WO2003075851A2 - Compositions et methodes de traitement de troubles ano-rectaux - Google Patents

Compositions et methodes de traitement de troubles ano-rectaux Download PDF

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WO2003075851A2
WO2003075851A2 PCT/US2003/007106 US0307106W WO03075851A2 WO 2003075851 A2 WO2003075851 A2 WO 2003075851A2 US 0307106 W US0307106 W US 0307106W WO 03075851 A2 WO03075851 A2 WO 03075851A2
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compound
adrenergic
inhibitors
compounds
group
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PCT/US2003/007106
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WO2003075851A3 (fr
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Thomas P. Parks
Vivien H. W. Mak
Jung-Chung Lee
Charles Lee
Stephen Grayson
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Cellegy Pharmaceuticals, Inc.
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Priority to AU2003213787A priority Critical patent/AU2003213787A1/en
Publication of WO2003075851A2 publication Critical patent/WO2003075851A2/fr
Publication of WO2003075851A3 publication Critical patent/WO2003075851A3/fr

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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

Definitions

  • This invention is directed to compositions and methods for treating anorectal disorders such as anal fissures, anal ulcer, hemorrhoidal diseases, constipation, and levator spasm by administering to an appropriate anal area (for example, the anal mucosa and the perianal region) 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, constipation, and levator spasm
  • compositions and methods for treating anorectal disorders with agents which relax the internal anal sphincter or induce increase in cyclic nucle ⁇ ides in the anal sphincter muscle or which mimic the actions of cyclic nucleotides or increase mucosal blood flow or reduce intracellular calcium concentrations in the affected anal sphincter muscle tissue, thereby reducing anal sphincter hypertonicity and/or spasm and facilitate healing in patients afflicted with such disorders.
  • anal fissure fissure-in-ano
  • anal ulcer a malignant neoplasm originating from a central nervous system
  • 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.
  • 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. The causes of hemorrhoids are not known. The most consistently demonstrated physiological abnormality is increased resting anal pressure (Hancock B.O., BrJSurg 64(2):92-5 (1975); Loder, P.B., RrJSwrg 81(7):946-54 (1994)). Patients with non-prolapsing hemorrhoids appear to have higher anal pressures than those with prolapsing hemorrhoids (Arabi, Y.
  • Acutely thrombosed external hemorrhoids are usually characterized by severe anal pain, and internal anal sphincter hypertonia may play a role in the etiology of this pain (Gorfine, S.R., Dis Colon Rectum 38(5): 453-7 (1995)). Surgical excision of symptomatic thrombosed external hemorrhoids is indicated within 48 to 72 hours of the onset of pain. Post-hemorrhoidectomy pain is severe, disproportionate to the surgery itself, and requires the use of narcotic analgesics, which unfortunately complicate recovery by causing constipation.
  • Anal 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. An anal fissure or ulcer can be associated with another systemic or local disease, but more frequently presents 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.
  • the exact causes of anal fissures remain unknown. They are often associated with trauma, e.g., passage of a hard stool, but can also occur during bouts of diarrhea, childbirth, or ulceration of a hemorrhoid (Lund, J.N. et al., Br JSurg. 83(10): 1335-44 (1996)).
  • An individual with an anal fissure or ulcer frequently experiences anal pain and bleeding, the pain being more pronounced during and after bowel movements, and may last for as long as 3 hours following bowel movements.
  • the most common symptom is pain at defecation, which can be quite severe and last for a variable time afterwards.
  • the pain is chiefly due to an intense spasm of the internal anal sphincter muscle.
  • Most anal fissures are adequately treated with sitz baths, stool softeners, and analgesics. Approximately 60% of acute anal fissures will heal within three weeks using this treatment regimen. Acute anal fissures, which do not heal, become chronic anal fissures or anal ulcers. Hypertonicity of the internal anal sphincter muscle and mucosal ischemia are thought to play an important role in the pathogenesis of chronic anal fissures ( Schouten W.R.
  • Anodermal blood flow at the posterior midline is less than other regions of the anal canal, and perfusion of the posterior mucosa is inversely related to anal pressure.
  • Chronic anal fissures are typically not responsive to conservative medical therapy.
  • Current treatments are therefore directed at relieving sphincter spasm, and include anal dilatation (under anesthesia), or more commonly, lateral sphincterotomy of the internal anal sphincter.
  • Healing occurs following surgical sphincterotomy in 95% of cases.
  • 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 IAS is largely responsible for resting anal sphincter pressure and continence which is maintained by intrinsic myo genie tone and regulated by both intrinsic innervation and extrinsic innervation from the extrinsic autonomic nervous system (Penninckx, F. et al., Baillieres Clin Gastroenterol 6(1)193-214 (1992); Speakman, CT. 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, E>ts Colon Rectum 39(2): 212-6 (1996); Antropoli, C. et al, Dis Colon Rectum 42(8): 1011-5 (1999); Carapeti, ⁇ .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 o ⁇ -adrenergic receptors (Frenckner, B., et al., Gut
  • the a - 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, CT. 1997 supra; Carapeti, ⁇ .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. ⁇ ., 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, CT., Eur J Gastroenterology 9(5):442-6 (1997)). Regadas and colleagues (Regadas, F.S.
  • the IAS relaxes in response to rectal distention (the rectoanal inhibitory reflex).
  • the nerves mediating the rectoanal inhibitory reflex lie entirely within the wall of the gut (enteric inhibitory neurons), and descend from the rectum to the IAS.
  • Electrical field stimulation (EFS) mimics the effects of intrinsic nerve stimulation on isolated smooth muscle strips. IAS strips are relaxed by EFS, an effect that is abolished by the neurotoxin tetrodotoxin, but is unaffected by antagonists of the classical neurotransmitters, acetylcholine or norepinephrine.
  • the inhibitory nerves are thus classified as non-adrenergic, non-cholinergic (NANC) nerves.
  • ATP ATP
  • vasoactive intestinal peptide VIP
  • ATP and VIP were first suggested as NANC neurotransmitter candidates since they mimicked the relaxation elicited by electrical stimulation of motor nerve fibers (Burnstock, G. et al., BrJ Pharmacol. 46(2):234-42 (1972); Bitar, K.N. et al., Science 216(4545): 531-3 (1982)).
  • ATP and VIP either separately or together, could not account for all inhibitory neurotransmission in gastrointestinal smooth muscle, and their roles have not been established in man (Burleigh, D.E.
  • NANC nerve-mediated relaxation of IAS strips in vitro was blocked by inhibition of NO synthase with L-NNA, and the block was reversed by L-arginine, but not D- arginine (Rattan, S. et al., Am J Physiol 262 (1 Pt 1):G107-12, (1992) and Rattan, S. et al., Gastroenterology 103(l):43-50 ( 1992)). Similar observations have been made using isolated muscle strips of human IAS (Burleigh Gastroenterology 102(2): 679-83 (1992); O'Kelly, TJ. et al., BrJ Surg 80(10): 1337-41, (1993)).
  • NOS containing nerves were absent from the non-relaxing segment, but present in the normal segment of the gut (O'Kelly, T.J. et al., JPediatric Surgery 29(2): 294-9 (1994)). These observations fulfill most of the criteria for NO as an inhibitory mediator or neurotransmitter.
  • NO donors e.g., nitroglycerin
  • coronary vasodilators 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, SJ. et al., BrJ Surgery 83(6):771-5, 1996; Lund, J.N. et al., Lancet 349: 9044 (1997)
  • isosorbide dinitrate have been used to effect a reversible chemical sphincterotomy in patients with chronic anal fissure.
  • Nitroglycerin has also been shown to reduce the throbbing pain of acute hemorrhoidal thrombosis and proctalgia fugax (Gorfine, S.R., Dis Colon Rectum 38(5):453-6 (1995); Lowenstein, B. et al., Dis Colon Rectum 41(5):667-8 (1998)).
  • the present invention is based on the discovery that compounds such as NO donors, calcium channel blockers, cholinergic modulators (including acetylcholine storage blocking agents and acetylcholine vesicle storage blocking agents), ⁇ -adrenergic receptor antagonists (including oci-adrenergic antagonists and ⁇ 2 -adrenergic antagonists), ⁇ - adrenergic receptor agonists (including ⁇ 2 -adrenergic antagonists and ⁇ 3 -adrenergic antagonists), phosphodiesterase inhibitors, cAMP-dependent protein kinase activators (e.g., cAMP mimetics), superoxide scavengers, potassium channel activators (including ATP- sensitive potassium channel activators and activators of the Maxi-K channels), estrogen-like compounds, testosterone-like compounds, benzodiazepines, adrenergic nerve inhibitors, antidiarrheal agents, HMG-
  • cholinergic modulators including ace
  • the present invention provides a method for treating anorectal disorders, the method comprising administering to a patient in need thereof a compound selected from the group consisting of cAMP-dependent protein kinase activators, superoxide scavengers, benzodiazepines, adenosine receptor modulators, antidiarrheal agents, HMG-CoA reductase inhibitors, endothelin receptor antagonists, adenylyl cyclase activators and potassium channel activators (including ATP-sensitive potassium channel activators as well as activators of the Maxi-K channel) in a therapeutically effective amount.
  • the anorectal disorder is selected from the group consisting of anal fissure, hemorrhoids, levator spasm, anal ulcer, and anorectal pain, burning, or itching, inflammation or inflammatory lesion in the rectal, anal or perianal region, post-surgical rectal, anal or perianal pain, and chronic idiopathic anal pain.
  • the compound may be administered via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route for systemic and/or local delivery.
  • parenteral intravenous, intramuscular or subcutaneous
  • transdermal pulmonary or transmucosal
  • pulmonary or transmucosal nasal, buccal, cervical, vaginal, anorectal
  • the compound may be formulated as a gel, ointment, cream, lotion, powder, solution, suspension, spray, paste, oil, or foam.
  • plastic dilators of the type used to progressively stretch the contracted muscles of the rectum can be impregnated with the compound to deliver the compound topically to the anorectal area while stretching the sphincter muscles.
  • the compound is delivered continuously.
  • a dermal patches containing the compound may be used or an anorectal suppository containing
  • the present invention provides a method of treating anorectal disorders, the method comprising administering to a patient in need thereof a compound selected from the group consisting of calcium channel blockers, cholinergic modulators, ⁇ -adrenergic agonists, and adrenergic nerve inhibitors.
  • a compound selected from the group consisting of calcium channel blockers, cholinergic modulators, ⁇ -adrenergic agonists, and adrenergic nerve inhibitors are administered to the patient.
  • a first compound selected from the group consisting of calcium channel blockers, cholinergic modulators, ⁇ -adrenergic agonists, and adrenergic nerve inhibitors and a second compound selected from the group consisting of cAMP-dependent protein kinase activators, superoxide scavengers, benzodiazepines, adenosine receptor modulators, antidiarrheal agents, HMG-CoA reductase inhibitors, endothelin receptor antagonists, adenylyl cyclase activators, potassium channel activators (e.g., ATP-sensitive potassium channel activators), calcium channel blockers, cholinergic modulators (e.g., acetylcholine storage blocking agents), ⁇ -adrenergic receptor antagonists, ⁇ -adrenergic agonists, adrenergic nerve inhibitors, NO donors, phosphodiesterase inhibitors, estrogen-like compounds, testosterone-like compounds, and smooth muscle relaxants
  • the compound may be administered via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route for systemic and/or local delivery.
  • parenteral intravenous, intramuscular or subcutaneous
  • transdermal pulmonary or transmucosal
  • pulmonary or transmucosal nasal, buccal, cervical, vaginal, anorectal
  • the compounds may be formulated as a gel, ointment, cream, lotion, powder, solution, suspension, spray, paste, oil, or foam.
  • Plastic dilators of the type used to progressively stretch the contracted muscles of the rectum impregnated with the compound can be used to deliver the compound topically to the anorectal region while simultaneously stretching the rectal muscles.
  • the compound may also be delivered continuously via a rectal suppository.
  • the present invention provides a method of treating an anorectal disorder, the method comprising administering to a patient in need thereof a compound selected from the group consisting of cholinergic modulators and adrenergic nerve inhibitors.
  • a compound selected from the group consisting of cholinergic modulators and adrenergic nerve inhibitors are administered to the patient.
  • a first compound selected from the group consisting of cholinergic modulators and adrenergic nerve inhibitors; and a second compound selected from the group consisting of cAMP-dependent protein kinase activators, superoxide scavengers, benzodiazepines, adenosine receptor modulators, antidiarrheal agents, HMG-CoA reductase inhibitors, endothelin receptor antagonists, adenylyl cyclase activators, potassium channel activators, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic receptor antagonists, ⁇ -adrenergic agonists, adrenergic nerve inhibitors, NO donors, phosphodiesterase inhibitors, estrogen-like compounds, testosterone-like compounds, and smooth muscle relaxants are administered to the patient.
