composition contains another agent selected from cAMP-hydrolyzing PDE inhibitors (e.g., a PDE IN inhibitor), nonspecific PDE inhibitors, cn-adrenergic antagonists, adenosine receptor antagonists
  • PDE inhibitors e.g., a PDE IN inhibitor
  • nonspecific PDE inhibitors e.g., a PDE IN inhibitor
  • cn-adrenergic antagonists e.g., adenosine receptor antagonists
  • the agent is a cAMP- hydrolyzing PDE inhibitor, more preferably a phosphodiesterase type IN inhibitor.
  • PDE inhibitor a phosphodiesterase type IN inhibitor.
  • Preferred phosphodiesterase type IV (also refe ⁇ ed to as PDE JN 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).
  • the PDE IN inhibitor is rolipram, Ro 20- 1724 or Etazolate.
  • the agent is a nonspecific PDE inhibitor such as, for example, LBMX, aminophylline, theophylline, pentoxifylline, theobromine, dyphylline, lisophylline and papaverine.
  • a nonspecific PDE inhibitor such as, for example, LBMX, aminophylline, theophylline, pentoxifylline, theobromine, dyphylline, lisophylline and papaverine.
  • the agent is an ⁇ i- adrenergic antagonist.
  • Suitable cci-adrenergic receptor antagonists e.g. prazosin, doxazosin, phentolamine, tolazoline, and the like
  • prazosin, doxazosin, phentolamine, tolazoline, and the like are described in Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. JG Hardman, et al. , McGraw- Hill (1996).
  • Preferred agents for use in these compositions are selected from prazosin, doxazosin, phentolamine, tolazoline and their derivatives.
  • the ⁇ -adrenergic receptor agonist is combined with an L-type Ca 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 RA et al., Ada Gastroent. Latinoamer. 27:247-251, 1997) and verapamil.
  • L-type Ca 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 RA et al., Ada Gastroent. Latinoamer. 27:247-251, 1997)
  • the ⁇ -adrenergic receptor agonist is combined with an ATP-sensitive K + channel activator.
  • Prefe ⁇ ed agents within this group are the same as those that have been provided above for use with NO donors.
  • compositions are those in which a ⁇ -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.
  • a second agent is preferably a K + ATP channel opener or an adenosine receptor antagonist.
  • a prefe ⁇ ed second agent is a compound selected from the group consisting of theophylline, dyphylline, minoxidil, and diazoxide. Potassium channel activator compositions
  • the present invention provides compositions for the treatment of anorectal disorders comprising an ATP-sensitive K + channel activator, either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, estrogens, ⁇ radrenergic antagonists, L-type Ca 2+ channel blockers, sympathetic nerve terminal destroyers, or smooth muscle relaxants, and a pharmaceutically acceptable carrier.
  • an ATP-sensitive K + channel activator either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, estrogens, ⁇ radrenergic antagonists, L-type Ca 2+ channel blockers, sympathetic nerve terminal destroyers, or smooth muscle relaxants.
  • 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 prefe ⁇ ed embodiments the potassium ion channel activator is diazoxide, minoxidil, PCO 400, pinocidil, levcromokalin, or cromokalim.
  • the composition comprises an additional agent which is a cAMP-dependent protein kinase activator, an estrogen or estrogen like compound, an cti-adrenergic antagonist, an L-type Ca channel blocker, a sympathetic nerve terminal destroyer, or a smooth muscle relaxant.
  • the cAMP-dependent protein kinase activator is a cAMP mimetic or a dual cGMP/cAMP-dependent protein kinase activator.
  • the cAMP mimetic is 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS, or Sp- cAMPS
  • the dual activator is selected from S ⁇ -8- ⁇ CPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT-cAMP.
  • an ⁇ ! -adrenergic antagonist is combined with an ATP-sensitive potassium ion channel activator.
  • the en -adrenergic antagonist is prazosin, phentolamine or tolazoline.
  • an L-type Ca 2+ channel blocker is combined with an ATP-sensitive potassium ion channel activator.
  • the L-type Ca 2+ channel blocker is nifedipine, nimodipine, felopidine, nicardipine, isradipine, amlodipine, diltiazem, menthol, pinavarium bromide (a gastrointestinal tract selective calcium channel blocker; Awad RA et al., Ada Gastroent. Latinoamer. 27:247-251, 1997) or verapamil.
  • 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 + 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.
  • 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.
  • a smooth muscle relaxant is combined with an ATP-sensitive potassium ion channel activator.
  • the smooth muscle relaxant is hydralazine, papaverine, tiropramide, cyclandelate, isoxsuprine or nylidrin.