  • the compounds may be administered via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route for systemic and/or local delivery.
  • the compounds are administered topically to the skin and/or mucous membranes and are in a form selected from the group consisting of gel, ointment, cream, lotion, powder, solution, suspension, spray, paste, oil, and foam.
  • the compound is delivered continuously by inserting a rectal suppository impregnated with the compound.
  • the present invention is directed to a method of treating an anorectal disorder, the method comprising administering to a patient in need thereof a compounds selected from the group consisting of NO donors, ⁇ -adrenergic agonists and phosphodiesterase inhibitors.
  • the method comprises administering to the patient at least two compounds selected from the group consisting of NO donors, ⁇ - adrenergic agonists, and phosphodiesterase inhibitors.
  • a first compound selected from the group consisting of NO donors, ⁇ -adrenergic agonists, and phosphodiesterase inhibitors; and a second compound selected from the group consisting of cAMP-dependent protein kinase activators, superoxide scavengers, benzodiazepines, adenosine receptor modulators, antidiarrheal agents, HMG-CoA reductase inhibitors, endothelin receptor antagonists, adenylyl cyclase activators, potassium channel activators (e.g., ATP-sensitive potassium channel activators), calcium channel blockers, cholinergic modulators, ⁇ -adrenergic receptor antagonists, ⁇ -adrenergic agonists, adrenergic nerve inhibitors, NO donors, phosphodiesterase inhibitors, estrogen-like compounds, testosterone- like compounds, and smooth muscle relaxants are administered to the patient.
  • the compounds are administered via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route for systemic and/or local delivery.
  • parenteral intravenous, intramuscular or subcutaneous
  • transdermal pulmonary or transmucosal
  • pulmonary or transmucosal nasal, buccal, cervical, vaginal, anorectal
  • the compounds are preferably in a form selected from the group consisting of gel, ointment, cream, lotion, powder, solution, suspension, spray, paste, oil, and foam.
  • the compound is delivered continuously.
  • a rectal suppository containing the compositions may be inserted.
  • a method of treating an anorectal disorder comprising administering to a patient in need thereof a compound selected from the group consisting of NO donors, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic antagonists, ⁇ -adrenergic agonists, phosphodiesterase inhibitors, adrenergic nerve inhibitors, and estrogen-like compounds.
  • the compounds may be administered alone or in combination.
  • At least two compounds selected from the group consisting of NO donors, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic antagonists, ⁇ -adrenergic agonists, phosphodiesterase inhibitors, adrenergic nerve inhibitors, and estrogen-like compounds are administered to the patient.
  • Administration may be via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route for systemic and/or local delivery.
  • parenteral intravenous, intramuscular or subcutaneous
  • transdermal pulmonary or transmucosal
  • pulmonary or transmucosal nasal, buccal, cervical, vaginal, anorectal
  • Administration can also be by continuous delivery.
  • a rectal suppository containing said compound is inserted.
  • a method for treating non-specific pain, itching or burning of the anorectal area comprising administering to a patient in need thereof a compound selected from the group consisting of NO donors, calcium channel blockers, cholinergic modulators (e.g., acetylcholine storage blocking agents and acetylcholine vesicle transport blocking agents), ⁇ -adrenergic receptor antagonists (e.g., adrenergic receptor antagonists and ⁇ 2 -adrenergic receptor antagonists), ⁇ -adrenergic agonists, phosphodiesterase inhibitors, adrenergic nerve inhibitors, estrogen-like compounds, testosterone-like compounds and smooth muscle relaxants.
  • cholinergic modulators e.g., acetylcholine storage blocking agents and acetylcholine vesicle transport blocking agents
  • ⁇ -adrenergic receptor antagonists e.g., adrenergic receptor antagonists and ⁇ 2 -adrenergic
  • the compounds may be administered alone or in combination, hi one embodiment, at least two compounds selected from the group consisting of NO donors, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic receptor antagonists (e.g., a, ⁇ -adrenergic receptor antagonists and ⁇ 2 -adrenergic receptor antagonists), ⁇ -adrenergic agonists, phosphodiesterase inhibitors, adrenergic nerve inhibitors, estrogen-like compounds, testosterone-like compounds and smooth muscle relaxants are administered to the patient.
  • ⁇ -adrenergic receptor antagonists e.g., a, ⁇ -adrenergic receptor antagonists and ⁇ 2 -adrenergic receptor antagonists
  • ⁇ -adrenergic agonists e.g., a, ⁇ -adrenergic receptor antagonists and ⁇ 2 -adrenergic receptor antagonists
  • ⁇ -adrenergic agonists e.g., a, ⁇
  • Administration may be via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route for systemic and/or local delivery.
  • parenteral intravenous, intramuscular or subcutaneous
  • transdermal pulmonary or transmucosal
  • pulmonary or transmucosal nasal, buccal, cervical, vaginal, anorectal
  • Administration can also be by continuous delivery.
  • a rectal suppository providing said compound is inserted.
  • a method for treating anorectal disorders comprising administering to a patient in need thereof a compound selected from the group consisting of cAMP-dependent protein kinase activators, superoxide scavengers, benzodiazepines, adenosine receptor modulators, antidiarrheal agents, HMG- CoA reductase inhibitors, endothelin receptor antagonists, adenylyl cyclase activators, potassium channel activators, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic agonists, adrenergic nerve inhibitors, NO donors, phosphodiesterase inhibitors, ⁇ -adrenergic receptor antagonists (e.g., ⁇ radrenergic receptor antagonists and ⁇ 2 -adrenergic receptor antagonists) and smooth muscle relaxants.
  • the compounds may be administered alone or in combination.
  • Administration may be via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route for systemic and/or local delivery.
  • parenteral intravenous, intramuscular or subcutaneous
  • transdermal pulmonary or transmucosal
  • pulmonary or transmucosal nasal, buccal, cervical, vaginal, anorectal
  • Administration can also be by continuous delivery.
  • a rectal suppository with said compound is inserted.
  • kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and/or compositions of the present invention are provided herein.
  • Such kits can also include, for example, other compounds and/or compositions (e.g., permeation enhancers, lubricants, etc.), a device(s) for administering the compound and/or compositions, and written instructions in a form prescribed by a government agency regulating the manufacture, use or sale of pharmaceuticals, medical devices or biological products, which instructions can also reflect approval by the agency of manufacture, use or sale for human administration.
  • the anorectal disorder is a colostomy and the invention provides a method of treating a colostomy patient, the method comprising administering to said patient a therapeutically effective amount of a composition comprising at least one agent selected from the group consisting of NO donors, phosphodiesterase type II inhibitors, phosphodiesterase type IV inhibitors, phosphodiesterase type V inhibitors, nonspecific phosphodiesterase inhibitors, superoxide scavengers, ⁇ -adrenergic agonists, calcium channel blockers, L-type Ca 2+ channel blockers, cAMP -dependent protein kinase activators, ⁇ -adrenergic antagonists (e.g., ⁇ ⁇ -adrenergic antagonists and ⁇ 2 adrenergic antagonists), estrogen-like compounds, endothelin receptor antagonists, adenylyl cyclase activators, potassium channel activators (e.g., ATP-sensitive potassium channel activators,
  • 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 c AMP or cGMP).
  • the second agent can be a phosphodiesterase type V (PDE V) inhibitor, a phosphodiesterase type II (PDE II) inhibitor, a phosphodiesterase type JV (PDE JV) 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.
  • PDE V phosphodiesterase type V
  • PDE II phosphodiesterase type II
  • PDE JV phosphodiesterase type JV
  • the agent can also be a superoxide anion (O 2 " ) scavenger, an ATP-sensitive K + channel activator, a adrenergic nerve inhibitor, or a smooth muscle relaxant, although these agents do not directly modulate either cAMP or cGMP levels.
  • the present invention further provides methods of using these compositions.
  • 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 V inhibitor, either alone or in combination with another agent selected from ⁇ -adrenergic receptor agonists, ⁇ -adrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, K + channel activators (e.g., ATP-sensitive K + channel activators or activators of the Maxi-K channel) 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 V inhibitor
  • the present invention provides 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 TV inhibitor), nonspecific PDE inhibitors, ⁇ i-adrenergic antagonists, estrogens or estrogen-like compounds, L-type Ca 2+ channel blockers, or K + channel activators (e.g., ATP-sensitive K + channel activators or activators of the Maxi-K channel), and methods of using those compositions.
  • PDE inhibitors e.g., a PDE TV inhibitor
  • nonspecific PDE inhibitors e.g., ⁇ i-adrenergic antagonists
  • ⁇ i-adrenergic antagonists e.g., estrogens or estrogen-like compounds
  • L-type Ca 2+ channel blockers e.g., ATP
  • the present invention provides compositions for the treatment of anorectal disorders comprising an K + channel activator (e.g., ATP-sensitive K channel activators or activators of the Maxi-K channel), either alone or in combination with another agent selected from cAMP-dependent protein kinase activators, a t -adrenergic antagonists, estrogens, L-type Ca 2+ channel blockers, or smooth muscle relaxants, and methods of using those compositions.
  • K + channel activator e.g., ATP-sensitive K channel activators or activators of the Maxi-K channel
  • 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 IV inhibitor) or smooth muscle relaxants, and methods of using those compositions.
  • an ⁇ i -adrenergic antagonist either alone or in combination with another agent selected from cAMP-hydrolyzing PDE inhibitors (preferably a PDE IV inhibitor) or smooth muscle relaxants, and methods of using those compositions.
  • the present invention provides compositions for the treatment of anorectal disorders comprising /3 2 -adrenergic agonists, either alone or in combination with another agent. Methods for the use of these compositions are also provided.
  • the j8 2 -adrenergic agonists are used alone.
  • the /3 2 -adrenergic agonists is combined with a phosphodiesterase inhibitor.
  • the /3 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 modulators, either alone or in combination with another agent. Methods for the use of these compositions are also provided. In one group of embodiments, adenosine receptor modulators are used alone. In another group of embodiments, the adenosine receptor modulators are combined with at least one other IAS relaxing agent. [38] In another aspect, the present invention provides compositions for the treatment of anorectal disorders comprising cyclic nucleotide-dependent protein kinase activators (e.g., cAMP- and cGMP-dependent protein kinase activators), either alone or in combination with another agent.
  • cyclic nucleotide-dependent protein kinase activators e.g., cAMP- and cGMP-dependent protein kinase activators
  • compositions 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 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. In one group of embodiments, estrogenic compounds are used alone.
  • the estrogenic compounds are used in combination with a second agent selected from phosphodiesterase inhibitors, ⁇ -adrenergic receptor agonists, a ⁇ - adrenergic antagonists, L-type Ca 2+ channel blockers, K + channel activators (e.g., ATP- sensitive K + channel activators or activators of the Maxi-K channel), or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier.
  • a second agent selected from phosphodiesterase inhibitors, ⁇ -adrenergic receptor agonists, a ⁇ - adrenergic antagonists, L-type Ca 2+ channel blockers, K + channel activators (e.g., ATP- sensitive K + channel activators or activators of the Maxi-K channel), or smooth muscle relaxants, in combination with a pharmaceutically acceptable carrier.
  • K + channel activators e.g., ATP- sensitive K + channel activators or activators of the Maxi-K channel
  • smooth muscle relaxants e.g., smooth muscle relaxants
  • 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.
  • NO has also been shown to mediate adaptive relaxation of other sphincters in the gastrointestinal tract including the lower esophageal sphincter (Conklin et al, Gastroenterology 104:1439-1444 (1993); Tottrup et al, BrJ Pharmacol 104:113-116 (1991)), pyloric sphincter (Bayguinov et ⁇ L, Am J Physiol 264:G975-983 (1993), sphincter of Oddi (Mourelle et al, Gastroenterology 105:1299-1305 (1993)), and the ileocolic sphincter (Ward et al, Rr J Pharmacol 105:776-782 (1992)).
  • the lower esophageal sphincter Conklin et al, Gastroenterology 104:1439-1444 (1993); Tottrup et al, BrJ Pharmacol 104:113-116 (1991)
  • the present invention provides compositions that are useful to overcome side effects and problems associated with the current therapies .
  • 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 IASP in a rat under conditions of a control experiment.
  • Figure 2 illustrates the waveform pattern for IASP 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.
  • FIG. 4 illustrates the effect of a type V phosphodiesterase inhibitor on internal anal sphincter pressure in a rat.
  • the figure shows a waveform pattern for IASP for a rat following administration of 20 ⁇ 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
  • 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 IAS, 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 LAS.
  • Figure 14 illustrates the effect on the IASP of a bolus dose of NTG applied topically to the IAS, wherein the first NTG dose is provided at 2.75 hours after a vehicle injection.
  • 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 LAS 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 TV 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- 1724 in DMSO/acetone/olive oil infused continuously at 20 ⁇ g/hour.
  • Figure 26 illustrates a vehicle control for the treatments provided in
  • 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 ⁇ i-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 adrenergic nerve inhibitor 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 ILLTV 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/JV 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 TTLITV 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.
  • Figure 44 illustrates the effect on the IASP of vesamicol when continuously infused at 100 ug/hour as compared to saline.
  • Figure 45 illustrates the effect on the IASP of yohimbine gel (0.05% and 0.01%) on the IASP when continuously infused at the rate of 100 ul/hr.
  • Figure 46 illustrates compounds that are useful in the methods and compositions of the present invention.
  • 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- ribofuranosylbenzimid
  • 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. This would also represent an improvement or a successful treatment. Preventing the deterioration of a recipient's status is also included by the term.
  • Therapeutic benefit includes any of a number of subjective or objective factors indicating a response of the condition being treated as discussed herein.
  • 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 that 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 or “anorectal region” 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.
  • peripheral area or “perianal region” is defined herein to include the area around, about or near, but not including, the anorectal area.
  • Hypertonicity refers to being in state of greater than normal muscular tension or of incomplete relaxation.
  • 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.
  • ubjecf'as used herein includes any animal, such as a mammal, including a human.
  • anorectal disorder includes any disorder associated with an anorectal 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 associated with hypertonicity or spasm of the anal sphincter muscle.
  • the term also includes inflammation and inflammatory lesions of the rectal, anal and perianal region such as those associated with Inflammatory Bowel Disease, including Crohn's Disease.
  • the term also refers to post-surgical pain associated with hemorrhoidectomy or other anorectal surgery that is associated with pain and/or intense anal spasms.
  • the term "anal fissure” is also referred to as “anal rhagades” and spasms of the anal sphincter are also referred to as “rectal tenesmus.” Additionally, the term is meant to include pain which can be associated with any of the above disorders or conditions.
  • signals 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 hyperpolarization of the cell membrane potential (i.e., a more negative membrane potential) caused by an increase in the flow of potassium ions from inside a cell to outside the cell via a potassium channel in the cell membrane.
  • pharmaceutical composition means a composition suitable for pharmaceutical use in a subject, including an animal or human.
  • a pharmaceutical composition generally comprises an effective amount of an active agent and a pha ⁇ naceutically 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 that delivers nitric oxide (e.g., a prodrug form of a NO donor, or a binary NO generating system).
  • the present invention provides novel, non-invasive methods for treating anorectal disorders using nitric oxide donors and other agents that either interfere with the downstream biochemical events leading to smooth muscle relaxation, or block signals for smooth muscle contraction.
  • Such compounds are effective for treating a variety of anorectal disorders including, but not limited to, 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 associated with hypertonicity or spasm of the anal sphincter muscle.
  • the term also refers to post-surgical pain associated with hemorrhoidectomy or other anorectal surgery that leads to intense anal spasms.
  • the term "anal fissure” is also referred to as “anal rhagades” and spasms of the anal sphincter are also referred to as "rectal tenesmus.”
  • the term is meant to include pain which can be associated with any of the above disorders or conditions.
  • the term can include anorectal itching, burning and pain.
  • Suitable compounds for use with the methods of the present invention include, in particular, NO donors, calcium channel blockers, cholinergic modulators (including acetylcholine storage blocking agents and acetylcholine vesicle storage blocking agents), ⁇ -adrenergic receptor antagonists (e.g., ⁇ i -adrenergic antagonists, ⁇ 2 -adrenergic antagonists, etc.), ⁇ -adrenergic receptor agonists (including ⁇ 2 - adrenergic antagonists and ⁇ 3 -adrenergic antagonists), phosphodiesterase inhibitors, cAMP- dependent protein kinase activators (e.g., cAMP mimetics), superoxide scavengers, potassium channel activators (including ATP-sensitive potassium channel activators and activators of the Maxi-K channels), estrogen-like compounds, testosterone-like compounds, benzodiazepines, adrenergic nerve inhibitors, antidiarrhe
  • the compounds of the present invention may be administered therapeutically to a patient affected with one or more of the above-listed disorders, as well as prior to proctologic examination. Administration can be via the oral, parenteral (intravenous, intramuscular or subcutaneous), transdermal, pulmonary or transmucosal (nasal, buccal, cervical, vaginal, anorectal) route, for systemic and/or local delivery, with local delivery being preferred.
  • plastic dilators impregnated with or otherwise providing the compound may be used to deliver the compound topically to the anorectal region while simultaneously stretching the sphincter muscles.
  • a rectal suppository or dermal patch containing one or more of the compounds described herein can be inserted to provide continuous delivery.
  • the present invention provides methods for treating the anorectal disorders described supra.
  • Suitable compounds for use with the methods of the present invention are well known in the art and are described, e.g., in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc. (1996); The Merck Index (12th Ed.), Merck & Co., Inc. (1996); The Physician 's Desk Reference (49th Ed.), Medical Economics (1995); and Drug Facts and Comparisons (1993 Ed.), Facts and Comparisons (1993).
  • the compounds of the present invention are NO donors.
  • 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. Additional suitable NO donors include 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, such as acidified nitrates), or compounds that serve as physiological precursor of nitric oxide, such as L-arginine and salts of L-arginine.
  • the NO donor may include 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), isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN) which may include isosorbide-2- mononitrate (IS2N) and/or isosorbide-5-mononitrate (IS5N), erythrityl tetranitrate (ETN), pentaerythrityl tetranitrate (PETN), ethylene glycol dinitrate, isopropyl nitrate, glyceryl-1- mononitrate, glyceryl-l,2-dinitrate, glyceryl-1,3 -dinitrate, butane-l,2,4-triol trinitrate, and the like.
  • Nitroglycerin and other organic nitrates including ISDN, ETN, and PETN have been given regulatory approval for use in treatments in other fields of medicine on human subjects.
  • Additional NO donors include sodium nitroprusside, N,O-diacetyl-N-hydroxy-4- chlorobenzenesulfonamide, N G -hydroxy-L-arginine (NOHA), hydroxy guanidine sulfate, molsidomine, 3-mo holinosydnonimine (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]
  • Ca 2+ channel blockers are compounds that inhibit the entry of Ca 2+ into the cell from the extracellular fluid.
  • Suitable Ca 2+ channel blockers for use with the methods of the present invention include, but are not limited to, nifedipine, nimodipine, felopidine, nicardipine, isradipine, amlodipine, diltiazem, bepridil, verapamil, etc. (see, e.g., WO 98/36733).
  • L-type Ca 2+ channel blockers are also available
  • cholinergic modulators include cholinergic modulators (see, e.g., WO 98/36733).
  • Cholinergic modulators suitable for use with the methods of the present invention include, but are not limited to, ambenonium, bethanechol, cisapride, edrophonium, neostigmine, physostigmine, pilocarpine, pyridostigmine, succinylcholine, tacrine, etc.
  • Compounds e.g., Botulinium Toxin
  • neurotransmitters e.g., acetylcholine
  • Acetylcholine storage blocking agents and acetylcholine vesicle transport blocking agents, such as vesamicol, are also preferred. Vesamicol prevents the storage of acetylcholine in the presynaptic storage vesicles as well as the release and transport of acetylcholine from these vesicles.
  • Additional preferred compounds for use in the context of the present invention include, e.g., ⁇ -adrenergic receptor antagonists and ⁇ -adrenergic receptor agonists.
  • Suitable ⁇ -adrenergic receptor antagonists include, for example, ⁇ j -adrenergic receptor antagonists, ⁇ 2 -adrenergic receptor antagonists and other nonspecific ⁇ -adrenergic receptor antagonists.
  • Preferred ⁇ i -adrenergic receptor antagonists include, but are not limited to, prazosin, doxazosin, phenoxybenzamine, phentolamine, terazosin, tolazoline, etc., and are described in Goodman and Gilman, "The Pharmaceutical Basis of Therapeutics," 9th Edition, Hardman, et al. (ed.), McGraw-Hill (1996).
  • Suitable ⁇ 2 -adrenergic receptor antagonists include, but are not limited to, yohimbine and are also described in Goodman and Gilman, "The Pharmaceutical Basis of Therapeutics," 9th Edition, Hardman, et al. (ed.), McGraw-Hill (1996).
  • ⁇ 2 -adrenergic antagonists include, for example, post-synaptic ⁇ 2 -adrenergic antagonists.
  • post-synaptic ⁇ 2 -adrenergic antagonists include, but are not limited to, imiloxan, ARC 239 dihydrochloride and other pharmaceutically acceptable salts thereof.
  • ARC 239 dihydrochloride is 2-[2-(4-(2- Methoxyphenyl) ⁇ iperazin- 1 -yl)ethyl] -4,4-dimethyl- 1 ,3 -(2H,4H)-isoquinolindone dihydrochloride.
  • Suitable post-synaptic ⁇ -adrenergic antagonists include, but are not limited to, idazoxan, rauwolscine, efaroxan, mianserin, and mirtazapine. Of these, mianserin and mirtazapine are particularly preferred.
  • Suitable /3-adrenergic receptor agonists for use with the methods of the present invention include, but are not limited to, ⁇ -adrenergic receptor agonists, ⁇ - adrenergic receptor agonists, /3 3 -adrenergic receptor agonists and other nonspecific ⁇ - adrenergic receptor agonists.
  • the ⁇ -adrenergic receptor agonist is a jS 2 -adrenergic receptor agonist or a 0 3 -adrenergic receptor agonists.
  • ⁇ - adrenergic receptor agonists suitable for use with the methods of the present invention include, but are not limited to, albuterol, bitolterol, salbutamol, terbutaline, metaproterenol, procaterol, salmeterol, clenbuterol, isoproterenol, zinterol, BRL 37344, CL316243, CGP- 12177 A, GS 332, L-757793, L-760087, L-764646, and L-766892, etc. (see, e.g., Goodman and Gilman, supra).
  • the compound is a phosphodiesterase inhibitor.
  • Cyclic nucleotide second messengers cAMP and cGMP
  • PDE cyclic nucleotide phosphodiesterases
  • Inhibitors of phosphodiesterases are agents that can either activate or suppress PDEs via allosteric interaction with the enzymes or binding to the active site of the enzymes.
  • the PDE family includes at least 19 different genes and at least 11 PDE isozyme families, with over 50 isozymes having been identified thus far.
  • the PDEs are distinguished by (a) substrate specificity, i.e., cGMP-specific, cAMP-specific or non-specific PDEs, (b) tissue, cellular or even sub-cellular distribution, and (c) regulation by distinct allosteric activators or inhibitors.
  • PDE inhibitors include both nonspecific PDE inhibitors and specific PDE inhibitors (those that inhibit a single type of phosphodiesterase with little, if any, effect on any other type of phosphodiesterase).
  • Still other useful PDE inhibitors are the dual selective PDE inhibitors (e.g., PDE TTUTV inhibitors or PDE TVTV inhibitors). Below is a table setting forth various PDE inhibitors that are useful in the methods of the present invention.
  • the PDE inhibitor is a PDE V inhibitor.
  • Useful phosphodiesterase type N inhibitors include, e.g., cialis, tanadafil, zaprinast, MBCQ, MY- 5445, dipyridamole and sildenafil.
  • the composition contains a phosphodiesterase type II (PDE II) inhibitor such as, e.g., EH ⁇ A.
  • the composition contains a phosphodiesterase type IN (PDE IN) inhibitor.
  • Suitable phosphodiesterase type TV inhibitors include, but are not limited to, roflumilast, ariflo (SB207499), RP73401, CDP840, rolipram, RO-20-1724, and LAS31025.
  • the phosphodiesterase inhibitor is a dual selective phosphodiesterase inhibitor such as, e.g., a PDE III/JN inhibitor (e.g., zardaverine).
  • the PDE inhibitor is an inhibitor of the PDE IN isozyme family, or cAMP-specific and rolipram sensitive PDEs, which preferentially hydrolyze cAMP.
  • the composition contains an agent that is a nonspecific phosphodiesterase inhibitor. Suitable nonspecific phosphodiesterase inhibitors include, but are not limited to, theobromine, dyfylline, LBMX, theophylline, aminophylline, pentoxifylline, papaverine, caffeine and other methylxanthine derivatives.
  • the compound used to treat the disorders described herein is a cAMP-dependent protein kinase activator.
  • cAMP-dependent protein kinase activators include cAMP mimetics or dual cGMP/cAMP-dependent protein kinase activators.
  • Suitable cAMP mimetics or analogs include those compounds that are structurally similar to cAMP and that have similar functions e.g., activities, as cAMP.
  • Suitable cAMP mimetics include, but are not limited to, 8- bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS, and Sp-cAMPS, and useful dual activators include compounds such as, e.g., S ⁇ -8-pCPT-cGMPS, S ⁇ -8-bromo-cGMPS and 8-CPT- cAMP.