  • a second agent is preferably a K + ATP channel opener, a ⁇ 2 -adrenergic receptor agonist, or an adenosine receptor antagonist.
  • a prefe ⁇ ed second agent is a compound selected from the group consisting of theophylline, dyphylline, terbutaline, and salbutamol.
  • the present invention provides compositions for the treatment of anorectal disorders comprising an ⁇ i-adrenergic antagonist, either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (preferably a PDE IN inhibitor), estrogens, sympathetic nerve terminal destroyers, or smooth muscle relaxants, and a pharmaceutically acceptable carrier.
  • PDE inhibitors preferably a PDE IN inhibitor
  • the present invention further provides methods of using those compositions.
  • oci-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. JG Hardman, et al., McGraw-Hill (1996).
  • Prefe ⁇ ed ⁇ radrenergic antagonists are prazosin, phentolamine and tolazoline.
  • an cn-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
  • a cAMP-hydrolyzing PDE inhibitor preferably a PDE IV inhibitor
  • an estrogen or estrogen like compound preferably 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.
  • a second agent is preferably a K + ATP channel opener, a ⁇ 2 -adrenergic receptor agonist or an adenosine receptor antagonist.
  • a preferred second agent is a compound selected from the group consisting of theophylline, dyphylline, minoxidil, diazoxide, terbutaline, and salbutamol.
  • Cyclic nucleotide-dependent protein kinase activator compositions [148]
  • 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.
  • cGMP-dependent protein kinase activators are used alone.
  • nonspecific cyclic nucleotide-dependent protein kinase activators are used alone.
  • nonspecific cyclic nucleotide-dependent protein kinase activators are used in combination with smooth muscle relaxants.
  • cAMP-dependent protein kinase activators are provided in combination with L-type Ca 2+ channel blockers.
  • a second agent is preferably a K + ATP channel opener, a ⁇ 2 -adrenergic receptor agonist or an adenosine receptor antagonist.
  • a prefe ⁇ ed second agent is a compound selected from the group consisting of theophylline, dyphylline, terbutaline, minoxidil, diazoxide and salbutamol.
  • prefe ⁇ ed members of the recited classes of compounds are those that have been described above for use alone or in other combinations. Estrogen and estrogen mimetic compositions
  • 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.
  • Esfrogen-like compounds include but are not limited to 17-beta-estrodiol, estrone, mestranol, estradiol valerate, estrodiol dypionate, ethinyl esfrodil, quinestrol, estrone sulfate, phytoestrogens such as flavones, isoflavones (e.g. genistein), resverafrol, coumestan derivatives, other synthetic estrogenic compounds including pesticides (e.g.
  • plasticizers e.g. bisphenol A
  • plasticizers e.g. polyphenol A
  • other industrial chemicals e.g. polychlorinated biphenyls
  • Prefe ⁇ ed 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.
  • a second agent is preferably a K + ATP channel opener, a ⁇ 2 -adrenergic receptor agonist or an adenosine receptor antagonist.
  • a prefe ⁇ ed second agent is a compound selected from the group consisting of theophylline, dyphylline, terbutaline, minoxidil, diazoxide and salbutamol.
  • 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 & Gihnan's THE
  • PHARMACOLOGICAL BASIS OF THERAPEUTICS ninth edition, ed. JG 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.
  • 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.
  • adenosine receptor antagonists include theophylline and dyphylline. See, Goodman & Gihnan's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. JG 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.
  • 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.
  • 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 infracellular 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 .
  • 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.
  • a second agent is preferably a K + ATP channel opener or a ⁇ 2 -adrenergic receptor agonist.
  • a prefe ⁇ ed second agent is a compound selected from the group consisting of terbutaline, minoxidil, diazoxide and salbutamol.
  • 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.
  • Prefe ⁇ ed 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.
  • compositions provided above will typically be presented in an appropriate pharmaceutical formulation comprising an effective amount of the noted agents (e.g., NO donors, ⁇ 2 - or ⁇ 3 -adrenergic receptor agonists, cAMP-hydrolyzing PDE inhibitors, nonspecific PDE inhibitors, a t -adrenergic antagonists, L-type Ca channel blockers, ATP-sensitive K + channel activators, adenosine receptor antagonists, and the like).
  • agents e.g., NO donors, ⁇ 2 - or ⁇ 3 -adrenergic receptor agonists, cAMP-hydrolyzing PDE inhibitors, nonspecific PDE inhibitors, a t -adrenergic antagonists, L-type Ca channel blockers, ATP-sensitive K + channel activators, adenosine receptor antagonists, and the like.