  • the compound used in the compositions and methods of the present invention is a superoxide anion (O 2 " ) scavenger.
  • Superoxide can react with NO and dramatically reduce its biological effects. Accordingly, agents that scavenge superoxide anions can enhance the effects of NO.
  • superoxide scavengers include, but are not limited to, exogenous Mn or Cu/Zn superoxide dismutase (SOD) or small molecule SOD mimetics such as, e.g., Mn(III) tetra(4-benzoic acid) porphyrin chloride (MnTBAP) and M40403 (see, e.g., Salvemini, et al., Science, 286(5438):304-306 (1999)).
  • SOD exogenous Mn or Cu/Zn superoxide dismutase
  • MnTBAP Mn(III) tetra(4-benzoic acid) porphyrin chloride
  • M40403 see, e.g., Salvemini, et al., Science, 286(5438):304-306 (1999)
  • the present invention provides pharmaceutical compositions comprising a potassium channel activator.
  • the potassium channel activator is an Potassium channel activator.
  • Synthetic compounds that activate ATP- sensitive K channels are smooth muscle relaxants. Such compounds include, but are not limited to, minoxidil, minoxidil sulfate, pinocidil, diazoxide, levcromokalim, cromokalim, etc. (see, e.g., White, et al., Eur. J. Pharmacol., 357:41-51 (1998)). Additional suitable ATP- sensitive K channel activators can be found in, e.g. , Bristol, et al. , "Annual Reports in Medicinal Chemistry," Vol. 29, Chap.
  • the potassium channel activator is a Maxi-K channel activator.
  • activators of the Maxi-K channels include, but are not limited to, estrogen-like compounds, such as estradiol (see, Valverde, et al, SCIENCE, 285:1929-1931).
  • the present invention provides pharmaceutical compositions comprising an estrogen-like compound.
  • Estrogen-like compounds include those compounds that bind to the estrogen receptor and act as agonists thereof.
  • Estrogen-like compounds include, but are not limited to, 17- ⁇ -estradiol, estrone, mestranol, estradiol valerate, estradiol dypionate, ethinyl estrodil, quinestrol, estrone sulfate, phytoestrogens such as flavones, isoflavones (e.g., genistein), resveratrol, coumestan derivatives, other synthetic estrogenic compounds including pesticides (e.g., p,p'-DDT), plasticizers (e.g., bisphenol A), and a variety of other industrial chemicals (e.g., polychlorinated biphenyls) (see, e.g., Goodman and Gilman, supra).
  • pesticides e.g., p,
  • the present invention provides pharmaceutical compositions comprising a testosterone-like compound.
  • Testosterone-like compounds include those compounds that bind to the testosterone receptor and act as agonists thereof.
  • Testosterone-like compounds include, but are not limited to, testosterone, testosterone propionate, testosterone enanthate, testosterone cypionate, testosterone undecenoate, dihydrotestosterone, danazol, fluoxymesterone, methyltestosterone, oxandrolone, DHEA and tibolone (see, e.g., Goodman and Gilman, supra).
  • the present invention provides pharmaceutical compositions comprising a benzodiazepine.
  • Suitable benzodiazepines include, but are not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam (see, e.g., Goodman and Gilman, supra).
  • L. Adrenergic Nerve Inhibitors include, but are not limited to, alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepate, demoxepam, diaze
  • the compounds of the present invention are compounds that inhibit adrenergic nerves.
  • Adrenergic nerve inhibitors include compounds that destroy sympathetic nerve terminals, such as 6-hydroxydopamine and its analogs (see, e.g., Goodman and Gilman, supra).
  • Adrenergic nerve inhibitors also include compounds that deplete norepinephrine storage, either by inhibiting norepinephrine biosynthesis or be depleting stores, and compounds that inhibit norepinephrine release.
  • Compounds that inhibit norepinephrine biosynthesis include, but are not limited to, ⁇ -methyltyrosine.
  • Compounds that deplete norepinephrine stores include, but are not limited to, reserpine, guanethidine and bretylium.
  • Compounds that inhibit norepinephrine release include, but are not limited to, clonidine and other ⁇ 2 -adrenergic receptor agonists.
  • Examples of sympathetic nerve terminal destroyers include, but are not limited to, ⁇ 2 -adrenergic receptor agonists.
  • the compounds of the present invention are antidiarrheal agents.
  • suitable antidiarrheal agents include, but are not limited to, diphenoxylate, loperamide, bismuth subsalicylate, octreotide, etc. (see, e.g., Goodman and Gilman, supra).
  • the compounds of the present invention are HMG- Co A reductase inhibitors.
  • HMG-CoA reductase inhibitors include, but are not limited to, mevastatin, lovastatin, simvastatin, pravastatin, cerivastatin, dalvastatin, atorvastatin, fluvastatin, etc. (see, e.g., Goodman and Gilman, supra).
  • the compounds of the present invention are smooth muscle relaxants such as, e.g., hydralazine, papaverine, tiropramide, cyclandelate, isoxsuprine and nylidrin.
  • smooth muscle relaxants such as, e.g., hydralazine, papaverine, tiropramide, cyclandelate, isoxsuprine and nylidrin.
  • the present invention provides compositions for the treatment of uro genital tract disorders comprising adenosine receptor modulators, either alone or in combination with another agent. Methods for the use of these compositions are also provided.
  • adenosine receptor modulators are used alone.
  • the adenosine receptor modulators are combined with at least one other urogenital muscle-relaxing agent.
  • the compounds of the present invention are adenosine receptor modulators such as methylxanthines. Examples of adenosine receptor modulators include theophylline and dyphylline. For other examples see, Goodman & Gilman, supra).
  • Preferred agents are selected from those described with reference to the compositions of single agents or combinations above.
  • Theophylline a plant-derived methylxanthine
  • Theophylline relaxes smooth muscle, notably bronchial muscle, that has been contacted 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 intracellular calcium concentrations via cell membrane hyperpolarization, 4) uncoupling of intracellular calcium increases with muscle contractile elements, and 5) antagonism of adenosine receptors.
  • a related compound i.e., dyphylline
  • dyphylline is a preferred adenosine receptor modulator. This compound 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.
  • compositions comprising adenylyl cyclase activators, either alone or in combination with other compounds or agents described herein.
  • the adenylyl cyclase activator forskolin is preferred.
  • adenylyl cyclase activators include, but are not limited to, N6 N6, O2'- dibutyryl-cAMP, 8-chloro-cAMP, and Rp-diastereomers of adenosine 3', 5'-cyclic monophosphorothioate, and related analogs, such as Rp-8-bromo-adenosine 3', 5'-cyclic monophosphorothioate, and derivatives of forskolin, including colforsin daropate hydrochloride.
  • the present invention provides compsitions comprising endothelin receptor antagonist, either alone or in combinaiton with other compounds disclosed herein.
  • endothelin receptor antagonists include, but are not limited to, BE 1827B, JKC-301, JKC- 302, BQ-610, W-7338A, LRL-1038, LRL-1620, bosetan, ABT 627, Ro 48-5695, Ro 61-1790, tesosentan (Ro 61-0612, ZD1611, BMS- 187308, BMS-182874, BMS-193884, sitaxsentan (TBC 11251), TBC 2576, TBC 3214, TBC- 10950, ABT-627, atrasentan, A-192621, A-308165, A-216546, CI-1020, EMD 122946, J- 104132 (L753037), LU 127043, LU 135252, LU 302872, TAK-044 (69), SB 209670
  • the present invention provides compositions comprising bisphosphonates, either alone or in combinaiton with other agents.
  • Suitable bisphosphonates suitable for use in the methods of the present invention include, but are not limited to, alendronate sodium (Fosamax), pamidronate disodium (Aredia), etidronate disodium Ididronel) and the like.
  • the present invention provides cGMP-dependent protein kinase activators, either alone or in combinaiton with other agents disclosed herein.
  • Suitable cGMP-dependent protein kinase activators include, but are not limited to, cGMP mimetics or dual cGMP/cAMP-dependent protein kinase activators.
  • Suitable cGMP mimetics or analogs include those compounds that are structurally similar to cGMP and that have similar functions, e.g., activities, as cGMP.
  • cGMP mimetics include, but are not limited to, 8-bromo-cGMP, dibutyryl-cGMP, Rp-cGMPS, and Sp- cGMPS
  • useful dual activators include compounds such as, e.g., Sp-8-pCPT-cGMPS, Sp- 8-bromo-cGMPS and 8-CPT-cAMP.
  • the present invention also provides pharmaceutical compositions for the administration of the herein-described compounds, e.g., the NO donors, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic antagonists, ⁇ -adrenergic agonists, phosphodiesterase inhibitors, cAMP kinase activators, superoxide scavengers, Potassium channel activators, adrenergic nerve inhibitors, estrogen-like compounds, benzodiazepines, antidiarrheal agents, HMG-CoA reductase inhibitors, adenosine receptor modulators, and smooth muscle relaxants to a patient in need thereof.
  • the herein-described compounds e.g., the NO donors, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic antagonists, ⁇ -adrenergic agonists, phosphodiesterase inhibitors, cAMP kinase activators, superoxide scavengers, Potassium
  • the term "patient” refers to a subject to which the compounds of the invention can be administered.
  • a patient is a mammal, e.g., a rodent, a primate or a human.
  • a patient may be affected with a disease, or may be free of detectable disease in which case the compounds and compositions of the present invention are administered prophylactically.
  • the compositions of the present invention can be administered to patients with a anorectal disorder.
  • compositions of single agents will be understood to also include compositions of two or more agents. Still further, different formulations can be used for those embodiments in which agents are administered separately or sequentially, by different routes of administration.
  • the compounds of the present invention can be formulated to be administered using any of a variety of routes, including, e.g., oral, intravenous, intramuscular, subcutaneous, oral, pulmonary, transdermal, nasal, cervical, vaginal, buccal, anorectal for systemic or local delivery or, preferably, topical administration, such as, e.g., to anorectal area, for prophylactic and/or therapeutic treatment.
  • routes including, e.g., oral, intravenous, intramuscular, subcutaneous, oral, pulmonary, transdermal, nasal, cervical, vaginal, buccal, anorectal for systemic or local delivery or, preferably, topical administration, such as, e.g., to anorectal area, for prophylactic and/or therapeutic treatment.
  • the present compounds can be incorporated into a variety of compositions for therapeutic and/or prophylactic administration.
  • a number of suitable formulations for use in the present invention are found in Remington, Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 17th ed. (1985); and in Dermatological Formulations: Percutaneous absorption, Barry (Ed.), Marcel Dekker Inc. (1983).
  • Dermatological Formulations Percutaneous absorption, Barry (Ed.), Marcel Dekker Inc. (1983).
  • Langer (1990) Science 249:1527-1533 see, Langer (1990) Science 249:1527-1533.
  • the pharmaceutical compositions described herein can be manufactured in a manner that is known to those of skill in the art, i.e., by means of conventional mixing, dissolving, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. It will be appreciated that the present methods and excipients are merely exemplary and are in no way limiting.
  • compositions useful for treating anorectal disorders and for treating spasms of mammals, including humans which comprise an effective amount of a compound that reduces the contraction of the musculature of the anal sphincter and a pharmaceutically acceptable carrier.
  • the compound for use in the topical compositions of the present invention include, but are not limited to, cAMP kinase activators, superoxide scavengers, Potassium channel activators, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic antagonists, ⁇ - adrenergic agonists, adrenergic nerve inhibitors, NO donors, phosphodiesterase inhibitors, estrogen-like compounds, benzodiazepines, antidiarrheal agents, HMG-CoA reductase inhibitors, and smooth muscle relaxants.
  • the present invention provides topical pharmaceutical compositions in unit dosage form comprising per unit dosage an amount of the compound or combination provided above, which is effective for treating a anorectal in a subject in need of such treatment.
  • the compounds are in combination with a pharmaceutically acceptable carrier.
  • Such compositions are useful for treating or reducing pain associated with anorectal disorders and for treating the disorders themselves , including spasms of the sphincter muscles, in particular the internal and external anal sphincters.
  • the topical compositions of the invention are also useful for treating conditions resulting from spasms of the musculature of the anal sphincter, including anal fissures, hemorrhoids, and the like.
  • topical compositions described herein are useful for relaxing the anal sphincter and reducing pain before, during and after proctologic and other examinations, including the insertion of instruments and procedures, such as surgery.
  • Dosage forms for the topical administration of the compounds 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 active ingredients at the anorectal area.
  • 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 compound of interest 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, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays also can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Preferred 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 prefened preparations include those in a suppository or sustained release format.
  • compositions include topical compositions comprising one or more of the following first pharmacological compounds: a cAMP kinase activator, superoxide scavenger, Potassium channel activator, calcium channel blocker, cholinergic modulator, ⁇ -adrenergic antagonist, ⁇ -adrenergic agonist, adrenergic nerve inhibitor, NO donor, phosphodiesterase inhibitor, adenosine receptor modulators, estrogen-like compound, benzodiazepine, antidiarrheal agent, HMG-CoA reductase inhibitor, and smooth muscle relaxant 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
  • the at least one first pharmacological compound is typically present in the composition in unit dosage form effective for the treatment of a first medical condition(s), such as anorecal disorder or pain.
  • the at least one second pharmacological compound is typically present in the composition in unit dosage effective for the 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 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% compound of the present invention.
  • the dosage of a specific compound depends upon many factors that are well known to those skilled in the art, for example, the particular compound; 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.
  • the present invention provides topical compositions useful for treating anorectal disorders (including those related to hypertonicity and/or spasm of the internal anal sphincter muscle, e.g.
  • the agent is an Potassium channel opener.
  • the agent is a phosphodiesterase inhibitor, a cyclic nucleotide mimetic, ⁇ -adrenergic agonist, an estrogen or estrogen like compound, an a t -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.
  • Such compositions are useful in treating or reducing pain associated with anal disorders, such as hemorrhoidal pain, and for treating spasms and/or hypertonicity of the sphincters, including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter.
  • the topical composition is also useful in treating conditions resulting from spasms and/or hypertonicity of sphincters of the anorectal region including anal fissure, post-operative rectal pain, hypertrophic pyloric stenosis, and pancreatitis, as well as conditions resulting from general spasm of the muscles of the GI tract including Zenkers diverticulum, achalasia, esophageal spasm (nutcracker esophagus), irritable bowel disease, and Hirshprungs disease (bowel obstruction).
  • 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.
  • the invention provides topical sustained and prolonged release pharmaceutical compositions comprising one or more pharmacological compounds described supra, and a pharmaceutically acceptable carrier, to treat anorectal disorders.
  • Such compositions are useful in the treatment of such anorectal disorders and in controlling and reducing pain associated therewith.
  • compositions may comprise a unit dosage of one or more particular active agent(s) (e.g., a NO donor, phosphodiesterase inhibitor, cAMP kinase activator, superoxide scavenger, Potassium channel activator, calcium channel blocker, cholinergic modulator, ⁇ -adrenergic antagonist, ⁇ -adrenergic , agonist, adrenergic nerve inhibitor, estrogen-like compound, benzodiazepine, antidiarrheal agent, HMG-CoA reductase inhibitor, or smooth muscle relaxant) which is effective in treating anorectal disorders and in controlling and alleviating pain associated therewith.
  • active agent(s) e.g., a NO donor, phosphodiesterase inhibitor, cAMP kinase activator, superoxide scavenger, Potassium channel activator, calcium channel blocker, cholinergic modulator, ⁇ -adrenergic antagonist, ⁇ -adrenergic , agonist,
  • Topical sustained and prolonged release compositions are typically variants which include 1) an absorbent in a hydrophilic base; 2) an absorbent in a hydrophobic base; and 3) coated beads containing an absorbent matrix dispersed in a suitable vehicle. Also provided are methods of treating anorectal disorders comprising topically administering an effective amount of such compositions (e.g., in unit dosage form) to the appropriate anorectal area of the subject in need of such treatment.
  • Such hydrophilic compositions and preparations of the invention comprise a compound of the invention 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 compound of interest to the polymer.
  • the compound-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 (i.e., the _ pharmaceutical compound) remains as a coating in the area to which it has been applied.
  • the pharmaceutical compound is then slowly released from this coating.
  • Hydrophobic compositions and preparations of the invention employ similar polymers as used in the hydrophilic preparations, but the polymer/compound 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 pharmaceutical compound.
  • the semi-solid composition forms a thin coating on the anorectal region to which the composition has been applied (such as, e.g., the anorectal area) and slowly releases the active compound. The prolonged action is controlled principally by the solubility of the active ingredient in the vehicle.
  • the present invention also provides coated beads which are produced by first absorbing a compound of the present invention, or a combination of compounds, 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 that regulates the release of the compound 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 cAMP kinase activator, superoxide scavenger, Potassium channel activator, calcium channel blocker, cholinergic modulator, ⁇ -adrenergic antagonist, ⁇ -adrenergic agonist, adrenergic nerve inhibitor, NO donor, phosphodiesterase inhibitor, estrogen-like compound, benzodiazepine, antidiarrheal agent, HMG-CoA reductase inhibitor or smooth muscle relaxant, and a pharmaceutically acceptable carrier.
  • Such compositions are useful for treating anorectal disorders, including those disorders and conditions described above.
  • an oral formulation such as a lozenge, tablet, or capsule is used.
  • Methods 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 compound or a substance containing the compound (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. Patent No. 4,940,587.
  • This buccal adhesive formulation when applied to the buccal mucosa, allows for controlled release of the 5 pharmacological agent into the mouth and through the buccal mucosa.
  • the compounds 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
  • 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 pharmacological compound of interest suspended in air or other carrier gas, which may be delivered by insufflation from an
  • the preferred range of concentration of the pharmacological agent is 0.1-100 mg/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
  • Solutions of the pharmacological agent may be converted into aerosols by any of the known means routinely used for making aerosol inhalant pharmaceuticals.
  • such methods comprise pressurizing or providing a means of pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice, thereby pulling droplets of the solution into the mouth and trachea of the animal
  • 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.
  • Transmucosal i.e., sublingual, rectal, colonic, pulmonary, buccal and vaginal
  • Transmucosal 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 polyvinylpyrrolidone (PVP, BASF, Germany), polycarbophil (Goodrich, USA), or sodium alginate (Hayashi Pure Chemicals, Tokyo, Japan), etc. are incorporated.
  • mucoadhesive polymers such as polyvinylpyrrolidone (PVP, BASF, Germany), polycarbophil (Goodrich, USA), or sodium alginate (Hayashi Pure Chemicals, Tokyo, Japan), etc. are incorporated.
  • This type of liquid suppository has a gelation temperature between 30 to 36°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, 59:163-172. 1999; Chem Pharm Bull, 46 (2):309-313, 1998; JPharm Sci, 81(11): 1119-1125, 1992; Chem Pharm Bull, 31 (3):166-110, 1989; J Pharmacobiodyn, 9(6):526-531,1986; J Pharm Sci. 84(l):15-20, 1995).
  • 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.
  • kits for the treatment of the anorectal disorders comprise an applicator, a container holding at least one unit dose of the pharmaceutical composition according to the invention, and instructions for applying the composition.
  • the composition is a topical composition and the instructions indicate the composition is to be applied to the anorectal region.
  • the applicator is disposable.
  • the applicator provides an extension of at least from 1 inch, 2 inches, or 3 inches from where it is held to the tip of the applicator or to a point where the applicator contacts the skin in applying the composition.
  • the applicator dispenses unit dosages.
  • the kit provides one or more applicators and containers wherein the applicators and containers are integral and provide one unit dose.
  • the present invention provides methods for treating anorectal disorders which comprise administering to or contacting an appropriate area or affected anorectal tissue (e.g., anus or rectum) of a subject in need of such treatment an effective amount of any of the compositions provided above.
  • an appropriate area or affected anorectal tissue e.g., anus or rectum
  • spasms of the musculature of the anorectal area e.g., anal sphincters
  • signs and symptoms associated with anorectal disorders e.g., anal fissure, hemonhoids, anal pain or anal itching or anal burning therewith are improved.
  • the methods described herein are also applicable to the treatment of recurrent anorectal diseases, and are also useful for relaxing the musculature of the anorectal region and reducing pain during procto logic exams (in patients with and without disorders), particularly during procedures where instruments are inserted into the rectum.
  • the present invention further provides methods of using the above- described compositions in combination with local anesthetic agents, such as, for example, lidocaine, prilocaine, etc.
  • local anesthetic agents such as, for example, lidocaine, prilocaine, etc.
  • Each of the compositions will typically be in a pharmaceutically acceptable dosage form as an effective treatment for a anorectal medical condition.
  • These pharmaceutical preparations are also useful in treating conditions resulting from spasms of the musculature, including, but not limited to, levator spasm.
  • the present invention provides methods for treating anorectal disorders which comprise administering an effective amount of one a composition described herein along with a local anesthetic agent to a subject in need of such treatment.
  • Such compositions can be administered orally, transdermally, transmucosally or parenterally.
  • the invention provides methods of using the above-described compositions in combination with local anti-inflammatory agents, for example, naproxen or piroxicam, in a pharmaceutically acceptable dosage form as an effective treatment for a anorectal medical condition such as, e.g., anal fissure, hemorrhoids, levator spasm, anorectal burning, itching or pain.
  • a pharmaceutically acceptable dosage form such as, e.g., anal fissure, hemorrhoids, levator spasm, anorectal burning, itching or pain.
  • anorectal medical condition such as, e.g., anal fissure, hemorrhoids, levator spasm, anorectal burning, itching or pain.
  • anorectal medical condition such as, e.g., anal fissure, hemorrhoids, levator spasm, anorectal burning, itching or pain.
  • These pharmaceutical preparations are also useful in treating conditions resulting from spasm
  • Additional methods provided by the present invention are those in which two or more agents selected from a cAMP kinase activator, superoxide scavenger, Potassium channel activator, calcium channel blocker, cholinergic modulator, ⁇ -adrenergic antagonist, ⁇ -adrenergic agonist, adrenergic nerve inhibitor, NO donor, phosphodiesterase inhibitor, estrogen-like compound, benzodiazepine, antidiarrheal agent, HMG-CoA reductase inhibitor and smooth muscle relaxant, are administered either in combination or sequentially to provide an enhanced therapeutic benefit.
  • the use of two compounds from those listed above can provide fewer and less severe side effects than equally effective doses of a single compound, if used alone. More particularly, the use of two compounds in combination allows for decreased amounts of each compound to be used to achieve the same benefit relative to a compound used alone, and provides significantly reduced occurrence and duration of side effects.
  • the present invention provides methods for treating anorectal disorders which comprise administering to an appropriate anal area or affected anal tissue (e.g., external or internal anal tissue or anal canal) of a subject in need of such treatment an effective amount of any of the compositions provided above.
  • anorectal hypertonicity and/or spasms are relieved, anal sphincter pressure is reduced, reduced anal sphincter pressure is maintained, and signs and symptoms associated with anorectal disorders, e.g. anal fissures, anal ulcers and hemorrhoids, and pain are improved.
  • the methods described herein are also applicable to the treatment of recurrent anal diseases, and are also useful for relaxing the anal sphincter and reducing pain during anorectal exams (in patients with and without disorders), particularly during procedures when instruments are inserted into the anus.
  • the present invention further provides methods of using the compositions above in combination with local anesthetic agents, for example lidocaine, prilocaine, etc.
  • Each of the compositions will typically be in a pharmaceutically acceptable dosage form as an effective treatment for a medical condition such as hemorrhoidal pain and for treating spasms and/or hypertonicity of the sphincters including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter.
  • 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 hemorrhoidal pain and for treating hypertonicity and/or spasms of the sphincters including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of Oddi, and the ileocolic sphincter.
  • local anti-inflammatory agents for example, naproxen, piroxicam, etc.
  • a pharmaceutically acceptable dosage form as an effective treatment for a medical condition such as hemorrhoidal pain and for treating hypertonicity and/or spasms of the sphincters including the internal anal sphincter, lower esophageal sphincter, pyloric sphincter, sphincter of Oddi, and the ile
  • 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.
  • 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 ⁇ t-adrenergic antagonist, a superoxide anion (O " ) scavenger, an ATP-sensitive K + channel activator, an estrogen or estrogen-like compound, a adrenergic nerve inhibitor, an adenosine receptor modulator, 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
  • an NO donor and a second agent from those provided above can provide fewer and less severe side effects than equally effective doses of NO donors, if used alone. More particularly, the use of an NO donor in combination with a second agent allows for decreased amounts of the NO donor to be used to achieve the same benefit relative to use alone, while extending the period of reduction of anal sphincter pressure, and provides significantly reduced occurrence and duration of headaches.
  • 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, i another group of embodiments the second agent is a phosphodiesterase type IN (PDE TV) inhibitor.
  • the second agent is a phosphodiesterase type II (PDE II) inhibitor, hi another group of embodiments 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 ⁇ j -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.
  • the NO donor is NTG.
  • Nitroglycerin and other organic nitrates including ISDN, ETN, and PETN have been given regulatory approval for use in treatments in other fields of medicine on human subjects.
  • Additional NO donors include sodium nitroprusside, N,O-diacetyl-N- hydroxy-4-chlorobenzenesulfonamide, N G -hydroxy-L-arginine (NOHA), hydroxyguanidine sulfate, molsidomine, 3-mo holinosydnonimine (SLN-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
  • 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 (e.g., PDE HI/IN 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. Suitable phosphodiesterase type II inhibitors include EH ⁇ A. [184] In yet another group of embodiments, the composition contains an agent which is a phosphodiesterase type TV (PDE TV) inhibitor. Suitable phosphodiesterase type TV inhibitors include ariflo (SB207499), RP73401, Ro-201724, CDP840, rolipram and LAS31025.