  • agents e.g., NO donors, ⁇ 2 - or ⁇ 3 -adrenergic receptor agonists, cAMP-
  • combinations of agents are employed in a single formulation, while in other embodiments, agents are formulated separately, but administered in combination, or sequentially.
  • compositions of single agents will be understood to also include compositions of two or more agents.
  • different formulations can be used for those embodiments in which agents are administered separately or sequentially, by different routes of administration.
  • Topical compositions useful for treating anorectal disorders (including those related to hypertonicity and/or spasm of the internal anal sphincter muscle, e.g. hemo ⁇ hoidal 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.
  • the agent is an ATP-sensitive potassium channel opener.
  • the agent is a phosphodiesterase inhibitor, a cyclic nucleotide mimic, ⁇ -adrenergic agonist, an estrogen or estrogen like compound, an on -adrenergic antagonist or a potassium channel opener.
  • 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.
  • the agents are in combination with a pharmaceutically acceptable carrier.
  • 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 diverticulurn, achalasia, esophageal spasm (nutcracker esophagus), irritable bowel disease, and Hirshprungs disease (bowel obstruction).
  • 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.
  • 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.
  • 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.
  • the ointments, pastes, creams and gels also may contain excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, fragacanth, 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 andpoiyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions include topical compositions comprising one or more of the following first pharmacologic agents: an NO donor, phosphodiesterase inhibitor, cyclic nucleotide mimetic, ⁇ -adrenergic agonist, L-type calcium channel blocker, ⁇ -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 anti- inflammatory 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.
  • PDGF platelet-derived growth factor
  • interleukin-11 interleukin-11
  • anti-microbial agent e.g., neosporin, polymyxin B sulfate, bacifracin zinc, etc.
  • mucoadhesive agent e.g., cellulose derivatives, etc.
  • cytoprotectant agent e.g., colloidal bismuth, misoprostol, etc., with the exception of sucralfate
  • an agent that promotes local tissue sclerosis e.g., alum, etc.
  • menthol e.g., 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).
  • 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, ⁇ -adrenergic receptor antagonist, or ⁇ -adrenergic receptor agonist, or potassium channel opener.
  • 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.
  • 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.
  • the invention provides compositions for treating anorectal disorders comprising a pharmaceutically acceptable carrier and an amount of from about 0.001% to about 15% sildenaf ⁇ l by weight.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • a selected potassium channel opener e.g. minoxidil
  • a liquid suppository in which mucoadhesive polymers such as polyvinylpy ⁇ olidone (PVP, BASF, Germany), polycarbophil (Goodrich, USA), or sodium alginate (Hayashi Pure Chemicals, Tokyo, Japan), etc. are incorporated.
  • mucoadhesive polymers such as polyvinylpy ⁇ olidone (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°C and has a mucoadhesive force of 430 to 5800 dyne/cm.
  • 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 JM et al., Journal of Controlled Release,
  • Prefe ⁇ ed formulations are either as solutions or semi-solid preparations (gel, ointment, suspension, lotion, cream, etc.).
  • Suitable excipients 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.
  • a cream or ointment preparation will typically be preferable.
  • oil phase, aqueous/organic phase and surfactant may be required to prepare the formulations.
  • the dosage forms can be designed and excipients can be chosen to formulate the prototype preparations.
  • Particularly prefe ⁇ ed preparations include those in a suppository or sustained release format.
  • 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 freat anorectal disorders.
  • 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 freat 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.
  • compositions are administered in unit dosage form to a subject in need of such treatment.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a suitable material such as a methacrylic-acrylic polymer, polyurethane, ethyl vinyl acetate copolymer, polyester, silastic, etc.
  • 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 ⁇ - adrenergic agonist, and a pharmaceutically acceptable carrier.
  • Such compositions are useful for treating anorectal disorders, including those disorders and conditions provided above.
  • 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. Patent 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.
  • aerosol For delivery to the nasal or bronchial membranes, typically an aerosol formulation is employed.
  • aerosol includes any gas-borne suspended phase of the pharmacological agent which is capable of being inhaled into the bronchioles or nasal passages.
  • 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.
  • the prefe ⁇ ed 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.
  • 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.
  • sodium chloride is added to adjust the osmolarity to the physiological range, preferably within 10% of isotonic.
  • 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 tlirough a small orifice, thereby pulling droplets of the solution into the mouth and frachea of the animal to which the drug is to be administered.
  • a mouthpiece is fitted to the outlet of the orifice to facilitate delivery into the mouth and trachea.
  • 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 ⁇ - adrenergic agonist, and a pharmaceutically acceptable carrier.
  • Such compositions are useful for treating anorectal disorders and conditions as described above.
  • 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 freatment an effective amount of any of the compositions provided above.
  • anorectal hypertonicity andor 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 freatment 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.
  • 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 freatment 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.
  • compositions 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).
  • 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.
  • 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 hemo ⁇ hoidal 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.
  • local anti-inflammatory agents for example, naproxen, piroxicam, etc.
  • a pharmaceutically acceptable dosage form as an effective treatment for a medical condition such as hemo ⁇ hoidal 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 ileocoli
  • compositions 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 fract including Zenkers diverticulum, achalasia, esophageal spasm (nutcracker esophagus), irritable bowel disease, and Hirschsprung's disease (bowel obstruction).
  • 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 freatment.
  • Such compositions can be administered orally, topically, or parenterally.
  • 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 ⁇ -adrenergic agonist, a cAMP-dependent protein kinase activator, an ⁇ adrenergic antagonist, a superoxide anion (O " ) scavenger, an ATP-sensitive K + 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.
  • PDE V phosphodiesterase type V
  • PDE II phosphodiesterase type II
  • O " ) scavenger an ATP-sensitive K + channel activator
  • an estrogen or estrogen mimetic a sympathetic nerve terminal destroyer
  • 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.
  • 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 occu ⁇ ence and duration of headaches.
  • 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.
  • the constriction relaxation measurement assembly included a Millar catheter/transducer (1.67mm diameter.) connected to a Digi-Med Low Pressure Analyzer (Micro-Med) accurate for pressure measurements between -50 and 150 mniHg.
  • 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.
  • Typical resting mean internal anal sphincter pressures varied between 30 and 60 rnmHg in this model.
  • the Millar catheter sensor allowed for accurate, isolated recordings of the LAS.
  • Figure 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 Figure 2.
  • Figure 2 shows that the effect of a cGMP mimetic, dibutyryl-cGMP was studied.
  • Figure 3 shows that 20 ⁇ l of a 10% solution of dibutyryl- cGMP 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%.
  • Example 2 [193] This example illustrates the effect of phosphodiesterase inhibitors in a rat internal anal sphincter relaxation model.
  • 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 lOO ⁇ l or 250 ⁇ l Hamilton syringes either manually or by infusion with a programmable Harvard automatic infusion pump.
  • NTG nitric oxide donor
  • Fig.7 demonstrates that a continuous infusion of NTG at 20 ⁇ g/hour produced a steady and sustained decline in resting IASP 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.
  • This example illustrates the varying ability of superoxide scavengers to potentiate the effect of nitric oxide/nitric oxide donors in vivo.
  • Zaprinast (10 mg in 100 ⁇ l 1M2P) was injected i.p. 30 minutes prior to bolus doses of NTG (20 ⁇ 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 Figure 13).
  • MBCQ (10 mg in lOO ⁇ l 1M2P) was injected i.p. 30 minutes prior to bolus doses of NTG (20 ⁇ g/min every 30 minutes). No noticeable potentiation of NTG was observed with this PDE V inhibitor in this experiment (see Figure 18). Bioavailabihty of MBCQ could be the cause of the minimal effect seen with this compound.
  • This example illustrates the effect of non-selective ⁇ -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.
  • PDE type TV inhibitors prevent degradation of cAMP by cAMP-specific PDE.
  • PDE IV inhibitor etazolate potentiation of the effects of the ⁇ 2 -adrenergic agonist, salbutamol, potentiation of agents which activate adenylyl cyclase, can be achieved with PDE type IN inhibitors.
  • IBMX Isobutyl methylxanthine
  • LBMX The non-selective PDE inhibitor, LBMX 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 & Gihnan's "The Pharmacological Basis of Therapeutics" 9 edition. Section IV-Autocoids; Drug Therapy of Inflammation).
  • Verapamil in saline was infused at 20 ⁇ g/hour.
  • the drug produced a dramatic and sustained drop in IASP for the duration of the experiment (see Figure 34).
  • 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.
  • 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)).
  • ACH acetylcholine
  • cholinergic innervation of the LAS is not thought to contribute significantly to LAS tone.
  • zardaverine (7.5 mg in lOO ⁇ l 1M2P) was injected i.p. followed in 30 minutes by a continuous infusion of 5% dextrose at 20 ⁇ 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 Figure 38).