  • the composition contains an agent which is a dual selective phosphodiesterase inhibitor, preferably a PDE III/IV 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 Therapeutics" The McGraw-Hill Companies, 1996).
  • the composition contains an agent that 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 that is a ⁇ -adrenergic agonist, preferably a ⁇ 2 - or ⁇ -adrenergic receptor agonist.
  • a ⁇ -adrenergic agonist preferably a ⁇ 2 - 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-dependent protein kinase activator.
  • a variety of cyclic nucleotide-dependent protein kinase activators are useful in the present invention including, for example, cAMP mimetics and dual cGMP/cAMP-dependent protein kinase activators.
  • cAMP mimetics are well known to those of skill in the art and include 8-bromo-cAMP, dibutyryl-cAMP, Rp-cAMPS, and Sp-cAMPS. Dual activators include Sp-8- ⁇ CPT-cGMPS, S ⁇ -8-bromo-cGMPS and 8-CPT-cAMP.
  • the composition contains an agent that 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 that 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-estradiol, estrone, mestranol, estradiol valerate, estradiol dypionate, ethinyl estradiol, 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 that is an ⁇ j -adrenergic antagonist.
  • the sympathetic neurotransmitter norepinephrine contracts sphincter smooth muscle via ⁇ i-adrenergic receptors.
  • Pharmacological interference with norepinephrine release or binding to ⁇ i -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 ⁇ i-adrenergic receptor antagonists (e.g.
  • the composition contains an alternative sympatholytic agent, such as an ⁇ 2 - 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 ⁇ 2 - 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, Pharmacol Rev. 24:509-81 (1972)).
  • ATP appears to act primarily by opening ATP-sensitive potassium (K ATP ) channels which hyperpolarize the cell membrane, reducing intracellular calcium concentrations, leading to smooth muscle relaxation.
  • K ATP 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.
  • 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 modulator.
  • second agents include theophylline, dyphylline, aminophylline, caffeine, and theobromine.
  • a second agent is a K + ATP channel opener, an adenosine receptor modulator, or a /32-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 TV inhibitor or a PDE V inhibitor, either alone or in combination with another agent selected from ⁇ -adrenergic receptor agonists, ⁇ i -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, J Cardiovasc. 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/IV 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 ⁇ -adrenergic receptor agonists, ⁇ i- adrenergic antagonists, L-type Ca 2+ channel blockers, estrogens, ATP-sensitive K + channel activators, adrenergic nerve inhibitors, adenosine receptor modulators, 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 modulator, 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 IN inhibitor), nonspecific PDE inhibitors, t -adrenergic 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 IN inhibitor
  • nonspecific PDE inhibitors e.g., t -adrenergic antagonists
  • estrogens e.g., L-type Ca 2+ channel blockers
  • ATP-sensitive K + channel activators e.g., ATP-sensitive K + channel activators, or smooth muscle relaxants
  • smooth muscle relaxants e.g.,
  • 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 ⁇ -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 /3 2 -adrenergic agonists commonly used for the long-term treatment of obstructive airway diseases and acute bronchospasm in asthma.
  • Beta-adrenergic agents like VIP, potently relax smooth muscle, including IAS smooth muscle by raising intracellular cyclic AMP levels (Parks et al, Gut 10(8): 674-7 (1969); Chakder, S. et al, Amer J Physiol 264 (1 pt 1):G7-12, (1993); Chakder, S. et al, AmerJ Physiol. 264 (4 pt 1): G702-7, (1993); O'Kelly, T.J.
  • Cyclic AMP induces smooth muscle relaxation through phosphorylation of smooth muscle regulatory proteins (e.g., myosin light chain kinase) and by decreasing intracellular calcium concentrations (e.g., via K -ATP channel activation).
  • smooth muscle regulatory proteins e.g., myosin light chain kinase
  • intracellular calcium concentrations e.g., via K -ATP channel activation.
  • Terbutaline and salbutamol have weaker cardiovascular effects than non-specific /3-receptor agonists, e.g., isoproterenol, because they do not stimulate cardiac ⁇ -adrenergic receptors at therapeutic doses. They are commonly administered by inhalation (i.e., topically).
  • Tolerance is a potential downside effect of j ⁇ - adrenergic agonists.
  • Long-term systemic administration of /3-adrenergic agonists leads to down-regulation of ⁇ receptors in some tissues and decreased pharmacological responses, and has been demonstrated in patients with asthma 1 .
  • 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 TV inhibitor), nonspecific PDE inhibitors, ⁇ i-adrenergic antagonists, adenosine receptor modulators including methyl xanthines, estrogens, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators or smooth muscle relaxants.
  • PDE inhibitors e.g., a PDE TV inhibitor
  • nonspecific PDE inhibitors e.g., ⁇ i-adrenergic antagonists
  • adenosine receptor modulators including methyl xanthines, estrogens, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators or smooth muscle relaxants.
  • the agent is a cAMP- hydrolyzing PDE inhibitor, more preferably a phosphodiesterase type TV inhibitor.
  • PDE IN also referred to as PDE IN and PDE4
  • PDE TV 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.
  • the agent is an ⁇ i- adrenergic antagonist. Suitable ⁇ radrenergic receptor antagonists (e.g. prazosin, doxazosin, phentolamine, tolazoline, and the like) are described in Goodman & Gilman' s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. 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, Acta 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, Acta Gastroent. Latinoamer. 27:247-251, 1997) and verapa
  • the ⁇ -adrenergic receptor agonist is combined with an ATP-sensitive K + channel activator.
  • Preferred 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 modulator.
  • a preferred 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, ⁇ -adrenergic antagonists, L-type Ca 2+ channel blockers, adrenergic nerve inhibitors, 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, ⁇ -adrenergic antagonists, L-type Ca 2+ channel blockers, adrenergic nerve inhibitors, 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).
  • 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 ⁇ i-adrenergic antagonist, an L-type Ca 2+ channel blocker, a adrenergic nerve inhibitor, 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 Sp-8-pCPT-cGMPS, Sp-8-bromo-cGMPS and 8-CPT-cAMP.
  • an a t -adrenergic antagonist is combined with an ATP-sensitive potassium ion channel activator.
  • the ⁇ i -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.
  • Baird and Muir demonstrated that cromakalim, aK + -ATP channel opener, inhibited spike discharge, hyperpolarized the membrane and relaxed the guinea pig IAS.
  • diazoxide and minoxidil relaxed the rat LAS in vivo.
  • the adverse effects of these drugs are predictable and can be divided into three major categories: 1) fluid and salt retention, 2) cardiovascular effects, and 3) hypertrichosis.
  • Topical minoxidil inspired by the hypertrichosis side effect, is marketed for stimulating hair growth. This product has an excellent safety record and is now sold over the counter.
  • 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 0 -adrenergic receptor agonist, or an adenosine receptor modulator.
  • a preferred 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 IV inhibitor), estrogens, adrenergic nerve inhibitors, or smooth muscle relaxants, and a pharmaceutically acceptable carrier.
  • PDE inhibitors preferably a PDE IV inhibitor
  • estrogens preferably a PDE IV inhibitor
  • adrenergic nerve inhibitors preferably a PDE IV inhibitor
  • smooth muscle relaxants preferably a PDE IV inhibitor
  • the present invention further provides methods of using those compositions.
  • a t -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).
  • Preferred ⁇ i-adrenergic antagonists are prazosin, phentolamine and tolazoline.
  • an ⁇ i -adrenergic antagonist is combined with a cAMP-hydrolyzing PDE inhibitor (preferably a PDE IN inhibitor), an estrogen or estrogen like compound, a adrenergic nerve inhibitor, or a smooth muscle relaxant
  • a cAMP-hydrolyzing PDE inhibitor preferably a PDE IN inhibitor
  • an estrogen or estrogen like compound preferably a adrenergic nerve inhibitor
  • a smooth muscle relaxant preferably a PDE IN inhibitor
  • the prefened 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 /3 2 -adrenergic receptor agonist or an adenosine receptor modulator.
  • 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 [225]
  • 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 3 2 -adrenergic receptor agonist or an adenosine receptor modulator.
  • a prefened 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 estrogen or an estrogen mimetic, either alone or in combination with another agent from any of the classes of agents described above.
  • Estrogen-like compounds include but are not limited to 17-beta-estradiol, estrone, mestranol, estradiol valerate, estradiol dypionate, ethinyl estradiol, quinestrol, estrone sulfate, phytoestrogens such as flavones, isoflavones (e.g. genistein), resveratrol, 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. polychlormated biphenyls
  • 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.
  • a second agent is preferably a K + ATP channel opener, a /3 2 -adrenergic receptor agonist or an adenosine receptor modulator.
  • a preferred 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 adrenergic nerve inhibitor, either alone or in combination with another agent from any of the classes of agents described above.
  • adrenergic nerve inhibitor compounds include but are not limited to 6- hydroxydopamine and its analogs See, Goodman & Gilman'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 modulator, either alone or in combination with another agent from any of the classes of agents described above.
  • adenosine receptor modulators include theophylline and dyphylline. See, Goodman & Gilman's THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, ninth edition, ed. JG Hardman, et al. , McGraw-Hill (1996).
  • Prefened 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 intracellular calcium concentrations via cell membrane hyperpolarization, 4) uncoupling of intracellular calcium increases with muscle contractile elements, and 5) antagonism of adenosine receptors.
  • Adenosine receptor antagonism is thought to be the most important factor responsible for most of the pharmacological effects of methylxanthines in therapeutically administered doses 2 .
  • 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 /3 -adrenergic receptor agonist.
  • a preferred second agent is a compound selected from the group consisting of terbutaline, minoxidil, diazoxide and salbutamol.
  • compositions provided herein 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. Prefened 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 proximate to the internal anal sphincter.
  • 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 ⁇ -adrenergic receptor agonists, cAMP-hydrolyzing PDE inhibitors, nonspecific PDE inhibitors, ⁇ i -adrenergic antagonists, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, adenosine receptor modulators, and the like).
  • agents e.g., NO donors, ⁇ 2 - or ⁇ -adrenergic receptor agonists, cAMP-hydrolyzing PDE inhibitors, nonspecific PDE inhibitors, ⁇ i -adrenergic antagonists, L-type Ca 2+ channel blockers, ATP-sensitive K + channel activators, adenosine receptor modulators, and the like).
  • compositions of single agents will be understood to also include compositions of two or more agents. Still further, different formulations can be used for those embodiments in which agents are administered separately or sequentially, by different routes of administration.
  • 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 mmHg. The data were integrated and converted to waveforms with the Digi-Med System Integrator software. Blood pressure changes were monitored using an arterial catheter/transducer and a Digi-Med Blood Pressure Analyzer with the DMSI software.
  • Typical resting mean internal anal sphincter pressures (IASP) varied between 30 and 60 mmHg in this model.
  • the Millar catheter sensor allowed for accurate, isolated recordings of the IAS.
  • 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.
  • Example 2 This example illustrates the effect of phosphodiesterase inhibitors in a rat internal anal sphincter relaxation model.
  • Example 3 This example illustrates the effect of a potassium channel opener (minoxidil) in a rat internal anal sphincter constriction/relaxation model.
  • Example 4 This example illustrates the use of a variety of compositions of the invention for the relaxation of the LAS.
  • 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.
  • NVG 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.
  • Example 8 This example illustrates the potentiation of NTG in the rat model by PDE V inhibitor blockage of the cGMP-specific PDE activity.
  • Zaprinast (10 mg in 100 ⁇ l 1M2P) was injected i.p. 30 minutes prior to bolus doses of NTG (20 ⁇ g/rnin 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).
  • the vehicle, 1-methyl 2-pyrollidinone (1M2P) was injected intraperitoneal (i.p.). (lOO ⁇ l), followed after 2.75 hours by the first dose of NTG (20 ⁇ g/min every 30 minutes). The duration of depression of IASP was consistent with each NTG dose (see Figure 14).
  • Example 9 This example illustrates the effect of non-selective ⁇ -adrenergic agonists using isoproterenol. These agonists activate adenylyl cyclase, thereby increasing cAMP levels, and act on the IASP through the direct smooth muscle relaxing activity of cAMP.
  • Example 11 This example illustrates the effects of cAMP levels on the IASP and the effects of PDE JN inhibitor blockage of the cAMP-specific PDE activity in the rat model.
  • Example 13 This example illustrates the effect of non-selective PDE Inhibitors on IASP in the rat model.
  • 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 & Gilman's "The Pharmacological Basis of Therapeutics" 9 th edition. Section JV-Autocoids; Drug Therapy of Inflammation).