  • Theophylline [259] Theophylline, an adenosine antagonist, was continuously infused at 200 ⁇ g/hour in 5% dextrose. A dramatic and sustained drop in IASP was observed throughout the 4 hour duration of the experiment (see Figure 40).
  • Figure 43 shows the LAS relaxing effects of a 20 ⁇ 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Treatment 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.
  • 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.
  • This example illustrates a method to reduce bleeding in patients with hemo ⁇ hoidal symptoms or diseases.
  • Patients with hemo ⁇ hoidal 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 hemo ⁇ hoidal symptoms will eventually lead to complete resolution of these anal rectal disorders.
  • 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.
  • 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 IN 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 ⁇ -agonists with gel base excipients such as oleic acid.
  • 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.
  • 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.
  • compositions 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.
  • 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
  • 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.
  • 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 cu ⁇ ent 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.
  • 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.
  • 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 sti ⁇ ed into the aqueous phase to form a uniform cream base.
  • 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.
  • 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.
  • the oral and topical treatment can be used in a defined regimen to achieve the best therapeutic effects.
  • a phosphodiesterase inhibitor for example aminophylline
  • a topical dosage form e.g. a cream.
  • 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.
  • a ⁇ -adrenergic agonist for example salbutamol
  • a suppository dosage form 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.
  • a topical dosage form e.g. a cream.
  • 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.
  • An ⁇ -adrenergic antagonist i.e. prazosin can be applied from a topical spray to patients diagnosed with hemo ⁇ hoidal disorders, alone or in combination with a local anesthetic, for example, lidocaine, or in combination with a mixed ⁇ 2 - and ⁇ 3 -adrenergic agonist, for example salbutamol, or in combination with a PDE IN 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.
  • a methylxanthine derivative for example diphylline or theophyllline
  • a topical dosage form e.g. a cream or a rectal suppository.
  • 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.

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MXPA03000931A MXPA03000931A (es) 2000-07-31 2001-07-30 Composiciones y metodos para el tratamientos de trastornos anorectales.
AU2001279104A AU2001279104A1 (en) 2000-07-31 2001-07-30 Compositions and methods for the treatment of anorectal disorders
KR1020037001579A KR100863758B1 (ko) 2000-07-31 2001-07-30 항문직장 장애의 치료 조성물 및 방법
EP01957348A EP1315499A4 (en) 2000-07-31 2001-07-30 COMPOSITIONS AND METHODS OF TREATING ANORCAL DISEASES
CA002417848A CA2417848A1 (en) 2000-07-31 2001-07-30 Compositions and methods for the treatment of anorectal disorders
IL15420201A IL154202A0 (en) 2000-07-31 2001-07-30 Pharmaceutical compositions for treating anorectal disorders
JP2002515267A JP2004516244A (ja) 2000-07-31 2001-07-30 肛門直腸障害の処置のための組成物および方法

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WO2002015893A2 (en) * 2000-08-21 2002-02-28 Pfizer Limited Treatment of wounds
US8598150B1 (en) 2008-04-02 2013-12-03 Jonathan R. Brestoff Composition and method for affecting obesity and related conditions
US8987245B2 (en) 2008-04-02 2015-03-24 Jonathan R. Brestoff Parker Composition and method for affecting obesity and related conditions

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KR101067443B1 (ko) 2009-06-23 2011-09-27 여오영 하이드록시클로로퀸을 함유하는 치핵 치료를 위한 국소투여용 주사제 조성물
CN102145004B (zh) * 2010-02-09 2012-03-21 鲁南制药集团股份有限公司 己酮可可碱在制备预防或治疗功能性便秘的药物中的用途

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CN1298309A (zh) * 1998-02-27 2001-06-06 同步神经元有限责任公司 治疗肛门区疼痛的方法及其组合物
AU764921B2 (en) * 1998-12-14 2003-09-04 Cellegy Pharmaceuticals, Inc. Compositions and methods for the treatment of anorectal disorders

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002015893A2 (en) * 2000-08-21 2002-02-28 Pfizer Limited Treatment of wounds
WO2002015893A3 (en) * 2000-08-21 2003-03-13 Pfizer Ltd Treatment of wounds
US8598150B1 (en) 2008-04-02 2013-12-03 Jonathan R. Brestoff Composition and method for affecting obesity and related conditions
US8809312B2 (en) 2008-04-02 2014-08-19 Jonathan R. Brestoff Composition and method for affecting obesity and related conditions
US8987245B2 (en) 2008-04-02 2015-03-24 Jonathan R. Brestoff Parker Composition and method for affecting obesity and related conditions

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AU2001279104A1 (en) 2002-02-13
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