  • Example 14 This example illustrates the use of K+-ATP Channel Openers to relax the LAS.
  • K + -ATP channel openers minoxidil and diazoxide, induce hyperpolarization of the cell membranes of smooth muscle, and thereby inactivate voltage- gated Ca 2+ channels.
  • Minoxidil (830 ⁇ g in 20 ⁇ l 62.5% propylene glycol/water) was delivered to the LAS. A significant and sustained drop in IASP was observed shortly after delivery of the drug (see Figure 31).
  • Diazoxide in 5% DMSO/Acetone:Olive oil 1 : 1 was infused at 20 ⁇ g/hour. A dramatic drop in IASP was observed for the duration of the experiment (see Figure 32).
  • Example 15 This example illustrates the use of Ca 2+ -channel blockers
  • 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).
  • Example 16 This example illustrates the use of adrenergic nerve inhibitors to achieve a long term reduction in IASP in the rat model following a short term administration of the active agent.
  • Neurogenic tone of the LAS is largely due to sympathetic adrenergic innervation; norepinephrine released by the nerves acts on ⁇ i-adrenergic receptors to contract smooth muscle.
  • ⁇ -blockers reduced anal pressure in man (Speakman, C.T., Dig Dis Sci 38(ll):1961-9 (1993); Parks, A.G., Gut 10(8): 674-7 (1969)).
  • botulinum toxin produced by Clostridium botulinum
  • Botulinum 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.
  • Example 17 This example illustrates the effects of a PDE III/IV inhibitor on IASP under a variety of experimental conditions.
  • 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).
  • Dyphylline [314]
  • Figure 43 shows the IAS 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 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 anorectal 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.
  • 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 anorectal disorders.
  • drugs that can effectively reduce anal sphincter pressure, maintain reduced anal sphincter pressure, or prevent recunence of the diseases and yet cause minimal or no adverse reactions such as headache will provide significant medical benefit.
  • Example 21 This example illustrates a method to reduce bleeding in patients with hemonhoidal symptoms or diseases.
  • Patients with hemonhoidal 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 hemonhoidal symptoms will eventually lead to complete resolution of these anorectal disorders.
  • drugs that can effectively reduce anal sphincter pressure, maintain reduced anal sphincter pressure, or prevent recunence of the diseases while causing minimal or no adverse reactions such as headache are of significant medical benefit.
  • Example 22 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 hemonhoidal diseases.
  • a topical composition comprises nitroglycerin at 0.1% concentration and sildenafil at 0.1% concentration can be incorporated in the same ointment base as mentioned above. This composition can be applied topically from a metered dosing device where a 50 mg to 1.5 gm dose of the composition is administered to the afflicted anorectal tissue to achieve the desired therapeutic effects.
  • 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.
  • a composition of aminophylline topical spray composition comprises 0.1 to 5.0% (w/w) of aminophylline, 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 current composition.
  • This composition can be sprayed directly onto the afflicted tissue once to four times daily to achieve the desired relief of signs and/or symptoms associated with anorectal disorders.
  • This composition can also include menthol and benzocaine to provide the immediate local pain relief and soothing sensation whereas aminophylline provides the longer lasting relaxation of anal sphincter pressure.
  • 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 stirred 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 hemonhoidal disorders, alone or in combination with a local anesthetic, for example, lidocaine, or in combination with a mixed j8 2 - and ⁇ 3 -adrenergic agonist, for example salbutamol, or in combination with a PDE TV 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 hemonhoidal disorders.
  • Example 30 This example illustrates the preparation of a theophylline topical formulation from theophylline oral tablets.
  • Five Theo-24 tablets 400 mg of theophylline per tablet; UCB Pharmaceuticals, Inc.
  • 50 ml of ethanol was added and the solution was stined at room temperature for 15 minutes.
  • 48 ml of propylene glycol and 100 ml of distilled water were added to the ethanol mixture while stirring. This mixture was stined for 15 minutes, at which time the powder was completely dissolved.
  • a solution of carbopol in distilled water was then added to the mixture while stirring, forming a 1% topical theophylline gel. The resulting gel was then stirred for another 15 minutes.
  • a methylxanthine derivative for example diphylline or theophylline
  • 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.
  • Example 32 Patients are first diagnosed with anal fissure, and a baseline severity score is established for each patient at baseline. Objective and subjective signs and symptoms may be scored. Nitroglycerin ointment is applied to the outer anorectal area, once to four times daily to relax the internal anal sphincter. Nitroglycerin ointment can also be applied as frequently as needed to achieve the desired effect. Alternatively, nitroglycerin ointment can be applied 5 to 15 minutes before a bowel movement to relax the sphincter muscles; thus allowing for successful effort. The nitroglycerin ointment concentration varies between 2.0% (w/v) to 0.05%, more preferably, between 0.1% to 0.6% to achieve the desired effect.
  • the desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow. Patients may also use commercially available Nitrobid®, Percutol® or Rectogesic® ointments as is or by diluting to the appropriate concentration.
  • Example 33 Patients are first diagnosed with hemonhoids and the severity of the disorder is scored at baseline. Objective and subjective signs and symptoms may be scored.Under physician assistance, a suppository containing diltiazem, a calcium channel blocker, is inserted into the patient's rectum. The controlled and continuous release of diltiazem from the suppository allows for relaxation of the internal anal sphincter and thus, a decreased intra-anal pressure. If desired, patients using a diltiazem suppository can also apply nitroglycerin ointment to maximize the relaxation.
  • Example 34 Patients are first diagnosed with levator spasm and the intensity of the spasm symptoms are scored for each patient at baseline. Objective and subjective signs and symptoms may be scored. If patients do not have other cardiovascular disease complication, oral nifedipine or other calcium channel blocker tablets (or caplets, capsules, etc) can be administered, approximately 45 minutes to 4 hours before coitus to produce the desired effects. Alternatively, patients can take the calcium channel blocker orally once to three times daily and apply nitroglycerin ointment or topical diltiazem cream as needed to maximize the desired effects. The desired effects can include immediate pain relief, local tissue relaxation, and increased blood flow.
  • Example 35 Patients are first diagnosed with anal fissure and the severity score for each patient is recorded at baseline. Objective and subjective signs and symptoms may be scored. Topical aminophylline cream is applied either externally to the anorectal area or internally to achieve pain relief, muscle relaxation, and increased blood flow. Alternatively, rectal suppositories or tablets containing aminophylline are inserted once daily or as needed to achieve the desired effects.
  • Example 36 Patients are first diagnosed with anal fissures. Loperamide solution is applied to the site to prevent pain, 1-4 times daily for several consecutive days for relief of pain. Pain prevention or relief is further improved by using either nitroglycerin ointment or a diltiazem cream in conjunction with or sequentially with the loperamide solution.
  • the concentration of diltiazem cream is 4.0% > (w/v) to 0.5%; more preferably, the diltiazem cream concentration is 3-1%, depending upon the efficacy.
  • Example 37 Example 37
  • Example 38 Patients suffering from anal ulcers.
  • a continuous source of lovastatin is provided to greatly facilitate the relief of the debilitating symptoms.
  • patients can take anti-inflammatory agents, such as glucocorticoids or NSALDS, orally at the frequency recommended by the physician while the lovastatin is being applied.
  • Another approach is to take oral antibiotic while patients are using the lovastatin suppository or dermal patch is being applied to further expedite the relief of symptoms.
  • Example 39 Patients with anal fissures are given 0.2 % nitroglycerin (NTG) ointment for use on an as needed basis. Patients are instructed to apply an effective amount of the nitroglycerin ointment to the affected area. Following the 0.2% NTG treatment, all patients are evaluated for improvement in pain reduction and ability conduct normal activity after the therapy. Signs of symptomatic relief, such as pain reduction, are assessed.
  • NTG nitroglycerin
  • Example 40 Patients are first diagnosed with anal fissures and scored at baseline as above.
  • Yohimbine gel is applied to the anorectal region once to four times daily to relax the anal sphincter.
  • Yohimbine gel can also be applied to the region as frequently as needed to achieve the desired effect.
  • yohimbine gel can be applied as needed for relief of symptoms of pain, itching, or burning.
  • the yohimbine gel concentration varies between 2.0% (w/v) to 0.05%, preferably, between 0.05% to 0.1%. or 0.1% to 0.5%, to achieve the desired effect.
  • the desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow.
  • Example 41 Patients are first diagnosed with anal fissure and evaluated at baseline as above.
  • Yohimbine tablets (10 mg) are taken orally, once to four times daily to relax the anal sphincter muscles.
  • yohimbine gel can be applied to the anorectal area as frequently as needed to achieve the desired effect.
  • yohimbine gel can be applied to relax the anal sphincter muscle.
  • the yohimbine gel concentration varies between 2.0% (w/v) to 0.05%, preferably, between 0.05% to 0.1 %. or 0.1 % to 0.5%, to achieve the desired effect.
  • the desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow.
  • Example 42 [347] Benzodiazepines can be useful in achieving anal sphincter relaxation.
  • Diazepam a benzodiazepine
  • the diazepam ointment can also be applied to the external anorectal area as frequently as needed to achieve the desired effect.
  • the diazepam ointment concentration varies between 2.0% (w/v) to 0.05%, preferably, between 0.05% to 0.1%. or 0.1% to 0.5%, to achieve the desired effect.
  • the desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow.
  • [348] Patients are first diagnosed with anal fissures.
  • a topical vesamicol solution or ointment is applied to the site to prevent pain, 1-4 times daily for several consecutive days for relief of pain. Pain prevention or relief may be further improved by using either nitroglycerin ointment or a diltiazem cream in conjunction with or sequentially with the vesamicol.
  • the concentration of diltiazem cream is 4.0% (w/v) to 0.5%; more preferably, the diltiazem cream concentration is 3-1%, depending upon the efficacy.
  • An ⁇ 2 -adrenergic receptor antagonist can be useful in the treatment of patients in need of relaxation of the internal anal sphincter. For instance, patients may be first diagnosed with anal fissure or hemorrhoids. Depending on the site of disease manifestation, a topical ⁇ 2 -adrenergic receptor antagonist (e.g. yohimbine) solution is applied to the site, 1-4 times daily for several consecutive days for relief of pain. Pain prevention or relief may be further improved by using either nitroglycerin ointment or a diltiazem cream in conjunction with or sequentially with the yohimbine. The concentration of diltiazem cream is 4.0% (w/v) to 0.5%; more preferably, the diltiazem cream concentration is 3-1%, depending upon the efficacy.
  • a topical ⁇ 2 -adrenergic receptor antagonist e.g. yohimbine
  • this compound can be formulated in an aqueous formulation of up to 0.8% in sterile water.
  • Yohimbine may also be formulated as topical composition comprising an aqueous or slightly alcoholic gel or in a cream or lotion for direct application to the anorectal region.
  • Acetylcholine storage blockers may be useful in patients in need of internal anal sphincter relaxation.
  • An acetylcholine storage blocker e.g., vesamicol
  • vesamicol ointment is applied to the skin of the anorectal region, once to four times daily to relax the anal sphincter.
  • the ointment can also be applied to the anorectal area as frequently as needed to achieve the desired effect.
  • the vesamicol ointment concentration varies between 2.0% (w/v) to 0.05%, preferably, between
  • Vesamicol can be applied in an aqueous gel or lotion type of formulation.
  • Adenosine receptor modulators may be useful in patients in need of relaxation of the internal anal sphincter.
  • An adenosine receptor modulator e.g., theophylline or dyphylline
  • An adenosine receptor modulator (e.g., theophylline or dyphylline) ointment is applied topically to the anorectal region, once to four times daily to relax the sphincter muscle.
  • the ointment can also be applied topically as frequently as needed to achieve the desired effect.
  • the ointment can be applied by suppository.
  • the adenosine receptor modulator ointment concentration varies between 2.0%
  • the desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow.
  • An adenosine receptor modulator may be useful in the treatment of patients in need of relaxation of the internal anal sphincter or suffering from elevated intraanal pressures. For instance, patients may be first diagnosed with levator spasm or anal fissures. Depending on the site of disease manifestation, a topical adenosine receptor modulator (e.g. theophylline or dyphylline) ointment is applied to the anorectal area to prevent pain and promote healing, 1-4 times daily for several consecutive days for relief of pain.
  • a topical adenosine receptor modulator e.g. theophylline or dyphylline
  • Pain prevention or relief may be further improved by using either nitroglycerin ointment or a diltiazem cream in conjunction with or sequentially with the yohimbine.
  • concentration of diltiazem cream is 4.0% (w/v) to 0.5%; more preferably, the diltiazem cream concentration is 3-1%, depending upon the efficacy.
  • Example 48 [354] Patients complaining of recurrent pain, itching or burning of the anorectal region will be evaluated for signs of inflammation and infection, previous history of surgery, and any other signs of pathology. If they are found to be free of any of these medical conditions and yet still have ongoing pain, itching or burning of the anorectal area, topical treatment with nitroglycerin will be prescribed.
  • a 0.2% topical nitroglycerin ointment will be applied to the affected area, either once daily or as frequent as needed to achieve efficacy, depending on the severity of the symptoms.
  • the efficacy of relief can be evaluated based on a visual analog scale of 10 cm or on the patients' self-assessment. If the patients are diagnosed with minor infection, topical nitroglycerin ointment can be used in conjunction with antibiotic treatment to facilitate faster relief of symptoms.
  • the anorectal disorder is a colostomy.
  • Smooth muscle relaxing agents may be used in the treatment of colostomy patients, particularly during irrigation of the colostomy, to improve their quality of life.
  • Colostomy irrigation improves the quality of life of colostomy patients by reducing episodes of fecal incontinence.
  • irrigation is often time consuming.
  • Administration of smooth muscle relaxing agents including particularly, for example, potassium channel openers can improve the effectiveness and efficiency of the irrigation process saving time and effort and thereby enhancing the acceptability of irrigation among colostomy patients.
  • a more thorough cleansing reduces the likelihood of later leakage.
  • a more efficient process saves time.
  • potassium channel openers for administration during the irrigation of a colostomy include minoxidil, minoxidil sulfate, pinocidil, diazoxide, levcromokalim, cromokalim, and PCO-400.
  • the potassium channel opener may be admimstered about or during the time period of the irrigation and may preferably be administered by being formulated with or as the irrigation fluid.
  • the amount of potassium channel opener or other smooth muscle relaxing agent will be sufficient to improve the time or extent of the colostomy irrigation.
  • the anorectal disorder is chronic idiopathic anal pain.
  • Smooth muscle relaxants including particularly NO donors, are used to treat chronic idiopathic anal or perineal pain, including proctalgia fugax and coccygodinia.
  • the patients may have no objective abnormalities on clinical examination.
  • the smooth muscle relaxant or NO donor can be administered as a topical ointment or suppository. Concentrations of the NO donor in an ointment formulation may range from 0.01% to 2%, and more preferably range from 0.1% to 0.4%, and more particularly, may be 0.2%.
  • the NO donor may be administered to the anorectal region as needed to relieve or prevent pain.
  • the NO donor may be co-administered or formulated with an analgesic.
  • a prefened NO donor is glycerol trinitrate.
  • EXAMPLE 51 Patients are first diagnosed with anal fissure and evaluated at baseline as above, mianserin is administered orally, once to four times daily in an amount sufficient to relax the anal sphincter muscles. Additionally or alternatively, mianserin gel can be applied to the anorectal area as frequently as needed to achieve the desired effect. Mianaserin gel can be applied to relax the anal sphincter muscle. The mianserin gel concentration varies between 2.0% (w/v) to 0.05%, preferably, between 0.05% to 0.1%. or 0.1% to 0.5%, to achieve the desired effect. The desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow.
  • EXAMPLE 52 [358] Patients are first diagnosed with anal fissure and evaluated at baseline as above, mirtazapine is administered orally, once to four times daily in an amount sufficient to relax the anal sphincter muscles. Additionally or alternatively, mirtazapine gel can be applied to the anorectal area as frequently as needed to achieve the desired effect, mirtazapine ointment can be applied to relax the anal sphincter muscle.
  • the mirtazapine gel concentration varies between 2.0% (w/v) to 0.05%, preferably, between 0.05% to 0.1%. or 0.1%) to 0.5%o, to achieve the desired effect.
  • the desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow.
  • EXAMPLE 53
  • Patients are first diagnosed with an anorectal disorder, such as anal pain and/or anal fissure or hemonhoids, and evaluated at baseline as above.
  • a compound or agent having a mixture of pharmacological properties comprising ⁇ -adrenergic receptor antagonism, ⁇ i -adrenergic receptor antagonism, serotonin receptor agonist activity, H ⁇ antagonist activity, and optionally muscarinic antagonism is administered.
  • the agent is mianserin or mirtazapine.
  • the agent is administered orally, once to four times daily in an amount sufficient to relax the anal sphincter muscles.
  • a gel containing the agent can be applied to the anorectal area as frequently as needed to achieve the desired effect.
  • the gel can be applied to relax the anal sphincter muscle.
  • Agent concentrations will generally vary between 2.0% (w/v) to 0.05%, preferably, between 0.05% to 0.1%. or 0.1% to 0.5%, to achieve the desired effect.
  • the desired effects include, but are not limited to, immediate pain relief, local tissue relaxation, and increase in blood flow.
  • 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 mmHg.
  • the data were integrated and converted to waveforms with the Digi-Med System Integrator software. Blood pressure changes were monitored using an arterial catheter/transducer and a Digi-Med Blood Pressure Analyzer with the DMSI software.
  • the anodermal blood flow in the rat can be measured non-invasively by laser Doppler velocimetry.
  • laser Doppler low power laser light is transmitted via an optic fiber to the tissue.
  • the light is scattered by moving red blood cells and its frequency shifted according to the Doppler effect; the average Doppler frequency shift being proportional to the average speed of the blood cells.
  • the scattered light is photodetected and the photocurrent signal electronically processed to produce the Doppler flux signal.
  • blood flow measurements were accomplished using a DRT4 laser Doppler monitor (Moor Instruments) which is interfaced with both channels of Digi-Med Analog System Analyzer (ASA) via BCN connectors and an ANO2 analog interface unit (Moor Instruments).
  • ASA Digi-Med Analog System Analyzer
  • the DRT4/ASA data was recorded using the DMSI software provided by Digi-Med.
  • blood flow measurements FLUX
  • changes in blood flow are measured in volts. The greater the volts, the greater the blood flow.
  • Flexible side delivery probes were inserted through the anal opening just past the optic sensor to rest adjacent to the IAS. The probes were adjusted so that the sensors were in line with the anterior anal mucosa of the IAS. Drug delivery was accomplished through two Hamilton syringes with no dead space using PE 10 tubing adjacent to the catheter sensor. Drugs typically were applied soon after stable baseline readings are recorded.
  • DRT4 laser Doppler and temperature monitor (Moor Instruments, Wilmington DE) equipped with an endoscopic side view probe.
  • low-energy laser light (780 nm, 1.0 mW, Class I) is delivered at a right angle via a 100- ⁇ m fiber optic within 2-5 mm of the probe tip (e.g., DP6ds endoscopic side view probe, flexible nylon sleeve, 1.34 mm OD, Moor Instruments, Wilmington DE).
  • the probe sensor can be aligned with the IAS and maintained in place by taping to the tail of the rat as described before.
  • the DRT4 system can store over 8 hours of data, which can accommodates the duration of many experiments. Faster collection rates (up to 40 data points per seconds) can be used for shorter protocols.
  • the DRT4 system also allows for simultaneous temperature monitoring providing the proper probes are used.
  • Example 56 The ability of diazepam to lower the IASP was also evaluated in the rat under similar conditions to those described above, hi these experiments, 1%, 0.1% and 0.01 ) diazepam in 5% DMSO/acetone:olive oil (1 : 1) were infused at a rate of 20 ul/hour. A dose-response relationship was observed with substantial and measurable effects at each dose level (i.e. 2, 20, or 200 ug/hour). See Figures 46-47.
  • Example 57 Increased blood flow in the anorectal region can increase healing and can reduce pain, particularly ischemic pain.
  • the ability of anal sphincter relaxing agents to increase blood flow in the anorectal region may be evaluated according to the method provided in Example 54. Prefened anal sphincter relaxing agents also increase blood flow in the anorectal region. For instance, an infusion to the anorectal region of an anal sphincter relaxing agent (0.01% to 2.0%) in water or other suitable vehicle at a rate of 100 ul/hour can be administered to increase blood flow in the anorectal region.
  • Infusion of a 0.2%, 0.1%, 0.05% and 0.01%> of the anal sphincter relaxing agent at rate of 100 ul per hour allows the dose response effect of the anal sphincter relaxing agent on increasing blood flow in the anorectal region to be assessed.
  • Such anal sphincter relaxing agents include cAMP kinase activators, superoxide scavengers, ATP-sensitive potassium channel activators, calcium channel blockers, cholinergic modulators, ⁇ -adrenergic antagonists, ⁇ -adrenergic agonists, adrenergic nerve inhibitors, NO donors, phosphodiesterase inhibitors, estrogen-like compounds, testosterone-like compounds, benzodiazepines, antidiarrheal agents, HMG-CoA reductase inhibitors, adenosine receptor modulators, and smooth muscle relaxants.
  • Prefened anal sphincter relaxing agents for this purpose include the
  • Example 58 Increased blood flow in the anorectal region can increase healing and can reduce pain, particularly ischemic pain.
  • the ability of anal sphincter relaxing agents to increase blood flow in the anorectal region may be evaluated according to the method provided in Example 54. For instance, an infusion to the anorectal region of yohimbine (0.01%) to 2.0%o) in water or other suitable vehicle at a rate of 100 ul/hour can be administered to increase blood flow in the anorectal region. Infusion of a 0.2%, 0.1 %, 0.05% and 0.01% of this anal sphincter relaxing agent at rate of 100 ul per hour allows the dose response effect of this agent on increasing blood flow in the anorectal region to be assessed.
  • Example 59 Increased blood flow in the anorectal region can increase healing and can reduce pain, particularly ischemic pain.
  • the ability of anal sphincter relaxing agents to increase blood flow in the anorectal region may be evaluated according to the method provided in Example 54. For instance, an infusion to the anorectal region of vesamicol (0.01% to 2.0%) in water or other suitable vehicle at a rate of 100 ul/hour can be administered to increase blood flow in the anorectal region. Infusion of a 0.2%, 0.1%, 0.05% and 0.01% of this anal sphincter relaxing agent at rate of 100 ul per hour allows the dose response effect of this agent on increasing blood flow in the anorectal region to be assessed.
  • EXAMPLE 60 EXAMPLE 60
  • preferred anal sphincter relaxing agents are those compounds which increase blood flow and especially prefened agents are those which increase blood flow while reducing IASP.
  • Anodermal blood flow in the subject e.g., human, rat
  • laser Doppler velocimetry low power laser light is transmitted via an optic fiber to the tissue. The light is scattered by moving red blood cells and its frequency shifted according to the Doppler effect; the average Doppler frequency shift being proportional to the average speed of the blood cells. The scattered light is photodetected and the photocunent signal electronically processed to produce the Doppler flux signal. Schouten et al.
  • EXAMPLE 61 In order to determine dose response and the time course of the anodermal blood flow response of a human to an administered anal sphincter relaxing agent, blood flow can be measured non-invasively by laser Doppler velocimetry.
  • laser Doppler technique low power laser light is transmitted via an optic fiber to the tissue. The light is scattered by moving red blood cells and its frequency shifted according to the Doppler effect; the average Doppler frequency shift being proportional to the average speed of the blood cells. The scattered light is photodetected and the photocunent signal electronically processed to produce the Doppler flux signal. Schouten et al.

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Abstract

L'invention concerne des compositions et des méthodes de traitement de patients souffrant de troubles ano-rectaux, tels que la colostomie. On peut citer, et sans caractère limitatif, parmi les composés et des combinaisons de ceux-ci utilisés dans ces compositions et procédés les composés suivants: des donneurs de NO, des bloqueurs calciques, des modulateurs cholinergiques (notamment des agents de blocage du stockage de l'acétylcholine et des agents de blocage du stockage de l'acétylcholine dans la vésicule), des antagonistes du récepteur α-adrénergique (notamment des antagonistes α1-adrénergiques et des antagonistes α2-adrénergiques), des agonistes du récepteur β-adrénergique (notamment des antagonistes β2-adrénergiques et des antagonistes β3-adrénergiques), des inhibiteurs de la phosphodiestérase, des activateurs de la protéine kinase dépendant de cAMP (par exemple, des substances mimétiques de cAMP), des entraîneurs de superoxyde, des activateurs du canal potassique (notamment des activateurs du canal potassique sensible à ATP et des activateurs des canaux Maxi-K), des composés de type oestrogène, des composés de type testostérone, des benzodiazépines, des inhibiteurs des nerfs adrénergiques, des agents anti-diarrhéiques, des inhibiteurs de la réductase HMG-CoA, des relaxants des muscles lisses, des modulateurs du récepteur de l'adénosine, des activateurs de l'adénylyl cyclase, des antagonistes du récepteur de l'endothéline, des bisphosphonates, des activateurs de la protéine kinase dépendant de cGMP (par exemple des substance mimétiques de cGMP).
PCT/US2003/007106 2002-03-06 2003-03-05 Compositions et methodes de traitement de troubles ano-rectaux WO2003075851A2 (fr)

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